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CLINICAL STUDY PROTOCOL

Study Title: A Phase 2a, single-blind, placebo-controlled safety and efficacy study of two doses of NRP2945 in patients showing drug-resistant typical absence epilepsy as a form of their genetic, generalized epilepsy pattern

Protocol Number: NRP2945-3

Sponsor: CuroNZ Pty Ltd6 Pemberton CloseStirling. WA 6021Australia

Study Product: NRP2945

Development Phase: 2A

Indication:

Clinical Trial Identifier:

Stable absence epilepsy

ACTRN12618001506280p

Principal InvestigatorPatrick Kwan, BMedSci, MB, BChir, PhD, FRCPHead of EpilepsyThe Royal Melbourne HospitalGrattan StreetMelbourne VIC 3010Australia

Protocol Version: 2.0

Date 14 September 2018

CONFIDENTIAL

This document is confidential and the property of CuroNZ Pty Ltd. No part of it may be disclosed, transmitted, reproduced, published, or used by other persons without prior written authorisation from

the study sponsor, and shall not be used except in the performance of this study.

NRP2945-3: Protocol P2a Stable absence epilepsy, version: 2.0_14 September 2018 Confidential of 49

PROTOCOL SIGNATURE PAGE

SPONSOR’S APPROVAL

The signature below constitutes CuroNZ Pty Ltd approval of this protocol.

14 Septmeber 2018

Frank Sieg, PhD.Chief Scientific OfficerCuroNZ Pty Ltd

Date (DD/MMM/YYYY)

INVESTIGATORS STATEMENTI have read the protocol, including all appendices, and I agree that it contains all of the necessary information for me and my staff to conduct this study as described. I will conduct this study as outlined herein, in accordance with the study protocol, the International Conference on Harmonisation Good Clinical Practice (ICH GCP) and any applicable national and local regulations.

I will ensure all study personnel under my supervision are adequately informed and trained about the study protocol, the investigational product and their study-related duties and functions, and provide copies of the protocol and any amendments and access to all information provided by CuroNZ Pty Ltd or specified designees as appropriate.

Signature of Site lnvestigator Date (DD/MMM/YYYY)

Print Name


changes on pages previous 1.0 version changed to - new 2.0 version

Page 1 and 2 Version 1.0 and signature date:

27 August 2018

Version 2.0 and signature date:

14 September 2018

Footnote throughout document NRP2945-3: Protocol P2a Stable absence epilepsy, version: 1.0_27 August 2018

NRP2945-3: Protocol P2a Stable absence epilepsy, version: 2.0_14 September 2018

Page 1 Clinical Trial Identifier:

U1111-1219-6485

Clinical Trial Identifier: ACTRN12618001506280p

Page 14 Addition was made (see next column)

FIH – First in Human

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…… consisting of generalized paroxysmal fast activity, generalized polyspike trains or spike-and wave complexes being measured…..

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….The here outlined NRP2945-3 clinical study…….due to small size.

Page 6 Deletion of text was made:

Observation of at least 3 instances of bilateral synchronous symmetrical spike waves of…….of observation period during the screening

Insertion of text was made:

Observation of at least 3 instances of bilateral synchronous symmetrical spike waves of ….. observation period during the screening.

Synopsis:

Title A Phase 2a, single-blind, placebo-controlled safety and efficacy study of two doses of NRP2945 in patients showing drug-resistant typical absence epilepsy as a form of their genetic, generalized epilepsy pattern

Protocol Number NRP2945-3

Sponsor CuroNZ Pty Ltd


Phase 2a

Investigational Product

NRP2945

Indication Drug-resistant typical absence epilepsy

Study Design The design is a single-blind, placebo-controlled, sequential dose study in a cross-over design to assess the safety and efficacy of NRP2945 in patients with known stable absence (spike-and-wave discharges) epilepsy.

Safety will be assessed by determining the incidence and type of adverse events (AEs), the tolerability of NRP2945 at injection site, and review of clinical laboratory tests and assessments.

Efficacy will be assessed by determining the pharmacodynamics on the cumulative response of the frequency of absence seizures (spike-and-wave discharges) analyzed from the electroencephalogram (EEG) of each subject following the sequential administration of Placebo and two doses of NRP2945 (5ug/kg and 7ug/kg).

Additional study assessments will include evaluations of concomitant use of anti-epileptic drugs (AED). The exploratory biomarker CXCR4 (gene expression profiling) will be performed at pre-determined time-points over the course of the study.

Study Duration (Subject)

Up to 13 weeks:

Up to 3 weeks screening period 10 week dosing period (dosing of study drug (either NRP2945 or Placebo)

with a latency period of 14 days between dosing cohorts)

Study Centre One study site in Australia

Study Objectives Primary Objective:

To assess the safety and tolerability of two doses of NRP2945 after subcutaneous bolus injection, 48 hours apart, in patients with typical absence epilepsy.

Secondary Objectives:

1. To evaluate the ability of NRP2945 to suppress the epileptic generalised discharges as compared to Placebo in patients with absence epilepsy.

2. To evaluate the effect of NRP2945 on the plasma concentrations of concomitantly taken anti-epileptic drugs following administration of NRP2945 (e.g. valproate, phenytoin and lamotrigine).

Exploratory Objective:


To evaluate the pharmacodynamic profile of, and effect of, NRP2945 on the biomarker CXCR4 compared to Placebo.

Number of Subjects 5 subjects

Investigational Product/doses

NRP2945, a novel peptidomimetic putative AED.

Two doses will be assessed:

NRP2945 5ug/kg NRP2945 7ug/kg

NRP2945 will be presented as a lyophilised powder containing 0.96mg NRP2945 and an excess of 255mg of D(+)-trehalose (170mg/ml). NRP2945 is to be reconstituted using 1.4ml of sterile physiological saline and filtered through a polyethersulfone (PES) filter mounted syringe. Reconstituted volume is 1.5ml.

Previous pre-clinical data suggest that the loss of peptide during the filtration process is approximately 1% (due to filter adsorption). The end concentration of net NRP2945 peptide is 0.64 mg/ml in the saline reconstituted solution.

NRP2945 vials must be stored at -20 C. Vials are to be brought to room temperature at least 1 hour prior to dose administration, and used within 2 hours of reconstitution and preparation.

Comparator Drug Placebo

Placebo vials contain a solution of 255 mg of D(+)-trehalose (170mg/ml) and sterile physiological saline. Final volume is 1.5 ml. The solution is filtered through a PES filter mounted syringe for administration.

Placebo vials must be stored at -20C. Vials are to be brought to room temperature at least 1 hour prior to dose administration, and used within 2 hours of preparation.

Treatment periods The study will have 3 sequential treatment periods. In treatment period 1, each subject will receive two administrations of Placebo; in treatment period 2, they will receive two administrations of NRP2945 5ug/kg; in treatment period 3, they will receive two administrations of NRP2945 7ug/kg. There will be a 14-day washout period after each treatment period as follows:

Treatment period 1-Placebo Day 1 and Day 3 (Study days 1, 3) Treatment period 2 -NRP2945 5ug/kg Day 1 and Day 3 (Study days 24, 26) Treatment period 3- NRP2945 7ug/kg Day 1 and Day 3 (study days 47, 49)

The study drug/product (NRP2945 or Placebo) will be delivered via subcutaneous bolus injection into the abdomen.

Eligibility Criteria Inclusion Criteria


1. Are male or female age 18-65 years.

2. Signed informed consent form (ICF) indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.

3. Males or non-pregnant, non-breastfeeding females 18 to 65 years-of-age

4. Clinical diagnosis of a genetic (idiopathic) generalised epilepsy syndrome (including, but not limited to, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, or Jeavons syndrome) with absence seizures consistent with the International League against Epilepsy Revised Classification of Seizures (2017).

5. Absence seizures persisting despite at least two documented standard anti-epileptic treatments (drug-resistance). Subjects are resistant to valproate and at least one other AED (e.g. phenytoin).

6. Observation of at least 3 instances of bilateral synchronous symmetrical spike waves of approximately 2.5 – 4.5 Hz consisting of generalized paroxysmal fast activity, generalized polyspike trains or spike-and wave complexes being measured within the time frame of 3 hrs of observation period during the screening.

7. On no therapy or taking stable doses of one or more anti-epileptic medication(s) for at least 30 days. If a subject is not on medication, adequate documentation justifying lack of therapy is acceptable.

8. Body Mass Index (BMI) of 18-35 at screening.

9. Subjects with reproductive capability including all males and women of child-bearing potential (WOCBP) must agree to practice continuous abstinence or adequate contraception methods (appropriate double barrier method or oral, patch, implant, or injectable contraception) from screening until at least 30 days after the last dose (i.e., intermittent abstinence based on "rhythm", temperature monitoring, or other means of timing is not acceptable).

10. Male subjects with a partner of child-bearing potential must be surgically sterilized or be willing to use condoms with spermicide from screening until at least 30 days after the last dose.

11. Able and willing to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria

1. Have any clinical condition that, in the opinion of the Investigator, might interfere with the results of the study or pose a risk to the subjects due to participation in the study

2. Have a history of alcoholism, drug abuse, or drug addiction within the past 12 months.

3. Have an active CNS infection, demyelinating disease, degenerative neurological disease or any CNS disease deemed to be progressive during


the course of the study that may confound the interpretation of the study results.

4. Have any clinically significant psychiatric illness, psychological or behavioral problems which, in the opinion of the Investigator, would make the patient unsuitable to participate in the study.

5. Have a haemoglobin or haematocrit below the site’s lower reference range value.

6. Clinically significant active liver disease, porphyria or have severe hepatic dysfunction indicated by AST and/or ALT greater than 3 x upper limit of normal.

7. Currently taking plerixafor® (AMD3100, a highly specific CXCR4 antagonist), or have stopped taking plerixafor® less than 4 weeks before the day of screening.

8. Participation in another clinical trial or administration of any investigational agent within 8 weeks or 5 half-lives (whichever is longer) prior to Day 1 or intent to participate in another clinical trial during the study.

9. A female who is pregnant or lactating10. An employee of the sponsor or research site personnel directly affiliated

with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.

Primary Endpoints Incidence of adverse events (AEs) after two doses of NRP2945 compared to Placebo

Changes in the neurological examination after two doses of NRP2945 compared to Placebo

Changes from baseline in clinical laboratory parameters, physical examination and vital signs after two doses of NRP2945 compared to Placebo.

Secondary Endpoints

The primary efficacy endpoint is:o Change of cumulative absence seizures as measured in seizure diary

in subjects after having received two doses of NRP2945 as compared to Placebo.

o Onset of cumulative absence seizures in subjects as related to the two doses of NRP2945 as compared to the Placebo.

o Plasma concentrations of either valproate, phenytoin or lamotrigine (concomitant AEDs) during administration of NRP2945 as compared to the Placebo for all AEDs.

Exploratory Endpoints

Pharmacodynamic profile of NRP2945 CXCR4 gene expression of PBMCs (surrogate marker for NRP2945 target

engagement in brain parenchyma).


Key Efficacy Procedure Requirements

1. % change in generalized epileptiform patterns (as defined above) of any duration in the 3-hour EEG during the treatment periods compared to baseline.

2. % change in generalized epileptiform patterns (as defined above) of >3 seconds in the 3-hour EEG during the treatment periods compared to baseline

Stopping Rules The study will be stopped, if two instances of the same worsening occur (1, 2, or 3 below), or a total of three worsening episodes occur across all subjects:

1. If a subject has an increase of the cumulative absence seizures or interictal discharges by more than 50% after dosing as compared to the screening day, the therapeutic intervention study will be terminated and the subject will be unable to participate in further testing.

2. If a subject experiences a generalised tonic-clonic seizure during any study day, and they have not had a generalised tonic-clonic seizure in the 6 months prior to enrollment, the study will be terminated for that subject. If any subject experiences a generalised tonic-clonic seizure during study days, the study will be terminated for that subject and he/she will not be permitted to participate in further dosing

3. If in the opinion of the Investigator a subject has evidence of pro-convulsive activity on the EEG after administration of the study product, (e.g. increase in spike-wave activity), then the study will be terminated for that subject and he/she will not be permitted to participate in further testing.

Statistical Methods and Analyses

Data from all subjects will be included in the statistics if they have received any dose of investigational product (NRP2945 or Placebo).

Descriptive statistics will be presented including the means and standard deviations of the cumulative response in regard to absence seizure frequencies for each patient, for each study day. Graphical displays of the data for each subject will allow exploration of inter- and intra-patient variability.

Further analysis populations and statistical analysis methods will be detailed in the Statistical Analysis Plan.

Committees There will be no formal Safety Review Committee. Safety reviews will occur on a regular basis by the Medical Monitor and Investigator and as required with the incidence of any of the Stopping Rules.


Table 1: Schedule of Assessments:

Assessment Number Visit 1 Visit 2

14 D

ay w

asho

ut b

etw

een

visit

s

Visit 3

14 D

ay w

asho

ut b

etw

een

visit

s

Visit 4

Study Day Day -28 to Day-1 1 3 10 24 25 26 47 48 49

Visit Windows 0 days 0 days 0 days 0 days +/-2 days 0 days 0 days +/-2 days 0 days 0 days

Study Stage/Cohort Screening Cohort 1 Day 1

Cohort 1 Day 3

Cohort 1Day 10

Cohort 2 Day 1

Cohort 2 Day 3

Cohort 2 Day 10

Cohort 3 Day 1

Cohort 3 Day 3

Cohort 3 Day 10

Procedures Dosing 1a Dosing 1b Dosing 2a Dosing 2b Dosing 3a Dosing 3b

Consent X

Review of Inclusion/Exclusion Criteria X X1 X1 X1

Demographics2 X

Medical History X

Physical Exam3 X X X X

Neurological Exam4 - Pre dose for Visit 2, 3, 4. X X X X X X X

Neurological Exam - 4 hours Post dose4 X X X X X X

Questionnaire-Survey (QoL measures) X5 X5 X5

Height X

Weight X X X X

Vital Signs X X6 X6 X6 X6 X6 X6 X6 X6 X6

Clinical Laboratory Evaluations7 X X X X X X X X X X

Pregnancy Test8 X X X X

EEG Assessment9 X X X X

Study Drug Adminstration10 X X X X X X

Injection site reaction11 X X X X X X

PD Sampling12 X X X X X X

AED Levels13 X X X X X X

Adverse Events X X X X X X X X X

Concomitant Medication X X X X X X X

NRP2945-3: Protocol P2aStable Absence Epilepsy, version: 2.0_14 September 2018 Confidential of 49

1. Confirm inclusion/exclusion criteria continue to be met prior to dosing.2. Demographics: date of birth, gender, race, ethnicity.3. Physical Examination should be performed and include: Head, eyes, ears, nose and throat (HEENT), heart, respiratory, abdomen, extremities. 4. Neurological Examination should be performed and include: Mental status, cranial nerves (I-XII), motor system, reflexes, sensory system, coordination and gait

assessments. 5. Questionnaire will put focus on subjective general health self-estimation and Quality of Life (QoL) outcomes at follow-up visit

6. Vitals signs include blood pressure (systolic and diastolic), heart rate, respiratory rate and body temperature. Assessed: Pre-dose, and at 15 minute (+/- 5 minute) and 2 hours (+/- 10 minute) post-dose before end of 3hrs EEG-recordings.

7. Clinical laboratory evaluations will be obtained for Screening (Visit 1), a Day 1 pre-dose sample for each dose group, and at day 10 Follow Up Visit. Blood samples will also be drawn approx. 6 hrs post-dose on Day 1 and 3 of each dose group.

Hematology: Hemoglobin, Hematocrit, RBC count, Platelet count, WBC count & differential (absolute neutrophils, eosinophils, monocytes, basophils, lymphocytes) Biochemistry: Sodium, Potassium, Chloride, Magnesium, Phosphate, BUN/Urea, Creatinine, Glucose (non-fasted), Calcium, AST, ALT, GGT, Total Bilirubin, Alkaline

phosphatase, Uric acid, Albumin, Total protein, C-Reactive Protein, Creatine Kinase, LDH

8. Urine pregnancy tests will be performed on females of childbearing potential using an acceptable pregnancy urine dipstick9. EEGs will be performed at the following time points, with assessment window for post dose EEGs of +/- 5 minute:

Screening (Visit 1): approximately for 3 hrs starting in the morning Dosing Day3: approximately 30 minute pre-dose and for 3 hrs continuously after post-dose;

10. Study drug will be administered at between 09:00 to 10:00 hours.11. Assessment of injection site reactions (local tolerability) will be assessed for pain, erythema and induration and classified as none, mild, moderate, severe. Assessments

to occur at 1, 2 and 6 hours post dose. Any reactions will be monitored until resolution by the Investigator. 12. PD samples will be collected on Dosing Day 1 and Day 3: approximately 30 minute pre-dose and 30 minute, 60 minute and 4 hours post dose. 13. AED levels will be collected on: Dosing Day 1 and Day 3: approximately 30minute pre-dose and 4 hours post-dose.

Reminder: If multiple procedures are scheduled at the same time point, the EEG session should be performed first, immediately followed by the PD draw, and then the AED draw. All other procedures can then be completed.


Table 2: Breakdown of Key Study Assessments:

Day 3

Estimated Time (24:00 clock) 0900 0905 0910 0915 0920 0930 1000 1130 1200 13001500

Time pointPre-dose 0

5min+/-

1min

10min+/-

1min

15min+/-

1min

20min+/-

1min

30min+/-

1min

60min+/-

5min

2hr+/-

10min

3hr+/-

10min

4hr+/-

10min

6hr+/-

10min

Procedures

Study Drug Administration10 X

Neurological Exam4 X4 X4

Vital Signs6 X6 X6 X6

Clinical Chemistry7 X7 X7

EEG Assessment8(only day 3) X8 X8 X8 X8 X8 X8 X8 X8 X8 X8

PD Sampling11 X11 X11 X11 X11

AED Levels12 X12 X12

Day 10

Estimated Time 0900 1000 1200

Time point post Day 3 dose168 hrs

+/- 120min169 hrs

+/- 120min171 hrs

+/- 120min

Procedures

Questionnaire-Survey (QoL measures) X5

Vital signs X6


Clinical Laboratory Evaluations7 X7


ContentsProtocol Signature Page............................................................................................................................2

Synopsis:..................................................................................................................................................3Table 1: Schedule of Assessments:................................................................................................................9Table 2: Breakdown of Key Study Assessments:.........................................................................................11

Abbreviations.........................................................................................................................................14

1. Introduction.....................................................................................................................................161.1 Background......................................................................................................................................161.2 Development of NRP2945................................................................................................................17

1.2.1 Non-Clinical Studies of NRP2945:..............................................................................................181.2.2 Clinical Studies of NRP2945.......................................................................................................18

1.3 Study and Dose Rationale................................................................................................................191.3.1 Study Rationale.........................................................................................................................191.3.2 Dose Rationale..........................................................................................................................19

2. Objectives and Endpoints.................................................................................................................20

3. Study Design....................................................................................................................................213.1 Number of Study Sites......................................................................................................................213.2 Study Duration.................................................................................................................................22

4. Study Population.............................................................................................................................224.1 Number of Subjects..........................................................................................................................224.2 Inclusion Criteria..............................................................................................................................224.3 Exclusion Criteria..............................................................................................................................234.4 Screen Failures.................................................................................................................................244.5 Prior/Concomitant Therapy..............................................................................................................244.6 Lifestyle Considerations....................................................................................................................244.7 Subjects Completion and Withdrawal..............................................................................................244.7.5 Lost to Follow Up..........................................................................................................................264.7.6 End of Study Definitions................................................................................................................26

5. Study Product..................................................................................................................................265.1 Study Products......................................................................................................................................265.2 Handling, Preparation, Storage and Accountability..............................................................................275.3 Randomisation and Blinding.................................................................................................................285.4 Dosage and Administration...................................................................................................................285.5 Compliance of Study Products...............................................................................................................295.6 Rescue Medicine...................................................................................................................................295.7 Drug interactions..................................................................................................................................295.8 Study Product Return............................................................................................................................29

6. Study Assessments...........................................................................................................................296.1 Survey – questionnaire on day 10 (follow-up visit)................................................................................296.2 EEG Assessment....................................................................................................................................316.3 Safety Assessments...............................................................................................................................316.4 Pharmacodynamic Samples..................................................................................................................326.5 Blood Volumes for Clinical Laboratory and PD Sampling......................................................................326.6 Maintaining the Blind...........................................................................................................................33

7. Study Procedures.............................................................................................................................33NRP2945-3: Protocol P2a Absence epilepsy study-, version: 2.0_14 September 2018 Confidential of 49

7.1 Screening Visit - Visit 1.....................................................................................................................337.2 Dosing Stages...................................................................................................................................34

7.2.1 Day 1.........................................................................................................................................347.2.2 Day 2.........................................................................................................................................357.2.3 Day 3.........................................................................................................................................35

8 Safety Management.........................................................................................................................368.1 Stopping Rules..................................................................................................................................368.2 Safety Monitoring Committee..........................................................................................................378.3 Adverse Event Management............................................................................................................37

8.3.1 Adverse Event...........................................................................................................................378.3.2 Serious Adverse Event...............................................................................................................38

8.3.3 Adverse Event Reporting Period...................................................................................................398.4 Reporting of Serious Adverse Events................................................................................................40

9 Statistical Considerations.................................................................................................................419.1 Sample Size......................................................................................................................................419.2 Analysis Sets.....................................................................................................................................419.3 Statistical Analysis............................................................................................................................41

9.3.2 Safety and Pharmacodynamic Analysis.....................................................................................41

10 Regulatory and Ethical Considerations..........................................................................................4110.1 Informed Consent.........................................................................................................................4210.2 Confidentiality..............................................................................................................................4210.3 Data Protection............................................................................................................................4310.4 Conflict of Interest........................................................................................................................43

11 Study Administration....................................................................................................................4311.1 Sponsor.........................................................................................................................................4311.2 Medical Monitoring......................................................................................................................4311.3 Insurance and Liability..................................................................................................................4311.4 Study Registration........................................................................................................................4311.5 Data Management..............................................................................................................................44

11.5.1 Source Documents....................................................................................................................4411.5.2 Case Report Forms....................................................................................................................44

11.6 Records Retention.........................................................................................................................4411.7 Study and Site Closure..................................................................................................................4511.8 Auditing and Inspecting................................................................................................................4511.9 Publication Plan............................................................................................................................45

References..............................................................................................................................................46

NRP2945-3: Protocol P2a Absence epilepsy study-, version: 2.0_14 September 2018 Confidential of 49

Abbreviations

AE Adverse Event

AED Anti-epileptic drug

ALT Alanine transaminase

AS Absence Seizures

AST Aspartate aminotransferase

BMI Body Mass Index

CACNA1H Calcium Voltage-Gated Channel Subunit Alpha1H

CCR3 CC chemokine receptor 3

CNS Central Nervous System

CXCR4 CXC chemokine receptor 4

EEG Electroencephalogram

Egr1 Early growth response protein 1

FIH First in Human

g-CSF Granulocyte colony stimulating factor

GABA Gamma aminobutyric acid

GABA A receptor Gamma aminobutyric acid A receptor

GABRB3 GABA A receptor beta-3 subunit

GAERS Genetic Absence Epilepsy Rats from Strasbourg

GCP Good Clinical Practice

GGE Genetic generalized seizure

GTCS Generalized tonic-clonic seizure

Hz Hertz

IB Investigator Brochure

ICH International Conference on Harmonisation

IEC Independent Ethics Committee

IMP/IP Investigational medicinal product/ Investigational Product

ILAE International League Against Epilepsy

IRB Institutional Review Board

ISR Injection site reactions

ITT Intention To Treat

hr hour

MAD Multiple Ascending Dosing

mg milligram


ms milliseconds

MS Myoclonic seizure

NRP2945 Neural Regeneration Peptide 2945

PBMC Peripheral Blood Mononuclear Cells

PD Pharmacodynamics

PES filter Polyethersulfone filter

PK Pharmacokinetics

PP Per Protocol

QoL Quality of Life measures

S second

SAE Serious Adverse Event

SWD Spike-and-Wave Discharges

µg microgram

VPA valproate

WHO World Health Organisation


1. Introduction

1.1 Background

Epilepsy is a chronic disorder of the brain that affects people of all ages, and is one of the most common neurological diseases globally, with approximately 50 million people worldwide having epilepsy (WHO, Feb 2017). It can occur as a result of a neurological injury, a structural brain lesion, as a part of many systemic medical diseases or may be genetic in origin. It is characterized by recurrent seizures, which are brief episodes of involuntary movement that may involve a part of the body (partial) or the entire body (generalized) and can vary from the minor lapses of attention or muscle jerks to severe and prolonged convulsions (WHO, Feb 2017).

The incidence of epilepsy is estimated to be twice as high in low to middle income countries, with annual new cases being up to 60 to 100 per 100,000 people in the general population, compared to the population in high-income countries (WHO, Feb 2017). Current anti-epileptic drugs (AEDs) are only effective and tolerated in approximately 70% of patients, leaving a substantial proportion of patients untreated (Dezsi et al., 2017).

Due to the intermittent, unpredictable nature of the clinical manifestations of epilepsy and the various types of the epilepsies having different aetiologies, different pathophysiological mechanisms, as well as different clinical and electroencephalographic expressions, it is generally difficult to assess efficacy of potentially new AEDs in humans.

The clinical manifestations of epilepsy are often intermittent and unpredictable, with epilepsies having different aetiologies, different pathophysiological mechanisms, as well as different clinical and electroencephalographic expressions. Genetic generalized epilepsy (GGE) is common and accounts for approximately 20% of epilepsy diagnoses (Jallon et al., 2005). A number of seizure types are seen in GGE. These include absence seizures (AS), myoclonic seizures (MS) and generalized tonic-clonic seizures (GTCS) as classified by the International League Against Epilepsy (ILAE) Commission on Classification in 1981 and mentioned in a commentary in 2017 again (Scheffer et al., 2017). Electrophysiological different biomarkers (SWD frequency: 1.5-2.5 Hz versus 2.5-4.5 Hz) differentiate atypical from typical AS, respectively. Although both types of AS are considered separately by ILAE there is evidence that there could be a continuum in development of these seizures (Holmes et al., 1987; Carney & Jackson, 2014). The typical AS occurring in children, adolescents and adults are normally effectively treatable by AEDs while the atypical form has a poorer outcome while often being more drug-resistant. Atypical seizures represent one of the hallmarks of the electrophysiological profile of children diagnosed with LGS (Stefan et al., 2008). Typical AS are correlated to thalamo-cortical network dysfunctions. Under physiological conditions there is a fine balance between excitatory thalamo-cortical and cortico-thalamic pathways. These projection neurons receives inhibitory input from the Nucleus reticularis in the thalamus (Steriade et al., 2005). If especially the inhibitory circuits of this fine-tuned thalamo-cortical network get interrupted by diminished GABA availability or through dysregulations of the GABA A receptor protein subunits, the propensity for the generation of absence seizures is increasing.

Very recently, the group around Prof Patrick Kwan discovered a novel electrophysiological biomarker for drug-resistant GGE with high incidence rates during sleeping patterns. This biomarker is named generalized polyspike train (Sun et al., 2018, in press). Although our clinical absence epilepsy study with NRP2945 will


not be analysing EEG profiles during night time, this particular EEG biomarker will guide us for the screening procedure.

In regard to the mechanism of action of NRP2945 which is ultimately leading within an hour after injection to upregulation of the ligand GABA, GABRA2 and GABRB3 subunits within the GABA A receptor without interfering with the phosphorylation status at the serine residues S407/408 of the GABRB3 subunit. This circumstance allows for a fast deactivation profile and lower de-sensitization response at the GABA A receptor and hitherto increasing the phasic inhibitory response in GABA A receptor transfected HEK cells (Hinkle & MacDonald, 2003).

It is hypothesized that NRP2945 will decrease the cumulative typical absence seizure frequency in the subjects.

1.2 Development of NRP2945

CuroNZ is developing a neural regeneration peptide (NRP). NRP2945 is a novel peptidomimetic putative AED deriving from the N-terminus of the human vesicular docking protein calcium dependent activator protein of secretion-2. The neuronal plasma membrane binding of NRP2945 and related NRPs has been established via a novel chemokine receptor complex consisting of CC chemokine-binding receptor 3 (CCR3) and CXC chemokine-binding receptor 4 (CXCR4) (Gorba et al., 2006; Singh et al., 2010). This pharmacodynamics (PD) activity sets an immediate inhibitory stimulus by GABA A receptor protein subunit upregulation of specific alpha and beta subunits in several analysed brain regions (Sajadian et al., 2015). Mutations or small nuclear polymorphism variations within GABA A receptor subunits have been shown to be important in epilepsy and autism (Hogart et al., 2007; Hirose, 2014). Targeted upregulation of even mutated GABA A receptor subunits can facilitate better plasma membrane integration causing elevated conductance and channel-open probabilities. In the past it has been shown that the AED lamotrigine can upregulate the expression of the gene GABRB3 (beta 3 subunit) after one week of continuous 0.1mM lamotrigine exposure to in vitro cultivated hippocampal neurons (Wang et al., 2002). That this lamotrigine effect is rather non-specific becomes clear by the fact that NRP2945 causes GABRB3 protein upregulation at 1 hour after single subcutaneous bolus of 20 ug/kg in naïve rats that is dependent on CXCR4 activation (unpublished results).

Currently another potential plasma membrane target interaction for NRP2945 is being investigated. NRP2945 has 82% homology to an extracellular domain of the slow voltage activated Calcium Voltage-Gated Channel Subunit Alpha1H (CACNA1H) and could therefore represent a peptide ligand modifying channel properties after binding. This calcium channel has been implicated in several epilepsy conditions. For example, previous non-parametric genetic linkage studies show epileptic photosensitivity associations with high probabilities to chromatin band 16p13.3 where CACNA1H is located, which validates the potential endophenotype status for the photoparoxysmal response to be genetically linked (de Kovel et al., 2010). This investigation is of high relevance because there is a high correlation between cyclical excitatory (spike) and inhibitory (wave) activity which is mediated by voltage-gated calcium channels like the t-type calcium channel containing CACNA1H subunit (Blumenfeld, 2005; Carney & Jackson, 2014). There is epidemiological evidence that the GABRB3 and CACNA1H genes are susceptibility genes for absence epilepsies (Yalcin, 2012).

Some of the human characterised missense mutations in the CACNA1H protein coding sequence are known to cause impaired activation and deactivation patterns of this calcium channel, with a likely impact on


thalamocortical driven absence seizures (Rzhepetskyy et al., 2016). Mutations in CACNA1H can lead to change in respective channel properties or enhanced cell surface expression influencing seizure susceptibility (Eckle et al., 2014).

This particular CACNA1H region has a low hydrophobicity index and could be accessible from outside. As NRP2945 provides the unique advantage of being able to cross the blood brain barrier and exerts its signaling effect via the CCR3/CXCR4 receptor complex on neurons by activating a number of pathways that counteract even severe epileptic conditions and provide an instant inhibitory tonus (pathways activated are: mitogen-activated protein kinase and phosphoinositide-3-kinase upregulating transcription factor early growth response protein 1 (Egr1) that increases glutamic acid decarboxylase (GAD- 65/67 isoforms) protein expression and hence the Gamma Amino Butyric Acid (GABA) production (Luo et al., 2008) as well as upregulation of specific GABA-A receptor subunits (Sajadian et al., 2015).

1.2.1 Non-Clinical Studies of NRP2945:

A number of non-clinical studies of NRP2945 have been conducted. One of these studies used rats that have received pentylenetetrazol (PTZ) after NRP2945 administration to assess the ability to suppress convulsive activity. An effective dosage of 20μg/kg suppressed convulsive activity by 100% in an acute PTZ-intoxication setting.

NRP2945 has also been tested in a chronic administration paradigm in a 30-day dosing study using male P100-aged Genetic Absence Epilepsy Rats from Strasbourg (GAERS rats). Ethosuximide has previously been shown to have long-term seizure diminishing effects when chronically administered to GAERS rats by showing disease modifying activities in open field tests after 2 months of chronic dosing (Dezsi et al., 2013). NRP2945 had immediate acute and chronic seizure diminishing effects and was controlled against the comparator valproate (VPA). NRP2945 action revealed higher seizure diminishing activity on typical absence seizures than VPA (Dezsi et al., 2017). Additionally, NRP2945 increased muscle weight of fast-twitching muscles like tibialis anterior and quadriceps, compared to chronic ethosuximide dosing, which led to even further weight loss in GAERS rats (Dezsi et al., 2013).

An acute pilocarpine-toxicity study in adult male rats was conducted and demonstrated anti-depressive effects of NRP2945 when dosing started 24hrs after status epilepticus induction. Animals showed close to physiological normal behaviour when tested in the elevated plus maze. This anxiolytic behavior also occurred after a long latency period, in which occurring spontaneous repetitive seizures under the pilocarpine intoxication paradigm results in unmedicated rats displaying depressive behaviour. Further evidence was found when analysing for novel objection recognition paradigms, in which unmedicated pilocarpine treated rats completely lose memory consolidation/retrieval abilities within their cognitive faculties over time. NRP2945-treated pilocarpine-intoxicated rats revealed close to physiological normal cognitive abilities (compared to before pilocarpine intoxication) at 3-week follow-up time frames. Lastly, NRP2945 was decreasing myoclonic (behavioral) seizures by 70% when administered in prophylactic fashion from day 1-7 after pilocarpine intoxication (unpublished results).

1.2.2 Clinical Studies of NRP2945

A first in human clinical study of NRP2945 was conducted in 49 healthy volunteers in early 2017 to determine the safety, pharmacokinetic (PK) profile and assessment of a blood-based biomarker (CXCR4 gene expression) to assess the ability of NRP2945 to reach its receptor target. A number of doses of NRP2945 were examined in a two part study: a single ascending dosing arm followed by a multiple ascending dose (MAD) arm, with safety, PK and pharmacodynamics (PD) assessed in both dosing


paradigms.

The study comprised seven cohorts with a 5:2 ratio (NRP2945 vs Placebo). The doses explored in the single ascending dose arm were: 1 µg/kg; 3 µg/kg, 10 µg/kg and 25 µg/kg as single subcutaneous bolus injection. The doses explored in the MAD arm of the study were: 5 µg/kg, 8 µg/kg and 25 µg/kg administered every 48 hours as single subcutaneous bolus injection, within a 28-day dosing period.

NRP2945 was considered safe and well tolerated, at all dose levels including the highest MAD-dosage of 25 µg/kg. There was one subject who showed slightly elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels within the time period of two subsequent injection days. No treatment was necessary, and the values returned to normal. At the highest MAD dosage there were more frequent mild injection site reactions (ISRs). Most of the ISRs comprised short-lived pain reactions, which also included erythema and were resolved within 1 to 2 hours after the respective injection. One subject reported mild fatigue for one day after receiving multiple doses at the 5ug/kg dosing level. Drug-related headaches as well as fatigue revealed respective incidence rates of less than 2% when analyzed over the entire 300 days of dosing days (SAD and MAD dosing periods combined). No other adverse events (AEs) were reported in regard to clinical laboratory parameters, vital signs (heart rate, blood pressure). The electrocardiogram profiles remained unchanged from baseline, with the CXCR4 mRNA concentration profiles showing no significant upregulation even at the highest tested MAD dosage of NRP2945. In contrast, within the pharmacodynamics range of NRP2945 downregulation of CXCR4 expression was recorded. The drug candidate NRP2945 did not yet reached a maximal sensitive dosage at the highest concentration tested. In conclusion, NRP2945 was considered safe and well-tolerated in healthy volunteers with only mild AEs reported. No serious adverse events were reported.

1.3 Study and Dose Rationale

1.3.1 Study Rationale

This study will evaluate two different doses of NRP2945, and its ability to reduce the cumulative absence seizure frequency of patients diagnosed with GGE.

NRP2945’s ability to suppress convulsive activity in the non-clinical setting is believed to be due to its mechanism of action of activating CXCR4/CCR3 receptor complexes. The measurement of the down-regulation of the mRNA level of the CXCR4 gene measured in isolated peripheral blood mononuclear cells (PBMCs) after NRP2945 contact serves as a surrogate marker for the physiological activation of the CXCR4/CCR3 receptor complex in neurons in the brain. This physiological activation of CXCR4 receptor has been shown in various in vitro neuronal experiments by the ligands lithium, granulocyte colony stimulating factor (g-CSF) and brain derived neurotrophic factor but require several hours to occur (Kim et al., 2006; Kim et al., 2007). In contrast, NRP2945 contact leads to more rapid downstream signaling and upregulation of GABA and GABA A receptor alpha and beta subunits, which causes an inhibition of the neural network and subsequently diminishing epileptiform activity. NRP2945 therefore represents a novel and safe therapeutic strategy for reducing seizure activity in patients with refractory epilepsy. Because of its tolerability profile, the drug candidate is ideally suited for a long-term chronic strategy of treating epileptiform activity of refractory nature.

1.3.2 Dose Rationale

The selection of the two NRP2945 doses has been based on the results of a Phase 1, healthy volunteer study, with doses of NRP2945 5ug/kg and 7ug/kg given by subcutaneous bolus injection to be used in this


study.

The rationale for selecting these two doses is based on their safety profile and that the biomarker CXCR4 gene revealed CXCR4 receptor gene expression down-regulation in human PBMCs even after repetitive dosing regimens (as seen in the MAD component of the Phase 1 study). These results indicate CXCR4 protein signaling activation at single and multiple doses of NRP2945 3ug/kg and 5ug/kg respectively. Down-regulation was maintained at day 21 during the MAD component of the study indicating that the CXCR4 receptor is kept at physiological activation levels at repetitive 5ug/kg subcutaneous bolus dosing. This biological activity may relate to the optimal pharmacodynamic range for NRP2945 dosing in relation to creation of an inhibitory neural network in central nervous system (CNS) tissue. This PBMC-related CXCR4 gene expression down-regulation is positively correlated to CXCR4 gene expression down-regulation in brain tissue (unpublished in vitro cultivated brain slice data) indicating the efficacy for both neuroprotection and neuroregeneration by NRP2945.

The higher dose of NRP2945 7ug/kg will be studied to evaluate any decrease of CXCR4 gene expression in blood PBMCs with simultaneous effects on EEG patterns after IPS. It is expected that this dosage will present the upper limit of effective NRP2945 dosage causing diminishing seizure activity in adult refractory patients.

2. Objectives and Endpoints

Objectives Endpoints

Primary:

To assess the safety and tolerability of two doses of NRP2945 after subcutaneous bolus injection, 48 hours apart, in patients with absence epilepsy

Incidence of adverse events after two doses of NRP2945 compared to doses of Placebo

Changes in the neurological examination after two doses of NRP2945 compared to doses of Placebo

Changes from baseline, in clinical laboratory parameters, physical examination and vital signs after two doses of NRP2945 compared to doses of Placebo

Secondary:

1. To evaluate the ability of NRP2945 to suppress the cumulative seizure rate as compared to Placebo in patients with absence epilepsy

2. To evaluate the effect on the plasma concentrations of concomitantly taken anti-epileptic drugs following administration of NRP2945

1. The primary efficacy endpoint is:a. Change in the cumulative frequency of

SWD in subjects receiving each dose of NRP2945 as compared to Placebo.

b. Onset and duration of SWD frequency changes in subjects as related to the two doses of NRP2945 as compared to the Placebo.

2. Plasma concentrations of concomitant AEDs during administration of NRP2945 as compared


to the Placebo days for all AEDs.

Tertiary/Exploratory:

To evaluate the pharmacodynamic profile of, and effect of, NRP2945 on the biomarker CXCR4 compared to Placebo.

Pharmacodynamic profile of NRP2945 after subcutaneous bolus injection.

Change in CXCR4 gene expression levels on day 1 and 3 dosing days at several time intervals after dosing

3. Study DesignThis is a single-blind, Placebo-controlled study of sequential doses of NRP2945, comparing the effect of Placebo, NRP2945 5ug/kg, and NRP2945 7ug/kg on the cumulative frequency response of absence seizures. Each dose of either Placebo or NRP2945 will be given over a 48-hour period. Five subjects will be enrolled.

The aim of this study is to evaluate two doses of NRP2945 in patients displaying absence epilepsy. Each subject will return for three visits called ‘Dosing Cohort’, with each dosing cohort being at least 14 days apart. Subjects will receive two doses each of Placebo and the two doses of NRP2945, in sequential order as follows:

Dosing Cohort One: o Day 1: Placeboo Day 3: Placebo

Dosing Cohort Two: o Day 24: NRP2945 5ug/kgo Day 26: NRP2945 5ug/kg

Dosing Cohort Three: o Day 47: NRP2945 7ug/kgo Day 49: NRP2945 7ug/kg

The study drug/product (either NRP2945 or Placebo) will be administered at the same time (approximately at 09:00-10.00hrs) via subcutaneous bolus injection by designated study personnel.

The subjects will be screened to ensure they have stable SWDs measured for 3hrs starting in the morning (9.00-10.00 am). Following confirmation of at least 3 absence seizure discharges during the 3 hrs screening time frame, their EEG profile will be measured at approximately 30 minute pre-dose up to 3 hours post-dose, on each day of dosing. On Day10, the EEG will be analyzed at approximately 168-171 hours post Day 1 dose. The cumulative frequency of the SWDs on dosing days and follow-up visit will be compared between the Placebo cohort and the two NRP2945 dosing cohorts. Time to onset of the potential pharmacodynamics effect of NRP2945 will be determined by the increasing length of the interictal latency compared to the last occurred SWD.

Assessments of NRP2945 PD parameters will occur throughout each dosing cohort.

Safety will be assessed throughout the study and at the end of study visit (Follow Up visit).


3.1 Number of Study Sites

It is planned for one study site to be involved in the conduct of this study.

3.2 Study Duration

The duration of the study for each subject is up to 16 weeks:

Up to 3 week screening period 13 week dosing period (dosing of study drug and/or Placebo with latency period of 14 days

between dosing cohorts)

4. Study PopulationPatients will be selected from the Site Investigator’s existing patient population. Their eligibility will be reviewed and documented by an appropriately qualified member of the Investigator’s study team before they are included in the study.

After screening, the subjects will be requested not to change concomitant AEDs (medication and/or dosage) for the duration of the study. Any change in concomitant AEDs or therapeutic diet during the study,

will require the subject to return for a repeat series of EEGs at which time, no study drug will be administered.

Investigators must keep a record of all patients who were screened for the study but were not enrolled.

4.1 Number of Subjects

It is planned that up to 5 male or female subjects with stable (drug-resistant) absence epilepsy will be enrolled in the study. In order to cater for a possible drop-out we will actively screen for 4 subjects to enroll into the study.

4.2 Inclusion Criteria

Patients are eligible for inclusion, if ALL of the following conditions are met:

1. Are male or female age 18-65 years.

2. Signed informed consent form (ICF) indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.

3. Five men or non-pregnant, non-breastfeeding women 18 to 65 years-of-age

4. Diagnosis: Clinical diagnosis of an epileptic syndrome (including, but not limited to, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, or Jeavons syndrome) with absence seizures consistent with the International League against Epilepsy Revised Classification of Seizures (2017).

5. Absence seizures persisting despite documented trials with at least two standard anti-epileptic treatments (drug-resistance). Subjects are resistant to valproate and at least one other AED (e.g. phenytoin).

6. Observation of at least 3 instances of bilateral synchronous symmetrical spike waves of approximately 2.5 – 4.5 Hz consisting of generalized paroxysmal fast activity, generalized polyspike trains or spike-and wave complexes being measured within the time frame of 3 hrs of observation period during the screening.


7. On no therapy or taking stable doses of one or more anti-epileptic medication(s) for at least 30 days. If a subject is not on medication, adequate documentation justifying lack of therapy is acceptable.

8. BMI: 18-35 kg/m2 at screening.

9. Subjects with reproductive capability including all males and women of child-bearing potential (WOCBP) must agree to practice continuous abstinence or adequate contraception methods (appropriate double barrier method or oral, patch, implant, or injectable contraception) from as soon as feasible during screening period until at least 30 days after the last dose (i.e., intermittent abstinence based on "rhythm", temperature monitoring, or other means of timing is not acceptable).

10. Male subjects with a partner of child-bearing potential must be surgically sterilized or be willing to use condoms with spermicide from as soon as feasible during screening period until at least 30 days after the last dose.

11. Able and willing to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

4.3 Exclusion Criteria

Patients are not eligible for this study if any of the following conditions exist:

1. Have any clinical condition that, in the opinion of the Investigator, might interfere with the results of the study or pose a risk to the subject due to participation in the study

2. Have a history of alcoholism, drug abuse, or drug addiction within the past 12 months.3. Have an active CNS infection, demyelinating disease, degenerative neurological disease or any CNS

disease deemed to be progressive during the course of the study that may confound the interpretation of the study results.

4. Have any clinically significant psychiatric illness, psychological or behavioral problems which, in the opinion of the Investigator, would make the patient unsuitable to participate in the study.

5. Have a haemoglobin or haematocrit below the site’s lower reference range value.6. Are suffering from clinically significant active liver disease, porphyria or have severe hepatic dysfunction

indicated by AST and/or ALT greater than 3 x upper limit of normal.7. Are currently on the drug plerixafor® (AMD3100, a highly specific CXCR4 antagonist), or alternatively

have stopped taking plerixafor® less than 4 weeks before first day of screening.8. Have participated in any other clinical studies involving an investigational product or investigational

device within 30 days of screening, or who intend to participate in another clinical study at any time during the conduct of this study.

Is a female who is pregnant or lactating or are of reproductive potential and does not agree to use effective birth control methods during the study period. Note: A female is considered to be of childbearing potential if post onset of menarche and before natural or induced menopause. Natural menopause is recognized to have occurred after 12 consecutive months of amenorrhea for which there is no other obvious pathological or physiological cause. Induced menopause is recognized to have occurred after hysterectomy, after bilateral oophorectomy, or iatrogenic ablation of ovarian function.

The following birth control methods are considered effective:

Abstinence Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30

days prior to informed consent Diaphragm with spermicide, tubal occlusion device Intrauterine device (IUD)


Tubal ligation Male partner using condom Male partner having been vasectomized at least six months prior to informed consent

For male subjects with a female partner of reproductive potential, one or more of the above effective birth control methods are to be utilized during the study period.

4.4 Screen Failures

Screen failures are defined as subjects who consent to participate in the clinical study but are not subsequently enrolled in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, reason for screen failure and details of eligibility criteria not met.

4.5 Prior/Concomitant Therapy

Subjects should not commence any new medications or alter therapeutic diet indicated for epilepsy during the study, including during the follow up period.

Concomitant medication maybe used to treat intercurrent acute or chronic diseases or conditions at the discretion of the Investigator. The dose of concomitant medication required for a chronic disease should be kept as constant as possible throughout the study.

Full details of all concomitant medications will be recorded in the subject medical records. Any relevant physical or other forms of treatment must also be recorded. No recording of intake of vitamins, supplements or herbals will be recorded.

4.5.1 Prohibited Therapy

The following medications and treatments are specifically not permitted for the specified periods prior to, and during, the study;

Plerixafor – administered currently or within 4 weeks of the first day of Screening (through to the completion of the Follow Up visit).

At the end of the follow up period the subject’s doctor will discuss appropriate future treatment for subjects epilepsy as required.

4.6 Lifestyle Considerations

4.6.1 Meals/Dietary Restrictions

There are no meal or other dietary restrictions required for this study.

4.7 Subjects Completion and Withdrawal

4.7.1 Subject Completion

A subject will have completed the study once all of their specific study-related procedures have been conducted and a final assessment at the Follow Up visit has been performed.


If the subject ceases treatment early (i.e., withdraws), the Follow Up visit assessments should be conducted at that time, as the end of study assessment.

Any AEs or SAEs still ongoing after the final study visit will be followed-up in accordance with Section 8.

4.7.2 Withdrawal of Subject

A subject may withdraw from the study at any time at his/her own request without prejudice to further treatment, or may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative reasons.

If the subject withdraws consent, the Sponsor may retain and continue to use any data collected before such a withdrawal of consent.

If a subject withdraws from the study, he/she may request destruction of any samples taken and not tested, and the Investigator must document this request in the subject’s source documentation.

See Schedule of Assessments for data to be collected at the time of study discontinuation and follow-up and for any further evaluations that need to be completed.

If a subject does discontinue from the Study, the reason for their discontinuation must be clearly documented in the source documentation. If possible, subjects should be seen and assessed by the Investigator and every effort must be made to have a safety follow-up visit 7 days after the last dose of Study Product.

Possible reasons for early discontinuation may include:

Withdrawal of consent Any unacceptable AEs, in the judgment of the Investigator Subject’s non-compliance with the protocol or dosing requirements New intercurrent disease, which may influence the effect of the Study Product The subject commencing a prohibited medication

Technical reasons e.g. change of physician/Investigator, change of residence, termination of the study by the Sponsor.

If a decision is made to discontinue a subject from the study, the Follow Up Visit assessments should be conducted at that time, as the end of study assessment.

4.7.3 Procedures for Handling Withdrawals

In the event that the subject withdraws from the study, the Investigator should record in the source documents:

the date of the withdrawal, the person who initiated withdrawal and the reason for withdrawal.

This information is to be entered into the relevant page of the subject’s Case Report Form (CRF).

4.7.4 Replacement of Subjects

Subjects who withdraw from the study prior to completing Day 3 of Dosing Stage 2 will be replaced. If a subject withdraws during any part of Dosing Stage 3 (including the washout period prior), no replacement will occur. NRP2945-3: Protocol P2a Absence epilepsy study-, version: 2.0_14 September 2018 Confidential of 49

4.7.5 Lost to Follow Up

A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site.

The following actions must be taken if a subject fails to return to the clinic for a required study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as possible and counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or should continue in the study.

Before a subject is deemed lost to follow up, the investigator or designee must make every effort to regain contact with the subject (where possible, at least three telephone calls and, if necessary, a certified letter to the subject’s last known mailing address or local equivalent methods). These contact attempts should be documented in the subject’s source documents.

Should the subject continue to be unreachable, he/she will be considered to have withdrawn from the study. The date of last contact will be considered the date of withdrawal.

4.7.6 End of Study Definitions

A subject is considered to have completed the study if s/he has completed all stages of the study including the Follow Up Visit.

The end of the study is defined as the date of the last visit of the last subject in the study.

5. Study Product

5.1 Study Products

The Investigational Product, NRP2945, and Placebo will be manufactured by Auspep, a GMP-certified manufacturer of peptides in Australia. The reconstitution of the lyophilized powder will be performed by qualified site personnel, delegated by the Investigator, according to the method outlined in the Study Manual.

Both the NRP2945 powder and Placebo solution will be packed into glass vials with rubber stopper and labeled, in accordance with specific Australian regulatory requirements.

Description of NRP2945

NRP2945 is supplied as lyophilized powder formulated with large excess of D(+)-trehalose which has been kept under nitrogen pressure (oxygen-free atmosphere). Key components of NRP2945 formulation are:

Component Concentration

NRP2945 0.96 mg NRP2945 (0.64 mg/mI net weight)

D(+) Trehalose 255 mg (170 mg/mL)

Physiological saline 1.4 ml

pH 7.3

Final volume of injectable 1.5 ml


The API containing vials will contain each 0.96mg net peptide weight corresponding to 0.64mg/mg net peptide concentration.

This volume of one vial will accommodate either of the two doses of NRP2945 to be the tested (5ug/kg or 7ug/kg) and is suitable for subjects weighing between 50-150 kg.

Description of Placebo

Components of the Placebo are:

Component Concentration

D(+) Trehalose 255 mg (170 mg/mL)

Physiological saline 1.4 ml

pH 7.3

Final volume of injectable 1.5 ml

5.2 Handling, Preparation, Storage and Accountability

Handling:

Do not touch or inhale NRP2945 powder or get the product into the eyes. If exposure does occur, rinse eyes or contacted skin with sufficient amounts of tap water. No health-related hazard is known for NRP2945.

Storage:

All study products (including Placebo) must be stored at -20 C in a secure area and protected from light.

Preparation:

Both NRP2945 and Placebo vials are to be brought to room temperature at least 1 hour before the scheduled dosing time.

The content of one vial of NRP2945 is be reconstituted with 1.4 ml of sterile physiological saline, resulting in a final volume of 1.5 ml. The reconstituted content will then sterile filtered through a polyethersulfone (PES) filter-mounted syringe, and the required dose prepared. A suitable administration needle will be attached to the syringe at the time of dosing.

The content of one vial of Placebo will be filtered through a PES filter-mounted syringe and the required dose prepared. A suitable administration needle will be attached to the syringe at the time of dosing.

One vial of NRP2945 or Placebo per subject will be used per dosing day.

Accountability:

Investigational Product and Placebo must only be used for subjects enrolled in this clinical study and should not be used for any other purpose.


The Investigator or designee is responsible for Study Product accountability, reconciliation and record maintenance. The Investigator or designated site personnel must maintain Study Product accountability records throughout the course of the study including records of the amount of Study Product received, the identification of the Subject for whom the Study Product was dispensed, the date(s) and quantity of the Study Product dispensed. Records must show the identification of the person who dispensed of the Study Product.

The Study Product vials and records must be available for inspection by a study monitor during the study. Study Product supplies, including unused vials, will be returned by the study site to the Sponsor or their agent for destruction. Empty used and partially used vials can be discarded at site per site procedures and following confirmation of study product accountability by the study monitor. At the end of the Study an overall Study Product accountability will be generated to check the conformity of the number of dispensed and used/lost/returned Study Product vials.

Used syringes must be disposed of immediately according to site procedures (e.g., into a medical waste sharps container).

5.3 Randomisation and Blinding

This is a single-blind study with no randomisation of Study Product allocation required.

The subjects will be blinded to the order of dosing cohorts. The Sponsor, Investigator and site personnel including the EEG technician will be aware of the order of the dosing regimens and be un-blinded to the study product on each day of dosing.

5.3.1 Subject Identification Number

A unique subject identification (ID) number will be allocated to each subject who is consented for the study so that subjects can be identified without making assumptions about their subsequent eligibility for the Study. Subjects will be allocated to sequential, ascending 3-digit ID numbers (001, 002, 003 etc.), which in combination with the 2-digit site number will provide a unique ID for each subject. For example, the second subject screened at the first site will receive the Subject ID number of 01-002.

The Subject will retain the same ID number for the duration of the study.

5.4 Dosage and Administration

All doses of NRP2945 and Placebo will be administered by subcutaneous injection by a qualified member of the site study team, into healthy and intact skin, with the abdomen being the preferred administration area.

There will be three treatment periods, given in sequential stages, with all 5 subjects receiving two doses of Placebo, two doses of NRP2945 5 ug/kg and two doses of NRP2945 7 ug/kg as follows:

Treatment Period One: o Day 1 of treatment period 1 / Day 1 of Study: Placeboo Day 3 of treatment period 1 / Day 3 of Study: Placebo

Treatment Period Two: o Day 1 of treatment period 2/ Day 24 of Study: NRP2945 5ug/kgo Day 3 of treatment period 2 / Day 26 of Study: NRP2945 5ug/kg

Treatment Period Three:


o Day 1 of treatment period 3 / Day 47 of Study: NRP2945 7ug/kgo Day 3 of treatment period 3 / Day 49 of Study: NRP2945 7ug/kg

The subjects will attend the study site on Day 1, Day 3 f each dosing for Study Product administration and/or assessment at day 10, respectively . There will be a minimum 14-day washout period between Day 3 of Dosing Cohort 1 and Day 1 of Dosing Cohort 2 AND Day 3 of Dosing Cohort 2 and Day 1 of Dosing Cohort 3 for each patient.

5.5 Compliance of Study Products

Two authorised study site personnel will prepare each dose of Study Product. The first individual will prepare the dose of Study Product with the second individual confirming the Study Product (Placebo or NRP2945), dose and volume of the injection. The dose and volume will be documented on the Study Product Dispensing and Accountability form, site administration forms and captured in the CRF. The actual time and location of each dose administration will also be recorded.

5.6 Rescue Medicine

There is no rescue medication available for NRP2945.

5.7 Drug interactions

NRP2945 is known to interact with the drug plerixafor® which is a highly specific CXCR4 antagonist. Simultaneous presence of NRP2945 and plerixafor® in blood stream has detrimental pharmacodynamic effects on NRP2945. No counter-measures are currently known or can be recommended if accidental adjunctive treatment of NRP2945 and plerixafor occurs.

5.8 Study Product Return

At the conclusion of the study, a final inventory will be performed. Reconciliation of Study Products will be logged on the relevant reconciliation form, signed and dated. Any discrepancies will be investigated, resolved, and documented. At the termination of the study, all unused study vials will be returned to the Sponsor or sponsors representative for destruction following completion of accountability activities.

6. Study Assessments

6.1 Survey – questionnaire on day 10 (follow-up visit)

At the end of every cohort assessment on day 10, the subjects will be asked to fill in a survey (questionnaire) by deciding for single-choice options which provide indication about their respective general physical and mental health status.

The questionnaire is depicted on the following page.


Day 10 Health Questionnaire

Protocol number: NRP2945-3Principal Investigator: Site Number:

Participant Identifier (initials/number):

Date: (dd/mmm/yyyy)

1) Compared to how you felt about your physical health in general before the two injections please indicate whether in you feel better, worse or the same as before on the following scale(circle once):

A: My health is a lot worse

B: My health is a little

worse

C: My health is the same

D: My health is a little better

E: My health is a lot better

2) Since the two injections have you noticed any change in your capacity to remember things (memory) in day to day life, by choosing the best answer about how you feel on this scale (circle once):

My memory is a lot worse

My memory is a little

worse

My memory is the same

My memory is a little better

My memory is a lot better

3) Since the two injections have you noticed any change in your perceived quality of life (performing daily activities like: ease of getting to work or to an appointment ) by choosing the best answer to describe how you feel on this scale (circle once):

My quality of life is a lot

worse

My quality of life is a little

worse

My quality of life is the same


better

My quality of life is a lot better

4) Since the two injections have you noticed any change in your perceived quality of life (eday-to-day happiness and feelings of mental wellbeing ) by choosing the best answer to describe how you feel on this scale (circle once):

My quality of life is a lot

worse


worse

My quality of life is the same


better

My quality of life is a lot better

If you have indicated some changes above ( i.e. measures are better or worse) since starting the


6.2 EEG Assessment

According to standard site practice, the Subject will have EEG electrodes placed and will undergo 3.5 hrs of recording starting 30 min before IP / placebo administration followed by 3 hrs continuous post-dose recordings on day 3 (2. Dose of IP or placebo).

EEG Measurement with Video Monitoring

EEG session will be recorded with standard 19-21-channel EEG equipment

Montage:

A 19-21-channel recording system will be used with a bipolar and transverse derivations with emphasis on the parieto-temporal-occipital area (maximum and spreading of EA): The display montage will include T4-T6-O2-O1-T5-T3 and T6-P4-Pz-P3-T5, apart from 2x4 (8) frontal to occipital leads.

Settings:

Amplification: 7-10 microV/mm

High Frequency Filter: 35-70 Hz

Time constant: 0.3-0.6 sec

Display speed: 30 mm/sec

Methods:

The cumulative absence frequency during the screening visit will be recorded for each patient in the CRF.

Visit 1(Screening), 3 hrs of continuous EEG recording will be performed.

Visits 2(Dosing Stage Day 3) EEG recording will be performed for 30 min pre-dose and continuous for 3 hrs post-dose.

Interpretation of Results:

Two copies of each subject’s EEG sessions including video will be stored and labeled on digital video disc (DVD).

6.3 Safety Assessments

The measures of safety used in this study are routine clinical procedures, reporting of AEs and any associated concomitant medication usage. The following clinical assessments will be conducted during this study:

o A detailed review of the subject’s medical history

o Height measurement (Screening only).

o Body weight measurement

o Body mass index will be calculated automatically in the CRF.


o Physical examination includes: Head, eyes, ears, nose and throat (HEENT), heart, respiratory, abdomen, extremities. Additional tests may be performed based on medical history or findings on examination. To be performed by the Investigator or a medically qualified delegate.

o Neurological examination includes: Mental status, cranial nerves (I-XII), motor system, reflexes, sensory system, coordination and gait assessments. Additional tests may be performed based on medical history or findings on examination. To be performed by the Investigator or a medically qualified delegate.

o Vital signs: Seated Blood Pressure (systolic and diastolic), heart rate and respiratory rate will be taken after the subject has rested for at least 5 minutes. Body temperature will be recorded using tympanic measurement.

o Local tolerability assessments - Injection site reaction will be assessed for pain, erythema, and induration at a minimum and classified as NONE, MILD, MODERATE or SEVERE per the Investigators judgement.

o Clinical laboratory tests:

Haematology assessments: Haemoglobin, haematocrit, red blood cell count, platelet count, white blood cell count and differential (absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils).

Biochemistry tests: Sodium, potassium, phosphate, chloride, calcium, blood urea nitrogen/urea, uric acid, creatinine, glucose (non-fasting), C-Reactive Protein, magnesium, total bilirubin, alkaline phosphatase, AST, ALT, GGT, total protein, lactate dehydrogenase, Creatine Kinase.

o Pregnancy test – by urine dip stick.

o Adverse Events: The subject will be reviewed for AEs at each visit and all AEs will be recorded throughout the study together with any related concomitant medications

o Any new or worsening clinically significant abnormalities on any laboratory parameter will be reported as an AE.

o Concomitant Medication use (medication, dosage, dosing regimen and reason for use).

6.4 Pharmacodynamic Samples

Pharmacodynamic samples will be harvested as whole blood samples and immediately collected by personnel from 360biolabs (Melbourne) for PBMC isolation and prepared for gene expression analysis.

6.5 Blood Volumes for Clinical Laboratory and PD Sampling

A number of blood samples will be collected throughout the study. The assessment, sample volume and the sampling frequency is summarised below (Table 3).


Table 3: Blood Collection Volume

AssessmentVolume (ml) per sample

Number of Samples

Total Volume

Biochemistry 8 15 120

Haematology 5 15 75

AED Levels 5 12 60

Pharmacodynamic 10 24 240

TOTAL 495

A total of 495 mL of blood will be drawn from each subject. The collection, handling processing, storage and transportation of all samples will be in accordance with the relevant procedures outlined in the Study Manual.

6.6 Maintaining the Blind

The study product will be provided to the administrator in pre-prepared syringes ensuring that the subject is shielded from knowing the treatment received.

7. Study Procedures The timings of Study Visits are as follows:

Assessment (Visit) Number

Study Stage Study Day Gap between next Stage

Visit 1 Screening Day -28 to Day -1 Maximum 28 days

Visit 2 Dosing Cohort 1 Day 1 to 3, 10 Minimum 14 days (2 weeks)

Visit 3 Dosing Cohort 2 Day 24 to 26, 33 Minimum 14 days (2 weeks)

Visit 4 Dosing Cohort 3 Day 47 to 49, 56 Minimum 7 days

Day 1 of each Dosing Cohort may be + 2 days. The Follow Up Visit at one week after last dosing allowing + 1 day

7.1 Screening Visit - Visit 1

The screening period should be performed from 28 days prior to the intended first day of Dosing Stage 1 (Day 1). All subjects must provide written informed consent before any study-specific assessments or procedures are performed.

The assessments to be performed at screening visit include:

o Review of inclusion and exclusion criteria


o Demographics: date of birth, gender, race, ethnicity

o Medical history, including diagnosis on EEG and/or epilepsy and any concomitant medications

o Height and body weight – body mass index will be calculated from these results in the database

o Physical examination

o Neurological examination

o Vital signs

o EEG assessment

o Clinical laboratory assessments: haematology and biochemistry

o Pregnancy test (female subjects)

Subjects who complete all of these assessments and who fulfil the eligibility criteria are able to be enrolled into the study.

7.2 Dosing Stages

The timing of key assessments and study product administration is critical in this study. The collection of AED levels and PD samples along with the EEG assessments should be performed at the times indicated prior to, and after administration of the Study Product.

For procedures that are required at the same time as others, the priority order of assessments is:

1. EEG2. PD sample collection3. AED sample collection4. Remainder of procedures/assessments.

7.2.1 Day 1

The following assessments are to be performed on Day 1 of each Dosing Cohort PRIOR to the administration of the Study Product.

The subject will present to the epilepsy center at approximately 0700hrs. Confirmation of continuing eligibility for the study will occur, and the EEG leads will be placed.



o Review of AEs and Concomitant medications

o Body weight

o Vital signs

o Blood samples: haematology, biochemistry, PD and AED levels:

A blood sample will be collected approx. 30 minutes prior to the administration of study product


o Urine Pregnancy test

Study Product Administration:

Following completion of the above assessments, the dose of Study Product (either Placebo or NRP2945) will be administered subcutaneously, by appropriately qualified site personnel (at approximately 09:00 to 10:00 hours). The exact time of administration will be noted and recorded in the CRF.

The assessments to be performed AFTER administration of Study Product are:

o Neurological examination: 4 hours post dose administration

o Vital signs: 15 minutes and 2 hours post dose administration

o Injection site assessment: 1, 2 and 6 hours after Study Product injection

o AED level assessment: A blood sample will be collected 4 hours post dose administration

o PD assessment: Blood samples will be collected 30 and 60 minutes and 4 hours post-dose administration

o Review of concomitant medications and AEs.

7.2.2 Day 2

No Study Product is administered on Day 2. The subject is not required to come to the clinic.

7.2.3 Day 3

The subject is to return to the site on Day 3 of each Dosing Cohort to receive the second dose of Study Product for that Cohort.

The following assessments are to be performed PRIOR to the administration of study product:

o Vital signs


o EEG assessment: An EEG will be performed 30 minutes prior to the administration of study product.

o Blood Samples: PD and AED levels:

A blood sample will be collected approx. 30 minutes prior to the administration of study product

o Review of concomitant medications and AEs

Study Product Administration:

Following completion of the above assessments, the dose of Study Product (either Placebo or NRP2945) will be administered subcutaneously by the appropriately qualified site personnel (at approximately 09:00 hours). The exact time of administration will be noted and recorded in the CRF.

The assessments to be performed AFTER administration of study product are:

o Neurological examination: 4 hours post dose administration

o Vital signs: 15 minutes and 2.5 hours post dose administration


o Injection site assessment: 1, 2 and 6 hours after Study Product injection.

o EEG assessment: An EEG will be performed for 30 min pre-dose and 3 hrs continuously post-dose

o Blood samples for Haematology and Biochemistry: 6 hours post dose administration

o PD assessment: Blood samples will be collected 30 and 60 minutes and 4 hours post dose administration

o AED level assessment: A blood sample will be collected at 4 hours after the study product dose has been administered

o Review of concomitant medications and AEs.

7.3 Follow Up

Following completion of the dosing days (day 1 and 3) of every cohort a follow-up visit on respective day 10 of will be performed:


o Body weight

o Vital signs

o Blood samples – haematology and biochemistry

o Pregnancy test

8 Safety ManagementIt is the responsibility of the Investigator to oversee the safety of the study at his/her site. This safety monitoring will include careful assessment and appropriate reporting of AEs as noted above and review of results from safety procedures.

The here outlined NRP2945-3 clinical study is not a First in Human (FIH) study and the safety of NRP2945 was established in FIH study in 49 healthy volunteers with Nucleus Network in 2017. The FIH study showed acceptable safety with only minor injection site reactions and was well tolerated in doses up to 25 ug/kg of NRP2945. The safety of study participants would be ensured by regular review of safety data by study Medical Monitor and Investigator. The planned study is only a Phase 2A study with 5 participants – a data safety and monitoring board is not deemed necessary due to the small size.

8.1 Stopping Rules

The study will be stopped, if two instances of the same worsening occur (1, 2, or 3 below), or a total of 3 worsening episodes occur across all subjects:

1. If a subject has an increase of the cumulative absence seizures or interictal discharges by more than 50% after dosing as compared to the screening day, the therapeutic intervention study will be terminated and the subject will be unable to participate in further testing.

2. If a subject experiences a generalised tonic-clonic seizure during any study day, and they have not had a generalised tonic-clonic seizure in the 6 months prior to enrollment, the study will be


terminated for that subject. If any subject experiences a generalised tonic-clonic seizure during the trial, the study will be terminated for that subject and he/she will not be permitted to participate in further testing.

3. If in the opinion of the Investigator a subject has evidence of pro-convulsive activity on the EEG after administration of the Study Product, (e.g. increase in spike-wave activity) then the study will be terminated for that subject and he/she will not be permitted to participate in further testing.

4. Death

If the stopping rules are met (as confirmed by the Investigator), a meeting will occur between the Medical Monitor and the Investigator and provide recommendations to the Sponsor on the continuation or early completion of the study.

8.2 Safety Monitoring Committee

There is no Safety Monitoring Committee planned for this study. A monthly meeting will be held between the Medical Monitor and the Investigator (starting after first subject is enrolled) to review the safety data and to confirm whether stopping rules have been met.

8.3 Adverse Event Management

The Investigator is responsible for ensuring that all AEs and other clinically significant findings are documented and accurately reported. All site personnel must understand the requirements and responsibilities related to safety reporting that are outlined below.

8.3.1 Adverse Event

An AE is defined by ICH as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product.

Adverse events do not include:

Events identified at screening that meet exclusion criteria Medical or surgical procedures (the condition that leads to the procedure is the AE) Situations where an untoward medical occurrence has not occurred. For example:

Planned hospitalisations due to pre-existing conditions, which have not worsened Hospitalisations that occur for procedures not due to an AE (e.g., cosmetic surgery)

Hospitalisations for a diagnostic procedure where the hospital stay is less than 24 hours in duration or for normal management procedures (e.g., chemotherapy)

At each clinical evaluation, the Investigator (or delegate) will determine whether any AEs have occurred. If known, the medical diagnosis of an AE should be recorded in preference to the listing of individual signs and symptoms.


Laboratory reference ranges are defined by upper or lower limits of parameters of the respective laboratory. The Investigator should ensure that each parameter out of the normal range is assessed for clinical significance and potential for being an AE. The Investigator should document any change in laboratory result as an AE if considered the change to be clinically significant, even if the absolute value is within the alert limit or reference range.

Assessment of Intensity:

The subject must be instructed to inform the Investigator about all AEs and these must be documented in the subject records and CRF together with their intensity;

Severe are those AEs which make normal daily routine impossible.

Moderate AEs that impact the normal daily routine.

Mild AEs that do not impact normal daily routine.

An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilised for rating the intensity of an event, and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 8.3.2.

Assessment of Causality:

The Investigator must assign causality to each adverse event in relation to Study Product (either NRP2945 or Placebo) based on the following scale:

Not related: AE for which there is evidence of another explanation, e.g. the AE is obviously explained by the subject’s disease(s), is in accordance with the known effect of a concomitant medication, or has occurred prior to first administration of study product.

Possibly related: AE with a reasonable time relationship to Study Product administration, but which could also be explained by disease or other drugs. Information on Study Product withdrawal may be lacking or unclear.

Probably related: AE with reasonable time relationship to Study Product administration that is unlikely to be attributed to disease or other drugs. Response to Study Product withdrawal is clinically reasonable. Re-challenge is not required.

Definitely related: AE with plausible time relationship to Study Product administration and which cannot be explained by concurrent disease or concomitant medications.

Expected AEs are defined as all AEs stated in the Investigator Brochure (IB). If an AE has not been previously reported (including type, degree, or frequency) in the IB, it is an unexpected adverse event. CuroNZ or designee is responsible for determining the expectedness of an AE, either at the time of the reporting of a serious AE or during the review of the safety data in reporting purposes.

If an AE leads to premature discontinuation of the study, the appropriate pages of the CRF must be completed.

8.3.2 Serious Adverse Event

A serious adverse event (SAE) is defined as any AE that is:

Fatal


o The event must be the cause of death for the SAE to meet the serious criteria of “fatal”. (Note: death is an outcome, not an event)

Life-threatening

o The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

Requires or prolongs in-patient hospitalization Results in persistent or significant disability or incapacity A congenital anomaly or birth defect An important medical event, according to the Investigators judgment

o Important medical events are those that may not be immediately life threatening, but are clearly of major clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the other serious outcomes noted above.

All AEs that do not meet any of the criteria for serious should be regarded as non-serious adverse events.

8.3.3 Adverse Event Reporting Period

At each contact with the subject, the investigator must seek information on AEs by specific questioning and, as appropriate, by examination. Information on all AEs should be recorded immediately in the source document, and also in the appropriate AE module of the CRF. All clearly related signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source document, though should be grouped under one diagnosis.

All AEs occurring from the first dose of Study Product must be recorded. The clinical course of each event should be followed until resolution, stabilisation, or until it has been determined that the study treatment or participation is not the cause. Serious adverse events that are still ongoing at the end of the study must be followed up to determine the final outcome. Any SAE that occurs after the end of the study and is considered to be possibly related to the Study Product or study participation should be recorded and reported immediately.

The study period during which AEs (including SAEs) must be reported is from Visit 2 (first dosing) to Visit 3 (Follow Up), regardless of the causal relationship to Study Product (NRP2945 or Placebo.

Any AEs reporting during the screening period will be captured as Medical History. All AEs reported after the first dose of Study Product are to be recorded on the AE page of the subject’s CRF.

8.3.3.1 Preexisting Condition

A preexisting condition is one that is present at the start of the study. A preexisting condition should be recorded as an AE if the frequency, intensity, or the character of the condition worsens during the study period.

8.3.3.2 General Physical Examination Findings

At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the end of the study, any new clinically significant findings/abnormalities that meet the definition of an AE must also be recorded and documented as an AE.


8.3.3.3 Post-study Adverse Event

All unresolved AEs should be followed by the Investigator until the events are resolved, the subject is lost to follow-up, or the AE is otherwise explained. At the last scheduled visit, the Investigator should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, believes might reasonably be related to participation in this study. The Investigator should notify the study Sponsor of any death or AE occurring at any time after a subject has discontinued or terminated study participation that may reasonably be related to this study.

8.4 Reporting of Serious Adverse Events

Investigators and other site personnel must report SAEs on the SAE form to the study safety group using the contact details noted in the Study Manual within 24 hours of becoming aware of the SAE, regardless of causality.

Any SAE must be reported by the Investigator if it occurs during the clinical study or within 4 weeks of the Subject having received the last dose of Study Product, whether or not the SAE is considered to be related to the Study Product.. Instances of death, congenital abnormality or an event that is of such clinical concern as to influence the overall assessment of safety, if brought to the attention of the investigator at any time after cessation of Study Product administration and linked by the Investigator to this study should be reported to the Sponsor.

The Investigator must report an SAE on an SAE Report Form and provide the SAE Report Form and any supportive information (e.g., concomitant medication details) to the Sponsor within 24 hours of becoming aware of the SAE and regardless of causality.

The investigator should not wait to receive additional information to document fully the event before notification of a SAE, though additional information may be requested. Where applicable, information from relevant laboratory results, hospital case records and autopsy reports should be obtained.

SAEs must be reported to the Australian CRO (Novotech) and the Medical Monitor at CuroNZ should be notified within 24 hours of the Investigator/Study Site becoming aware of them.

Follow-up information on SAEs must also be reported by the investigational site within the same time frame. If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided within 24 hours.

All SAEs will be recorded in the subject records and the CRF. CuroNZ or designee is responsible for informing the regulatory authorities of the SAE as appropriate.

If required, the Investigator must notify their Independent Ethics Committee (IEC) of any SAEs occurring at their site, within the time period specific by the IEC.

This may be done via telephone or by scanning or faxing a copy of the CRF AE page to the addresses indicated elsewhere.

Pregnancy Reporting

If a subject or a subject’s partner becomes pregnant they will be asked to consent to follow up of the pregnancy. All pregnancies in a female subject or in a female partner of a male study subject should be reported on a Pregnancy Report Form following the same reporting process and timelines required for SAEs.


9 Statistical ConsiderationsThe statistical analysis principles described below will be supplemented by a statistical analysis plan (SAP), which will be finalised before the database is locked. Any changes to the statistical plans will be described and justified in the final report.

9.1 Sample Size

It is expected that at least 5 evaluable subjects will complete the study, which is sufficient to determine whether there is a reduction of PPR with the study drug.

9.2 Analysis Sets

Subjects will be considered evaluable if they have received any dose of Study Product (NRP2945 or Placebo)

The following sets will be used for the statistical analyses:

o Full analysis set: All subjects in the study.

o Safety set: All subjects who received any study product

o Primary-Analysis (PA) set: Subjects that have completed at least 1 Placebo day and 1 active drug day with acquired absence epilepsy data being interpretable at 80% or more of the time points.

o Per-protocol (PP) set: All subjects from the ITT population who essentially completed the study in compliance with the protocol and who reported no major deviations from the study protocol. The final decision to exclude a subject from the per-protocol population will be taken during the study data review meeting.

9.3 Statistical Analysis

9.3.1 Efficacy Analysis

Descriptive statistics will be presented including the means and standard deviations of number of interictal generalized epileptiform patterns for each subject, for each day of assessment, stratified by duration of the discharge (up to or more than 3 seconds). Graphical displays of the data for each subject will allow exploration of inter- and intra-patient variability. It is expected that at least 5 evaluable subjects will complete the study, which is sufficient to determine whether there is a reduction of the cumulative frequency of absence seizures with the study drug.

9.3.2 Safety and Pharmacodynamic Analysis

Descriptive statistics will be presented for each of the primary safety endpoints and secondary PD endpoints

10 Regulatory and Ethical ConsiderationsThis study will be conducted in accordance with the protocol and with GCP and applicable regulatory requirements.


This protocol and any amendments, informed consent form (ICF), IB, and other relevant documents (e.g., advertisements) will be submitted by the Investigator to a properly constituted IEC or Institutional Review Board (IRB), in agreement with local requirements for formal ethical and governance approval of the study. The decision of the IEC/IRB concerning the conduct of the study is to be made in writing to the Investigator.

The Investigator must submit written IEC approval to the Sponsor or designee before the study can be initiated and before enrollment of any subject into the study

Any amendments to the protocol will require IEC/IRB approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study subjects.

The deviations from or changes to the protocol which were implemented to eliminate an immediate hazard to the study subject and the proposed amendment, if appropriate, should be submitted to the IEC/IRB for review and approval as soon as possible.

The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IEC/IRB annually or more frequently in accordance with the requirements, policies, and procedures established by the IEC/IRB

Notifying the IEC/IRB of SAEs or other significant safety findings as required by IEC/IRB procedures

Providing oversight of the conduct of the study at the site and adherence to requirements of ICH GCP and all other applicable local regulations.

10.1 Informed Consent

The Investigator or his/her qualified representative will explain the nature of the study to the subject or his/her legally authorised representative/guardian (representative) and answer all questions regarding the study. The subject/representative should be given the opportunity to ask questions and should be allowed time to consider the information provided.

Subjects must be informed that their participation is voluntary. Subjects (or their representative) will be required to sign a statement of informed consent that meets the requirements ICH GCP and local regulations as well as the IEC/IRB and the study site’s governance requirements.

The medical records/source documents for the subject must include a statement that written informed consent was obtained before the subject started any study specific screening procedures and enrolled in the study and the date the written consent was obtained. If study procedures begin on the same day as informed consent is obtained, then the time of consent must also be recorded in the subject’s medical record. The authorised person obtaining the informed consent must also sign and date the ICF.

Subjects must be re-consented to the most current version of the ICF(s) during their participation in the study.

A copy of the completed ICF(s) must be provided to the subject/representative. The Investigator must maintain and store the original, signed ICF.

10.2 Confidentiality

Information about study subjects will be kept confidential and managed according to applicable legal and regulatory requirements of Australia.


10.3 Data Protection

Subjects will be assigned a unique identifier. Any subject records or datasets that are transferred to the sponsor will contain the identifier only; subject names or any information which would make the subject identifiable will not be transferred.

The subject must be informed that his/her personal study-related data will be used by the sponsor in accordance with local data protection law.

The subject must be informed that his/her medical records may be examined by authorised personnel appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

10.4 Conflict of Interest

If the Investigator or any staff of the Investigator has a conflict of interest with this study (patent ownership, royalties, or financial gain greater than the minimum allowable by their institution, etc.) they must declare this and be approved by the Sponsor prior to their participation in the conduct of the study at the site.

11 Study Administration

11.1 Sponsor

The study is being sponsored by CuroNZ Limited.

The EEG reviews of the clinical principal investigator will be to be sent for final collation of statistical EEG data to CCDRD, the provider delegated by the Sponsor to perform the data management and statistical analysis activities for the study.

Details of Investigators, study site, Sponsor, Sponsor Medical Monitor, contract research organisation (or similar), study monitor and designee contacts will be detailed in the Sponsor and Investigator Site File.

11.2 Medical Monitoring

Details of the CuroNZ Medical Monitor will be provided in the Sponsor and Investigator Site File and Study Manual.

11.3 Insurance and Liability

CuroNZ has appropriate liability insurance cover in accordance with all local legal requirements. Further details of this and financial arrangements are specified in the agreements with the Study sites.

11.4 Study Registration

Prior to commencing recruitment, a description of this clinical Study will be available on the Australia New Zealand Clinical Trials Registry (ANZCTR) website. This website will not include information that can identify subjects.


11.5 Data Management

All subject data relating to the study will be recorded on an electronic CRF unless transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is responsible for verifying that data entries are accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the information entered in the CRF. The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including quality checking of the data. Study monitors will perform ongoing source data verification to confirm that data entered into the CRF by authorised site personnel are accurate, complete, and verifiable from source documents; that the safety and rights of subjects are being protected; and that the study is being conducted in accordance with the currently approved protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements.

11.5.1 Source Documents

Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents.

Source documents provide evidence for the existence of the subject and substantiate the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the CRF that are transcribed from source documents must be consistent with the source documents or the discrepancies must be explained. The Investigator may need to request previous medical records or transfer records, depending on the study. Also, current medical records must be available.

Examples of these original documents and data records include: hospital records, clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial.

11.5.2 Case Report Forms

Guidance for completion of the CRF will be provided to the Investigator prior to the initiation of the study at the site.

11.6 Records Retention

Records and documents, including signed ICFs, pertaining to the conduct of this study must be retained by the investigator for 15 years after study completion unless local regulations or institutional policies require a longer retention period.

No records may be destroyed without the written approval of the sponsor.

No records may be transferred to another location or party without written notification to the sponsor.

The Investigator is responsible for the archiving of the Study records for their site.


If the Investigator leaves an investigational site for whatever reason, the responsibility for all study related records must be transferred to another person at site.

11.7 Study and Site Closure

CuroNZ reserves the right to close or discontinue the clinical study at any time for any reason at their discretion as the Sponsor. Study sites will be closed upon study completion. A study site is considered closed when all required documents and study supplies have been collected and a study-site closure visit has been performed.Reasons for the early closure of a study site by the sponsor may include but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator Discontinuation of further study product development

11.8 Auditing and Inspecting

The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, government regulatory bodies, and of all study related documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).

11.9 Publication Plan

The results of this study may be published or presented at scientific meetings.

By signing the study protocol, the Investigator agrees with the use of results of the study for the purposes of national and international registration, publication and information for medical and pharmaceutical professionals. If necessary, the authorities will be notified of the Investigator's name, address, qualifications and extent of involvement.

The Investigator agrees to submit all manuscripts, slide presentations or abstracts to the sponsor before submission to allow the sponsor sufficient time to protect proprietary information and to provide comments. All data and results are the exclusive property of CuroNZ.

The sponsor will comply with the requirements for publication of study results. In accordance with standard editorial and ethical practice, the sponsor will generally support publication of multicenter studies only in their entirety and not as individual site data. In this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International Committee of Medical Journal Editors authorship requirements.


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