trial synopsis 1305.1 ds dr - boehringer ingelheim · the synopsis ‐ which is part of the...

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Name of company: Boehringer Ingelheim

Tabulated Trial Report

ABCD

Synopsis No.:

Name of finished product:

Not applicable

EudraCT No.:

2012-000405-68

Name of active ingredient:

BI 1015550

Page:

1 of 4

Module:

Volume:

Report date: 21 JUN 2013

Trial No. / U No.: 1305.1 / U13-1792-01

Dates of trial: 10 MAY 2012 – 21 SEP 2012

Date of revision: Not applicable

Proprietary confidential information © 2013 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Title of trial: Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1015550 in healthy male volunteers (a partially randomised, single-blinded, placebo-controlled Phase I study)

Principal Investigator:

Trial site: Human Pharmacology Centre, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, Ingelheim/Rhein, Germany

Publication: Data from this trial have not been published.

Clinical phase: I

Objectives: The primary objective was to investigate the safety and tolerability of BI 1015550 in healthy male subjects following oral administration of single rising doses of 0.02 mg, 0.06 mg, 0.2 mg, 0.6 mg, 2 mg, 4 mg, 8 mg, 16 mg, and 24 mg (originally 26 mg planned and reduced due to PK interim analysis results of previous dose group). A secondary objective was to explore the pharmacokinetics (PK) of BI 1015550 after a single dose. To gain information on a potential PK - pharmacodynamic relationship, exploratory biomarkers (tumor necrosis factor-α and leukotriene B4) were analyzed in ex-vivo assays based on whole blood samples of treated subjects.

Methodology: Partially randomised, placebo-controlled within dose groups, single-blinded, single-rising-dose, single-centre study; 9 dose groups, per dose group 2 cohorts of 4 subjects each (3 on active treatment, one on placebo), first cohort with defined treatment sequence (active-placebo-active-active)

No. of subjects:

planned: entered: 72 subjects (8 per dose group, 6 on BI 1015550 and 2 on placebo)

actual: entered: 70 subjects

BI 1015550: entered: 54 treated: 54 analysed (for primary endpoint): 54 Placebo: entered: 16 treated: 16 analysed (for primary endpoint): 16

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ABCD

Synopsis No.:


Not applicable

EudraCT No.:

2012-000405-68


BI 1015550

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2 of 4

Module:

Volume:


Trial No. / U No.: 1305.1 / U13-1792-01

Date of trial: 10 MAY 2012 – 21 SEP 2012




Diagnosis and main criteria for inclusion:

Healthy males, age ≥18 and ≤45 years, body mass index (BMI) ≥18.5 and ≤29.9 kg/m2

Test product: BI 1015550, as a powder for oral solution reconstituted with solvent tartaric acid and solvent component hydroxy-propyl-β-cyclodextrin (HPβCD)

doses: 0.02 mg, 0.06 mg, 0.2 mg, 0.6 mg, 2 mg, 4 mg, 8 mg, 16 mg, and 24 mg

mode of admin.: Oral administration with 240 mL water after an overnight fast

batch nos.: BI 1015550: B121000196 (30 mg as powder) solvent tartaric acid: B101004730 (5 mg/mL, 80 mL as solution) solvent component HPβCD: B121000197 (8.602 g as powder)

Reference therapy: Placebo

dose: Not applicable

mode of admin.: Oral

batch nos.: Placebo: solvent tartaric acid: B101004730 (5 mg/mL, 80 mL as solution) solvent component HPβCD: B121000197 (8.602 g as powder)

Duration of treatment: Single dose

Criteria for evaluation:

Clinical pharmacology:

PK parameters of BI 1015550 with the key secondary endpoints: Cmax, AUC0-∞ and several other endpoints

Safety: Savety and tolerability were primary endpoints. Analysis of adverse events (AEs), clinical laboratory tests (haematology, haemoccult® test, clinical chemistry, and urinalyis), vital signs (blood pressure, pulse rate, respiratory rate, oral body temperature, orthostasis test), 12-lead ECG, physical examinations, and tolerability as assessed by the investigator

Statistical methods: Descriptive statistical methods to describe safety and PK endpoints were used. Dose proportionality of BI 1015550 was explored using a linear regression model. A 2-sided 95% confidence interval for the intercept and slope was computed.

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Not applicable

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2012-000405-68


BI 1015550

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SUMMARY – CONCLUSIONS:

Clinical pharmacology results:

A total of 70 healthy male subjects (all of White race, mean age was 35.3 years) were entered into 9 dose groups. In each dose group, 6 subjects received BI 1015550 and up to 2 subjects received placebo (in total 16 subjects). All subjects completed the trial. During the conduct of the trial the originally planned highest dose of 26 mg had been reduced to 24 mg due to PK interim analysis of the previous dose group (Cmax data of 16 mg dose group). The extrapolated free fraction of Cmax for the originally planned 26 mg dose (110.6 nM) was above rat NOAEL Cmax (103 nM). Therefore the highest dose was slightly reduced to 24 mg, for which the extrapolated free fraction Cmax (102 nM) was below rat NOAEL Cmax.

Pharmacokinetics

BI 1015550 was rapidly absorbed after single oral dose with a median tmax range of 0.517 to 1.25 h. After attainment of Cmax, plasma concentrations declined in a biphasic manner (ie., a rapid distribution phase and a slower elimination phase). The lowest dose group 0.02 mg was excluded from interpretation because BI 1015550 was below the detection limit. The gMean t1/2 ranged from 19.6 to 29.2 h. BI 1015550 exposure (Cmax and AUC0-∞) increased dose proportionally over the dose range of 0.06 to 24 mg. The gMean Cmax values ranged from 1.42 nmol/L for the 0.06 mg dose to 542 nmol/L for the 24 mg dose. The gMean AUC0-∞ ranged from 7.44 nmol•h/L for the 0.06 mg dose to 3650 nmol•h/L for the 24 mg dose. Oral clearance was moderate with gMean values ranging from 219 to 273 mL/min in the dose range from 2 to 24 mg. The gMean values of Vz/F ranged from 415 to 552 L in the dose range from 2 to 24 mg. The amount of unchanged drug excreted in urine over 24 h ranged from 9.94 to 14.3% of the administered dose of BI 1015550. The gMean renal clearance was in the range of 33.5 to 50.2 mL/min for all dose groups.

Pharmacodynamics

The inhibitory effect on TNF-α release increased with BI 1015550 dose and was observed for all doses higher than 4 mg. Maximum median inhibition of 60% was reached with the 24 mg dose 2 h post-drug administration. No effect of BI 1015550 was observed on LTB4 release. Results of both assays, TNF-α and LTB4 release, showed substantial inter-individual and technical variability.

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Safety results: There were no SAEs, no protocol-specified significant or other significant adverse events (according to ICH E3) in this study. The majority of the subjects reported AEs of mild intensity. The total number of subject reported AEs was 27/70. The AE with the highest incidence in this trial was headache (9/70 subjects: 8/54 subjects on BI 1015550 and 1/16 subject on placebo). In the 2 highest dose groups (16 mg and 24 mg) headache was not reported. Diarrhoea was reported by 3/70 subjects: (1/16 subject on placebo, 2/54 subjects on BI 1015550. Application site irritation (i.e., skin irritation at the ECG electrode site) was reported for 3/70 subjects, all on BI 1015550. A total of 9 subjects (12.9%) were reported with drug-related AEs; 8 subjects reported each 1 AE of mild intensity, and 1 subject in the 8 mg group reported 3 AEs of moderate intensity: nausea, vomiting, and headache. This subject took paracetamol and vertigo-vomex because of headache and nausea. All events of all subjects had resolved by the end of the study. Assessment of laboratory parameters, vital signs, and ECG did not suggest any changes resulting from administration of BI 1015550. Global tolerability was assessed by the investigator as good for all 70 subjects entered. In summary, there were no notable differences between the dose groups with respect to safety and tolerability. It appeared safe to administer single doses of up to 24 mg BI 1015550 to the trial volunteers.

Conclusions: BI 1015550 was rapidly absorbed following oral administration and showed a biphasic decline. Increase in exposure was approximately proportional with dose from 0.06 to 24 mg. The terminal elimination half-life ranged from 0.517 to 1.25 h. Oral clearance was moderate (219 to 273 mL/min). The amount of unchanged drug excreted in the urine ranged from 9.94 to 14.3% of the administered BI 1015550 dose indicating that urinary excretion is not the major mode of excretion for BI 1015550.

Single doses of BI 1015550 of up to 24 mg were well tolerated and no safety issues arose in this trial that would preclude further clinical development of BI 1015550.

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Boehringer Ingelheim BI trial number 1305.01 Trial Synopsis - Appendix

Trial Synopsis - Appendix

The appended tables on the following pages supplement the trial results presented in the Trial

Synopsis. They complement primary and secondary endpoints of the trial.

Note that not all endpoints defined in the trial protocol are presented in this synopsis because

their number was too large to allow meaningful presentation in this format.

Results for presented in

Adverse events (overall summary) Table 15.3.2: 1

Analysis of dose proportionality for Cmax [nmol/L] Table 15.5.1.1.2: 1

Analysis of dose proportionality for AUC0-∞ [nmol∙h/L] Table 15.5.1.2.2: 1

Pharmacokinetic parameter results including gMean of Cmax [nmol/L] and of AUC0-∞ [nmol∙h/L]

Table 15.6.3: 1

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Table 15.3.2: 1 Adverse event overall summary − treated set

_______________________________________________________________________________________________________________________________________ Placebo 0.02 mg 0.06 mg 0.2 mg 0.6 mg 2 mg N (%) N (%) N (%) N (%) N (%) N (%)_______________________________________________________________________________________________________________________________________

Number of subjects 16 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0)

Subjects with any AE 5 ( 31.3) 2 ( 33.3) 2 ( 33.3) 3 ( 50.0) 3 ( 50.0) 1 ( 16.7)

Subjects with severe AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Subjects with investigator defined drug−related 1 ( 6.3) 0 ( 0.0) 2 ( 33.3) 1 ( 16.7) 0 ( 0.0) 0 ( 0.0)AEs

Subjects with other significant AEs (according to 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)ICH E3)

Subjects with AEs leading to discontinuation of 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)trial drug

Subjects with significant AEs (pre−specified 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)events)

Subjects with serious AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)_______________________________________________________________________________________________________________________________________

A subject may be counted in more than one seriousness criterion.Percentages are calculated using total number of subjects per treatment as the denominator.MedDRA version used for reporting: 15.1

Source data: Appendix 16.2.7, Listing 2.1 s15\et_ae.sas 29NOV2012

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Table 15.3.2: 1 Adverse event overall summary − treated set

_________________________________________________________________________________________________________________ ____________ ________ 4 mg 8 mg 16 mg 24 mg BI Total Total N (%) N (%) N (%) N (%) N (%) N (%)_______________________________________________________________________________________________________________________________________

Number of subjects 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 54 (100.0) 70 (100.0)

Subjects with any AE 3 ( 50.0) 3 ( 50.0) 2 ( 33.3) 3 ( 50.0) 22 ( 40.7) 27 ( 38.6)

Subjects with severe AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Subjects with investigator defined drug−related 2 ( 33.3) 1 ( 16.7) 1 ( 16.7) 1 ( 16.7) 8 ( 14.8) 9 ( 12.9)AEs

Subjects with other significant AEs (according to 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)ICH E3)

Subjects with AEs leading to discontinuation of 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)trial drug

Subjects with significant AEs (pre−specified 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)events)

Subjects with serious AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)_______________________________________________________________________________________________________________________________________

A subject may be counted in more than one seriousness criterion.Percentages are calculated using total number of subjects per treatment as the denominator.MedDRA version used for reporting: 15.1

Source data: Appendix 16.2.7, Listing 2.1 s15\et_ae.sas 29NOV2012

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Table 15.5.1.1.2: 1 Summary of power model (PK endpoint on the log−transformed scale) PK set Cmax [nmol/L] for BI 1015550 (PLASMA EDTA)

N ß SE(ß) 95% Confidence interval

50 0.9702 0.0151 0.9400 1.0005

Source data: Appendix 16.1.9.3, Statdoc 1.1.2.1 stat\pk15_dp.sas 12FEB2013

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Table 15.5.1.2.2: 1 Summary of power model (PK endpoint on the log−transformed scale) PK set AUCinfpred [nmol*h/L] for BI 1015550 (PLASMA EDTA)

N ß SE(ß) 95% Confidence interval

48 1.0442 0.0148 1.0145 1.0740

Source data: Appendix 16.1.9.3, Statdoc 1.2.2.1 stat\pk15_dp.sas 12FEB2013

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Table 15.6.3: 1 Comparison of pharmacokinetic parameters (N, gMean and gCV [%]) of BI 1015550 by treatment

____________________________________________________________________________________________________________________________________

0.02 mg 0.06 mg 0.2 mg 0.6 mg N gMean gCV [%] N gMean gCV [%] N gMean gCV [%] N gMean gCV [%]____________________________________________________________________________________________________________________________________

AUC0−∞ [nmol*h/L] −−− −−− −−− 6 7.44 12.7 6 24.1 13.9 6 67.9 15.6AUC0−∞,norm [nmol*h/L/mg] −−− −−− −−− 6 124 12.7 6 121 13.9 6 113 15.6Cmax [nmol/L] −−− −−− −−− 6 1.42 23.2 6 5.02 20.1 6 13.7 14.2Cmax,norm [nmol/L/mg] −−− −−− −−− 6 23.6 23.2 6 25.1 20.1 6 22.8 14.2t½ [h] −−− −−− −−− 6 3.93 27.0 6 4.21 25.6 6 6.13 54.8λZ [1/h] −−− −−− −−− 6 0.176 27.0 6 0.165 25.6 6 0.113 54.8MRTpo [h] −−− −−− −−− 6 5.96 20.7 6 5.84 16.2 6 7.39 33.4CL/F [mL/min] −−− −−− −−− 6 299 12.7 6 308 13.9 6 328 15.6VZ/F [L] −−− −−− −−− 6 102 28.6 6 112 22.9 6 174 44.4Ae0−24 [nmol] 6 7.05 17.2 5 18.6 12.9 6 58.5 25.2 6 192 21.7fe0−24 [%] 6 15.8 17.2 5 13.9 12.9 6 13.1 25.2 6 14.3 21.7CLR,0−24 [mL/min] −−− −−− −−− 5 43.0 16.7 6 41.3 20.6 6 50.2 18.2

____________________________________________________________________________________________________________________________________

For corresponding tmax please refer to Section 15.6, Table 3: 3.Source data: Section 15.6, Table 2.1: 1 to Table 2.1: 9, Table 1.2: 49 to Table 1.2: 66

pk\pkover.sas 22MAY2013

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____________________________________________________________________________________________________________________________________

2 mg 4 mg 8 mg 16 mg N gMean gCV [%] N gMean gCV [%] N gMean gCV [%] N gMean gCV [%]____________________________________________________________________________________________________________________________________

AUC0−∞ [nmol*h/L] 6 287 14.9 6 679 32.0 6 1210 18.3 6 2180 19.9AUC0−∞,norm [nmol*h/L/mg] 6 144 14.9 6 170 32.0 6 152 18.3 6 136 19.9Cmax [nmol/L] 6 46.9 38.9 6 113 20.4 6 176 12.6 6 292 22.2Cmax,norm [nmol/L/mg] 6 23.4 38.9 6 28.1 20.4 6 22.0 12.6 6 18.3 22.2t½ [h] 6 20.0 59.6 6 29.2 31.2 6 19.6 21.2 6 20.7 31.5λZ [1/h] 6 0.0347 59.6 6 0.0238 31.2 6 0.0354 21.2 6 0.0334 31.5MRTpo [h] 6 15.5 40.7 6 19.7 22.9 6 14.8 16.5 6 15.3 33.8CL/F [mL/min] 6 259 14.9 6 219 32.0 6 245 18.3 6 273 19.9VZ/F [L] 6 447 57.0 6 552 33.4 6 415 24.4 6 490 24.3Ae0−24 [nmol] 6 516 19.7 6 1110 28.2 4 2220 19.3 6 3540 17.1fe0−24 [%] 6 11.6 19.7 6 12.5 28.2 4 12.5 19.3 6 9.94 17.1CLR,0−24 [mL/min] 6 37.0 24.8 6 36.4 24.1 4 36.1 25.1 6 33.5 23.4

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____________________________________________________________________________________________________________________________________

24 mg N gMean gCV [%]____________________________________________________________________________________________________________________________________

AUC0−∞ [nmol*h/L] 6 3650 22.6AUC0−∞,norm [nmol*h/L/mg] 6 152 22.6Cmax [nmol/L] 6 542 12.1Cmax,norm [nmol/L/mg] 6 22.6 12.1t½ [h] 6 26.1 41.6λZ [1/h] 6 0.0266 41.6MRTpo [h] 6 15.8 42.9CL/F [mL/min] 6 244 22.6VZ/F [L] 6 551 34.8Ae0−24 [nmol] 6 6310 20.4fe0−24 [%] 6 11.8 20.4CLR,0−24 [mL/min] 6 35.4 11.5

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trial synopsis 1305.1 ds dr - boehringer ingelheim · the synopsis ‐ which is part of the...

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