Clinical TrialsClinical Trials

J. Jill Hopkins, M.D.J. Jill Hopkins, M.D.

Retina Vitreous AssociatesRetina Vitreous Associates

Los Angeles, CALos Angeles, CA

OVERVIEWOVERVIEW

►General introduction to Clinical TrialsGeneral introduction to Clinical Trials What they are, what you need to knowWhat they are, what you need to know

►CNTF Clinical Trials CNTF Clinical Trials Illustrating how clinical trials bring new Illustrating how clinical trials bring new

treatments to patientstreatments to patients

►Questions and AnswersQuestions and Answers

What is a Clinical Trial?What is a Clinical Trial?

►National Institutes of HealthNational Institutes of Health www.clinicaltrials.govwww.clinicaltrials.gov

►Biomedical or health-related research Biomedical or health-related research studies in human beings that follow a studies in human beings that follow a pre-defined protocolpre-defined protocol

► Interventional or ObservationalInterventional or Observational

Clinical TrialsClinical Trials

►Interventional studies:Interventional studies: research subjects are assigned by research subjects are assigned by

the investigator to a treatment (or the investigator to a treatment (or other intervention)other intervention)

outcomes are measured outcomes are measured

Clinical TrialsClinical Trials

►Observational studies:Observational studies: individuals are observed and their individuals are observed and their

outcomes are measured by the outcomes are measured by the investigators investigators

Types of Clinical TrialsTypes of Clinical Trials►Treatment trialsTreatment trials

►Prevention trialsPrevention trials

►Diagnostic trialsDiagnostic trials

►Screening trialsScreening trials

►Quality of Life trialsQuality of Life trials

Treatment TrialsTreatment Trials

►Test experimental treatments, Test experimental treatments, new combinations of drugs, or new combinations of drugs, or new approaches to surgery or new approaches to surgery or radiation therapyradiation therapy

Prevention TrialsPrevention Trials

►Investigate ways to prevent a Investigate ways to prevent a disease in people who have never disease in people who have never had it or to prevent a disease from had it or to prevent a disease from returningreturning

►Approaches may include Approaches may include medicines, vitamins, vaccines, medicines, vitamins, vaccines, minerals, or lifestyle changesminerals, or lifestyle changes

Diagnostic TrialsDiagnostic Trials

►Investigate better tests or Investigate better tests or procedures for diagnosing a procedures for diagnosing a particular disease or conditionparticular disease or condition

Screening TrialsScreening Trials

►Investigate the best way to Investigate the best way to detect certain diseases or detect certain diseases or health conditionshealth conditions

Quality of Life trialsQuality of Life trials

►Supportive Care trialsSupportive Care trials

►Explore ways to improve Explore ways to improve

comfort/quality of life for comfort/quality of life for individuals with a chronic individuals with a chronic

diseasedisease

KEY DEFINITIONS - KEY DEFINITIONS - PROTOCOLPROTOCOL

►A study plan on which all clinical A study plan on which all clinical trials are basedtrials are based

►The plan is carefully designed to The plan is carefully designed to safeguard the health of the safeguard the health of the participants as well as answer participants as well as answer specific research questions specific research questions

ProtocolProtocol

►A protocol describes:A protocol describes:► what types of people may participate what types of people may participate

in the trial in the trial ►the schedule of tests, procedures, the schedule of tests, procedures,

medications, and dosagesmedications, and dosages►the length of the studythe length of the study

ProtocolProtocol

►While in a clinical trial, participants While in a clinical trial, participants following a protocol are seen regularly following a protocol are seen regularly by the research staff to monitor their by the research staff to monitor their health and to determine the safety health and to determine the safety and effectiveness of their treatmentand effectiveness of their treatment

KEY DEFINITIONS - PLACEBOKEY DEFINITIONS - PLACEBO

►an inactive pill, liquid, or powder that an inactive pill, liquid, or powder that has no treatment value. has no treatment value.

►experimental treatments are often experimental treatments are often compared with placebos to assess the compared with placebos to assess the experimental treatment's effectiveness. experimental treatment's effectiveness.

► In some studies, participants in the In some studies, participants in the control groupcontrol group will receive placebo will receive placebo instead of active drug or experimental instead of active drug or experimental treatment. treatment.

What is a control/control What is a control/control group?group?

►A control is the standard by which A control is the standard by which experimental observations are experimental observations are evaluated.evaluated.

►one group of patients will be given an one group of patients will be given an experimental drug or treatment, while experimental drug or treatment, while the control group is given either a the control group is given either a standard treatment for the illness or a standard treatment for the illness or a placebo. placebo.

Important DefinitionsImportant Definitions

►Primary Outcome: the main efficacy Primary Outcome: the main efficacy variable being studiedvariable being studied Visual acuityVisual acuity

►Secondary Outcome: additional Secondary Outcome: additional variables thought to be importantvariables thought to be important Quality of LifeQuality of Life

Phases of Clinical TrialsPhases of Clinical Trials

► Phase IPhase I - researchers test an - researchers test an experimental drug or treatment experimental drug or treatment small group of people (10-80) small group of people (10-80) first time to be evaluatedfirst time to be evaluated determine safety, safe dosage range, and determine safety, safe dosage range, and

identify side effects identify side effects

► Phase IIPhase II - experimental study drug or - experimental study drug or treatment given to a larger group of treatment given to a larger group of people (100-300) people (100-300) see if it is effective, further evaluate its see if it is effective, further evaluate its

safety safety

Phases of Clinical TrialsPhases of Clinical Trials

► Phase IIIPhase III - experimental study drug or - experimental study drug or treatment given to large groups of people treatment given to large groups of people (1,000-3,000) (1,000-3,000) confirm its effectiveness, monitor side effects, confirm its effectiveness, monitor side effects,

compare it to commonly used treatments, and compare it to commonly used treatments, and collect information that will allow the experimental collect information that will allow the experimental drug or treatment to be used safely drug or treatment to be used safely

► Phase IV Phase IV - post marketing studies delineate - post marketing studies delineate additional information including the drug's additional information including the drug's risks, benefits, and optimal use risks, benefits, and optimal use

Participating in a Clinical TrialParticipating in a Clinical Trial

►INCLUSION/EXCLUSION CRITERIA:INCLUSION/EXCLUSION CRITERIA:

►medical or social standards medical or social standards determining whether a person may determining whether a person may or may not be allowed to enter a or may not be allowed to enter a clinical trialclinical trial

INCLUSION/EXCLUSIONINCLUSION/EXCLUSION

Criteria based on such factors as age, Criteria based on such factors as age, gender, type and stage of a disease, gender, type and stage of a disease, previous treatment history, and other previous treatment history, and other medical conditionsmedical conditions

Criteria not used to reject people Criteria not used to reject people

personally, but rather to identify personally, but rather to identify appropriate participants and keep appropriate participants and keep them safethem safe

Participating in a Clinical TrialParticipating in a Clinical Trial

►What is Informed Consent?What is Informed Consent? the process of learning the key facts the process of learning the key facts

about a clinical trial before deciding about a clinical trial before deciding whether or not to participatewhether or not to participate

a continuing process throughout the a continuing process throughout the studystudy

doctors and nurses involved in the trial doctors and nurses involved in the trial explain the details of the studyexplain the details of the study

Informed Consent Informed Consent

the research team provides an the research team provides an informed consent documentinformed consent document that that includes details about the study includes details about the study including purpose, duration, required including purpose, duration, required procedures, and key contactsprocedures, and key contacts

Informed Consent Informed Consent

Risks and potential benefits are Risks and potential benefits are explained in the informed consent explained in the informed consent documentdocument

The participant then decides whether or The participant then decides whether or not to sign the documentnot to sign the document

Informed consent is not a contract, and Informed consent is not a contract, and the participant may withdraw from the the participant may withdraw from the trial at any timetrial at any time

Clinical Trials - Benefits Clinical Trials - Benefits

Clinical trials are an approach for Clinical trials are an approach for eligible participants to:eligible participants to:►Play an active role in their own health Play an active role in their own health

carecare►Gain access to new research Gain access to new research

treatments before they are widely treatments before they are widely availableavailable

►Obtain expert medical care at leading Obtain expert medical care at leading health care facilities during the trial health care facilities during the trial

►Help others by contributing to medical Help others by contributing to medical researchresearch

Clinical Trials - Risks Clinical Trials - Risks ► RisksRisks

May be unpleasant, serious or even life-May be unpleasant, serious or even life-threatening side effects to experimental threatening side effects to experimental treatment treatment

The experimental treatment may not be The experimental treatment may not be effective for the participanteffective for the participant

The The protocolprotocol may require more time and may require more time and attention than a non-protocol treatment, attention than a non-protocol treatment, including trips to the study site, more including trips to the study site, more treatments, hospital stays or complex treatments, hospital stays or complex dosage requirementsdosage requirements

Important ConsiderationsImportant Considerations

►What is the purpose of the study? What is the purpose of the study?

►Who is going to be in the study? Who is going to be in the study?

►Why do researchers believe the Why do researchers believe the experimental treatment being experimental treatment being tested may be effective? Has it tested may be effective? Has it been tested before?been tested before?

Important Considerations Important Considerations ►What kinds of tests and experimental What kinds of tests and experimental

treatments are involved?treatments are involved?

►How do the possible risks, side How do the possible risks, side effects, and benefits in the study effects, and benefits in the study compare with my current treatment? compare with my current treatment?

►How might this trial affect my daily How might this trial affect my daily life? life?

Important Considerations Important Considerations

►How long will the trial last?How long will the trial last? ►Will hospitalization be required? Will hospitalization be required?

►Who will pay for the experimental Who will pay for the experimental treatment? treatment?

►Will I be reimbursed for other Will I be reimbursed for other expenses?expenses?

Important ConsiderationsImportant Considerations

►What type of long-term follow up care What type of long-term follow up care is part of this study? is part of this study?

►How will I know that the experimental How will I know that the experimental treatment is working? Will results of treatment is working? Will results of the trials be provided to me? the trials be provided to me?

►Who will be in charge of my care? Who will be in charge of my care?

Developing Clinical TrialsDeveloping Clinical Trials

►Repair/Prevent Initial InsultRepair/Prevent Initial Insult Gene TherapyGene Therapy

►Protect cells from Programmed Protect cells from Programmed deathdeath Neuronal Survival AgentsNeuronal Survival Agents

►Replace or Bypass Abnormal Replace or Bypass Abnormal Structure and FunctionStructure and Function Transplantation/ImplantationTransplantation/Implantation

CNTF Trials in RP and CNTF Trials in RP and AMDAMD

Neuronal Survival AgentsNeuronal Survival Agents

RENOIR STUDIES by NEUROTECHRENOIR STUDIES by NEUROTECH

Neuronal Survival AgentsNeuronal Survival Agents

►Not cure (restoration) but perhaps Not cure (restoration) but perhaps stabilization (preservation) over stabilization (preservation) over the lifetime of an individualthe lifetime of an individual ““If I could just stay where I am”If I could just stay where I am”

►Can have quite advanced Can have quite advanced degeneration and still see effects degeneration and still see effects of therapyof therapy

Ciliary Neurotrophic Ciliary Neurotrophic FactorFactor

►Extensively studied growth factorExtensively studied growth factor

►Retinal cell rescue capabilities across Retinal cell rescue capabilities across 13 different animal models of retinal 13 different animal models of retinal degenerationdegeneration

► Increase in outer nuclear layer cell Increase in outer nuclear layer cell counts from 1 to greater than 6 layerscounts from 1 to greater than 6 layers

FIGURE 3. Retinalphotomicrographsrats with rhodopsinmutation S334ter (A) S334ter untreated

eye (B) NTC-200 parental

cell– treated eye(C) NTC-201 cell–

treated eye.

CNTF DeviceCNTF Device► Surgically implantedSurgically implanted► Local anaesthetic/15 minute procedureLocal anaesthetic/15 minute procedure► Achieves controlled, continuous, sustained Achieves controlled, continuous, sustained

delivery of ciliary neurotrophic factor (CNTFdelivery of ciliary neurotrophic factor (CNTF

Neurotech CNTF TrialsNeurotech CNTF Trials

► 2003 – Phase 1A Safety of Device2003 – Phase 1A Safety of Device 5 patients with advanced RP5 patients with advanced RP

► 2004 – Phase 1B Safety of Therapeutic 2004 – Phase 1B Safety of Therapeutic Doses Doses 5 patients with advanced RP5 patients with advanced RP

Safety ProfileSafety Profile

►No systemic or ocular complications No systemic or ocular complications ensuedensued

►Shallow choroidal detachment in oneShallow choroidal detachment in one

eye receiving the lower-dose deviceeye receiving the lower-dose device

Efficacy ResultsEfficacy Results

►Three of seven study eyes for which Three of seven study eyes for which acuity could be tracked showed acuity could be tracked showed increases of 10–15 letters over baselineincreases of 10–15 letters over baseline

►Equivalent to 2–3 lines of conventional Equivalent to 2–3 lines of conventional Snellen acuity Snellen acuity

►These increases were maintained 6 These increases were maintained 6 months after the implants had been months after the implants had been removedremoved

Neurotech CNTF TrialsNeurotech CNTF Trials

►Phase I StudiesPhase I Studies – excellent Safety – excellent Safety profileprofile Improvement experienced by someImprovement experienced by some

►Phase II/III StudiesPhase II/III Studies – Efficacy – Efficacy designdesign

►Can CNTF improve:Can CNTF improve: Visual Acuity, Visual Field in Retinitis Visual Acuity, Visual Field in Retinitis

PigmentosaPigmentosa Visual acuity in Geographic Atrophy Visual acuity in Geographic Atrophy

ARMDARMD

Retinal Neurotrophic Ocular Implant Research (RENOIR) for ARMD

Inclusion Criteria:Inclusion Criteria:

Best-corrected visual acuity in the Best-corrected visual acuity in the study eye study eye << 20/63 - 20/63 - > > 20/160 (58-20/160 (58->39 letter score) as measured >39 letter score) as measured using EVAusing EVA

Presence in the study and/or Presence in the study and/or fellow eye of geographic atrophy fellow eye of geographic atrophy (GA) compatible with category 3 (GA) compatible with category 3 or 4 age-related macular or 4 age-related macular degeneration (AMD) degeneration (AMD)

GA must be at least 175 microns GA must be at least 175 microns in areain area

Exclusion Criteria:Exclusion Criteria: Participant < 50 years of age Participant < 50 years of age

Evidence of classic or occult Evidence of classic or occult choroidal neovascularization in choroidal neovascularization in either eye, which may include either eye, which may include serous RPE detachment, stippling serous RPE detachment, stippling on fluorescein angiogram, macular on fluorescein angiogram, macular edema, evidence of hemorrhage edema, evidence of hemorrhage and lipid, and disciform scarand lipid, and disciform scar

CNTF 2 – ARMD Geographic CNTF 2 – ARMD Geographic AtrophyAtrophy

►Treatment/Placebo Trial – N=32 Treatment/Placebo Trial – N=32 ►1 eye randomized to low dose, high 1 eye randomized to low dose, high

dose or placebodose or placebo►Primary outcome measure –Primary outcome measure –

Visual acuity at 4 monthsVisual acuity at 4 months

Retinal Neurotrophic Ocular Implant Research (RENOIR) for RP

CNTF 3 – RP AcuityCNTF 3 – RP Acuity

►Inclusion Criteria:Inclusion Criteria: Participant must be older than 18, but Participant must be older than 18, but

less than 65 years of ageless than 65 years of age Each eye has a visual acuity score of at Each eye has a visual acuity score of at

least 24 (20/320) and no more than 58 least 24 (20/320) and no more than 58 (20/80) letters(20/80) letters

Clinical diagnosis must be consistent Clinical diagnosis must be consistent with retinal degeneration with retinal degeneration

Exclusion Criteria:Exclusion Criteria: Glaucoma (defined as independent Glaucoma (defined as independent

optic atrophy causing vision loss)optic atrophy causing vision loss) Classic syndromic RPClassic syndromic RP Participant has optic nerve atrophy Participant has optic nerve atrophy

beyond modest pallor, primary cone-rod beyond modest pallor, primary cone-rod dystrophy, unilateral bulls-eye dystrophy, unilateral bulls-eye maculopathy, maculopathy, cystoid maculopathycystoid maculopathy as as judged by OCT, or other retinal judged by OCT, or other retinal dystrophydystrophy

Lens opacitiesLens opacities

CNTF 3 – RP AcuityCNTF 3 – RP Acuity►Randomized treatment trialRandomized treatment trial

►Both eyes must be eligibleBoth eyes must be eligible

►Randomization to treatment eye vs. Randomization to treatment eye vs. sham eyesham eye

►Randomization of treatment eye to low Randomization of treatment eye to low or high dose deviceor high dose device

CNTF 3 – RP AcuityCNTF 3 – RP Acuity

►Primary Outcome – visual acuity Primary Outcome – visual acuity at 12 monthsat 12 months

►N = 60 across USAN = 60 across USA

CNTF 4 – RP Visual FieldCNTF 4 – RP Visual Field► Inclusion Criteria:Inclusion Criteria:

Same as for CNTF 3 with respect to Same as for CNTF 3 with respect to age and retinal degeneration age and retinal degeneration diagnosisdiagnosis

At least two full threshold Humphrey At least two full threshold Humphrey Visual Field 30-2 tests prior to Visual Field 30-2 tests prior to initiating the screening field tests for initiating the screening field tests for this studythis study

Each eye has a visual acuity score of Each eye has a visual acuity score of at least 59 (20/63) and no more than at least 59 (20/63) and no more than 83 (20/25) letters83 (20/25) letters

CNTF 4 – Inclusion contCNTF 4 – Inclusion cont Each eye has a mean sensitivity Each eye has a mean sensitivity

deviation (MD) of at least 6 dBdeviation (MD) of at least 6 dB The difference between the average The difference between the average

field values in the two eyes must be field values in the two eyes must be 25% of the smaller of the two average 25% of the smaller of the two average field valuesfield values

Each eye sensitivity must have non-Each eye sensitivity must have non-zero for at least 30 locations in the zero for at least 30 locations in the periphery, and the horizontal field periphery, and the horizontal field extent must be 20 degrees or greater extent must be 20 degrees or greater

CNTF 4 – RP Visual FieldCNTF 4 – RP Visual Field

►Exclusion CriteriaExclusion Criteria Same as for CNTF 3Same as for CNTF 3

►Study Design – same as Study Design – same as CNTF 3, though CNTF 3, though primary outcome is primary outcome is improvement in meanimprovement in meanvisual field sensitivity visual field sensitivity

CNTF TrialsCNTF Trials

►Results expected in 12 to 18 monthsResults expected in 12 to 18 months

►Regular Data Safety MonitoringRegular Data Safety Monitoring

►Will answer many questionsWill answer many questions

Clinical TrialsClinical Trials►A new era of investigation in retinal A new era of investigation in retinal

degenerative diseasesdegenerative diseases

►Hope and potential on the horizonHope and potential on the horizon

►Be informed, ask questions, be Be informed, ask questions, be comfortable with the information you are comfortable with the information you are being given and the path you are takingbeing given and the path you are taking

►We are all in this together…We are all in this together…

Clinical TrialsClinical Trials

►Thank youThank you

►Q and AQ and A