Safety and Efficacy of CERE-120 in Subjects With Parkinson's Disease

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety and potential benefits of CERE-120 in the treatment of Parkinson's disease.

Detailed Description
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CERE-120 is an experimental drug that consists of an adeno-associated virus (AAV) that was engineered to carry the human gene for neurturin, a neurotrophic (growth) factor. Similar to other growth factors (such as GDNF), neurturin is capable of restoring function and protecting brain cells from further damage. The virus used in CERE-120 is not known to cause disease in people. CERE-120 is delivered directly to the brain cells most affected in Parkinson's disease - the dopamine producing neurons. CERE-120 is injected during brain surgery. Once in place, CERE-120 continuously produces neurturin. During the first, open-label, part of the study (Phase 1), subjects with Parkinson's disease received CERE-120 at one of two dose levels. In the second part of the study (Phase 2), subjects were randomized 1:1 to receive CERE-120 or a sham surgery where no medication was injected. Participants in both phases of the study were followed for up to five years after surgery.

Official Title
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A Phase 1/2 Trial Assessing the Safety and Efficacy of Bilateral Intraputaminal and Intranigral Administration of CERE-120 (Adeno-Associated Virus Serotype 2 [AAV2]-Neurturin [NTN]) in Subjects With Idiopathic Parkinson's Disease

Conditions
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Idiopathic Parkinson's Disease

Intervention / Treatment
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* Biological: CERE-120: Adeno-Associated Virus Delivery of Neurturin
* Procedure: Sham Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, ages 35 to 70 years old (inclusive) A diagnosis of idiopathic Parkinson's disease based on UK Brain Bank criteria, including bradykinesia and at least 1 of the following PD features: resting tremor or rigidity A Hoehn and Yahr score of no greater than 3 in the off condition at Screening A robust response to dopaminergic therapy as judged by the investigator based on the UPDRS Part III: Motor Examination Experiencing motor complications despite adequate antiparkinsonian therapy A stable, optimized regimen of antiparkinsonian medications and stable parkinsonian features for at least 6 weeks prior to Screening Subject is willing not to undergo DBS for at least 12 months after the study surgical procedure (Phase 1 subjects) or while the study is blinded (Phase 2 subjects) and the investigator believes that this is medically acceptable Medically fit to undergo the study surgical procedure as determined by medical history, clinical and laboratory evaluations, and any other pre-surgical evaluations that are standard at the institution where the subject will undergo surgery Physically and mentally capable of performing all protocol-specified assessments and complying with the study visit schedule Subjects must be able to travel to study visits alone or able to identify a partner or caregiver who agrees to accompany the subject to the study visits Females of childbearing potential must have a negative β-HCG pregnancy test at Screening and again before surgery on Day 0 All subjects, both male and female, must agree to practice adequate barrier method contraception for at least 6 months after the surgical procedure Provides written informed consent to participate before any study-specific procedures are conducted Exclusion Criteria: Atypical or secondary parkinsonism, including, but not limited to, multiple system atrophy (MSA) or progressive supranuclear palsy Any subject for whom participation in the study would pose a substantial safety risk Any condition that would compromise the ability of the subject to undergo study procedures, including allergy to gadolinium Presence of any known brain abnormality that could interfere with the assessment of safety or efficacy or represents a surgical risk to the subject Evidence of significant brain atrophy on the Baseline MRI History of any cancer other than basal or squamous cell skin cancer within the 3 years prior to Screening Any chemotherapy, cytotoxic therapy, or immunotherapy (e.g., IL-2, IL-12, interferon) within the 3 months prior to Screening Any prior treatment for PD with a procedure involving intracranial surgery or implantation of a device (e.g. DBS, pallidotomy) Any prior treatment for a neurological or psychiatric disorders with a procedure involving the implantation of a device (e.g. spinal cord stimulator, vagus nerve stimulator) History of any prior gene transfer therapy Treatment with any investigational agent within the 3 months prior to Screening Anticipated need for antiplatelet agents or anticoagulation therapy, including gingko biloba, during the 10 days prior to the projected surgery date Any vaccinations within the 30 days prior to the projected surgery date Note: Vaccinations are not allowed for 30 days after the surgical procedure, unless deemed necessary by the investigator for the subject's well-being Not likely to be available for the duration of the trial, likely to be noncompliant with the protocol, or who are deemed unsuitable by the investigator for any other reason Participation in a previous surgical treatment study for Parkinson's disease

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In the first part of the study (Phase 1), 2 escalating dose cohorts received CERE-120. In the second part of the study (Phase 2), subjects were randomized 1:1 to receive CERE-120 or Sham Surgery.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Cohort 1<br>CERE-120 9.4 x 10^11 vg, injected by a neurosurgeon directly in the substantia nigra and in the putamen | Biological: CERE-120: Adeno-Associated Virus Delivery of Neurturin<br> <br> * Other names: AAV2-Neurturin;|
| Experimental: Phase 1: Cohort 2<br>CERE-120 2.4 x 10^12 vg, injected by a neurosurgeon directly in the substantia nigra and in the putamen | Biological: CERE-120: Adeno-Associated Virus Delivery of Neurturin<br> <br> * Other names: AAV2-Neurturin;|
| Experimental: Phase 2: CERE-120<br>CERE-120 2.4 x 10^12 vg, injected by a neurosurgeon directly in the substantia nigra and in the putamen | Biological: CERE-120: Adeno-Associated Virus Delivery of Neurturin<br> <br> * Other names: AAV2-Neurturin;|
| Sham Comparator: Phase 2: Sham Surgery<br>Neurosurgical procedure that mimics the procedure for CERE-120 delivery. No injections were administered during sham surgery. | Procedure: Sham Surgery<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Received CERE-120 Treatment | Number of Participants who received CERE-120 Treatment | 5 years | 
| Phase 1 and Phase 2: Change From Baseline in Motor Examination Part III Total Score in the Off Condition for the CERE-120 Group as Compared to the Sham Surgery Control Group at the Last Double-blind Assessment. | UPDRS is a tool to evaluate the impact of symptomatic and potential disease modifying treatments. Part III focuses on 14 motor functions, assessing each on a scale from 0 (normal) to 4 (severe) with total score 0 - 56. The 5 Feb 2003 version of the UPDRS Rating was used in this trial. The total score is the sum of 14 motor functions. Change from baseline in total score is reported. The last double blind assessment for each subject is defined as the most recent assessment at the time when the final randomized subject completes the Month 15 Visit. The length of the double-blind follow-up period for each subject ranged from 15 to 24 months, depending on the enrollment rate. | Baseline, Months 15, 18, 21 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DBS, Parkinson's disease, Movement Disorders, Gene Therapy, Neurotrophic Factors, GDNF, Neurturin, Dopamine