GDNF Gene Therapy for Multiple System Atrophy

Study Overview
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Brief Summary
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The objective of this randomized, double-blinded, placebo-controlled Phase 1 investigation is to evaluate the safety and potential clinical effect of AAV2-GDNF delivered to the putamen in subjects with either a possible or probable diagnosis of Multiple System Atrophy.

Official Title
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Randomized, Double-Blind, Placebo-controlled Safety Study of Glial Cell Line-Derived Neurotrophic Factor Gene Transfer (AAV2-GDNF) in Multiple System Atrophy

Conditions
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Multiple System Atrophy

Intervention / Treatment
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* Biological: AAV2-GDNF gene therapy
* Procedure: Sham (Placebo) Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female 35-75 years of age (inclusive) Clinical diagnosis of MSA, parkinsonian type with symptoms onset sporadic, progressive and > 30 years of age Less than 5 years from MSA parkinsonian diagnosis with expected survival more than 3 years Stable anti-parkinsonian medication regimen Ability to walk a distance of 25 feet with or without an assistive device Exclusion Criteria: Presence of idiopathic Parkinson's disease (PD) or any PD-related mutation or other neurological diseases Presence of dementia, psychosis, substance abuse or poorly controlled depression Prior brain surgery (i.e., deep brain stimulator implantation) or other brain imaging abnormalities History of cancer or poorly controlled medical conditions that would increase surgical risk Received investigational agent within 12 weeks Inability to tolerate laying flat in an MRI and/or allergy to gadolinium NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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: Up to 9 study participants meeting eligibility criteria will be randomized in a 2:1 fashion to receive either the investigational medicinal product or sham surgery in this Phase 1 trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Treatment<br> | Biological: AAV2-GDNF gene therapy<br>* Bilateral image-guided infusion of AAV2-GDNF into putamen, single dose<br>|
| Sham Comparator: Placebo Surgery<br> | Procedure: Sham (Placebo) Surgery<br>* Bilateral partial burr/twist holes without dural penetration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of Treatment-Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) assessed clinically by physical and neurological examinations | Number of TEAE and SAE's reported post-treatment. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MSA symptoms/signs as assessed by the Unified Multiple System Atrophy Rating Scale (UMSARS) | Change from baseline in the Unified Multiple System Atrophy Rating Scale (UMSARS) and compared to placebo. UMSARS total scores range from 0-104 points with higher scores indicating greater severity of impairment. | 12 months | 
| Change in striatal dopamine transporter binding as measured by [123-I] Ioflupane | Percent and absolute change in ratio of specific to non-specific binding of 123I FP-CIT to DaT from baseline and compared to placebo by Single Photon Emission Computed Tomography (SPECT) dopamine transporter (DaT) imaging | 12 months | 
| Change in the quality of life as measured by Multiple System Atrophy Quality of Life (MSA-QoL) | Change from baseline and compared to placebo in the Multiple System Atrophy Quality of Life (MSA-QoL) scale. MSA-QoL is a self-reported questionnaire that measures MSA impact in day to day activities. Scale consists of 40 items with a five response option format (0 - no problem to 4 extreme problem) and a not applicable response option. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSA, Multiple System Atrophy, Neurotrophic factor, Growth factor, Glial cell line-derived neurotrophic factor, GDNF, AAV, Gene therapy