A Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AVE8112 in Patients With Parkinson's Disease

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, multiple-ascending dose study of orally administered AVE8112 in patients with Parkinson's Disease (PD).

Detailed Description
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This is a randomized, double-blind, placebo-controlled, multiple-ascending dose study of orally administered AVE8112 in patients with Parkinson's Disease (PD). Sequential cohorts of eight patients with PD will be administered ascending oral doses of AVE8112 (n=6) or placebo (n=2) once a day for 14 days. Dosing for subsequent cohorts will only proceed, and the dose level selected, after the safety and tolerability of the previous cohort has been reviewed. Doses are planned to be 1.0, 2.0, 3.0, and 4.0 mg once a day for 14 days. These are planned treatments, but doses may be modified based on safety review of previous cohort(s). In addition, cohorts may be added to reconfirm a previously administered dose, and/or a titration strategy may be employed to reach a desired dose. Patients will be assessed in clinic for 30 hours following the initial oral dose of AVE8112 or placebo. Subsequent dosing will occur on an outpatient basis. Patients will receive telephone calls on Days 3 and 10 to monitor for adverse events (AEs) and concomitant medications, and will also be assessed in the clinic on Study Days 7 (outpatient), 14 (outpatient), and 28 (± 3 days) (Follow-up visit). Safety assessments will include physical examinations, vital signs, ECGs, clinical laboratory evaluations, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and Columbia Suicide Severity Rating Scale (C-SSRS). Pharmacodynamic assessment will include the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

Official Title
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A Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AVE8112 in Patients With Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: AVE8112
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 35 to 70, inclusive, with a diagnosis of PD, currently being treated with a stable regimen (at least 4 weeks) of anti-parkinsonian drugs which include at least one L 3,4 dihydroxyphenylalanine (L DOPA)-containing therapy with or without dopamine agonist at Screening. Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia), or gait disturbances as assessed during physical/neurological exam at the Screening visit. A diagnosis of PD for 10 years or less at Screening. Hoehn and Yahr stage I - III. Male or female age 30 years or older at time of PD diagnosis. Body Mass Index (BMI) of approximately ≥18 to ≤32 kg/m2; and a total body weight > 50 kg (l10 lbs). Female patients must be of non-childbearing potential. Exclusion Criteria: Clinically significant history or evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, neurological, immunological, or psychiatric disorder(s) as determined by the Investigator or designee. Female patients that are breastfeeding or female patients with a positive serum pregnancy test. Use of cholinergic medications or those with cholinergic effects. History of orthostatic hypotension or symptomatic drop in SBP. Any subject who has advanced Parkinson's Disease. Evidence of severe depression (score of >10 on Quick Inventory of Depressive Symptomatology - Self Rated [QIDS-SR]). Personal and/or familial history of a significant suicide attempt.

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Group<br>Sequential cohorts of eight patients with PD will be administered ascending oral doses of AVE8112 (n=6) or placebo (n=2) once a day for 14 days. Patients will be assessed in clinic for 30 hours following the initial oral dose of AVE8112 or placebo | Drug: Placebo<br> <br> |
| Active Comparator: AVE8112<br>Sequential cohorts of eight patients with PD will be administered ascending oral doses of AVE8112 (n=6) or placebo (n=2) once a day for 14 days. Dosing for subsequent cohorts will only proceed, and the dose level selected, after the safety and tolerability of the previous cohort has been reviewed. Doses are planned to be 1.0, 2.0, 3.0, and 4.0 mg once a day for 14 days. These are planned treatments, but doses may be modified based on safety review of previous cohort(s). In addition, cohorts may be added to reconfirm a previously administered dose, and/or a titration strategy may be employed to reach a desired dose. Patients will be assessed in clinic for 30 hours following the initial oral dose of AVE8112 or placebo | Drug: AVE8112<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) |  | Continuous; Patients will be assessed for a period of 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics |  | Continuous; Patients will be assesed for a period of 28 days | 
| Pharmacokinetics |  | Continuous; Patients will be assessed for a period of 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, cognitive impairment, movement disorder