Efficacy of L-threo DOPS on Orthostatic Hypotension Symptoms and Other Non-motor Symptoms in Patients With MSA

Study Overview
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Brief Summary
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Evaluate the effects of L-Threo DOPS on orthostatic hypotension symptoms and other non-motor symptoms in patients with Multiple System Atrophy (MSA) after 12 weeks following randomization to continued therapy with droxidopa or placebo.

Detailed Description
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Background : Multiple system atrophy (MSA) is a rare, sporadic progressive neurodegenerative disorder, rapidly leading to severe disability and impairment of quality of life. MSA is characterized by a variable combination of a poor levodopa parkinsonism and /or cerebellar ataxia and autonomic failure (cardiovascular and / or bladder and sexual dysfunction) (Gilman et al, 2008). The prevalence is approximately 4-5 cases per 100 000 inhabitants. Orthostatic hypotension (OH) is one of the major symptoms of MSA, present in a large majority of patients, leading to significant disability because of impaired balance, falls and possibly syncope. Drugs available to treat OH in this disease are very limited. L-ThreoDOPS (L DOPS or DroxiDopa) is an orally administered synthetic catecholamine acid that is converted to the sympathetic neurotransmitter norepinephrine (NE) through a single step of decarboxylation by the endogenous enzyme 3,4-dihydroxyphenylalanine (DOPA) decarboxylase. It prevents symptoms related to OH by central and/peripheral mechanisms. This drug is currently developed for neurogenic OH by Chelsea Therapeutics on the basis of short duration placebo-controlled randomized trials. Besides an expected effect on OH, L-DOPS may also, by noradrenergic stimulation, improve some motor and non-motor symptoms common and disabling in MSA patients such as akinesia and fatigue. In this context, the French reference center for MSA and the 12 national centers with identified skills to manage this disease, propose to conduct a national multicenter randomized clinical trial versus placebo to evaluate the long term efficacy (3 months) of L-threo DOPS on the OH and other non-motor symptoms in MSA patients.

Official Title
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Evaluate the Long-term (3 Months) Efficacy of L-threo DOPS (DroxiDopa) on Orthostatic Hypotension Symptoms and Other Non-motor Symptoms in Patients With Multiple System Atrophy (MSA). Comparative Study Versus Placebo

Conditions
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Multiple System Atrophy

Intervention / Treatment
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* Drug: L-Threo DOPS
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MSA patients (possible or probable, MSA-P or C (according to revised criteria, Gilman et al 2008)). Aged 30 to 80 years, Able to walk at least 10 meters With symptomatic OH (score of at least 3 at one of the items of Part I of the OH scale (OHQ)) Documented fall in systolic blood pressure of at least 20 mmHg, and/or in diastolic blood pressure of at least 10 mmHg, within 3 minutes after standing. Able to fill in the evaluation questionnaires with or without help With no significant problems with swallowing. Stable anti-parkinsonian, dysautonomia and depression treatments for the 4 weeks before the study and during the entire study Signed written informed consent for the present study. Exclusion Criteria: Dementia (DSM-IV, Mini-Mental State Examination (MMSE) < 24/30) Concomitant use of vaso-constrictive drugs, other than midodrine. Patients taking vasoconstrictor agents such as ephedrine, dihydroergotamine, must stop taking these drugs at least 2 days or 7 half-lives prior to their baseline visit (Visit 1); the association with midodrine may be kept at a stable dose not exceeding 3 tablets (7.5 mg) / day if the patient has no CV history. This will be discussed case by case with the coordinating center and the safety committee of this study. Taking anti-hypertensive medication

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-Threo DOPS<br>patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with L-Threo DOPS | Drug: L-Threo DOPS<br>* initial dose titration period (4 weeks) followed by 8 weeks at the max tolerated dose<br>* Other names: L DOPS or DroxiDopa;|
| Placebo Comparator: placebo<br>patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with placebo | Drug: placebo<br>* initial period (4 weeks) followed by 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of long term efficacy of L-threo DOPS | Evaluate the efficacy of long term efficacy of L-threo DOPS (droxidopa) in MSA patients (probable or possible - cerebellar (C) or parkinsonian (P) type) with symptomatic NOH as measured by the relative change in mean score of Orthostatic Hypotension Symptom Assessment (OHSA) (Part I of the questionnaire on the symptoms OH (OHQ) (Kaufmann et al., 2011)) 12 weeks following randomization to therapy with droxidopa or placebo (including 8 weeks to maximum tolerated dose). | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| efficacy of L-ThreoDOPS on symptomatic OH | Evaluate and compare the efficacy of L-ThreoDOPS on symptomatic OH (measured by the relative change in mean score of Item 1 of the Orthostatic Hypotension Symptom Assessment (OHSA)) in MSA patients 4, 8 and 12 weeks following randomization to continued therapy with droxidopa or placebo | 12 weeks | 
| effects of L-Threo DOPS on motor symptoms | Evaluate the effects of L-Threo DOPS on motor symptoms (UMSARS I and II) in MSA patients after 12 weeks following randomization to continued therapy with droxidopa or placebo | 12 weeks | 
| effect of L-Threo DOPS on dysautonomic symptoms | Evaluate the effect of L-Threo DOPS on dysautonomic symptoms (COMPASS) in MSA patients after 4, 8 and 12 weeks following randomization to continued therapy with droxidopa or placebo | 12 weeks | 
| safety of high doses of L-ThreoDOPS | Determine the safety of high doses of L-ThreoDOPS in MSA patients based on the occurrence of treatment-emergent adverse events | 12 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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L-threo DOPS (DroxiDopa), Orthostatic Hypotension, Multiple system atrophy