Efficacy of L-threo DOPS on Orthostatic Hypotension Symptoms and Other Non-motor Symptoms in Patients With MSA
Keywords
Abstract
Description
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.
Dates
| Last Verified: | 07/31/2020 |
| First Submitted: | 02/20/2014 |
| Estimated Enrollment Submitted: | 02/20/2014 |
| First Posted: | 02/24/2014 |
| Last Update Submitted: | 08/23/2020 |
| Last Update Posted: | 08/24/2020 |
| Actual Study Start Date: | 01/20/2014 |
| Estimated Primary Completion Date: | 10/27/2019 |
| Estimated Study Completion Date: | 10/27/2019 |
Condition or disease
Intervention/treatment
Drug: L-Threo DOPS
Drug: placebo
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: L-Threo DOPS patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with L-Threo DOPS | Drug: L-Threo DOPS initial dose titration period (4 weeks) followed by 8 weeks at the max tolerated dose |
| Placebo Comparator: placebo patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with placebo | Drug: placebo initial period (4 weeks) followed by 8 weeks |
Eligibility Criteria
| Ages Eligible for Study | 30 Years To 30 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | 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 |
Outcome
Primary Outcome Measures
1. Evaluate the efficacy of long term efficacy of L-threo DOPS [12 weeks]
Secondary Outcome Measures
1. efficacy of L-ThreoDOPS on symptomatic OH [12 weeks]
2. effects of L-Threo DOPS on motor symptoms [12 weeks]
3. effect of L-Threo DOPS on dysautonomic symptoms [12 weeks]
4. safety of high doses of L-ThreoDOPS [12 Weeks]
