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

Multiple System Atrophy Clinical Trial

— DOPS-AMS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02071459
• Other study ID #: 12 554 01
• Secondary ID: 12-018-0200
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: January 21, 2014
• Est. completion date: October 28, 2019

Study information

• Verified date: August 2020
• Source: University Hospital, Toulouse
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: October 28, 2019
• Est. primary completion date: October 28, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Atrophy
• Hypotension
• Hypotension, Orthostatic
• Multiple System Atrophy
• Shy-Drager Syndrome

Intervention

Drug:
• L-Threo DOPS
initial dose titration period (4 weeks) followed by 8 weeks at the max tolerated dose
• placebo
initial period (4 weeks) followed by 8 weeks

Locations

Country	Name	City	State
France	Centre hospitalier d'Angers	Angers
France	CHU bordeaux	Bordeaux
France	CHU de Clermont-Ferrand	Clermont-Ferrand
France	CHU de Dijon	Dijon
France	CHRU de lille	Lille
France	CHU de limoges	Limoges
France	Hôpital La Timone	Marseille
France	Hôpital G. & R. Laennec	Nantes
France	Hôpital Pitié-Salpétrière	Paris
France	CHU de Poitiers	Poitiers
France	CHU Pontchaillou	Rennes
France	CHU de Rouen	Rouen
France	chu de Strasbourg	Strasbourg

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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