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

• ClinicalTrials.gov Identifier: NCT02071459
• Recruitment Status: Completed
• First Posted: February 25, 2014
• Last Update Posted: August 25, 2020
• Sponsor: University Hospital, Toulouse
• Information provided by (Responsible Party): University Hospital, Toulouse

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Multiple System Atrophy	Drug: L-Threo DOPS; Drug: placebo	Phase 2; Phase 3

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 107 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 21, 2014
• Actual Primary Completion Date: October 28, 2019
• Actual Study Completion Date: October 28, 2019

Arms and Interventions

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; Other Name: L DOPS or DroxiDopa
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

Outcome Measures

Primary Outcome Measures :

1. Evaluate the efficacy of long term efficacy of L-threo DOPS [ Time Frame: 12 weeks ]
   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).

Secondary Outcome Measures :

1. efficacy of L-ThreoDOPS on symptomatic OH [ Time Frame: 12 weeks ]
   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
2. effects of L-Threo DOPS on motor symptoms [ Time Frame: 12 weeks ]
   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
3. effect of L-Threo DOPS on dysautonomic symptoms [ Time Frame: 12 weeks ]
   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
4. safety of high doses of L-ThreoDOPS [ Time Frame: 12 Weeks ]
   Determine the safety of high doses of L-ThreoDOPS in MSA patients based on the occurrence of treatment-emergent adverse events

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

France

Centre hospitalier d'Angers

Angers, France, 49933

CHU bordeaux

Bordeaux, France

CHU de Clermont-Ferrand

Clermont-Ferrand, France, 63000

CHU de Dijon

Dijon, France, 21000

CHRU de lille

Lille, France, 59037

CHU de limoges

Limoges, France, 87042

Hôpital La Timone

Marseille, France, 13000

Hôpital G. & R. Laennec

Nantes, France, 44093

Hôpital Pitié-Salpétrière

Paris, France, 75013

CHU de Poitiers

Poitiers, France, 86021

CHU Pontchaillou

Rennes, France, 35033

CHU de Rouen

Rouen, France, 76031

chu de Strasbourg

Strasbourg, France, 67091

Sponsors and Collaborators

University Hospital, Toulouse

Investigators

• Principal Investigator: Anne PAVY-LE-TRAON, PHD; CHU Toulouse

More Information

• Responsible Party: University Hospital, Toulouse
• ClinicalTrials.gov Identifier: NCT02071459
• Other Study ID Numbers: 12 554 01; 12-018-0200 ( Other Grant/Funding Number: French Ministry of Health, PHRC 2012 )
• First Posted: February 25, 2014
• Last Update Posted: August 25, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by University Hospital, Toulouse:

L-threo DOPS (DroxiDopa); Orthostatic Hypotension; Multiple system atrophy

Additional relevant MeSH terms:

Multiple System Atrophy; Shy-Drager Syndrome; Hypotension, Orthostatic; Hypotension; Atrophy; Pathological Conditions, Anatomical; Vascular Diseases; Cardiovascular Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Orthostatic Intolerance; Droxidopa; Antiparkinson Agents; Anti-Dyskinesia Agents