A phase II study of metformin in myotonic dystrophy type 1 patients

• Register: EUCTR
• Last refreshed on: 19 February 2018
• Main ID: EUCTR2013-001732-21-FR
• Date of registration: 18/02/2014
• Prospective Registration: No
• Primary sponsor: Centre d'Etude des Cellules Souches (CECS)
• Public title: A phase II study of metformin in myotonic dystrophy type 1 patients
• Scientific title: A randomized, double blind, placebo-controlled phase II study of metformin in myotonic dystrophy type 1 patients - Myomet
• Date of first enrolment: 06/09/2013
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-001732-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France

Contacts

• Name: Clinical Trial Information
• Affiliation: CECS

• Name: Clinical Trial Information
• Affiliation: CECS

Key inclusion & exclusion criteria

Inclusion criteria:
A diagnosis of DM1, confirmed by DM1 genetic mutation
Male or female patients, age =18 to = 60 years
Muscular Impairment Rating Scale (MIRS) score 2 or 3
Ambulatory, able to perform the 6 Minute Walk Test (6MWT)
All laboratory parameters must be grade 0 or 1 (as per CTCAE criteria) except for AST, ALT for which a grade 2 will be allowed if stated non clinically significant
For women of child-bearing potential, i.e. with no history of hysterectomy or tubal ligation, use of one effective method of birth control during the conduct of the study
Written informed consent
Patient covered by a national health insurance scheme affiliated with the French healthcare system
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 40
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Serious concomitant medical disorder, evidence of renal dysfunction (creatinine clearance < 60 ml/min), blood dyscrasia, hepatic insufficiency, symptomatic pancreatitis, cardiac diseases not controlled, congestive heart failure (NYHA score > 3), cardiac rhythm anomalies (supra-ventricular or ventricular) not controlled or severe conduction abnormalities (AVB I, II or III or HV > 70 ms) without medical device (patients with pacemaker could be included) [echocardiography in the year before the inclusion], congenital heart defect, known history of heart attack, metabolic acidosis, hypertension, significant central nervous system impairment, or neurodegenerative or neuromuscular disease other than DM1
History of psychiatric conditions including, but not limited to, psychosis, suicidal ideations, or major depression. Patients with mild to moderate depression in the past may be enrolled if, in the Investigator’s opinion, they are suitable for treatment
Drug or alcohol abuse within 12 months of enrollment
Other medical condition (besides DM1) that would significantly impact ambulation
Any history of malignancy except for cases of remission (remission > 12 months) and surgically cured skin cancer or pilomatricoma (benign tumor of the hair follicle that is associated with DM1)
Vital capacity < 60% or total lung capacity < 60%, hypercapnia (PCO2 = 50 mmHg)
or other signs of poor respiratory status which is expected to require the initiation of BiPAP within the study period (patients with nocturnal non-invasive ventilation CPAP or BiPAP could be included)
Use of medications intended for the treatment of DM1 including glucocorticoids, anabolic steroids, testosterone, growth hormone, or insulin-like growth factor I (IGF-I) within 1 year of entry
Any medical contraindications to metformin
Known allergy to metformin and/or his excipients
Symptomatic insulin requiring diabetes or type 2 diabetes requiring oral anti-diabetic agents
Women who are pregnant or breast-feeding
Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period (participation in natural history study is allowed)
Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study
Patient unable or unwilling to comply with the protocol requirements


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Myotonic dystrophy type 1 (DM1) also known as Steinert disease

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Trade Name: metformin 500mg
Pharmaceutical Form: Tablet
INN or Proposed INN: METFORMIN
CAS Number: 657-24-9
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: To determine the efficacy of metformin on myotonia, insulin resistance, cholesterol and triglycerides, muscle function and strength, quality of life, gastrointestinal function, and cardiac function
To determine the safety of metformin
To determine the INSRA and INSRB Messenger Ribonucleic Acid (mRNA) ratio in blood, as well as FAS ATP2A1 and LMNA splice variants

Main Objective: To evaluate the efficacy of metformin on ambulation in patients with myotonic dystrophy type 1.

Primary end point(s): Efficacy: At week 52, change from baseline in distance walked at the 6MWT (6MWT)

Timepoint(s) of evaluation of this end point: Evaluation at week 52

Secondary Outcome(s)

Secondary end point(s): Safety: Overall incidence of adverse events and serious adverse events as well as laboratory assessments will be evaluated for each arm and for the study as a whole.
Efficacy:
MyoTone test (performed with the hand grip) at W52: improvement = 20% of relaxation phase from baseline
Muscle MRI at W52: stabilization from baseline of the volume of residual muscle tissue in TA muscle, of the mean T2-relaxation-time of residual muscle tissue, and of the mean fat-to-water ratio in the entire TA muscle
Insulin resistance, cholesterol and triglycerides will be measured and compared to baseline over time
Muscle function and strength measured by the grip test (Handgrip) and the Quantitative Muscle Testing (QMT) test at W52: improvement = 5% of the muscle strength from baseline
Cardiac: 12-lead resting ECG will be analyzed at W52 compared to baseline
Activity and social participation: Scores of DM1-Activ scale and InQoL questionnaires at baseline and over 52 weeks will be analyzed
Biomarker Assays: Change of level in blood INSRA and INSRB Messenger Ribonucleic Acid (mRNA), FAS ATP2A1 and LMNA splice variants from screening, W2, W4, W16, and W52

Timepoint(s) of evaluation of this end point: Safety will be evaluated during the whole study.
Efficacy endpoints will be evaluated at week 52 compared to baseline.
Biomarkers will be mesured at screening, at Week 2, Week 4, Week 16, and Week 52

Secondary ID(s)

MET001

Source(s) of Monetary Support

CECS