X Linked Myotubular Myopathy
Conditions
Keywords
tamoxifen, X-linked myotubular myopathy
Brief summary
This is a phase 1 / 2, randomized, double-blinded, single cross-over study, with a washout period between treatment regimens, to test the efficacy and safety of tamoxifen therapy to improve motor and respiratory function in males with XLMTM.
Detailed description
Pre-clinical studies in Mtm1 knockout mice (a model of XLMTM) demonstrated prolonged survival, increased motor function (including muscle strength), and improved muscle histopathology with tamoxifen treatment. Based on these data, and the known safety profile of the drug in humans, we hypothesize that tamoxifen treatment will be safe and will improve motor and respiratory function in XLMTM patients. This is a randomized, double-blinded, single crossover clinical trial to test this hypothesis and determine the safety and efficacy of tamoxifen in improving motor and respiratory function in MTM patients. Each subject will serve as his own control during the placebo phase of the study. As treatments for XLMTM are current not available, this study addresses a critical unmet need by testing a therapy that, if effective, may serve as a primary treatment, or in the future as an adjunct to other therapies in development.
Interventions
DRUGApoTamox 10mg
All participants will receive tamoxifen (ApoTamox) for approximately 6 months (6 months + 1 week). Participants and study staff will be blinded as to whether the participants are starting with the placebo or the drug. Depending on randomization, drug or placebo will be dispensed at the end of the t=0 study visit (Phase 1). Dosing will commence the day after the t=0 study visit. At the end of Phase 1, participants will enter a 'washout' period, when they will cease treatment. After approximately 3 months of washout, participants will cross-over to the other treatment regimen and receive the other interventional product (IP) for the final 6 months of their study participation (Phase 2).
DRUGPlacebo
placebo comparator
Sponsors
Canadian Institutes of Health Research (CIHR)
Cures Within Reach
The Joshua Frase Foundation USA
Will Cure USA
Mogford Campbell Family Chair Fund
Myotubular Trust
Great Ormond Street Hospital Charity
Sparks
James Dowling
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study is a placebo-controlled double-blinded design. A select few (pharmacist and study staff in charge of pharmacokinetics) and Data Safety Monitoring Board (DSMB) are unblinded.
Intervention model description
Double-blinded, placebo-controlled, single cross-over study with washout period before cross-over
Eligibility
Sex/Gender
MALE
Age
6 Months to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male 2. Patients ages 6 months and older may participate. 3. XLMTM resulting from a confirmed mutation in the Myotubularin 1 (MTM1) gene 4. Patients over 18 years of age and parent(s)/legal guardian(s) of patients \<18 years of age must provide written informed consent prior to participating in the study and informed assent will be obtained from minors, or at least 7 years of age when required by regulation. 5. Willing and able to comply with all protocol requirements and procedures.
Exclusion criteria
1. Other disease which may significantly interfere with the assessment of myotubular myopathy (MTM) and is clearly not related to the disease, at the discretion of the qualified investigator. 2. Has undergone surgery or hospitalization \< 3 months before starting TAM4MTM (at t = -3 months), or has surgery scheduled during the 18 months of participation in TAM4MTM, which will impede motor assessments in the opinion of the Investigator. 3. Has a history of thromboembolic events 4. Currently enrolled in a treatment study for XLMTM or receiving treatment with an experimental therapy other than pyridostigmine. 5. Treatment with pyridostigmine for \< 6 weeks duration (must be greater than 6 weeks to be included in TAM4MTM). 6. Use of concomitant medication known to inhibit CYP2D6 and/or CYP3A4, including clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit, paroxetine, troleandomycin, rifampin, phenobarbital, aminoglutethimide, medroxyprogesterone, amiodarone, haloperidol, indinavir, ritonavir, quinidine, rifampicin, or any selective serotonin reuptake inhibitor (SSRI). 7. Subject has a contraindication to tamoxifen or its ingredients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Motor Function Measure 32 (MFM32) | Baseline to 15 Months | Mean change from baseline of Motor Function Measure 32 for subjects aged 4 and older |
| Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years (CHOP INTEND) | Baseline to 15 months | Mean change from baseline of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years |
| 10 meter walk test | Baseline to 15 months | Mean change from baseline in velocity in 10 meter walk test for ambulant participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in pulmonary function testing scores 4) Maximum Expiratory Pressure | Baseline to 15 months | Mean change from baseline in participants without invasive respiratory support |
| Change in pulmonary function testing scores 5) Maximum Inspiratory Pressure or Sniff Inspiratory Pressure | Baseline to 15 months | Mean change from baseline in participants without invasive respiratory support |
| Change in pulmonary function testing scores 1) Forced Expiratory Volume in the first second | Baseline to 15 months | Mean change from baseline in participants without invasive respiratory support |
| Incidence and severity of Adverse Events related to the treatment [ Time Frame: 15 Months ] | Baseline to 15 months | Incidence of serious adverse events and adverse events throughout the study, as assessed by CTCAE v4.0 |
| micro RNA 133a (miR133a) | Baseline to 15 months | Assess miR133a as a biomarker of XLMTM |
| invasive ventilation - time off ventilation | Baseline to 15 months | Mean change in time off ventilator for participants dependent on invasive respiratory support |
| Change in pulmonary function testing scores 2) Forced Vital Capacity | Baseline to 15 months | Mean change from baseline in participants without invasive respiratory support |
| Change in pulmonary function testing scores 3) Peak Cough Flow | Baseline to 15 months | Mean change from baseline in participants without invasive respiratory support |
Countries
Canada, United Kingdom, United States
Outcome results
None listed