Clinical trial NCT04915846: Tamoxifen Therapy for Myotubular Myopathy
Official title: TAM4MTM: a Phase 1/2 Randomized, Placebo-Controlled, Double-Blinded, Single Crossover Study to Determine the Safety and Efficacy of Tamoxifen Therapy for Myotubular Myopathy (XLMTM)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: X Linked Myotubular Myopathy
Keywords: tamoxifen
X-linked myotubular myopathy
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Cures Within Reach
name: The Joshua Frase Foundation USA
name: Will Cure USA
name: Mogford Campbell Family Chair Fund
name: Myotubular Trust
name: Great Ormond Street Hospital Charity
name: Sparks
First posted: 2021-06-07
Enrollment: 6
Sex: MALE
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double-blinded, placebo-controlled, single cross-over study with washout period before cross-over
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Motor Function Measure 32 (MFM32)
timeFrame: Baseline to 15 Months
measure: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years (CHOP INTEND)
timeFrame: Baseline to 15 months
measure: 10 meter walk test
timeFrame: Baseline to 15 months
Secondary outcomes:
measure: Change in pulmonary function testing scores 1) Forced Expiratory Volume in the first second
timeFrame: Baseline to 15 months
measure: Change in pulmonary function testing scores 2) Forced Vital Capacity
timeFrame: Baseline to 15 months
measure: Change in pulmonary function testing scores 3) Peak Cough Flow
timeFrame: Baseline to 15 months
measure: Change in pulmonary function testing scores 4) Maximum Expiratory Pressure
timeFrame: Baseline to 15 months
measure: Change in pulmonary function testing scores 5) Maximum Inspiratory Pressure or Sniff Inspiratory Pressure
timeFrame: Baseline to 15 months
measure: invasive ventilation - time off ventilation
timeFrame: Baseline to 15 months
measure: Incidence and severity of Adverse Events related to the treatment [ Time Frame: 15 Months ]
timeFrame: Baseline to 15 months
measure: micro RNA 133a (miR133a)
timeFrame: Baseline to 15 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Rockville
country: United States
facility: National Institutes of Health
state: Maryland
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
Study officials:
affiliation: The Hospital for Sick Children
name: Jame J Dowling, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Amburgey K, Tsuchiya E, de Chastonay S, Glueck M, Alverez R, Nguyen CT, Rutkowski A, Hornyak J, Beggs AH, Dowling JJ. A natural history study of X-linked myotubular myopathy. Neurology. 2017 Sep 26;89(13):1355-1364. doi: 10.1212/WNL.0000000000004415. Epub 2017 Aug 25.
citation: Maani N, Sabha N, Rezai K, Ramani A, Groom L, Eltayeb N, Mavandadnejad F, Pang A, Russo G, Brudno M, Haucke V, Dirksen RT, Dowling JJ. Tamoxifen therapy in a murine model of myotubular myopathy. Nat Commun. 2018 Nov 19;9(1):4849. doi: 10.1038/s41467-018-07057-5.
citation: Gayi E, Neff LA, Massana Munoz X, Ismail HM, Sierra M, Mercier T, Decosterd LA, Laporte J, Cowling BS, Dorchies OM, Scapozza L. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. Nat Commun. 2018 Nov 19;9(1):4848. doi: 10.1038/s41467-018-07058-4.