Tamoxifen Therapy for Myotubular Myopathy (TAM4MTM)

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)

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.

Study Overview

• Status: Terminated
• Conditions: X Linked Myotubular Myopathy
• Intervention / Treatment: Drug: Placebo; Drug: ApoTamox 10mg

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • Hospital for Sick Children
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Maryland
    • Rockville, Maryland, United States, 20892
      • National Institutes of Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug: ApoTamox 10mg; Drug: Tamoxifen (tamoxifen citrate); ApoTamox 10 mg tablets orally twice daily for 6 months	Drug: ApoTamox 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).; Other Names: Tamoxifen Citrate
Placebo Comparator: Placebo; Placebo (no active ingredients) tablets orally twice daily for 6 months	Drug: Placebo; placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor Function Measure 32 (MFM32)	Mean change from baseline of Motor Function Measure 32 for subjects aged 4 and older	Baseline to 15 Months
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years (CHOP INTEND)	Mean change from baseline of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years	Baseline to 15 months
10 meter walk test	Mean change from baseline in velocity in 10 meter walk test for ambulant participants	Baseline to 15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pulmonary function testing scores 1) Forced Expiratory Volume in the first second	Mean change from baseline in participants without invasive respiratory support	Baseline to 15 months
Change in pulmonary function testing scores 2) Forced Vital Capacity	Mean change from baseline in participants without invasive respiratory support	Baseline to 15 months
Change in pulmonary function testing scores 3) Peak Cough Flow	Mean change from baseline in participants without invasive respiratory support	Baseline to 15 months
Change in pulmonary function testing scores 4) Maximum Expiratory Pressure	Mean change from baseline in participants without invasive respiratory support	Baseline to 15 months
Change in pulmonary function testing scores 5) Maximum Inspiratory Pressure or Sniff Inspiratory Pressure	Mean change from baseline in participants without invasive respiratory support	Baseline to 15 months
invasive ventilation - time off ventilation	Mean change in time off ventilator for participants dependent on invasive respiratory support	Baseline to 15 months
Incidence and severity of Adverse Events related to the treatment [ Time Frame: 15 Months ]	Incidence of serious adverse events and adverse events throughout the study, as assessed by CTCAE v4.0	Baseline to 15 months
micro RNA 133a (miR133a)	Assess miR133a as a biomarker of XLMTM	Baseline to 15 months

Collaborators and Investigators

• Sponsor: James Dowling
• Collaborators: 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
• Investigators: Principal Investigator: Jame J Dowling, MD, PhD, The Hospital for Sick Children

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2020
• Primary Completion (Actual): May 9, 2024
• Study Completion (Actual): May 9, 2024

Study Registration Dates

• First Submitted: May 6, 2021
• First Submitted That Met QC Criteria: June 4, 2021
• First Posted (Actual): June 7, 2021

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: tamoxifen; X-linked myotubular myopathy
• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Muscular Diseases; Myopathies, Structural, Congenital; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: TAM4MTM / OZM-098

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No