Tamoxifen Therapy for Myotubular Myopathy

NCT04915846 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: TAM4MTM / OZM-098
• Study Type: interventional
• Target: 6
• Locations: 3 countries
• Sites: 4

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.

Conditions

X Linked Myotubular Myopathy

Keywords

tamoxifen; X-linked myotubular myopathy

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (8)

• Change in pulmonary function testing scores 1) Forced Expiratory Volume in the first second

  Baseline to 15 months

• Change in pulmonary function testing scores 2) Forced Vital Capacity

  Baseline to 15 months

• Change in pulmonary function testing scores 3) Peak Cough Flow

  Baseline to 15 months

• Change in pulmonary function testing scores 4) Maximum Expiratory Pressure

  Baseline to 15 months

• Change in pulmonary function testing scores 5) Maximum Inspiratory Pressure or Sniff Inspiratory Pressure

  Baseline to 15 months

Study Arms (2)

Drug: ApoTamox 10mg

EXPERIMENTAL

Drug: Tamoxifen (tamoxifen citrate); ApoTamox 10 mg tablets orally twice daily for 6 months

Drug: ApoTamox 10mg

Placebo

PLACEBO COMPARATOR

Placebo (no active ingredients) tablets orally twice daily for 6 months

Drug: Placebo

Interventions

ApoTamox 10mg DRUG

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).

Also known as: Tamoxifen Citrate

Drug: ApoTamox 10mg

Placebo DRUG

placebo comparator

Placebo

Eligibility Criteria

• Age: 6 Months+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male
• Patients ages 6 months and older may participate.
• XLMTM resulting from a confirmed mutation in the Myotubularin 1 (MTM1) gene
• 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.
• Willing and able to comply with all protocol requirements and procedures.

You may not qualify if:

• 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.
• 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.
• Has a history of thromboembolic events
• Currently enrolled in a treatment study for XLMTM or receiving treatment with an experimental therapy other than pyridostigmine.
• Treatment with pyridostigmine for \< 6 weeks duration (must be greater than 6 weeks to be included in TAM4MTM).
• 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).
• Subject has a contraindication to tamoxifen or its ingredients

Sponsors & Collaborators

• James Dowling: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Cures Within Reach: collaborator
• The Joshua Frase Foundation USA: collaborator
• Will Cure USA: collaborator
• Mogford Campbell Family Chair Fund: collaborator
• Myotubular Trust: collaborator
• Great Ormond Street Hospital Charity: collaborator
• Sparks: collaborator

Study Sites (4)

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

National Institutes of Health

Rockville, Maryland, 20892, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

Great Ormond Street Hospital for Children

London, WC1N 3JH, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 28842446 BACKGROUND

• 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.

  PMID: 30451841 BACKGROUND

• 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.

  PMID: 30451843 BACKGROUND

MeSH Terms

Conditions

Myopathies, Structural, Congenital

Interventions

Tamoxifen

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Jame J Dowling, MD, PhD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Staff clinician and senior scientist

Model Details: Double-blinded, placebo-controlled, single cross-over study with washout period before cross-over

Study Record Dates

• First Submitted: May 6, 2021
• First Posted: June 7, 2021
• Study Start: December 18, 2020
• Primary Completion: May 9, 2024
• Study Completion: May 9, 2024
• Last Updated: September 19, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); CA (1); GB (1)