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Tamoxifen Therapy for Myotubular Myopathy (TAM4MTM)

Primary Purpose

X Linked Myotubular Myopathy

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

ApoTamox 10mg

Placebo

About this trial

This is an interventional treatment trial for X Linked Myotubular Myopathy focused on measuring tamoxifen, X-linked myotubular myopathy

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

INCLUSION CRITERIA

Male
Patients ages 2 years 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.

EXCLUSION CRITERIA

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

Sites / Locations

Ann and Robert H. Lurie Children's Hospital of Chicago
National Institutes of Health
Hospital for Sick ChildrenRecruiting
Great Ormond Street Hospital for Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Drug: ApoTamox 10mg

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Motor Function Measure 32 (MFM32)

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)

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

Mean change from baseline in velocity in 10 meter walk test for ambulant participants

Secondary Outcome Measures

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

Mean change from baseline in participants without invasive respiratory support

Change in pulmonary function testing scores 2) Forced Vital Capacity

Mean change from baseline in participants without invasive respiratory support

Change in pulmonary function testing scores 3) Peak Cough Flow

Mean change from baseline in participants without invasive respiratory support

Change in pulmonary function testing scores 4) Maximum Expiratory Pressure

Mean change from baseline in participants without invasive respiratory support

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

Mean change from baseline in participants without invasive respiratory support

invasive ventilation - time off ventilation

Mean change in time off ventilator for participants dependent on invasive respiratory support

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

micro RNA 133a (miR133a)

Assess miR133a as a biomarker of XLMTM

Full Information

NCT ID

NCT04915846

First Posted

May 6, 2021

Last Updated

June 17, 2021

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

1. Study Identification

Unique Protocol Identification Number

NCT04915846

Brief Title

Tamoxifen Therapy for Myotubular Myopathy

Acronym

TAM4MTM

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

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Recruiting

Study Start Date

December 18, 2020 (Actual)

Primary Completion Date

July 31, 2023 (Anticipated)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

James Dowling

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

X Linked Myotubular Myopathy

Keywords

tamoxifen, X-linked myotubular myopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Crossover Assignment

Model Description

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

Masking

ParticipantCare ProviderInvestigatorOutcomes 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.

Allocation

Randomized

Enrollment

16 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Drug: ApoTamox 10mg

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

ApoTamox 10mg

Other Intervention Name(s)

Tamoxifen Citrate

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

placebo comparator

Primary Outcome Measure Information:

Title

Motor Function Measure 32 (MFM32)

Description

Mean change from baseline of Motor Function Measure 32 for subjects aged 4 and older

Time Frame

Baseline to 15 Months

Title

Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years (CHOP INTEND)

Description

Mean change from baseline of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for subjects aged 2-4 years

Time Frame

Baseline to 15 months

Title

10 meter walk test

Description

Mean change from baseline in velocity in 10 meter walk test for ambulant participants

Time Frame

Baseline to 15 months

Secondary Outcome Measure Information:

Title

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

Description

Mean change from baseline in participants without invasive respiratory support

Time Frame

Baseline to 15 months

Title

Change in pulmonary function testing scores 2) Forced Vital Capacity

Description

Mean change from baseline in participants without invasive respiratory support

Time Frame

Baseline to 15 months

Title

Change in pulmonary function testing scores 3) Peak Cough Flow

Description

Mean change from baseline in participants without invasive respiratory support

Time Frame

Baseline to 15 months

Title

Change in pulmonary function testing scores 4) Maximum Expiratory Pressure

Description

Mean change from baseline in participants without invasive respiratory support

Time Frame

Baseline to 15 months

Title

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

Description

Mean change from baseline in participants without invasive respiratory support

Time Frame

Baseline to 15 months

Title

invasive ventilation - time off ventilation

Description

Mean change in time off ventilator for participants dependent on invasive respiratory support

Time Frame

Baseline to 15 months

Title

Incidence and severity of Adverse Events related to the treatment [ Time Frame: 15 Months ]

Description

Incidence of serious adverse events and adverse events throughout the study, as assessed by CTCAE v4.0

Time Frame

Baseline to 15 months

Title

micro RNA 133a (miR133a)

Description

Assess miR133a as a biomarker of XLMTM

Time Frame

Baseline to 15 months

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

2 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA Male Patients ages 2 years 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. EXCLUSION CRITERIA 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Etsuko Tsuchiya, PhD

Phone

4168137654

Ext

309448

etsuko.tsuchiya@sickkids.ca

First Name & Middle Initial & Last Name or Official Title & Degree

Kim Amburgey, MS

Phone

4168137654

Ext

301707

kim.amburgey@sickkids.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jame J Dowling, MD, PhD

Organizational Affiliation

The Hospital for Sick Children

Official's Role

Principal Investigator

Facility Information:

Facility Name

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

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nancy L Kuntz, MD

Facility Name

National Institutes of Health

City

Rockville

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Office of patient recruitment

Phone

800-411-1222

Ext

TTY8664111010

prpl@cc.nih.gov

First Name & Middle Initial & Last Name & Degree

Carsten Bonnemann

Facility Name

Hospital for Sick Children

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G1X8

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Etsuko Tsuchiya, PhD

Phone

4168137654

etsuko.tsuchiya@sickkids.ca

First Name & Middle Initial & Last Name & Degree

Kim Amburgey, MS

Phone

4168137654

kim.amburgey@sickkids.ca

Facility Name

Great Ormond Street Hospital for Children

City

London

ZIP/Postal Code

WC1N 3JH

Country

United Kingdom

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Giovanni Baranello, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

28842446

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.

Results Reference

background

PubMed Identifier

30451841

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.

Results Reference

background

PubMed Identifier

30451843

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.

Results Reference

background

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Tamoxifen Therapy for Myotubular Myopathy

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