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Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies (Unite-CNM)

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ClinicalTrials.gov Identifier: NCT04033159
Recruitment Status : Recruiting
First Posted : July 25, 2019
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
Dynacure

Tracking Information
First Submitted Date  ICMJE June 12, 2019
First Posted Date  ICMJE July 25, 2019
Last Update Posted Date September 16, 2021
Actual Study Start Date  ICMJE January 9, 2020
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 24, 2019)
incidence of drug-related Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline until Week 25 ]
Incidence of drug-related, treatment-emergent AEs during the study period (through to Week 25).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies
Official Title  ICMJE A Phase 1/2 Trial on the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Exploratory Efficacy of DYN101 in Patients ≥ 16 Years of Age With Centronuclear Myopathies Caused by Mutations in DNM2 or MTM1.
Brief Summary

There are no available treatments aside from supportive care for patients with Centronuclear myopathy (CNM). This trial will assess the safety, tolerability, PK and PD/preliminary efficacy of a new medicine called DYN101 in patients ≥ 16 years of age with CNM caused by mutations in DNM2 or MTM1.

The trial will consist of a consent, a screening period, a run-in period (if applicable), a Single dose treatment part (SAD) with 4 weeks of follow-up after the drug administration and a washout period of at least 12 weeks (followed by follow-up phone calls), a Multiple dose treatment part (MAD) of 12 weeks of weekly dosing, and a Multiple dose extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD extension parts, unless they withdraw. During this time, multiple test will be performed in order to better understand how the drug is distributed and then later removed from the body and whether there any signs of an effect.

As this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their disease.

Detailed Description

There are currently no available treatments aside from supportive care for patients with Centronuclear myopathy (CNM). This trial will assess the safety, tolerability, PK and PD/preliminary efficacy of DYN101 in patients ≥ 16 years of age with CNM caused by mutations in DNM2 or MTM1.

DYN101 is a synthetically manufactured constrained ethyl gapmer ASO directed against DNM2 pre-mRNA. DYN101 will be provided as a sterile concentrated solution for reconstitution into an infusion solution for intravenous (IV) administration, and will be diluted into a 0.9% sodium chloride solution before administration.

The trial will consist of a pre-screening consent, a screening period, a run-in period (if applicable), a SAD part with 4 weeks of follow-up after IMP administration and a washout period of at least 12 weeks (followed by follow-up phone calls until the MAD part starts), a MAD part of 12 weeks, and a MAD extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD extension parts, unless they withdraw. End-of-treatment assessments will be performed after 24 weeks of MAD treatment have been completed, i.e. at the Week 25 visit. Subjects will be followed up on adverse events (AEs) and concomitant medications 3 months after the last IMP administration.

An interim analysis will be performed when all subjects in cohort 1 and 2 have completed 12 weeks of MAD treatment. The primary analysis will be performed when all subjects in all cohorts have completed 12 weeks of MAD treatment or discontinued earlier. The final analysis will be performed when all subjects have completed 24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD extension part; Week 25 visit) or discontinued earlier.

As this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their pathology, and the knowledge that they contribute to RNA-targeted therapy for CNM patients carrying MTM1 and DNM2 mutations.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Trial consisting of pre-screening consent, screening period, run-in period (if applicable), SAD part with 4 weeks follow-up after IMP and washout period of ≥ 12 weeks, MAD part of 12 weeks and MAD extension part of 12 weeks. All subjects to participate in SAD, MAD, and MAD extension unless they withdraw. Subjects to receive DYN101 in a low (1.5 mg/kg), middle (4.5 mg/kg) or high (9 mg/kg) dose in Cohorts 1, 2 and 3 respectively, and remain on assigned dose throughout the trial (unless IDMC advises otherwise). Each cohort will have 3-4 subjects with a DNM2 mutation and 2-3 subjects with a MTM1 mutation. Cohorts will enroll in a sequential staggered approach with an interval of ≥7 days between dosing of the first and the next subject in a cohort (after Medical Monitor 48hr safety data review).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Centronuclear Myopathy
Intervention  ICMJE Drug: DYN101
DYN101, is a constrained ethyl gapmer ASO directed against human DNM2 RNA
Other Name: there is no other intervention name
Study Arms  ICMJE
  • Experimental: cohort 1
    DYN101 in a low dose (1.5 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).
    Intervention: Drug: DYN101
  • Experimental: cohort 2
    DYN101 in a middle dose (4.5 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).
    Intervention: Drug: DYN101
  • Experimental: cohort 3
    DYN101 in a high dose (9 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).
    Intervention: Drug: DYN101
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 24, 2019)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Male or female aged ≥ 16 years on the date of signing the main Informed Consent Form (ICF).
  2. Have a documented mutation in DNM2 or MTM1.
  3. Have a symptomatic CNM in the opinion of the investigator, at least mild to moderately affected, i.e. showing clinical symptoms in at least 2 of the relevant 4 domains that will be investigated in this trial (respiratory, muscle strength, muscle function, and dysphagia), and be ambulatory, i.e. being able to walk 10 steps, if needed with support/assisted. If a subject is non-ambulatory but highly functioning in the view of the investigator, he/she may be included following discussion with the sponsor.

5. Have an understanding, ability, and willingness to fully comply with visit frequency, trial procedures and restrictions, including contraceptive requirements.

6. Able to provide written, signed and dated informed consent/assent to participate in the trial. Parental consent (one or both parents) and an assent for subjects < 18 years may be required per local legislation.

Exclusion Criteria:

  1. Clinically significant liver disease.
  2. Clinically significant renal disease.
  3. Presence of significant co-morbidities or conditions other than CNM or clinically significant (CS) findings during screening of medical history, physical examination, laboratory testing, vital signs or ECG recording for which, in the opinion of the investigator and the medical monitor, participation would not be in the best interest of the subject (e.g. compromise the safety or well-being) or that could prevent, limit, or confound the protocol-specified assessments (e.g. taking a muscle biopsy).
  4. For female subjects of child-bearing potential: pregnant or breastfeeding, or planning to become pregnant during the trial.
  5. Current or past abuse of alcohol or recreational/narcotic drugs (with the exception of caffeine and nicotine), which in the investigator's opinion would compromise the subject's safety and/or compliance with the trial procedures.
  6. Currently enrolled in any interventional trial or scheduled to participate in such a trial whilst participating in this trial. Subjects are allowed to participate in registry studies.
  7. Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the IMP or procedures.
  8. Intake of any disallowed therapies as noted in Section 5.5 within 12 weeks before the planned first IMP administration.
  9. Known or suspected intolerance or hypersensitivity to IMP ingredients or closely-related compounds, or history of a significant allergic reaction to IMP ingredients as determined by the investigator, such as anaphylaxis requiring hospitalization.
  10. Legally incapacitated or have limited legal capacity. Lack of mental capacity to fully understand the protocol requirements and complete all study required procedures.

Note: Retesting of subjects should always be discussed with the sponsor and/or medical monitor. Retesting of laboratory values that lead to exclusion will be allowed once using an unscheduled visit during the screening period to assess eligibility. This visit should be at least 2 weeks later than the original screening visit.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Chris Freitag, MD +33 6 98 75 98 44 chris.freitag@dynacure.com
Listed Location Countries  ICMJE Belgium,   Denmark,   France,   Germany,   Netherlands,   United Kingdom
Removed Location Countries United States
 
Administrative Information
NCT Number  ICMJE NCT04033159
Other Study ID Numbers  ICMJE DYN101-C101
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dynacure
Study Sponsor  ICMJE Dynacure
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Chris Freitag, MD Dynacure
Principal Investigator: N.C. Voermans, MD, PhD Radboud University
PRS Account Dynacure
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP