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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 : Not yet recruiting
First Posted : July 25, 2019
Last Update Posted : October 18, 2019
Sponsor:
Information provided by (Responsible Party):
Dynacure SAS

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.


Condition or disease Intervention/treatment Phase
Centronuclear Myopathy Drug: DYN101 Phase 1 Phase 2

Detailed Description:

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 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.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
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 subjects with a DNM2 mutation and 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
Official Title: 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.
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2021


Arm Intervention/treatment
Experimental: cohort 1
DYN101 in a low dose (1.5 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3 subjects with a mutation in DNM2 (subcohort a) and 3 subjects with a mutation in MTM1 (subcohort b).
Drug: DYN101
DYN101, is a constrained ethyl gapmer ASO directed against human DNM2 RNA
Other Name: there is no other intervention name

Experimental: cohort 2
DYN101 in a middle dose (4.5 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3 subjects with a mutation in DNM2 (subcohort a) and 3 subjects with a mutation in MTM1 (subcohort b).
Drug: DYN101
DYN101, is a constrained ethyl gapmer ASO directed against human DNM2 RNA
Other Name: there is no other intervention name

Experimental: cohort 3
DYN101 in a high dose (9 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3 subjects with a mutation in DNM2 (subcohort a) and 3 subjects with a mutation in MTM1 (subcohort b).
Drug: DYN101
DYN101, is a constrained ethyl gapmer ASO directed against human DNM2 RNA
Other Name: there is no other intervention name




Primary Outcome Measures :
  1. 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female aged ≥ 16 years on the date of signing the main ICF.
  2. Have a documented mutation in DNM2 or MTM1.
  3. Meet the following laboratory criteria at screening:

    • Platelet count > 150,000/µL,
    • Normal kidney function, as determined by values of blood urea nitrogen (BUN), creatinine, cystatin C, and eGFR within normal laboratory reference ranges,
    • Normal liver function, as determined by values of ALT, AST, GGT, and bilirubin within normal laboratory reference ranges (see Section 6.2.2.2).

    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.

  4. 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 domains that will be investigated in this trial (respiratory, muscle strength and function, 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. Have clinical, laboratory or ultrasound evidence of liver disease. Note: Liver ultrasound at screening is mandatory for MTM1 subjects.
  2. 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).
  3. For female subjects of child-bearing potential: pregnant or breastfeeding, or planning to become pregnant during the trial.
  4. Have a body weight of <34kg.
  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 another investigational trial or scheduled to participate in another trial whilst participating in this trial.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04033159


Contacts
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Contact: Chris Freitag, MD +33 6 98 75 98 44 chris.freitag@dynacure.com

Locations
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Belgium
Antwerp University Hospital (UZA) Not yet recruiting
Edegem, Belgium
Contact: Jonathan Baets, Professor    0032 3821 5760    jonathan.baets@uza.be   
Denmark
Rigshospitalet, Copenhagen Neuromuscular Center, Neurocentret Not yet recruiting
Kopenhagen, Denmark
Contact: John Vissing    0045 3545 2562    vissing@rh.dk   
France
Institut de Myologie Not yet recruiting
Paris, France
Contact: Behin Anthony    0033 142 163 713    anthony.behin@aphp.fr   
Contact: Tanya Stojkovic    0033 142 163 780    tanya.stojkovic@aphp.fr   
Germany
Friedrich Baur Institut - Neurologische Klinik LMV, Klinikum Innenstadt Not yet recruiting
München, Germany
Contact: Frederica Montagnese    0049 089 4400 57400    studien.fbi@med.uni-muenchen.de   
Netherlands
Radboud University Medical Centre Not yet recruiting
Nijmegen, Netherlands
Contact: N.C. Voermans, MD PhD    0031 24 3616 600    nicol.voermans@radboudumc.nl   
United Kingdom
MRC centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery Not yet recruiting
London, United Kingdom
Contact: Rosaline Quinlivan, Professor    0044 7527 442 063    r.quinlivan@ucl.ac.uk   
Royal Victoria Infirmary Not yet recruiting
Newcastle Upon Tyne, United Kingdom
Contact: Sam Fitzsimmons    0044 191 241 8649    sam.fitzsimmons@newcastle.ac.uk   
Sponsors and Collaborators
Dynacure SAS
Investigators
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Study Director: Chris Freitag, MD Dynacure SAS
Principal Investigator: N.C. Voermans, MD, PhD Radboud University

Additional Information:
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Responsible Party: Dynacure SAS
ClinicalTrials.gov Identifier: NCT04033159     History of Changes
Other Study ID Numbers: DYN101-C101
First Posted: July 25, 2019    Key Record Dates
Last Update Posted: October 18, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Diseases
Myopathies, Structural, Congenital
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases