An early phase human drug trial (called phase 1/2) to investigate DYN101 in patients = 16 years of age with a rare muscle disease group called the centronuclear myopathies caused by genetic changes in DNM2 or MTM1 for the drug’s safety, tolerability, how the body processes the drug as well as interactions of the drug with the body and preliminary effects of the drug.

Phase 1

• Conditions: MedDRA version: 20.0Level: HLTClassification code 10028640Term: MyopathiesSystem Organ Class: 100000004859; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]; Centronuclear myopathies (CNMs) in patients = 16 years of age with mutations in DNM2 or MTM1

• Registration Number: EUCTR2018-004089-33-GB
• Lead Sponsor: Dynacure

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-09-05
• Last Update Posted: 29 June 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1. Male or female aged = 16 years of age* on the date of signing the main ICF. The first subject (i.e. the sentinel subject) in each cohort must be = 18 years of age. *for Germany, the subject must be = 18 years of age in accordance with local and national regulations.
2. Have a documented mutation in DNM2 or MTM1.
3. Meet the following criteria at screening:
• Platelet count > 150,000/µL,
• Normal kidney function, supported by values of blood urea nitrogen,
creatinine, cystatin C, and estimated glomerular filtration rate all
abnormal results of these tests should have a medically plausible reason
and should be discussed with the medical monitor before the subject
may be screened and/or dosed for the study.
• Normal liver function, supported by values of alanine and aspartate aminotransferase, gamma glutamyltransferase, and bilirubin not higher than 1.5 times the upper limit of normal .There should be a medically plausible reason for the elevation of these parameters outside of the normal range, and a discussion with the medical monitor should occur in this situation before the subject may be screened and/or dosed for the study.
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.

Are the trial subjects under 18? yes
Number of subjects for this age range: 6
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion Criteria

1. Have clinical 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 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. 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.
5. Currently enrolled in any interventional trial or scheduled to participate in another trial whilst participating in this trial. Subjects are allowed to participate in registry studies.
6. 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.
7. Intake of any disallowed therapies as noted in the protocol within 12 weeks before the planned first IMP administration.
8. 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.
9. Legally incapacitated or have limited legal capacity. Lack of mental capacity to fully understand the protocol requirements and complete all study required procedures.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the safety and tolerability of 3 single ascending dose (SAD) levels and 3 multiple ascending dose (MAD) levels of DYN101;Secondary Objective: • To assess the pharmacokinetics (PK) of SAD and MAD of DYN101.<br>• To explore target engagement in muscle of DYN101.<br>;Primary end point(s): Comparison of adverse event (AE, SAE, AESI) frequency and severity by dose (cohort), for single or multiple administration, and by mutated gene (subcohort) and overall using the Safety Analysis set following 12 weeks of MAD treatment and after 24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD extension part; Week 25 visit) or discontinued earlier.;Timepoint(s) of evaluation of this end point: All visits from baseline to W25 visit and safety End-of-Treatment follow up visit 3 months after last dose.