A Randomized, Placebo-Controlled, Multiple Ascending Dose Study Assessing Safety, Tolerability, Pharmacodynamics, Efficacy, and Pharmacokinetics of DYNE-101 Administered to Participants With Myotonic Dystrophy Type 1
概览
- 阶段
- 1 期
- 干预措施
- Placebo
- 疾病 / 适应症
- Myotonic Dystrophy Type 1 (DM1)
- 发起方
- Dyne Therapeutics
- 入组人数
- 116
- 试验地点
- 29
- 主要终点
- MAD Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
- 状态
- 招募中
- 最后更新
- 上个月
概览
简要总结
The primary purpose of the study is to evaluate the safety and tolerability of multiple intravenous (IV) doses of DYNE-101 administered to participants with Myotonic Dystrophy Type 1 (DM1).
The study consists of 4 periods: A Screening Period (up to 8 weeks), a Placebo-Controlled Period (24 weeks), a Treatment Period (24 weeks) and a Long-Term Extension (LTE) Period (168 weeks) in both multiple-ascending dose (MAD) and dose expansion cohorts.
研究者
入排标准
入选标准
- •Diagnosis of DM1 with trinucleotide repeat size \>
- •Age of onset of DM1 muscle symptoms ≥12 years.
- •Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds in the opinion of the Investigator.
- •Hand grip strength and ankle dorsiflexion strength.
- •Able to complete 10-MWRT, stair ascend/descend (MAD cohorts only), and 5×STS at screening without the use of assistive devices such as canes, walkers, or orthoses.
排除标准
- •History of major surgical procedure within 12 weeks prior to the start of investigative product administration or an expectation of a major surgical procedure (eg, implantation of cardiac defibrillator) during the study.
- •History of anaphylaxis.
- •Medical condition other than DM1 that would significantly impact ambulation or participation in functional assessments.
- •Treatment with medications that can improve myotonia within a period of 5 half-lives of the medication prior to performing screening assessments.
- •Electrocardiogram (ECG) with the corrected QT interval by Fridericia's Formula (QTcF) ≥450 milliseconds (ms) in men and QTcF ≥460 ms in women, PR ≥240 ms, left bundle-branch block, or a conduction defect, which is clinically significant in the opinion of the Investigator.
- •Percent predicted forced vital capacity (FVC) \<50%.
- •History of tibialis anterior biopsy within 3 months of Day 1 or planning to undergo tibialis anterior biopsies during study period for reasons unrelated to the study.
- •Participant has a history of suicide attempt, suicidal behavior, or has any suicidal ideation within 6 months prior to Screening that meets criteria at a level of 4 or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS) or who, in the opinion of the Investigator, is at significant risk to commit suicide.
- •Use of glucagon-like peptide 1 (GLP-1) agonist medications including semaglutide, dulaglutide, liraglutide, exenatide, or tirzepatide within a period of 5 half-lives of the medication prior to performing screening assessments.
- •Significant weight loss during study participation may impact weight-based dosing, performance on muscle function assessments, and pharmacodynamic (PD) biomarkers.
研究组 & 干预措施
MAD Cohort: Placebo-Controlled Period: Placebo
Participants will be randomized to receive DYNE-101 matching placebo, Q4W or Q8W for up to 24 weeks.
干预措施: Placebo
MAD Cohort: Treatment Period: DYNE-101
Participants who receive DYNE-101 in Placebo-Controlled Period will continue to receive DYNE-101, Q4W or Q8W for up to 24 weeks. Participants who receive placebo in Placebo-Controlled Period will receive DYNE-101, Q4W or Q8W for up to 24 weeks.
干预措施: DYNE-101
MAD Cohort: Treatment Period: DYNE-101
Participants who receive DYNE-101 in Placebo-Controlled Period will continue to receive DYNE-101, Q4W or Q8W for up to 24 weeks. Participants who receive placebo in Placebo-Controlled Period will receive DYNE-101, Q4W or Q8W for up to 24 weeks.
干预措施: Placebo
MAD Cohort: Long-Term Extension Period: DYNE-101
Participants will receive DYNE-101, Q4W or Q8W for up to 168 weeks.
干预措施: DYNE-101
Dose Expansion Cohort: Placebo-Controlled Period: DYNE-101
Participants will receive DYNE-101, Q8W for up to 24 weeks.
干预措施: DYNE-101
Dose Expansion Cohort: Placebo-Controlled Period: Placebo
Participants will receive DYNE-101 matching placebo, Q8W for up to 24 weeks.
干预措施: Placebo
Dose Expansion Cohort: Treatment Period: DYNE-101
Participants who receive DYNE-101 in Placebo-Controlled Period will continue to receive DYNE-101, Q8W for up to 24 weeks. Participants who receive placebo in Placebo-Controlled Period will receive DYNE-101, Q8W for up to 24 weeks.
干预措施: DYNE-101
Dose Expansion Cohort: Treatment Period: DYNE-101
Participants who receive DYNE-101 in Placebo-Controlled Period will continue to receive DYNE-101, Q8W for up to 24 weeks. Participants who receive placebo in Placebo-Controlled Period will receive DYNE-101, Q8W for up to 24 weeks.
干预措施: Placebo
Dose Expansion Cohort: Long-Term Extension Period: DYNE-101
Participants will receive DYNE-101, Q8W for up to 168 weeks.
干预措施: DYNE-101
MAD Cohort: Placebo-Controlled Period: DYNE-101
Participants will be randomized to receive ascending doses of DYNE-101, once every 4 weeks (Q4W) or once every 8 weeks (Q8W) for up to 24 weeks.
干预措施: DYNE-101
结局指标
主要结局
MAD Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: Through study completion, up to Week 217
Dose Expansion Cohorts: Change From Baseline in Myotonia as Measured by Video Hand Opening Time (vHOT)
时间窗: Baseline up to Week 25
次要结局
- MAD Cohorts: Change From Baseline in Composite Alternative Splicing Index (CASI) in Skeletal Muscle Tissue(Baseline up to Week 45)
- MAD Cohorts: Change From Baseline in Dystrophia Myotonica Protein Kinase (DMPK) Ribonucleic Acid (RNA) Expression in Muscle Tissue(Baseline up to Week 45)
- MAD Cohorts: Change From Baseline in Hand Grip Relaxation Time(Baseline up to Week 121)
- MAD Cohorts: Change From Baseline in Myotonia as Measured by vHOT(Baseline up to Week 193)
- MAD Cohorts: Change From Baseline in Quantitative Myometry Testing (QMT)(Baseline up to Week 193)
- MAD Cohorts: Change From Baseline in 10-Meter Walk/Run Test (10-MWRT)(Baseline up to Week 193)
- MAD Cohorts: Change From Baseline in Stair-Ascend/Descend Test(Baseline up to Week 121)
- MAD Cohorts: Change From Baseline in 5 Times Sit to Stand (5×STS)(Baseline up to Week 193)
- MAD Cohorts: Change From Baseline in 9-Hole Peg Test (9-HPT)(Baseline up to Week 193)
- MAD Cohorts: Maximum Observed Plasma Drug Concentration (Cmax) of DYNE-101(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Time to Maximum Observed Plasma Concentration (tmax) of DYNE-101(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Plasma Concentration (AUCtlast) of DYNE-101(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC∞) of DYNE-101 in Plasma(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Apparent Terminal Elimination Rate Constant (λz) of DYNE-101 in Plasma(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Apparent Terminal Elimination Half-Life (t1/2) of DYNE-101 in Plasma(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Clearance (CL) of DYNE-101 in Plasma(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Volume of Distribution at the Terminal Phase (Vz) of DYNE-101 in Plasma(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Volume of Distribution at Steady State (Vss) of DYNE-101 in Plasma(Pre-dose, and at multiple timepoints up to Week 217)
- MAD Cohorts: Antisense Oligonucleotide (ASO) Concentration of DYNE-101 in Muscle Tissue(Up to Week 45)
- MAD Cohorts: Number of Participants With Antidrug Antibodies (ADAs)(Up to Week 217)
- Dose Expansion Cohorts: Change From Baseline in CASI in Skeletal Muscle Tissue(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in QMT Total(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in 10-MWRT(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in 5×STS(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in 9-HPT(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in Myotonic Dystrophy Health Index (MDHI) Total Score(Baseline up to Week 25)
- Dose Expansion Cohorts: Patient Global Impression of Change (PGI-C)(Baseline up to Week 25)
- Clinician Global Impression of Change (CGI-C)(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in Patient Global Impression of Severity (PGI-S)(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in Clinician Global Impression of Severity (CGI-S)(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in MDHI Subscale Scores(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline at in Myotonic Dystrophy type 1 Activity and Participation Scale (DM1-ACTIV^C) Total Score(Baseline up to Week 25)
- Dose Expansion Cohorts: Change From Baseline in Percent Predicted Hand Grip Strength(Baseline up to Week 25)