2023-510353-42-00招募中2 期
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
Dyne Therapeutics Inc.8 个研究点 分布在 4 个国家目标入组 93 人开始时间: 2024年4月22日最近更新:
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 93
- 试验地点
- 8
- 主要终点
- MAD Cohorts: Number and proportion of participants with treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), TEAEs considered related to study drug, and TEAEs leading to discontinuation from study drug and discontinuation from the study.
研究概览
简要总结
MAD Cohorts: To evaluate the safety and tolerability of multiple IV doses of DYNE-101 administered to participants with DM1 Dose Expansion Cohort: To evaluate the effect of multiple intravenous doses of DYNE-101 administered to participants with DM1 on muscle tissue
入排标准
- 年龄范围
- 18 years 至 64 years（18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •MAD Cohort: Age 18 to < 50 years, at the time of signing the informed consent., Dose Expansion Cohort: Age 18 to ≤ 65 years, at the time of signing the informed consent Type of Participant and Disease Characteristics
- •Diagnosis of DM1 confirmed by molecular genetics with trinucleotide repeat size >
- •Historical results from clinical testing are acceptable
- •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 a. Hand grip strength averaged from both sides ≥ 20% and ≤ 80% (±5%) predicted for age, sex, and height at screening b. Ankle dorsiflexion strength averaged from both sides ≥ 20% and ≤80% (± 10%) predicted for age, sex, and height at screening Note: Two sets of functional assessments must be performed during the Screening Period. Participants must meet inclusion criterion #5 on both sets of functional assessments for study eligibility
- •Able to complete 10-MWRT, stair ascend/descend, and 5×STS at screening without the use of assistive devices such as canes, walkers, or orthoses. The use of submalleolar orthoses and inserts or supports that do not extend above the malleolus are permitted during testing
- •Body mass index (BMI) < 35kg/m2
- •If being treated with testosterone, on a stable replacement dose for 30 days prior to screening Sex and Contraceptive/Barrier Requirements
- •Participants must agree to follow protocol-specified contraception guidance
- •Female participants must not be pregnant or breastfeeding Informed Consent
- •Capable of giving signed informed consent in compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol Other Inclusions
- •Willingness and ability of participant to comply with and tolerate scheduled visits, dosing administration plan, and study assessments, including multiple needle muscle biopsy procedures over the duration of the study
排除标准
- •Previous or ongoing medical condition, medical history, physical findings, or laboratory abnormalities that in the opinion of the Investigator could affect safety, make it unlikely that dosing schedule and follow-up will be correctly completed, and/or impair the assessment and interpretation of study results
- •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 course of the study
- •History of anaphylaxis
- •History of clinically significant liver disease or ongoing treatment for liver disease, or confirmed elevated alanine aminotransferase (ALT) > 3× upper limit of normal (ULN), at Screening.
- •History of clinically significant hematologic disease or have any of the following hematologic results at Screening: platelets or hemoglobin below the lower limit of normal for age and sex.
- •History of clinically significant kidney disease, ongoing treatment for kidney disease (treatment for hypertension is permitted) or estimated glomerular filtration rate (eGFR) < 60 mL/min as calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Cystatin C Equation at screening
- •Active malignancy or history within the last 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
- •Recent history (within previous 12 months) of drug or alcohol abuse
- •Medical condition other than DM1 that would significantly impact ambulation or participation in functional assessments
- •Current insulin-dependent diabetes mellitus or uncontrolled diabetes mellitus, congestive heart failure, symptomatic cardiomyopathy, symptomatic coronary artery disease, multiple sclerosis, or other serious medical illness
- •Second- or third-degree heart block, symptomatic first-degree heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, pacemakers, implanted defibrillator, or is receiving medication for treatment of cardiac arrhythmia
- •Treatment with medications that can improve myotonia or clinical functional endpoints within a period of 5 half-lives of the medication prior to performing screening assessments. May include but not limited to mexiletine, phenytoin, carbamazepine, procainamide, disopyramide, ranolazine, flecainide, lamotrigine, nifedipine, acetazolamide, clomipramine, imipramine, amitriptyline, taurine, quinine, or metformin.
- •Use of anticoagulant such as warfarin or a direct oral anticoagulant (eg, dabigatran) due to the increased risk of bleeding
- •Current treatment with immunosuppressive therapy
- •Receipt of another investigational drug, biologic agent, or device within 5 half-lives (if known) of the agent, or within 4 months prior to the start of Screening, whichever is longer. Individuals previously treated with oligonucleotide therapies (including small interfering RNA [siRNA]) may be eligible if the last dose of the investigational drug was received ≥ 3 years ago
- •ECG with the corrected QT interval by Fridericia's Formula (QTcF) ≥450 ms in men and QTcF ≥ 460 ms in women, PR ≥ 240 ms, left bundlebranch 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
- •Inability, or impaired ability, to complete study procedures and/or complete the study, due to physical or cognitive impairment, in the judgment of the Investigator
- •Inability to undergo venipuncture successfully or tolerate venous access
- •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.
- •Use of nephrotoxic medications within a period of 5 half-lives of the medication prior to performing screening assessments. May include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides (eg, gentamicin, streptomycin), bisphosphonates, and antiviral agents (eg, acyclovir, adefovir). Planned procedures that require contrast during the study are also exclusionary.
- •Acute kidney injury within 12 weeks prior to Screening, characterized by an increase in serum creatinine of 0.3 mg/dL within 48 hours, or of 1.5-fold within a week (Khwaja 2012)
- •Hematuria > 5 red blood cells per high power field (RBC/HPF) on urinalysis at Screening
- •Persistent systolic blood pressure < 90 mm Hg or signs or symptoms of hypotension or volume depletion/dehydration
- •Prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
- •Recent physical inactivity (eg, immobilization of ≥ 3 days)
结局指标
主要结局
MAD Cohorts: Number and proportion of participants with treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), TEAEs considered related to study drug, and TEAEs leading to discontinuation from study drug and discontinuation from the study.
MAD Cohorts: Number and proportion of participants with treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), TEAEs considered related to study drug, and TEAEs leading to discontinuation from study drug and discontinuation from the study.
Dose Expansion Cohort: Change from baseline in CASI in skeletal muscle tissue at Week 13
Dose Expansion Cohort: Change from baseline in CASI in skeletal muscle tissue at Week 13
次要结局
- Change from baseline in CASI in skeletal muscle tissue Change from baseline in DMPK RNA expression in muscle tissue
- MAD Cohorts Change from baseline in hand grip relaxation time by a dynamometer Change from baseline in myotonia as measured by vHOT Change from baseline in Quantitative Myometry Testing (QMT) Change from baseline in 10-meter walk/run test (10-MWRT) Change from baseline in stair-ascend/descend test Change from baseline in 5 times sit to stand (5×STS) Change from baseline in 9-Hole Peg Test (9-HPT)
- Dose Expansion Cohort Change from baseline in myotonia as measured by vHOT (middle finger) at Week 25 Change from baseline in 10-MWRT at Week 25 Change from baseline in QMT subtotal of four muscle groups (percent predicted of handgrip strength, ankle dorsiflexion, knee flexion, and knee extension) at Week 25 Change from baseline in 5×STS at Week 25 Change from baseline in percent predicted hand grip strength at Week 25 Change from baseline in MDHI total score at Week 25
- MAD Cohorts Plasma endpoints: Max observed plasma drug concentration Time to max observed plasma drug concentration Area under the plasma-drug concentration-time curve from time 0 to the last quantifiable concentration AUC extrapolated to time infinity Apparent terminal phase elimination rate constant and elimination half-life Plasma clearance Volume of distribution at the terminal phase, if appropriate and at steady state, if appropriate Muscle tissue endpoint: Tissue ASO concentration
- MAD Cohorts Incidence of antidrug antibodies (ADAs)
研究者
Dyne Clinical Trials
Scientific
Dyne Therapeutics Inc.
研究点 (8)
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