A Phase 1b, Multi-Center, Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled Study of the Safety, Tolerability, and Hepatic Pharmacodynamics of Resmetirom in Patients With Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Heart Failure With Preserved Ejection Fraction (HFpEF)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 90
- 主要终点
- Incidence of treatment-emergent adverse events (TEAEs)
研究概览
简要总结
This Phase 1b multicenter randomized double-blind placebo-controlled study evaluates the safety, tolerability and hepatic pharmacodynamic effects of resmetirom in adults with metabolic dysfunction-associated steatohepatitis (MASH) and heart failure with preserved ejection fraction (HFpEF). Participants are randomized 2:1 to resmetirom or placebo for 24 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must be willing to participate in the study and provide written informed consent.
- •Male and female adults ≥18 years of age.
- •Suspected or confirmed diagnosis of fibrotic MASH suggested by the historical data and meets at least 1 criteria for fibrotic MASH
- •Confirmed diagnosis of HFpEF
- •Structural and/or functional heart disease based on echocardiographic evaluation.
- •eGFR ≥45 mL/min/1.73 m2
- •Female patients of reproductive potential are eligible if they have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use 1 highly effective birth control method during the study and for at least 30 days after study drug administration. Highly effective birth control methods include hormonal and non-hormonal intrauterine device, combination estrogen-progesterone hormonal contraception (oral, transdermal, or vaginal), tubal ligation, a vasectomized or sterile male partner, or sexual abstinence (defined as refraining from heterosexual intercourse), from Screening, throughout the study and for at least 30 days after study drug administration.
排除标准
- •Patients with cirrhosis and other etiologies of chronic liver disease
- •PEth value of ≥20 ng/mL measured at Screening OR history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening.
- •Thyroid disease:
- •Active hyperthyroidism
- •Untreated clinical hypothyroidism defined by TSH >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms
- •History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study
- •Weight gain or loss >5% total body weight within 12 weeks prior to randomization
- •HbA1c >9.0%
- •Diagnosis of HCC
- •MELD score ≥12, as determined at Screening, due to liver disease
- •Hepatic decompensation or impairment.
- •Has an active autoimmune disease, including actively treated lupus, rheumatoid arthritis, inflammatory bowel disease, or autoimmune hepatitis, requiring systemic treatment within the past 12 weeks or a documented history of clinically severe autoimmune disease, including autoimmune liver disease, or a syndrome that requires systemic steroids or immunosuppressive agents
- •Serum ALT >250 U/L
- •Platelet count <140,000/mm
- •Patients with platelets <140,000 and ≥120,000/mm3 are eligible if FIB-4 score <3.
- •History of biliary diversion
- •Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure >170 mmHg or a diastolic blood pressure >100 mmHg at Screening
- •Confirmed QTcF >450 msec for males and >470 msec for females at the Screening ECG assessment;
- •Presence of sustained atrial fibrillation at time of Screening or history of paroxysmal atrial fibrillation episodes for the last 3 months prior to Screening
研究组 & 干预措施
Arm 2 - Placebo Comparator
Participants will receive matching placebo orally once daily for 24 weeks.
干预措施: Placebo (Drug)
Arm 1 - Resmetirom
Participants will receive resmetirom orally once daily for 24 weeks. Resmetirom dose will be based on actual body weight: 80 mg once daily for participants weighing <100 kg and 100 mg once daily for participants weighing ≥100 kg. Dose reduction by 20 mg will be implemented for concomitant use of a moderate CYP2C8 inhibitor, as specified in the protocol
干预措施: Resmetirom (Drug)
结局指标
主要结局
Incidence of treatment-emergent adverse events (TEAEs)
时间窗: From first dose through End of Study follow-up (28 days after last dose)
Incidence of treatment-emergent serious adverse events (SAES)
时间窗: From first dose through End of Study follow-up (28 days after last dose)
Change from baseline in physical examination findings assessed by investigator physical examination
时间窗: Baseline to Week 24
Physical examination findings will be assessed by the Investigator and include general appearance, skin, head and neck, heart, lungs, abdomen, extremities, and neuromuscular assessments. After Screening and successful Randomization, physical examinations may be targeted to evaluation of new symptoms or signs.
Change from baseline in body temperature
时间窗: Baseline to Week 24
Body temperature will be measure in °C, resting heart rate in beats per minute, respiratory rate in breaths per minute, systolic blood pressure in mmHg, and diastolic blood pressure in mmHg
Change from baseline resting heart rate
时间窗: Baseline to Week 24
Resting heart rate will be measured in beats per minute (bpm)
Change from baseline in respiratory rate
时间窗: Baseline to Week 24
Respiratory rate will be measured in breaths per minute.
Change from baseline in seated systolic blood pressure
时间窗: Baseline to Week 24
Resting seated systolic blood pressure will be measured in millimeters of mercury (mmHg)
Change from baseline in seated diastolic blood pressure
时间窗: Baseline to Week 24
Resting seated diastolic blood pressure will be measured in millimeters of mercury (mmHg)
Change from baseline in PR interval on 12-lead ECG in milliseconds (ms)
时间窗: Baseline to Week 24
Change from baseline in QRS interval on 12-lead ECG in milliseconds (ms)
时间窗: Baseline to Week 24
Change from baseline in heart rate on 12-lead ECG in beats per minute (bpm)
时间窗: Baseline to Week 24
Change from baseline in RR interval on 12-lead ECG in milliseconds (ms)
时间窗: Baseline to Week 24
Change from baseline in QT interval on 12-lead ECG in milliseconds (ms)
时间窗: Baseline to Week 24
Change from baseline in QT interval corrected using Bazett's formula (QTcB) in milliseconds (ms)
时间窗: Baseline to Week 24
Change from baseline in QT interval corrected using Fridericia's formula (QTcF) in milliseconds (ms)
时间窗: Baseline to Week 24
Number of participants with clinically significant abnormalities in hematology laboratory parameters
时间窗: Baseline to Week 24
Hematology laboratory parameters include hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, red blood cell indices, and differential leukocyte counts. The number of participants with clinically significant abnormalities, as determined by the Investigator, will be summarized by treatment group.
Number of participants with clinically significant abnormalities in blood chemistry laboratory parameters
时间窗: Baseline to Week 24
Blood chemistry laboratory parameters include measures of hepatic function, renal function, glucose metabolism, pancreatic function, electrolytes, bilirubin, and serum proteins. The number of participants with clinically significant abnormalities, as determined by the Investigator, will be summarized by treatment group.
Number of participants with clinically significant abnormalities in urinalysis parameters
时间窗: Baseline to Week 24
Urinalysis parameters include pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, and leukocyte esterase. The number of participants with clinically significant abnormalities, as determined by the Investigator, will be summarized by treatment group.
Percent change from baseline in liver fat content measured by MRI-Proton Density Fat Fraction (MRI-PDFF)
时间窗: Baseline to Week 24
次要结局
未报告次要终点