A Phase 1, First-in-Human, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Intravenous and Subcutaneous Administration of MER511 in Adults With Graves' Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 17
- 主要终点
- Number of participants with TEAEs (Treatment-emergent adverse events)
研究概览
简要总结
The purpose of this study is to evaluate how well MER511 is tolerated and what side effects may occur in adults who have Graves' disease. The study drug will be administered either intravenously (into a vein in the arm) or subcutaneously (under the skin).
Blood tests will be performed to investigate how the body processes the study drug and how the study drug affects the body.
详细描述
This Phase 1, first-in-human, multicenter study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of single and multiple ascending doses of MER511 administered to adults (18 to 65 years of age, inclusive) with GD (Graves' disease).
The study will consist of 2 sequential parts: a single ascending dose (SAD) part (Part A) followed by a multiple ascending dose (MAD) part (Part B).
Part A will employ a placebo-controlled, sponsor-open, participant- and investigator-blind design to evaluate the safety, tolerability, PK, PD, and immunogenicity of single ascending intravenous doses and a single subcutaneous dose of MER511.
Part B will employ a placebo-controlled, sponsor-open, participant- and investigator-blind design to assess the safety, tolerability, PK, PD, and immunogenicity of multiple subcutaneous doses of MER511.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Sponsor-open label, participant- and investigator-blind (Masked)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults 18 to 65 years of age, inclusive, at the time of signing the ICF
- •Documented GD diagnosis,
- •Receiving stable dose of ATD (Antithyroid drug)
- •Body weight at least 50 kg (110 lb) and body mass index (BMI) 18.0-35.0 kg/m2, inclusive
- •Women of childbearing potential must agree to use highly effective contraceptive methods
- •Men with partners of childbearing potential or who are pregnant must agree to use a condom or strict abstinence
- •Signed informed consent to participate in the study
- •Willingness and ability, in the opinion of the investigator, to comply with protocol requirements and restrictions (eg, dosing, schedule of assessments).
排除标准
- •History of:
- •total thyroidectomy.
- •History of hyperthyroidism not caused by GD (eg, toxic adenoma, toxic multinodular goiter).
- •History of thyroid storm.
- •History of agranulocytosis, anemia, leukopenia, thrombocytopenia, vasculitis, or liver toxicity due to prior ATD therapy Treatment with RAI therapy within 12 months prior to Screening
- •Likely to require definitive treatment for GD (RAI therapy or thyroidectomy) during the study, based on GD history and anticipated prognosis.
- •Use of levothyroxine, desiccated thyroid extract, or T3 at any dose within 6 weeks prior to Screening.
- •Current active or chronic moderate-to-severe TED per EUropean Group On Graves' Orbitopathy (EUGOGO) criteria as judged by the investigator at Screening
- •History of TED-directed medical treatment (including IV/oral steroids, immunosuppressants, or teprotumumab), surgical treatment, and/or orbital radiation within 3 months prior to Screening, or per required prohibited concomitant therapy washout criteria in the protocol (whichever is longer)
- •Major surgery or use of iodinated contrast within 3 months prior to planned IMP dosing.
- •Active systemic autoimmune disease requiring treatment that causes undue risk in the opinion of the investigator.
- •History of cardiovascular, respiratory, renal, gastrointestinal, endocrinological (other than GD), hematological, immunodeficiency, or neurological disorders that may constitute a risk when taking the IMP or interfere with data interpretation.
- •History of liver disease
- •Pregnant, breastfeeding, or planning to become pregnant during the study
- •Treatment with prohibited medications prior to planned IMP dosing or likely to require prohibited concomitant therapy during the study
- •Live vaccine(s) or mRNA vaccine(s) within 1 month prior to IMP dosing, or plans to receive such vaccines during the study
- •Treatment with any investigational drug within within 3 months or 5 half-lives (whichever is longer) prior to enrollment
- •Total IgG level <700 mg/dL at Screening
- •Any of the following at Screening (confirmed by single repeat measurement, if deemed necessary):
- •ALT or AST >1.5 × ULN
- •Total bilirubin >1.5 × ULN
- •Estimated glomerular filtration rate (eGFR) <75 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation
- •Positive result for HIV antibody, HBsAg, or hepatitis C antibody with detectable viral RNA levels at Screening
- •Positive drug screen or positive test for alcohol
- •12-lead ECG demonstrating any of the following at Screening:
- •QTcF interval >450 ms
- •QRS interval >120 ms
- •PR interval >220 ms
- •Blood pressure measurements demonstrating any of the following at Screening:
- •Systolic blood pressure ≥140 mmHg
- •Diastolic blood pressure ≥90 mmHg
- •Heart rate <45 bpm or >100 bpm
- •Donated more than 500 mL of blood in the 2 months prior to signing the ICF
- •Current enrollment or past participation within 3 months or 5 half-lives (whichever is longer) prior to signing the ICF in any other clinical trial involving an IMP
- •Refusal to adhere to lifestyle considerations as defined in the protocol
- •Employee of the investigator, clinic, or sponsor with direct involvement in the proposed study or other studies under the direction of the investigator or clinic, as well as family members of the employee or investigator
- •Any other conditions that, in the opinion of the investigator or the sponsor, could interfere with participation in or completion of the study
研究组 & 干预措施
Part A (SAD) MER511 IV
For Cohorts 1-7 , each cohort participant will receive a single ascending dose of MER511 via IV administration on Day 1
干预措施: MER511 (IV) (Biological)
Part A (SAD) placebo IV
For Cohorts 1-7, each cohort participant will receive a single dose of placebo via IV administration on Day 1
干预措施: Placebo comparator (IV) (Biological)
Part A (SAD) placebo SC
For Cohort 8, participants will receive a single dose of placebo (determined from Cohort 1-7) via SC administration on Day 1
干预措施: Placebo comparator (SC) (Biological)
Part A (SAD) MER511 SC
For Cohort 8, participants will receive a single dose of MER511 (determined from Cohort 1-7) via SC administration on Day 1
干预措施: MER511 (SC) (Biological)
Part B (MAD) MER511 SC
Up to 3 cohorts of participants will receive multiple ascending doses of MER511 via SC administration assigned for their cohort on Day 1 and Day 29
干预措施: MER511 (SC) for MAD (Biological)
- Part B (MAD) placebo SC
Up to 3 cohorts of participants will receive multiple doses of placebo via SC administration assigned for their cohort on Day 1 and Day 29
干预措施: Placebo comparator (SC) for MAD (Biological)
结局指标
主要结局
Number of participants with TEAEs (Treatment-emergent adverse events)
时间窗: - Part A (SAD) Cohorts: Day 1 up to Week 16 - Part B (MAD) Cohorts: Day 1 up to Week 24
Adverse events that start or worsen in severity after the start of study drug will be categorized as TEAEs
Number of participants with clinically significant changes in ECGs, vital signs, clinical laboratory values, and physical examination
时间窗: - Part A (SAD) Cohorts: Day 1 up to Week 16 - Part B (MAD) Cohorts: Day 1 up to Week 24
Incidence of clinically significant abnormalities in ECGs, vital signs, clinical laboratory values, and physical examination
次要结局
- Serum tmax (Time to maximum concentration)(- Part A (SAD) Cohorts: Day 1 (Week 0 dosing day) Through Week 16 - Part B (MAD) Cohorts: Day 1 (Week 0 dosing day) Through Week 24)
- Serum AUCinf (area under concentration-time curve from time zero to infinity)(Part A (SAD) Only: Day 1 (Week 0) Dosing Through Week 16)
- Serum AUC0-tau (area under concentration-time curve during the dosing interval)(Part B (MAD) Only: Day 1 (Week 0) Dosing Through Week 24)
- Number of participants with ADAs (Anti-drug antibody)(- Part A (SAD) Cohorts: Day 1 (Week 0) Dosing Through Week 16 or Early Discontinuation - Part B (MAD) Cohorts: Day 1 (Week 0) Dosing Through Week 24)
- Serum Cmax (Maximum observed concentration)(- Part A (SAD) Cohorts: Day 1 (Week 0 dosing day) through Week 16- Part B (MAD) Cohorts: Day 1 (Week 0 dosing Day) Through Week 24)
- Serum tmax (Time to maximum concentration)(- Part A (SAD) Cohorts: Day 1 (Week 0 dosing day) Through Week 16 - Part B (MAD) Cohorts: Day 1 (Week 0 dosing day) Through Week 24)
- Serum AUCinf (area under concentration-time curve from time zero to infinity)(Part A (SAD) Only: Day 1 (Week 0) Dosing Through Week 16)
- Serum AUC0-tau (area under concentration-time curve during the dosing interval)(Part B (MAD) Only: Day 1 (Week 0) Dosing Through Week 24)
- Number of participants with ADAs (Anti-drug antibody)(- Part A (SAD) Cohorts: Day 1 (Week 0) Dosing Through Week 16 or Early Discontinuation - Part B (MAD) Cohorts: Day 1 (Week 0) Dosing Through Week 24)