A Phase 1b/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Participants With LGMD2I
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events
研究概览
简要总结
The investigational product PF 06252616, a humanized anti myostatin monoclonal antibody that neutralizes myostatin (GDF8) is in development for the treatment of Limb Girdle Muscular Dystrophy 2I (LGMD2I) to preserve and/or improve muscle function.
This study will provide the clinical assessment of the safety, tolerability, Pharmacokinetics and Pharmacodynamics of PF 06252616 following repeat IV doses in ambulatory adults with LGMD2I.
详细描述
This study is a Phase 1b/2, open-label multiple ascending dose escalation study to evaluate the safety, tolerability, efficacy, PK and PD of PF 06252616 in ambulatory adults with LGMD2I. The study design is intended to determine the optimal safe and pharmacologically active dose of PF 06252616 in LGMD2I while providing an opportunity for all subjects to receive active drug for a rare and disabling disorder. The study will be conducted in three periods: Lead-In, Treatment and Follow-up periods. The Lead-In and Follow-up periods will each be 16 weeks to allow an assessment of the change of various outcome measures of this period of time and comparison of change in function before, during and after treatment. The Treatment period will be 32 weeks. Three cohorts of participants will be enrolled and receive escalating doses of PF 06252616. The first cohort will have the option to crossover to the highest dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients age ≥ 18
- •Diagnosis of LGMD2I as defined by clinical presentation consistent with LGMD2I and FKRP gene testing showing biallelic alterations known or likely to be pathogenic. Diagnosis must be confirmed in subject's medical history and by genetic testing obtained during routine clinical care for diagnostic purposes as reported from an appropriate regulated laboratory using a clinically validated genetic test (genetic testing is not provided by the sponsor).
- •Ability to walk/run 10m
- •Ability to rise from chair
- •Adequate hepatic and renal function on screening laboratory assessments
- •Iron content estimate on the screening liver MRI within the normal range as determined by R2* value (R2* ≤ 139 Hz at 3.0T).
- •Participant must provide written informed consent for participating in study.
- •Participant must possess the ability, per the Principal Investigator (PI), to understand and comply with protocol instruction for the entire duration of the study.
排除标准
- •Known cognitive impairment or behavioral issues that would impede the ability to provide informed consent or to follow study instructions.
- •History of major surgical procedure within 6 weeks of signing the informed consent or planned surgery during the study.
- •Any injury which may impact functional testing. Previous injuries must be fully healed prior to consent. Prior lower limb fractures must be fully healed and at least 3 months from injury dates.
- •Previous treatment with another investigational product within 30 days or 5 half-lives, (whichever is longer) prior to consenting.
- •Corticosteroid treatment within 3 months prior to consenting.
- •Compromised cardiac function (left ventricular ejection fraction <50%).
- •Unwilling or unable (e.g. metal implants, requires sedation) to undergo examination with closed MRI without sedation.
- •History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein.
- •Female subjects who are pregnant or nursing.
- •Subjects who, are biologically capable of having children who are unwilling or unable to use highly effective methods of contraception (as outlined in this protocol) during sexual activity for the duration of the study and through completion of final study visit.
- •Predisposition to iron accumulation. (Serum iron >1.2 X ULN, serum ferritin >1.2 ULNN).
- •Underlying disposition for bleeding disorder on screening laboratory assessment (PT/INR>1.25 X ULN, aPTT > 1.25 ULN, fecal occult blood is positive)
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurologic, or allergic disease.
- •Unwillingness or inability to comply with the requirements of this protocol (in the opinion of the PI) including, but not limited to, the presence of any condition (physical, mental, or social) that is likely to affect the participant's ability to return for study visits or adhere to the visit schedule.
研究组 & 干预措施
Low Dose, Cohort 1
4 subjects will be enrolled in cohort 1 and will receive an initial dose of 5mg/kg PF 06252616 IV every 4 weeks. Following 32 weeks of treatment and a safety review, if no stopping rules have been met, subjects will be receive an additional 32 weeks of treatment with 40 mg/kg PF 06252616 IV every 4 weeks.
干预措施: PF 06252616 (Drug)
Middle dose, Cohort 2
8 subjects will be enrolled in cohort 2 and receive 20 mg/kg of PF 06252616 IV every 4 weeks for 32 weeks.
干预措施: PF 06252616 (Drug)
High dose, Cohort 3
8 subjects will be enrolled in cohort 3 and receive 40 mg/kg of PF06252616 IV every 4 weeks for 32 weeks.
干预措施: PF 06252616 (Drug)
结局指标
主要结局
Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events
时间窗: Baseline through 64 weeks
Adverse events include subject-reported symptoms as well as clinically-significant changes in laboratory testing, vital signs, and suicide screening (based on the Columbia Suicide Severity Rating Scale).
次要结局
- Maximum Observed Serum Concentration at Steady State (Cmax, ss) of GDF-8(Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3)
- Mean Change From Baseline of Forced Vital Capacity in Liters(Baseline through 32 weeks)
- Minimum Observed Serum Trough Concentration at Steady State (Ctrough,ss) of GDF-8(Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3)
- Maximum Observed Serum Concentration (Cmax) of PF-06252616(Day 113 and Day 169)
- Minimum Observed Serum Trough Concentration (Ctrough) of PF-06252616(Day 113 and Day 169)
- Mean Change From Baseline in 2MWD in Meters(Baseline through 32 weeks)
- Mean Change From Baseline in TUG in Seconds(Baseline through 32 weeks)
- Immunogenicity: Incidence of Anti-drug Antibody(Baseline through 96 weeks)
- Mean Change From Baseline in 10 Meter Walk/Run Time in Seconds(Baseline through 32 weeks)
- Mean Change From Baseline in Muscle Strength as Measured by Modified MRC Scale(Baseline through 32 weeks)
研究者
Kathryn Wagner
Director, Center for Genetic Muscle Disorders
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.