A Randomized, Single-blind Trial to Evaluate the Safety and Efficacy of Apraglutide in Subjects With Grade II to IV (MAGIC) Steroid Refractory Gastrointestinal (GI) Acute Graft Versus Host Disease on Best Available Therapy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- VectivBio AG
- 入组人数
- 31
- 试验地点
- 13
- 主要终点
- Number of Participants With Adverse Events (AEs)
研究概览
简要总结
The aim of this trial is to assess safety and efficacy of apraglutide in subjects with steroid refractory gastrointestinal aGVHD.
详细描述
This is an international, multicenter, randomized proof-of-concept trial to evaluate safety, tolerability, efficacy, durability of response, and clinical outcomes of apraglutide administration to subjects with steroid-refractory (SR) aGVHD of the lower GI tract being treated with systemic steroids (SS) and ruxolitinib (RUX).
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
- Single (Participant)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to give informed consent and agree to follow the details of participation as outlined in the protocol
- •Male or female subjects aged 12 years or above at the time of consent and who weigh a minimum of 40 kg. Only subjects aged 18 years and above will be included in Germany.
- •Clinically confirmed steroid refractory lower GI-aGVHD (MAGIC stage 1-4) prior to randomization
- •Have undergone alloSCT from any donor source, any conditioning regimen
- •Treated with SS plus RUX (RUX starts concomitantly to apraglutide or a maximum of 72 hours before apraglutide initiation)
- •Women of childbearing potential (WOCBP): highly effective method of contraception and refrain from donating eggs during the trial and for 4 weeks after the End of Trial (EOT) visit
- •Male subjects with partner WOCBP: contraception and abstention from sperm donation during the trial and for 2 weeks after the EOT visit
排除标准
- •Treatment with any systemic GVHD therapy other than SS and RUX including methotrexate and mycophenolate mofetil at the time of randomization / Day 0
- •Concomitant treatment with Janus kinase inhibitor other than RUX at the time of randomization
- •Failed alloSCT due to relapse of underlying malignant disease
- •Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-emptive treatment of malignancy recurrence
- •Any use of enteral glutamine or GLP analogs or known ADA, within 6 months prior to randomization / Day 0
- •Significant organ system failures (respiratory renal hepatic and cardiac)
- •Presence of relapsed primary malignancy or treatment for relapse after alloHSCT
- •Presence or history of GI tumors (including the hepatobiliary system and pancreas) within the last five years before randomization
- •Presence of colonic polyps not removed
- •Active clinically uncontrolled infection or active tuberculosis
- •Known chronic GVHD
- •Known active GI inflammation not related to GI-aGVHD
- •Major abdominal surgery in the last 6-months prior to randomization or history of clinically significant intestinal adhesions
- •Abnormal liver function tests
研究组 & 干预措施
Apraglutide Low Dose
Low-dose, weight-based apraglutide subcutaneous (SC) injections (1.4 to 3.5 mg) once weekly for up to 13 weeks (with optional treatment up to an additional 13 weeks), for participants with body weight of more than 50.0 kg.
干预措施: Apraglutide (Drug)
Apraglutide High Dose
High-dose, weight-based apraglutide SC injections (3.5 to 7.6 mg) once weekly for up to 13 weeks (with optional treatment up to an additional 13 weeks), for participants with body weight of more than 50.0 kg.
干预措施: Apraglutide (Drug)
Apraglutide Standard Dose
Standard-dose apraglutide SC injections (1.4 mg) once weekly for up to 13 weeks (with optional treatment up to an additional 13 weeks), for participants with body weight between 40.0 kg to 49.9 kg.
干预措施: Apraglutide (Drug)
结局指标
主要结局
Number of Participants With Adverse Events (AEs)
时间窗: Screening (up to 12 weeks) through End of Trial (up to 2 years/104 weeks) for a total of up to 116 weeks
AE=any untoward medical occurrence which does not necessarily have a causal relationship with study drug. Serious AE (SAE)=any AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother or father exposed to study drug; is a clinically significant event in the Investigator's judgment. Treatment-emergent AE (TEAE)=AE with a start on or after the first administration of apraglutide (or present prior to the first dose of apraglutide but worsening in severity after starting treatment relative to the pre-treatment state) up to 28 days after the last dose of apraglutide. Pre-treatment AE=occurs after informed consent and before first dose; post-treatment AE=occurs after 28 days from last dose. AE are graded as follows: mild (1), moderate (2), severe (3), life-threatening (4), death (5).
Number of Participants With Treatment-Emergent Adverse Events of Special Interest (AESIs)
时间窗: From first dose of study drug through End of Trial (up to 2 years/104 weeks) for a total of up to 116 weeks
An AESI (serious or non-serious) is an AE of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring, additional information, and rapid communication by the Investigator to the Sponsor is appropriate. AESIs include: * Injection site reactions * Gastrointestinal obstructions * Gallbladder, biliary, and pancreatic disease * Fluid overload * Colorectal polyps * Newly diagnosed malignancies * Systemic hypersensitivity
Number of Participants With Clinically Significant Changes From Baseline Over Time in Vital Signs
时间窗: Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial
Systolic Blood Pressure: * High is defined as \>= 160 mmHg AND \>=20 mmHg increase from baseline * Low is defined as \<= 90 mmHg AND \>=20 mmHg decrease from baseline Diastolic Blood Pressure: * High is defined as \>= 100 mmHg AND \>=15 mmHg increase from baseline * Low is defined as \<= 50 mmHg AND \>=15 mmHg decrease from baseline Heart Rate: * High is defined as \>= 120 bpm AND \>= 15 bpm increase from baseline * Low is defined as \<= 50 bpm AND \>= 15 bpm decrease from baseline Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Potentially Clinically Significant Values Over Time in Liver Function Tests: Potential Hy's Law Cases
时间窗: Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial
Potential Hy's Law cases were defined as ALT or AST \>= 3 x ULN AND total bilirubin \>= 2 x ULN AND alkaline phosphatase (ALP) \<= 2 x ULN at the same visit. Baseline is defined as the last measurement prior to the first dose of apraglutide.
Number of Participants With Clinically Significant Changes From Baseline Over Time in QT Corrected for Heart Rate Using Fridericia's Formula (QTcF)
时间窗: Baseline, Weeks 26, 52, 104/End of Trial
Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Potentially Clinically Significant Values Over Time in Liver Function Tests: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
时间窗: Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial
Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Potentially Clinically Significant Values Over Time in Liver Function Tests: Total Bilirubin
时间窗: Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial
Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Anti-drug Antibodies (ADAs) Over Time
时间窗: Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial
Shift Table From Baseline to Worst Post-Treatment (WPT) Physical Examinations
时间窗: Baseline (BL), up to Week 104/End of Treatment
次要结局
- Overall Response Rate at Day 56 on the Lower Gastrointestinal (GI) Tract Mount Sinai aGVHD International Consortium (MAGIC) Stage(Day 56)
- Overall Response Rate Over Time on the Lower GI Tract MAGIC Stage(Days 14, 28, 56, 91, 119, 147, and 182)
- Overall Response Rate Over Time on the Total MAGIC Stage(Days 14, 28, 56, 91, 119, 147, and 182)
- Durable Overall Response Rates on the Lower GI and Total MAGIC Score From Day 28 to Day 56(Day 28 to Day 56)
- Duration of Response From Day 56 on the Total MAGIC Score(From Day 56 up to 2 years of follow up after the first dose)
- Duration of Response From Day 28 on the Total MAGIC Score(From Day 28 up to 2 years of follow up after the first dose)
- Duration of Lower GI Response Per MAGIC Score(Up to Day 147)
- Duration of Lower GI Response Per MAGIC Score In Retreated Participants(Up to Day 147)
- Time to Partial or Complete Lower GI Response (PR or CR) Per MAGIC Score(From first injection of apraglutide up to Day 57)
- Best Overall Lower GI Response and Total Response at Any Time Point Up to and Including Day 91(From first injection of apraglutide up to Day 91)
- Failure-Free Survival Post-First Dose of Apraglutide(Baseline up to 2 years)
- Time to Non-Relapse Mortality up to 2 Years Post Treatment Start(From first dose of apraglutide up to 2 years)
- Overall Survival(Baseline up to 2 years post-first dose of apraglutide)
- Percentage of Participants With Hematologic Malignancy Relapse/Progression(Baseline to 2 years)
- Percentage of Participants With Graft Failure Up to 2 Years Post-first Dose of Apraglutide(From first dose of apraglutide up to 2 years post-first dose)
- Percentage of Participants Who Experienced Lower-GI Flare by Day 182 After Earlier Cessation of Treatment Due to CR(From first apraglutide dose up to Day 182)
- Cumulative Ruxolitinib (RUX) and Systemic Steroid (SS) Doses From Start of the RUX Treatment up to Day 91 After the First Dose of Apraglutide(From start of the RUX treatment up to Day 91 after the first dose of apraglutide)
- Number of Participants With Treatment-Emergent Infections and Sepsis(From baseline to Day 91 and overall (up to 2 years after the first dose of apraglutide))