Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 145
- 试验地点
- 14
- 主要终点
- Change From Baseline Epistaxis Severity Score
研究概览
简要总结
This is a Phase II placebo-controlled double-blind study of pomalidomide in patients with hereditary hemorrhagic telangiectasia (HHT) with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks. Mean change from baseline to 24 weeks in the Epistaxis Severity Score (ESS) will be compared between treatment groups to determine pomalidomide efficacy.
详细描述
HHT is associated with substantial morbidity, leading to a reduced quality of life, decreased rate of employment and a high incidence of depression. There currently exists no medical therapy recognized as consistently efficacious in HHT. Reports of the efficacy of thalidomide in HHT, as well as interim results of a pilot trial of pomalidomide in HHT provide evidence of efficacy with minimal toxicity. The favorable efficacy:toxicity ratio of pomalidomide suggest that it may benefit patients with HHT.
This study is designed as a Phase II placebo-controlled double-blind study of pomalidomide in HHT patients with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks.
Primary Objective: To determine efficacy of pomalidomide compared to placebo for the reduction in severity of epistaxis after 24 weeks of treatment.
Secondary Objectives: To determine the safety and tolerability of pomalidomide for the treatment of HHT; to determine if pomalidomide treatment improves quality of life in HHT; to determine whether a continued response to pomalidomide is evident 4 weeks after treatment discontinuation; to develop a biorepository for future studies to define biomarkers predictive of pomalidomide response and allow investigations into the biology of HHT and mechanisms of pomalidomide.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •A clinical diagnosis of HHT as defined by the Curacao criteria
- •Age ≥ 18 years
- •Platelet count ≥ 100,000/µl
- •White Blood Count (WBC) ≥ 2,500/µl
- •International Normalized Ratio (INR) ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or partial thromboplastin time (PTT) per local laboratory designation) by local laboratory criteria (except for patients on a stable dose of warfarin or direct oral anticoagulants)
- •Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the screening visit
- •A requirement for anemia, as determined by local laboratory hemoglobin assessment and normal ranges, and/or parenteral infusion of at least 250 mg of iron or transfusion of 1 unit of blood over the 24 weeks preceding the screening visit
- •All study participants must agree to be registered into the FDA mandated POMALYST Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program
- •Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the POMALYST REMS program. FCBP must have a negative pregnancy test with a sensitivity of at least 50 milli-international units per milliliter (mIU/mL) within 10 - 14 days prior to and again within 24 hours prior to prescribing pomalidomide and must either commit to continued abstinence from heterosexual intercourse or use two (2) acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking pomalidomide, during therapy and for at least 4 weeks following discontinuation of therapy. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy.
- •Ability to understand and sign informed consent
排除标准
- •Women currently breast feeding
- •Renal insufficiency, serum creatinine > 2.0 mg/dl
- •Hepatic insufficiency, bilirubin > 2.0 (or >4.0 in the setting of a prior clinical or genetic diagnosis of Gilbert's syndrome) or transaminases > 3.0x normal
- •Prior treatment with thalidomide or other Immunomodulatory imide drugs within previous 6 months
- •Prior treatment with bevacizumab (systemic or nasal) within previous 6 weeks*
- •Prior treatment with pazopanib within previous 6 weeks*
- •The use of octreotide or oral estrogens within the previous month*
- •History of prior unprovoked thromboembolism confirmed by venous ultrasound or other imaging modalities
- •Peripheral neuropathy, confirmed by neurologic consultation
- •Known underlying hypoproliferative anemia (i.e. myelodysplasia, aplastic anemia)
- •Currently enrolled in other interventional trials
- •Known hypersensitivity to thalidomide or lenalidomide.
- •The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
- •Known SMAD Family Member 4 (SMAD-4) mutation, unless there has been a colonoscopy with normal (negative) results, or in which the patient has had no more than 5 small (in the opinion of the gastroenterologist) colonic polyps completely removed within the preceding 18 months
- •Anything that in the investigator's opinion is likely to interfere with completion of the study
- •* Use of these treatments is not permitted during study participation.
研究组 & 干预措施
Pomalidomide
Oral Pomalidomide will be provided as a capsule at 4 mg/day dose. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.
干预措施: Pomalidomide Oral Product (Drug)
Placebo
A placebo matching the study drug will be provided as a capsule. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.
干预措施: Placebo oral capsule (Drug)
结局指标
主要结局
Change From Baseline Epistaxis Severity Score
时间窗: 4, 8, 12, 16, 20, and 24 Weeks and 4 weeks post treatment
The primary outcome measure is the change from baseline in Epistaxis Severity Score (ESS) after 6 months of treatment administration to compare the outcomes of Pomalidomide versus Placebo. The ESS ranges from 0-10 with higher scores indicating worse condition in the prior 4 weeks. The minimal important difference is 0.71
次要结局
- Average Total Daily Duration of Nosebleeds - Change From Baseline(After 12 and 24 weeks of treatment, and 4 weeks post-treatment)
- Weighted Average Total Daily Duration of Nosebleeds - Change From Baseline(After 12 and 24 weeks of treatment, and 4 weeks post-treatment)
- Total Iron Infused(12 through 24 Weeks)
- Patients With Any Packed Red Blood Cells Transfusion Through 24 Weeks(Baseline through 24 Weeks)
- Patients With Any Packed Red Blood Cells Transfusion Through 12 Weeks(Baseline through 12 Weeks)
- Patients With Any Packed Red Blood Cells Transfusion 12-24 Weeks(12 through 24 Weeks)
- Neuro-QoL - Satisfaction With Social Roles and Activities - T Score(Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment)
- Patient Reported Outcomes Measurement Information System (PROMIS) - Emotional Distress - Depression - T Score(Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment)
- PROMIS - Fatigue - T Score(Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment)
- HHT-Specific QOL Questionnaire - Score(Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment)
研究者
Keith McCrae
Director, Benign Hematology
The Cleveland Clinic