A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients With Hereditary Angioedema
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 8
- 主要终点
- Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17
研究概览
简要总结
The purpose of this study was to evaluate the clinical efficacy, safety, and tolerability of donidalorsen in participants with hereditary angioedema (HAE) type 1 (HAE-1), HAE type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH) and to evaluate the effect of donidalorsen on plasma prekallikrein (PKK) and other relevant biomarkers.
详细描述
This was a randomized, double-blind, placebo-controlled study in 23 participants conducted concurrently in 2 parts (Part A and Part B); participants were allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or HAE-nC1-INH in Part B). Part A was randomized, double-blind, and placebo-controlled; and Part B was open-label. The length of participation in the study was approximately 8 months, which included an up to 8-week screening period, a 12-week treatment period, and a 13-week post-treatment period.
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
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Part A was randomized, double-blind; Part B was open-label.
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
- •Documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or HAE-nC1-INH (for inclusion in Part B)
- •Participants must have experienced a minimum of 2 HAE attacks (assessed by the Angioedema Activity Score [AAS] and confirmed by the investigator) during the screening period
- •Access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks
排除标准
- •Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the screening or study periods
- •Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema
- •Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
- •Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
- •Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of screening
- •Exposure to any of the following medications:
- •Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to screening
- •Chronic prophylaxis with Lanadelumab within 10 weeks prior to screening
- •Oligonucleotides (including small interfering ribonucleic acid [RNA]) within 4 months of screening (if single dose received) or within 12 months of screening (if multiple doses received)
研究组 & 干预措施
Part A: Placebo
Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.
干预措施: Placebo (Drug)
Part A: Donidalorsen 80 mg
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
干预措施: Donidalorsen (Drug)
Part B: Donidalorsen 80 mg
Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
干预措施: Donidalorsen (Drug)
结局指标
主要结局
Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17
时间窗: Week 1 to Week 17
The Week 1 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks occurring from Week 1 to 28 days after the last dose date divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).
次要结局
- Prekallikrein (PKK) Activity Levels at Weeks 9 and 17(Weeks 9 and 17)
- Number of Participants Who Consumed On-demand Medication at Weeks 9 and 17(Weeks 9 and 17)
- Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17(Week 5 to Week 17)
- Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17(Week 5 to Week 17)
- Number of Participants With Clinical Response by Week 17(Week 5 to Week 17)
- Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17(Week 5 to Week 17)
- Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17(Weeks 9 and 17)
- Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17(Baseline, Weeks 9 and 17)