Oral Deucrictibant for the Prophylactic and Acute Treatment in Patients With Bradykinin Mediated Angioedema With Normal C1 Inhibitor (BK-AE-nC1INH)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Part-2: Efficacy of active on-demand treatment versus placebo in achieving angioedema symptom relief during acute attacks
研究概览
简要总结
To assess the efficacy of prophylactic treatment with deucrictibant extended release (XR) tablet versus placebo in preventing angioedema attacks, and to also assess the efficacy of deucrictibant soft capsules as on-demand treatment versus placebo in achieving angioedema symptom relief during acute attacks.
详细描述
Study Design:
The study has 2-parts, studying the efficacy of deucrictibant versus placebo for prophylactic and on-demand treatment of angioedema attacks will be assessed in adult participants with BK-AE-nC1INH. Each part of the study is designed a randomized, double-blind, placebo-controlled cross-over trial. Up to 10 patients to be enrolled.
Deucrictibant has been adopted as the international nonproprietary name (INN) for the active ingredient, previously referred to as PHA121 or PHA-022121. Deucrictibant is under development as an orally administered bradykinin B2 receptor antagonist with potential for both acute therapeutic and prophylactic use in patients with different types of BK-mediated angioedema, including HAE-1/2, HAE with normal C1INH, acquired angioedema due to C1INH deficiency, and non-hereditary BK-mediated angioedema with normal C1INH.
Throughout the study (Parts 1 and 2), a diary will be used to record all symptoms and details of angioedema attacks, including on-demand treatments, as well as Patient Reported Outcomes (PROs). Participants need to have access to FDA approved on-demand angioedema medication and be able to treat any angioedema attack that may occur using standard of care on-demand therapies. In addition to the collected data on angioedema attacks, the diary will be used as a dosing diary for the daily intake of study drug treatment in Part 1.
Part 1 will evaluate the efficacy and safety of deucrictibant administered orally for prophylaxis against angioedema attacks in patients with BK-AE-nC1INH. After providing written informed consent, participants will be screened for eligibility. Eligible participants will be enrolled in the study. Participants receiving angioedema medications for long-term prophylaxis (LTP) will discontinue and washout these medications prior to Screening.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of written informed consent.
- •Male or female, aged ≥18 at the time of provision of informed consent.
- •Diagnosis of bradykinin-mediated angioedema based upon all of the following:
- •Clinical history consistent with angioedema (subcutaneous or mucosal, nonpruritic swelling without accompanying urticaria), not responsive to treatments of anti-histamine, corticosteroid, and/or omalizumab.
- •Tried and failed at least 2 weeks of cetirizine 20 mg twice a day (or its equivalent alternative antihistamines, such as fexofenadine, loratadine, desloratadine or levocetirizine, etc.).
- •Total blood BK peptide levels following 3 days cold activation is above the diagnostic value in non-attack and/or attack period*.
- •*The "attack period" is defined as within 24 hours after an attack.
- •Documented diagnostic testing results: C1INH antigen concentration and functional activity within normal range; C4 antigen concentration within normal range.
- •Documented history of at least 2 angioedema attacks in the previous 2 months.
- •Reliable access and experience to use standard of care medication to effectively manage acute angioedema attacks.
排除标准
- •Any diagnosis of angioedema other than BK-AE-nC1INH.
- •Participation in a clinical study with any other investigational drug within the previous 30 days or within 5 half-lives of the investigational drug at Screening (whichever was longer).
- •Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks of Screening.
- •Receiving prophylactic treatment for BK-AE-nC1INH. Participants who have previously received prophylactic therapy but have stopped can participate in this study provided a sufficiently long washout period (≥5 half-life) is observed before the participant is screened. Exclusion includes use of:
- •Short-term prophylaxis for BK-AE-nC1INH within 7 days prior to Screening.
- •Any females who are pregnant, plan to become pregnant, or are currently breast-feeding.
- •Abnormal hepatic function (aspartate aminotransferase >2× upper limit of normal, alanine aminotransferase >2× ULN, or total bilirubin >1.5× upper limit of normal). Participants with Gilbert's syndrome, defined as isolated increase of total bilirubin ≤3× upper limit of normal and aspartate aminotransferase and alanine aminotransferase within the normal range, are not excluded.
- •Abnormal renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).
- •Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, uncontrolled hypertension, bradycardia, or any other clinically significant cardiovascular abnormality within the previous year that, in the opinion of the Investigator, would interfere with the participant's safety or ability to participate in the study.
- •History of epilepsy and other significant neurological diseases.
- •Any clinically significant gastrointestinal dysfunction (eg, diarrhea, inflammatory bowel disease) which may impact on study drug absorption.
- •History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse.
- •Use of concomitant medications with systemic absorption that are moderate and strong inhibitors or strong inducers of CYP3A4, such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, and grapefruit juice as well as carbamazepine, and rifampin within the last 30◦days or within 5◦half-lives (whichever is longer) of the time of randomization.
- •Known hypersensitivity to deucrictibant or any of the excipients of study drug.
研究组 & 干预措施
Deucrictibant XR tablet, 40 mg, prophylaxis
Deucrictibant XR tablet, 40 mg, QD, oral use for 12 weeks
干预措施: Deucrictibant XR tablet (Drug)
Placebo to deucrictibant XR tablet, 40 mg, prophylaxis
Placebo tablets, 40 mg equivalent, QD, oral use for 12 weeks
干预措施: Placebo comparator to XR tablet (Drug)
On-demand deucrictibant 20 capsule, oral use
Single 20 capsule orally for treatment of on-demand angioedema attack, for up to 16 weeks
干预措施: Deucrictibant 20 mg capsule (Drug)
Placebo comparator to on-demand deucrictibant 20 capsule, oral use
Placebo capsules for treatment of on-demand angioedema attacks, for up to 16 weeks
干预措施: Placebo comparator to 20 mg capsule (Drug)
结局指标
主要结局
Part-2: Efficacy of active on-demand treatment versus placebo in achieving angioedema symptom relief during acute attacks
时间窗: 16 weeks
Part-2: Time to onset of symptom relief of active drug versus placebo, defined as Patient Global Impression of Change (PGI-C) rating of at least "a little better" for 2 consecutive timepoints within 12 hours post-treatment. Time to complete symptom resolution, defined as achieving PGI-S rating of "none" within 48 hours post-treatment.
Part-1: Incidence and quality of HAE attacks comparing active versus placebo arms.
时间窗: 24 weeks
Part-1: Time-normalized number of Investigator-confirmed moderate or severe angioedema attacks during the Treatment Period. Time-normalized number of Investigator-confirmed angioedema attacks treated with on-demand medication during the Treatment Period.
次要结局
- Safety assessment of oral deucrictibant extended release (XR) tablet (Part 1), and deucrictibant oral on-demand tablets (Part 2).(40 weeks)
- Part-1: Change in Health-Related Quality of Life (HRQoL) Scores Between Active Drug and Placebo Periods(16 weeks)