NCT04206605已完成3 期
A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
Takeda45 个研究点 分布在 10 个国家目标入组 77 人开始时间: 2020年5月4日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 77
- 试验地点
- 45
- 主要终点
- Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
研究概览
简要总结
The main aim of this study is to check if repeated subcutaneous (SC) injections of lanadelumab can prevent angioedema attacks in teenagers and adults with non-histaminergic angioedema with normal C1-INH. Another aim is to check if they tolerate the repeated SC injections.
Participants will receive a SC injection of lanadelumab every two weeks for 26 weeks. The first two doses of lanadelumab will be given at the study clinic. Once a participant (and/or parent/caregiver) has been appropriately trained, lanadelumab can be self-injected. Visits to the study clinic are planned for the first, third and fourth week and then every 4 weeks.
详细描述
This study consists of non-histaminergic normal C1-INH angioedema population with 12 years of age and above. Participants will be randomized 2:1 to receive repeated SC administrations of lanadelumab or placebo in a double-blind fashion. Randomization will be stratified based on baseline angioedema attack rate (1 to less than (<) 2 attacks/4 weeks, and greater than (>=) 2 attacks/4 weeks), as well as subtype (known mutations, family history and unknown mutation, idiopathic).
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
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The Participant will not be considered eligible for the study without meeting all of the applicable population criteria below.
- •Males and females, 12 years of age and older for participants with non-histaminergic normal C1-INH angioedema at the time of signing of the informed consent form (ICF).
- •Documented clinical history of recurrent attacks of angioedema in the absence of wheals/urticaria.
- •Investigator-confirmed diagnosis of non-histaminergic bradykinin-mediated angioedema with normal C1-INH as documented by a history of angioedema attack(s) at screening and occurrence of attacks during the observation period:
- •History of recurrent angioedema with at least an average of 1 angioedema attack per 4 weeks prior to screening and this attack rate must be confirmed during the observation period while treated with chronic high-dose antihistamine (cetirizine 40 milligram per day [mg/day] or equivalent high-dose second-generation antihistamine medication).
- •Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH function >= 50 percent (%) of normal and C4 level not below the normal range. With prior sponsor approval, participants may be retested during the observation period if results are incongruent with clinical history.
- •Clinical history of not responding to high-dose antihistamine treatment (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine medication), which must be confirmed during the observation period with at least 1 angioedema attack per 4 weeks with chronic high-dose antihistamine treatment and no significant difference (as assessed by the investigator and in consultation with the sponsor's medical monitor, as necessary) from the historic attack rate without high-dose antihistamine treatment.
- •Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
- •Participants >= 18 years of age must be willing to use icatibant as the rescue medication during the observation and treatment period. During the observation period, participants need to be treated with icatibant for at least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the investigator, participants with no response to icatibant for acute angioedema attacks in the past medical history/screening, or no improvement or worsened attack severity 2 hours after icatibant treatment during the observation period (based on totality of assessments), will not be included. Note: For participants 12 to < 18 years of age, standard of care therapy per local protocols should be provided.
- •Males, or non-pregnant, non-lactating females who are of child-bearing potential and who agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study. Female participants of childbearing potential must have a negative serum pregnancy test at screening and must be willing to undergo pregnancy tests throughout the study. Females of non-childbearing potential are defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months.
- •The participants (or the participant's parent/legal guardian, if applicable) has provided written informed consent approved by the institutional review board/research ethics board/ethics committee (IRB/REB/EC).
- •If the participants is an adult, be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
- •If the participants is a minor (i.e. < 18 years of age), have a parent/legal guardian who is informed of the nature of the study provide written informed consent (i.e. permission) for the minor to participate in the study before any study-specific procedures are performed. Assent will be obtained from minor participants.
- •Exclusion Criteria
- •The participant will be excluded from the study if any of the following exclusion criteria are met.
- •Concomitant diagnosis of Type I or Type II HAE, or recurrent angioedema associated with urticaria.
- •Dosing with any investigational drug or exposure to an investigational device within 4 weeks prior to screening.
- •Exposure to angiotensin-converting enzyme (ACE) inhibitors or rituximab within 6 months prior to screening.
- •Use of any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
- •Response to omalizumab (prophylactic) or corticosteroid (acute/prophylactic) or epinephrine (acute) or anti-leukotrienes (prophylactic) treatments in the past.
- •Use of long-term prophylactic therapy for HAE, e.g. C1-INH, attenuated androgens (e.g. danazol, methyltestosterone, testosterone), or anti-fibrinolytics within 2 weeks prior to entering the observation period as long as the investigator determines that doing so would not place the participant at any undue safety risk, and that the participant is at least 18 years of age.
- •Any exposure to prophylactic plasma kallikrein inhibitors prior to screening.
- •Use of short-term prophylaxis for HAE within 7 days prior to entering the observation period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from medically indicated procedures.
- •Have any active infectious illness or fever defined as an oral temperature greater than (>) 38°C (100.4°F), tympanic > 38.5°C (101.3°F), axillary > 38°C (100.4°F), or rectal/core > 38.5°C (101.3°F) within 24 hours prior to the first dose of study drug in the treatment period.
- •Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of Gilbert's syndrome).
- •Pregnancy or breast feeding.
- •Participant has a known hypersensitivity to the investigational product or its components.
- •Have any uncontrolled underlying medical condition which would require treatment adjustment during the study treatment period that, in the opinion of the investigator or sponsor, may confound the results of the safety assessments or may place the participant at risk. Participants with stable treatment for at least 3 months prior to screening and NOT expecting any change to their treatment regimen for 6 months during the study treatment period, will not be excluded.
- •Have any condition (surgical or medical) that, in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude the successful conduct of the study, or interfere with interpretation of the results (e.g. significant pre-existing illness or other major comorbidities that the investigator considers may confound the interpretation of study results).
排除标准
- 未提供
研究组 & 干预措施
Placebo
Placebo Comparator
Participants received placebo-matching lanadelumab subcutaneous (SC) injection once every 2 weeks (q2w) for up to 7 months.
干预措施: Placebo (Other)
Lanadelumab 300mg
Experimental
Participants received 300 mg of lanadelumab solution in a prefilled syringe (PFS) as SC injection once (q2w) for up to 6 months.
干预措施: Lanadelumab (Drug)
结局指标
主要结局
Number of Investigator-Confirmed Angioedema Attacks During the Treatment Period of Day 0 Through Day 182
时间窗: Day 0 through Day 182
An angioedema attack was defined as the symptoms or signs consistent with an attack in at least 1 of the following 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). Attack rate was calculated for each participant as the number of attacks occurring during the specified period divided by the number of days the participant contributed to the specified period multiplied by 28 days. Number of investigator-confirmed angioedema attacks during the treatment period of Day 0 through Day 182 was assessed.
次要结局
- Number of Participants With Maximum Attack Severity During Treatment Period of Day 0 Through Day 182(Day 0 through Day 182)
- Number of Participants Achieving Attack-Free Status During the Treatment Period of Day 0 Through Day 182(Day 0 through Day 182)
- Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Treatment Period of Day 0 Through Day 182(Day 0 Through Day 182)
- Number of Participants With Maximum Attack Severity During Presumed Steady State Period of Day 70 Through Day 182(Day 70 through Day 182)
- Number of Participants Achieving at Least 50 %, 70%, 90% and 100% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) Per 4 Weeks During Each of the Efficacy Evaluation Periods Relative to the Observation Period NNA(Day 0 Through Day 182)
- Number of Investigator-Confirmed Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182(Day 70 through Day 182)
- Number of Participants Achieving Attack-Free Status During the Presumed Steady State Period of Day 70 Through Day 182(Day 70 through Day 182)
- Number of Investigator-Confirmed Moderate or Severe Angioedema Attacks During the Presumed Steady State Period of Day 70 Through Day 182(Day 70 through Day 182)
- Time to First Angioedema Attack After Day 0 Through Day 182(Day 0 Through Day 182)
- Number of Participants Achieving Normalized Number of Attacks (NNA) Less Than (<)1.0 Per 4 Weeks During Each of the Efficacy Evaluation Periods(Day 0 through Day 182, Day 70 through Day 182)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs)(From the first study drug administration up to follow-up (Day 196))
- Time to First Angioedema Attack After Day 70 Through Day 182(Day 70 through Day 182)
- Plasma Concentrations of Lanadelumab(Pre-dose and post-dose at Days 0, 4, 14, 28, 56, 84, 112, 140, 168 and 182)
- Plasma Kallikrein (pKal) Activity(Pre-dose and post-dose at Days 4, 14, 28, 56, 84, 112, 140, 168 and 182)
- Number of Participants With Neutralizing or Non-neutralizing Antidrug Antibodies (ADA) in Plasma(Pre-dose and post-dose at Days 28, 56, 84, 112, 140, 168 and 182)
- Number of Participants With Change in Total Angioedema Quality of Life (AE-QoL) Questionnaire Score During the Treatment Period of Day 0 Through Day 182(Baseline through Day 182)
研究者
研究点 (45)
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