A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Efficacy and Safety of Oral BTK Inhibitor Rilzabrutinib (PRN1008) in Moderate to Severe Pemphigus
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 131
- 试验地点
- 1
- 主要终点
- Percentage of Participants Who Achieved Complete Remission (CR) With a Corticosteroids Dose of Less Than or Equal to (<=) 10 mg/Day From Week 29 to Week 37: Pemphigus Vulgaris Participants in Modified Intent-to-Treat (PV mITT) Population
研究概览
简要总结
This was a Phase 3 randomized, parallel-group, double-blind, placebo-controlled trial (blinded treatment [BT] period) followed by an open-label extension [OLE] period intended to evaluate the efficacy and safety of oral PRN1008 in moderate to severe pemphigus. After completing the open-label extension period, eligible participants might continue in a long term extension (LTE) Period of 48 weeks.
详细描述
A total of 131 male or female participants with newly diagnosed or relapsing moderate to severe pemphigus (pemphigus vulgaris [PV] or pemphigus foliaceus [PF]) were enrolled in the trial worldwide.
The trial would last 68 weeks (approximately 17 months) for each participant. For participants eligible to enroll in the LTE, the trial might last up to 116 weeks.
Participants were randomized at Day 1, using a 1:1 ratio to receive PRN1008 or placebo twice per day, by relapsing/newly diagnosed disease history (newly diagnosed defined as within 6 months of screening).
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participants, aged 18 to 80 years old with moderate to severe, newly diagnosed or relapsing PV or PF, with a clinical presentation and histopathology consistent with PV or PF.
- •Positive circulating anti-desmoglein 1 (anti-dsg1) or 3 autoantibody titer.
- •At screening, pemphigus disease area index score of at least 9 points for relapsing participants or at least 15 points for newly diagnosed participants.
- •Adequate hematologic, hepatic, and renal function.
- •Effective means of contraception.
排除标准
- •Suspected paraneoplastic pemphigus and other forms of pemphigus that were not PV or PF.
- •Previous use of a Bruton tyrosine kinase inhibitor.
- •Pregnant or lactating women.
- •Electrocardiogram clinically significant abnormalities.
- •A history of malignancy of any type within 5 years before Day 1, other than surgically excised non-melanoma skin cancers or in situ cervical cancer.
- •Use of immunologic response modifiers as concomitant medication and with the washout period.
- •Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of Day
- •Concomitant use of known strong-to-moderate inducers or inhibitors of cytochrome P450 3A (CYP3A) within 3 days or 5 half-lives (whichever is longer) of Day 1
- •Use of CYP3A-sensitive substrate drugs.
- •Had received any investigational drug within the 30 days before Day
- •History of drug abuse within the previous 12 months.
- •Alcoholism or excessive alcohol use.
- •Any other clinically significant disease, condition or medical history that, in the opinion of the Investigator, would interfere with participant safety, trial evaluations, and/or trial procedures.
研究组 & 干预措施
Placebo Then Rilzabrutinib
In BT period, participants received placebo orally twice daily (BID) up to 37 weeks along with sponsor-provided corticosteroids (CS). After at least two weeks of control of disease activity (CDA; no new lesions and established lesions begin to heal), based on protocol-specified clinical criteria, investigators could decrease the CS dose to a minimum of 5 milligrams (mg) prednisone/prednisolone per day from Week 29 to Week 37. Post completion of BT period, eligible participants received rilzabrutinib 400 mg BID up to Week 61 in OLE period and those who were eligible after OLE period completion, continued the same treatment until Week 109 in LTE period according to protocol-specified criteria.
干预措施: Rilzabrutinib (Drug)
Placebo Then Rilzabrutinib
In BT period, participants received placebo orally twice daily (BID) up to 37 weeks along with sponsor-provided corticosteroids (CS). After at least two weeks of control of disease activity (CDA; no new lesions and established lesions begin to heal), based on protocol-specified clinical criteria, investigators could decrease the CS dose to a minimum of 5 milligrams (mg) prednisone/prednisolone per day from Week 29 to Week 37. Post completion of BT period, eligible participants received rilzabrutinib 400 mg BID up to Week 61 in OLE period and those who were eligible after OLE period completion, continued the same treatment until Week 109 in LTE period according to protocol-specified criteria.
干预措施: Placebo (Drug)
Rilzabrutinib Then Rilzabrutinib
In BT period, participants received rilzabrutinib 400 mg orally BID up to 37 weeks along with sponsor-provided CS. After at least two weeks of CDA (no new lesions and established lesions begin to heal), based on protocol-specified clinical criteria, investigators could decrease the CS dose to a minimum of 5 mg prednisone/prednisolone per day from Week 29 to Week 37. Post completion of BT period, eligible participants received rilzabrutinib 400 mg BID up to Week 61 in OLE period and those who were eligible after OLE period completion, continued the same treatment until Week 109 in LTE period according to protocol-specified criteria.
干预措施: Rilzabrutinib (Drug)
结局指标
主要结局
Percentage of Participants Who Achieved Complete Remission (CR) With a Corticosteroids Dose of Less Than or Equal to (<=) 10 mg/Day From Week 29 to Week 37: Pemphigus Vulgaris Participants in Modified Intent-to-Treat (PV mITT) Population
时间窗: From Week 29 to Week 37
Complete remission was defined as absence of new and established lesions and was intended to mean "no disease activity" for 2 consecutive weeks, with Pemphigus Disease Area Index (PDAI) activity score =0 and CS dose \<=10 mg. PDAI score weighted for number and size of lesions with score of 0 (absent) to 10 given for skin (12 body locations), scalp and mucous membrane showing disease activity (erosions/blisters or new erythema). PDAI total score ranged from 0 to 250 points representing disease activity (120 points for skin activity; 10 points for scalp activity; 120 points for mucosal activity). Higher score indicated more disease activity. In this outcome measure (OM), percentage of participants who achieved CR while on a daily corticosteroids dose of \<=10 mg/day were reported.
Percentage of Participants Who Achieved Complete Remission With a Corticosteroids Dose of <=10 mg/Day From Week 29 to Week 37: Modified Intent-to-Treat (mITT) Population
时间窗: From Week 29 to Week 37
Complete remission was defined as absence of new and established lesions and was intended to mean "no disease activity" for 2 consecutive weeks, with PDAI activity score =0 and CS dose \<=10 mg. PDAI score weighted for number and size of lesions with score of 0 (absent) to 10 given for skin (12 body locations), scalp and mucous membrane showing disease activity (erosions/blisters or new erythema). PDAI total score ranged from 0 to 250 points representing disease activity (120 points for skin activity; 10 points for scalp activity; 120 points for mucosal activity). Higher score indicated more disease activity. In this OM, percentage of participants who achieved CR while on a daily corticosteroids dose of \<=10 mg/day were reported.
次要结局
- Cumulative Oral Corticosteroid Dose From Baseline to Week 37: PV mITT Population(Baseline to Week 37)
- Cumulative Oral Corticosteroid Dose From Baseline to Week 37: mITT Population(Baseline to Week 37)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Week 37: PV mITT Population(Baseline to Week 37)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Week 37: mITT Population(Baseline to Week 37)
- Time to First Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Week 37: PV mITT Population(Baseline to Week 37)
- Time to First Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Week 37: mITT Population(Baseline to Week 37)
- Percentage of Participants Who Achieved Complete Remission With a Corticosteroids Dose of <=5 mg/Day From Week 29 to Week 37: PV mITT Population(From Week 29 to Week 37)
- Percentage of Participants Who Achieved Complete Remission With a Corticosteroids Dose of <=5 mg/Day From Week 29 to Week 37: mITT Population(From Week 29 to Week 37)
- Percentage of Participants Who Had Pemphigus Disease Area Index (PDAI) Score <3 With a Corticosteroids Dose <=10 mg/Day From Week 29 to Week 37: PV mITT Population(From Week 29 to Week 37)
- Percentage of Participants Who Had Pemphigus Disease Area Index Score <3 With a Corticosteroids Dose <=10 mg/Day From Week 29 to Week 37: mITT Population(From Week 29 to Week 37)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Weeks 61 and 109: PV mITT Population(Baseline to Week 61 and Baseline to Week 109)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Weeks 61 and 109: mITT Population(Baseline to Weeks 61 and Baseline to Week 109)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose = 0 mg/Day From Baseline to Weeks 61 and 109: PV mITT Population(Baseline to Week 61 and Baseline to Week 109)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose = 0 mg/Day From Baseline to Weeks 61 and 109: mITT Population(Baseline to Week 61 and Baseline to Week 109)
- Change From Baseline in Pemphigus Disease Area Index Score at Weeks 5, 13, 25, 37, 61, and 109: mITT Population(Baseline, Weeks 5, 13, 25, 37, 61, and 109)
- Glucocorticoid Toxicity Index (GTI) - Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS) at Week 37: PV mITT Population(At Week 37)
- Glucocorticoid Toxicity Index - Cumulative Worsening Score and Aggregate Improvement Score at Week 37: mITT Population(At Week 37)
- Change From Baseline in Pemphigus Disease Area Index Score at Weeks 5, 13, 25, 37, 61, and 109: PV mITT Population(Baseline, Weeks 5, 13, 25, 37, 61, and 109)
- Change From Baseline in Autoimmune Bullous Disease Quality of Life (ABQOL) Score at Weeks 5, 13, 25, 37, 61, and 109: PV mITT Population(Baseline, Weeks 5, 13, 25, 37, 61, and 109)
- Change From Baseline in Autoimmune Bullous Disease Quality of Life Score at Weeks 5, 13, 25, 37, 61, and 109: mITT Population(Baseline, Weeks 5, 13, 25, 37, 61, and 109)
- Percentage of Participants With Autoimmune Bullous Disease Quality of Life Score of Zero at Weeks 5, 13, 25, 37, 61, and 109: PV mITT Population(At Weeks 5, 13, 25, 37, 61, and 109)
- Percentage of Participants With Autoimmune Bullous Disease Quality of Life Score of Zero at Weeks 5, 13, 25, 37, 61, and 109: mITT Population(At Weeks 5, 13, 25, 37, 61, and 109)
- Change From Baseline in the European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogue Scale (VAS) Scores at Weeks 5, 13, 25, 37, 61, and 109(Baseline, Weeks 5, 13, 25, 37, 61, and 109)
- Change From Baseline in the European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Individual Dimension at Weeks 5, 13, 25, 37, 61, and 109(Baseline, Weeks 5, 13, 25, 37, 61, and 109)
- Time to First Complete Remission With a Corticosteroids Dose <=10 mg/Day From Baseline to Weeks 61 and 109(Baseline to Week 61 and Baseline to Week 109)
- Total Number of Disease Relapses/Flares From Initial Control of Disease Activity (CDA) to Week 37: PV mITT Population(From initial CDA up to Week 37 (i.e., during any time from Baseline up to Week 37))
- Total Number of Disease Relapses/Flares From Initial Control of Disease Activity to Week 37: mITT Population(From initial CDA up to Week 37 (i.e., during any time from Baseline up to Week 37))
- Time to Initial Relapse/Flare From Initial Control of Disease Activity to Week 37: PV mITT Population(From initial CDA up to Week 37 (i.e., during any time from Baseline up to Week 37))
- Time to Initial Relapse/Flare From Initial Control of Disease Activity to Week 37: mITT Population(From initial CDA up to Week 37 (i.e., during any time from Baseline up to Week 37))
- Percentage of Participants With 3 or More New Lesions Within 1 Month That do Not Heal Spontaneously Within 1 Week, or With Extension of Established Lesions at Week 37: PV mITT Population(At Week 37)
- Percentage of Participants With 3 or More New Lesions Within 1 Month That do Not Heal Spontaneously Within 1 Week, or With Extension of Established Lesions at Week 37: mITT Population(At Week 37)
- Percentage of Participants With at Least One Disease Relapse/Flare From Initial Control of Disease Activity to Week 37: PV mITT Population(From initial CDA up to Week 37 (i.e., during any time from Baseline up to Week 37))
- Percentage of Participants With at Least One Disease Relapse/Flare From Initial Control of Disease Activity to Week 37: mITT Population(From initial CDA up to Week 37 (i.e., during any time from Baseline up to Week 37))
- Cumulative Duration of Complete Remission With a Corticosteroids Dose <=10 mg/Day From Week 37 to Week 61: PV mITT Population(From Week 37 to Week 61)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose <=10 mg/Day From Week 37 to Week 61: mITT Population(From Week 37 to Week 61)
- Cumulative Duration of Complete Remission With a Corticosteroids Dose = 0 mg/Day From Week 37 to Week 61: PV mITT Population(From Week 37 to Week 61)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(BT Period: From Day 1 of Week 1 to Week 37, OLE Period: from Week 37 to Week 61 and LTE Period: from Week 61 up to 4 weeks after the last dose at Week 109 (i.e., up to Week 113))
- Cumulative Duration of Complete Remission With a Corticosteroids Dose = 0 mg/Day From Week 37 to Week 61: mITT Population(From Week 37 to Week 61)
- Pharmacokinetics (PK): Plasma Concentration of Rilzabrutinib(Pre-dose and 2 hours post-dose on Day 1)
- Pharmacodynamics: Change From Baseline in Antibody Levels - Anti-desmoglein 1 (Anti-dsg 1) and Anti-desmoglein 3 (Anti-dsg 3) at Weeks 13, 25, 37, 49, 61, 73, 85, 97 and 109: mITT Population(Baseline, Weeks 13, 25, 37, 49, 61, 73, 85, 97, and 109)
- Pharmacodynamics (PD): Change From Baseline in Antibody Levels - Anti-desmoglein 1 (Anti-dsg 1) and Anti-desmoglein 3 (Anti-dsg 3) at Weeks 13, 25, 37, 49, 61, 73, 85, 97, and 109: PV mITT Population(Baseline, Weeks 13, 25, 37, 49, 61, 73, 85, 97, and 109)