ATLAS-A/B: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 120
- 试验地点
- 64
- 主要终点
- Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
研究概览
简要总结
Primary Objective:
-To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by the frequency of bleeding episodes.
Secondary Objectives:
-
To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by:
-
The frequency of spontaneous bleeding episodes.
-
The frequency of joint bleeding episodes.
-
Health-related quality of life (HRQOL) in participants >=17 years of age.
-
To determine the frequency of bleeding episodes during the onset period.
-
To determine the safety and tolerability of fitusiran.
详细描述
The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, was up to 11 months for all participants in the factor on-demand arm and for participants in the fitusiran arm who enrolled in the extension study (LTE15174). The estimated total time on the study was up to 17 months for participants in the fitusiran treatment arm who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.
Participants who completed the study will be eligible for an open-label extension study LTE15174 (NCT03754790).
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
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Males, >=12 years of age.
- •Severe hemophilia A or B without inhibitors.
- •Severity confirmed by a central laboratory where FVIII level was less than (<) 1 percent (%) or Factor IX (FIX) level was less than or equal to (<=) 2% at Screening.
- •On-demand use of factor concentrate to manage bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:
- •Nijmegen modified Bethesda assay inhibitor titer of <0.6 Bethesda units per milliliter (BU/mL) at Screening.
- •No use of Bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening.
- •No history of immune tolerance induction therapy within the last 3 years prior to Screening.
- •A minimum of 6 bleeding episodes requiring factor concentrate treatment within the last 6 months prior to Screening.
- •Willing and complied with the study requirements and to provide written informed consent and assent.
排除标准
- •Known co-existing bleeding disorders other than hemophilia A or B, i.e., Von Willebrand's disease, additional factor deficiencies, or platelet disorders.
- •Antithrombin (AT) activity <60% at Screening.
- •Co-existing thrombophilic disorder.
- •Clinically significant liver disease.
- •Active hepatitis C virus infection.
- •HIV positive with a cluster of differentiation-4 count of <200 cells/microliter.
- •History of arterial or venous thromboembolism.
- •Inadequate renal function.
- •History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine (GalNAc).
- •History of intolerance to SC injection(s).
- •Any other conditions or comorbidities that would make the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment.
研究组 & 干预措施
Factor On-demand
Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.
干预措施: factor concentrates (Drug)
Fitusiran 80 mg Prophylaxis
Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
干预措施: fitusiran (Drug)
Fitusiran 80 mg Prophylaxis
Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
干预措施: factor concentrates (Drug)
结局指标
主要结局
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
时间窗: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP\*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections \<=72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on the data collected during EP).
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
时间窗: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of by-passing agents (BPA) or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to (\<=) 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) presents estimated results (i.e., results received by applying negative binomial \[NB\] regression model on data collected during EP).
次要结局
- Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period(From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest)
- Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period(From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest)
- Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period(From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest)
- Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period(From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest)
- Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period(From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest)
- Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period(From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest)
- Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score at Month 9(Baseline (Day 1), Month 9)
- Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9(Baseline (Day 1), Month 9)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)(From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up))
- Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period(From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest)