An Open-label Extension Study of Subcutaneously Administered Fitusiran in Patients With Moderate or Severe Hemophilia A or B Who Have Participated in a Previous Clinical Study With Fitusiran
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)
研究概览
简要总结
Primary Objective:
To evaluate the long-term safety and tolerability of fitusiran in male patients with moderate or severe hemophilia A or B
Secondary Objectives:
- To investigate the long-term efficacy of fitusiran
- To characterize the safety and efficacy of concomitantly administered Factor VIII (FVIII), Factor IX (FIX) or bypassing agents (BPA) and fitusiran for treatment of bleeding episodes
- To assess changes in health-related quality of life (QOL) over time
- To characterize antithrombin (AT) reduction and thrombin generation (TG) increase
- To characterize the pharmacokinetics (PK) of fitusiran
详细描述
It is anticipated that patients in this study will receive treatment with open label fitusiran for approximately 7 years or until fitusiran becomes commercially available, whichever occurs first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Completed and tolerated study drug dosing in study TDR14767 (ALN-AT3SC-001)
- •Male aged ≥18 years
- •Moderate or severe, clinically stable hemophilia A or B as evidenced by a laboratory FVIII or FIX level ≤5% at screening. Patients with a FVIII or FIX level >5% at screening will be eligible on provision of a historic laboratory report indicating a trough level ≤5%
- •Willing and able to comply with the study requirements and provide written informed consent
排除标准
- •Clinically significant liver disease
- •Patients known to be human immunodeficiency virus seropositive and have a CD4 count <200 cells/μL
- •History of venous thromboembolism
- •Current serious mental illness that, in the judgment of the Investigator, may compromise patient safety, ability to participate in all study assessments, or study integrity
- •Clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, neurological, inflammatory, or other diseases that, in the judgment of the Investigator, precludes study participation
研究组 & 干预措施
Fitusiran
Patients will be administered subcutaneous (SC) fitusiran once monthly or every 2 months according to the dose selection rules defined in protocol.
干预措施: Fitusiran (SAR439774) (Drug)
结局指标
主要结局
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An SAE is any untoward medical occurrence that results: death or life-threatening or inpatient hospitalization or prolongation of existing hospitalization or persistent or significant disability or congenital anomaly or medically important event. All AEs collected in LTE14762 were considered TEAE because all participants received dose in the parent study. AEs of special interest (AESI) are alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations \>3× upper limit of normal (ULN) or suspected or confirmed thromboembolic events or severe or serious injection site reactions or systemic injection associated reactions or cholecystitis or cholelithiasis.
Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Physical examination included, at a minimum, an assessment of the participant's general appearance; skin; head, eyes, ears, nose, and throat; examinations of lymph nodes, abdomen, extremities/joints, neurological and mental status; heart and respiratory auscultation; peripheral arterial pulse; and pupil, knee, achilles, and plantar reflexes.
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Blood samples were collected to determine the hematology laboratory significant abnormalities. Here, DFB = decrease from baseline, NB = non-black, and B = black.
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Blood samples were collected to determine the clinical chemistry laboratory abnormalities. Here, mmol/L = millimoles per liter, LLN = lower limit of normal, mg/L = milligram per liter, umol/L = micromoles per liter, mL/min = milliliter per minute, m\^2 = meter square, CB = conjugated bilirubin, and DB = direct bilirubin.
Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Urine samples collected to determine the significant abnormalities in urine.
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Participants vital signs were examined to determine the abnormalities. Vital signs included weight, supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP). Here, mmHg = millimeter of mercury, and IFB = increase from baseline.
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG)
时间窗: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Standard 12-lead ECGs were recorded after at least 15 minutes in the supine position using an electrocardiographic device. The following were assessed: heart rate, rhythm, interval between the peaks of successive QRS complexes (RR), interval from the beginning of the P wave until the beginning of the QRS complex (PR), interval from start of the Q wave to the end of the S wave (QRS), interval between the start of the Q wave and the end of the T wave (QT), QT interval corrected for heart rate (QTc) automatic correction evaluation, QRS axis, left ventricular hypertrophy criteria, right ventricular hypertrophy criteria, repolarization charges, and overall cardiac impression for each participant. Here, msec = milliseconds.
次要结局
- Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24)
- Apparent Total Body Clearance (CL/F) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12)
- Terminal Half-Life (t1/2z) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12)
- Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12)
- Annualized Bleeding Rate (ABR) During the Efficacy Period(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Thrombin Generation at the End of Treatment Regimen(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Maximum Observed Concentration (Cmax) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24)
- Time to Reach the Maximum Concentration (Tmax) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24)
- Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran(Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12)
- Annualized Spontaneous Bleeding Rate During the Efficacy Period(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Annualized Joint Bleeding Rate During the Efficacy Period(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Time Intervals Between Bleeding Events(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX)(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa)(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Activated Prothrombin Complex Concentrate (aPCC)(From Day 29 up to end of the study, maximum of up to 76 months)
- Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24(Baseline and Month 24)
- Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24(Baseline and Month 24)
- Antithrombin Activity Level at the End of Treatment Regimen(From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months))
- Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration(Postdose, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours at Month 24)