Hemophilia A, Hemophilia B
Conditions
Keywords
Hemophilia, RNAi therapeutic
Brief summary
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
Detailed description
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.
Interventions
Pharmaceutical form: solution for injection Route of administration : subcutaneous (sc)
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | 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 (PCSA): Hematology | 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 | 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 | 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 | 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) | 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. |
| Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | The EQ-5D-5L is a standardized and disease-generic instrument for use as a measure of quality of life (QoL) outcome. The EQ-5D-5L consists of 2 parts: EQ-5D descriptive system and EQ VAS. The EQ-5D descriptive system included questions for each of following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The VAS recorded participant's self-rated health on a vertical 20-centimeter. VAS scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The EQ-5D-5L questionnaire scores range from 0-100, where 0= worst self-perceived health and 100= best self-perceived health. Positive change from baseline indicates an improvement in QoL. Baseline refers to the last non-missing value on or before the first significant treatment in TDR14767(ALN-AT3SC-001) or LTE14762 study. |
| 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 | The Haem-A-QoL questionnaire is psychometrically tested QoL assessment instrument for participants with hemophilia and includes 46 items contributing to 10 QoL domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item is based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5= all the time), and the physical health and total transformed scores range from 0 to 100. Higher scores indicated greater impairment. Baseline refers to the last non-missing value on or before the first significant treatment in TDR14767(ALN-AT3SC-001) or LTE14762 study. |
| 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) | The AT activity level was analyzed up to end of treatment regimen. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose. |
| 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) | The TG data was analyzed by CoagScope and assay performed using calibrated automated thrombogram method. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose. |
| 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 | Cmax was defined as maximum plasma concentration observed. The non-compartmental Pharmacokinetic (PK) analysis was performed. |
| 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 | tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed. |
| 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) | The ABR was annualized for each participant using the following formula: ABR = total number of bleeding events/total number of days in the respective period x 365.25. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2). |
| 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 | AUCinf was defined as area under the concentration versus time curve extrapolated to infinity. The non-compartmental PK analysis was performed. |
| 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 | t1/2z associated with the terminal slope (λz) determined according to the following equation: t1/2z = 0.693/λz; where, λz is the slope of the regression line of the terminal phase of the plasma concentration versus time curve, in semi-logarithmic scale. The non-compartmental PK analysis was performed. |
| 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 | CL/F was defined as apparent clearance of study drug from the body. The non-compartmental PK analysis was performed. |
| 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 | Vss/F was defined as apparent volume of distribution of study drug at steady state concentration. The non-compartmental PK analysis was performed. |
| 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 | fe was defined as the amount of fitusiran excreted in urine in 0-24 hour. The non-compartmental PK analysis was performed. |
| 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 | AUClast was defined as area under the concentration versus time curve from time 0 to the last measurable concentration. The non-compartmental PK analysis was performed. |
| 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) | A spontaneous bleeding episode was defined as a bleeding event that occurred for no apparent or known reason, particularly into the joints, muscles, and soft tissues. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2). |
| 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) | A joint bleeding episode was defined as an event that is characterized by an unusual sensation in the joint (aura) in combination with 1) increasing swelling or warmth over the skin over the joint; 2) increasing pain; or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2). |
| 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) | Bleed-free duration was defined as the time interval between 2 protocol-defined treated bleeding events, excluding events that occurred during the intercurrent periods. |
| 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) | Number of coagulation factor injections per bleed was determined. IU= international units, and kg= kilogram. |
| 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) | Number of BPA injections per bleed was determined. |
| 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 | Number of BPA injections per bleed was determined. |
Countries
Bulgaria, Russia, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 13 centers in 5 countries between 18 September 2015 and 21 March 2023. A total of 34 participants were enrolled in this study.
Pre-assignment details
Participants were rolled over from the parent study TDR14767 (NCT02035605).
Participants by arm
| Arm | Count |
|---|---|
| Original Dose Regimen (SAS 1) Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| AT-Based Dose Regimen (SAS 2) | Adverse Event | 0 | 1 |
| AT-Based Dose Regimen (SAS 2) | More than 1 AT measurement <15% | 0 | 1 |
| AT-Based Dose Regimen (SAS 2) | Other | 0 | 3 |
| AT-Based Dose Regimen (SAS 2) | Withdrawal by Subject | 0 | 1 |
| Original Dose Regimen (SAS 1) | Adverse Event | 3 | 0 |
| Original Dose Regimen (SAS 1) | Death | 1 | 0 |
| Original Dose Regimen (SAS 1) | Other | 4 | 0 |
| Original Dose Regimen (SAS 1) | Physician Decision | 1 | 0 |
| Original Dose Regimen (SAS 1) | Withdrawal by Subject | 7 | 0 |
Baseline characteristics
| Characteristic | Original Dose Regimen (SAS 1) |
|---|---|
| Age, Continuous | 36.6 years STANDARD_DEVIATION 10.7 |
| Race/Ethnicity, Customized Asian/Oriental | 1 Participants |
| Race/Ethnicity, Customized Caucasian/White | 33 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 34 | 0 / 18 |
| other Total, other adverse events | 33 / 34 | 13 / 18 |
| serious Total, serious adverse events | 13 / 34 | 1 / 18 |
Outcome results
Primary
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry
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.
Time frame: 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)
Population: The SAS included all participants who received at least a partial dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Uric Acid: > 408 umol/L | 20 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine: >= 150 umol/L | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 1 ULN | 30 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Sodium: <= 129 mmol/L | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 3 ULN | 14 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine: >= 30% change from baseline | 13 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 5 ULN | 6 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Glucose: <= 3.9 mmol/L and < LLN | 13 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 10 ULN | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine: >= 100% change from baseline | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 20 ULN | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Potassium: < 3 mmol/L | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 1 ULN | 22 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine Clearance: >= 60 - < 90 mL/min/1.73m^2 | 18 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 3 ULN | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | C-Reactive Protein: > 2 ULN or > 10 mg/L | 20 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 5 ULN | 5 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 10 ULN | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine Clearance: >= 15 - < 30 mL/min/1.73m^2 | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Alkaline Phosphatase: > 1.5 ULN | 4 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Potassium: >= 5.5 mmol/L | 5 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Total Bilirubin: > 1.5 ULN | 4 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Uric Acid: < 120 umol/L | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | CB: DB >35% Bilirubin and Bilirubin >1.5 ULN | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Glucose:>=11.1 mmol/L(unfasted);>=7 mmol/L(fasted) | 10 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | CB: DB >35% Bilirubin and Bilirubin >1.5 ULN | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Glucose: <= 3.9 mmol/L and < LLN | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Glucose:>=11.1 mmol/L(unfasted);>=7 mmol/L(fasted) | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | C-Reactive Protein: > 2 ULN or > 10 mg/L | 7 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Sodium: <= 129 mmol/L | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Potassium: < 3 mmol/L | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Potassium: >= 5.5 mmol/L | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine: >= 150 umol/L | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine: >= 30% change from baseline | 7 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine: >= 100% change from baseline | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine Clearance: >= 60 - < 90 mL/min/1.73m^2 | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Creatinine Clearance: >= 15 - < 30 mL/min/1.73m^2 | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Uric Acid: < 120 umol/L | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Uric Acid: > 408 umol/L | 8 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 1 ULN | 6 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 3 ULN | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 5 ULN | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 10 ULN | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | ALT: > 20 ULN | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 1 ULN | 7 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 3 ULN | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 10 ULN | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Alkaline Phosphatase: > 1.5 ULN | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | Total Bilirubin: > 1.5 ULN | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry | AST: > 5 ULN | 0 Participants |
Primary
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG)
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.
Time frame: 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)
Population: The SAS included all participants who received at least a partial dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: < 50 beats/min | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: > 90 beats/min | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: >90 beats/min;IFB >=20 beats/min | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: > 100 beats/min | 5 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate:>100 beats/min;IFB >=20 beats/min | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 200 msec | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 200 msec; IFB >= 25% | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 220 msec | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 220 msec; IFB >= 25% | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 240 msec | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 240 msec;IFB >= 25% | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 110 msec | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 110 msec; IFB >= 25% | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 120 msec | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 120 msec; IFB >= 25% | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Bazett: > 450 msec | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Bazett: > 480 msec | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Bazett: IFB (30-60) msec | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Fridericia: > 450 msec | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Fridericia: > 480 msec | 0 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Fridericia: IFB (30-60) msec | 4 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 240 msec;IFB >= 25% | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: < 50 beats/min | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Fridericia: > 450 msec | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: > 90 beats/min | 5 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 110 msec | 3 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: >90 beats/min;IFB >=20 beats/min | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Bazett: > 480 msec | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate: > 100 beats/min | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 110 msec; IFB >= 25% | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | Ventricular Rate:>100 beats/min;IFB >=20 beats/min | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Fridericia: IFB (30-60) msec | 4 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 200 msec | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 120 msec | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 200 msec; IFB >= 25% | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Bazett: IFB (30-60) msec | 4 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 220 msec | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QRS Interval: > 120 msec; IFB >= 25% | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 220 msec; IFB >= 25% | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Fridericia: > 480 msec | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | PR Interval: > 240 msec | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) | QTc Bazett: > 450 msec | 4 Participants |
Primary
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology
Blood samples were collected to determine the hematology laboratory significant abnormalities. Here, DFB = decrease from baseline, NB = non-black, and B = black.
Time frame: 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)
Population: The SAS included all participants who received at least a partial dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hemoglobin: <= 115 gram per liter (g/L) | 5 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hemoglobin: >= 185 g/L | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hemoglobin: DFB >= 20 g/L | 10 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hematocrit: <= 0.37 fraction of 1 | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hematocrit: >= 0.55 fraction of 1 | 5 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Erythrocyte Count: >= 6 x 10^12/L | 9 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Platelet Count: < 100 x 10^9/L | 2 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Leukocyte Count: <3 x 10^9/L (NB); <2 x 10^9/L (B) | 3 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Leukocyte Count: >= 16 x 10^9/L | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Neutrophils: <1.5 x 10^9/L (NB); <1 x 10^9/L (B) | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Lymphocytes: > 4 x 10^9/L | 0 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Monocytes: > 0.7 x 10^9/L | 15 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Basophils: > 0.1 x 10^9/L | 4 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Eosinophils:>0.5x10^9/L or >ULN (ULN >=0.5x10^9/L) | 11 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Lymphocytes: > 4 x 10^9/L | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hemoglobin: <= 115 gram per liter (g/L) | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Leukocyte Count: <3 x 10^9/L (NB); <2 x 10^9/L (B) | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hemoglobin: >= 185 g/L | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Basophils: > 0.1 x 10^9/L | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hemoglobin: DFB >= 20 g/L | 3 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Leukocyte Count: >= 16 x 10^9/L | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hematocrit: <= 0.37 fraction of 1 | 3 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Monocytes: > 0.7 x 10^9/L | 3 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Hematocrit: >= 0.55 fraction of 1 | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Neutrophils: <1.5 x 10^9/L (NB); <1 x 10^9/L (B) | 2 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Erythrocyte Count: >= 6 x 10^12/L | 3 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Eosinophils:>0.5x10^9/L or >ULN (ULN >=0.5x10^9/L) | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology | Platelet Count: < 100 x 10^9/L | 0 Participants |
Primary
Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination
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.
Time frame: 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)
Population: The SAS included all participants who received at least a partial dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination | 17 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination | 2 Participants |
Primary
Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis
Urine samples collected to determine the significant abnormalities in urine.
Time frame: 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)
Population: The SAS included all participants who received at least a partial dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis | 0 Participants |
Primary
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs
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.
Time frame: 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)
Population: The SAS included all participants who received at least a partial dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | SSBP: >= 160 mmHg; IFB >= 20 mmHg | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | Weight: >= 5% DFB | 8 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | SDBP: <= 45 mmHg; DFB >= 20 mmHg | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | Weight: >= 5% IFB | 15 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | SDBP: <= 45 mmHg; DFB >= 20 mmHg | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | SSBP: >= 160 mmHg; IFB >= 20 mmHg | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | Weight: >= 5% IFB | 9 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs | Weight: >= 5% DFB | 3 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)
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.
Time frame: 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)
Population: Safety analysis set (SAS) included all participants who received at least a partial dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any Treatment-emergent SAE | 13 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any TEAE leading to study drug discontinuation | 5 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any Treatment-emergent AESI | 11 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any TEAE leading to death | 1 Participants |
| Original Dose Regimen (SAS 1) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any TEAE | 33 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any TEAE leading to death | 0 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any TEAE | 14 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any Treatment-emergent SAE | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any Treatment-emergent AESI | 1 Participants |
| AT-Based Dose Regimen (SAS 2) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) | Any TEAE leading to study drug discontinuation | 1 Participants |
Secondary
Annualized Bleeding Rate (ABR) During the Efficacy Period
The ABR was annualized for each participant using the following formula: ABR = total number of bleeding events/total number of days in the respective period x 365.25. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2).
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: Full analysis set (FAS) included all participants in SAS.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Original Dose Regimen (SAS 1) | Annualized Bleeding Rate (ABR) During the Efficacy Period | 3.035 bleeding events per year |
| AT-Based Dose Regimen (SAS 2) | Annualized Bleeding Rate (ABR) During the Efficacy Period | 3.929 bleeding events per year |
Secondary
Annualized Joint Bleeding Rate During the Efficacy Period
A joint bleeding episode was defined as an event that is characterized by an unusual sensation in the joint (aura) in combination with 1) increasing swelling or warmth over the skin over the joint; 2) increasing pain; or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2).
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: The FAS included all participants in SAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Annualized Joint Bleeding Rate During the Efficacy Period | 3.51 bleeding events per year | Standard Deviation 6.97 |
| AT-Based Dose Regimen (SAS 2) | Annualized Joint Bleeding Rate During the Efficacy Period | 4.78 bleeding events per year | Standard Deviation 11.76 |
Secondary
Annualized Spontaneous Bleeding Rate During the Efficacy Period
A spontaneous bleeding episode was defined as a bleeding event that occurred for no apparent or known reason, particularly into the joints, muscles, and soft tissues. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2).
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: The FAS included all participants in SAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Annualized Spontaneous Bleeding Rate During the Efficacy Period | 2.60 bleeding events per year | Standard Deviation 5.96 |
| AT-Based Dose Regimen (SAS 2) | Annualized Spontaneous Bleeding Rate During the Efficacy Period | 3.96 bleeding events per year | Standard Deviation 11.64 |
Secondary
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Activated Prothrombin Complex Concentrate (aPCC)
Number of BPA injections per bleed was determined.
Time frame: From Day 29 up to end of the study, maximum of up to 76 months
Population: The FAS included all participants in SAS. Only participants analyzed for this outcome measure are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Activated Prothrombin Complex Concentrate (aPCC) | 381.81 units/kg per year | Standard Deviation 409.82 |
Secondary
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa)
Number of BPA injections per bleed was determined.
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: The FAS included all participants in SAS. Only participants analyzed for specific factor are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa) | 1316.19 microgram/kg per year | Standard Deviation 2631.87 |
| AT-Based Dose Regimen (SAS 2) | Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa) | 1431.84 microgram/kg per year | Standard Deviation 2369.29 |
Secondary
Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX)
Number of coagulation factor injections per bleed was determined. IU= international units, and kg= kilogram.
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: The FAS included all participants in SAS. Only participants analyzed for specific factor are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) | FVIII | 63.66 IU/kg per year | Standard Deviation 81.29 |
| Original Dose Regimen (SAS 1) | Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) | FIXs | 110.26 IU/kg per year | Standard Deviation 93.74 |
| AT-Based Dose Regimen (SAS 2) | Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) | FVIII | 52.13 IU/kg per year | Standard Deviation 8.5 |
| AT-Based Dose Regimen (SAS 2) | Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) | FIXs | 108.63 IU/kg per year | Standard Deviation 138.42 |
Secondary
Antithrombin Activity Level at the End of Treatment Regimen
The AT activity level was analyzed up to end of treatment regimen. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose.
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: Pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of study drug and had at least 1 blood sample collection post dose to determine plasma AT and thrombin generation (TG) levels.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Antithrombin Activity Level at the End of Treatment Regimen | 16.28 percentage | Standard Deviation 4.53 |
| AT-Based Dose Regimen (SAS 2) | Antithrombin Activity Level at the End of Treatment Regimen | 24.76 percentage | Standard Deviation 7.36 |
Secondary
Apparent Total Body Clearance (CL/F) of Fitusiran
CL/F was defined as apparent clearance of study drug from the body. The non-compartmental PK analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Apparent Total Body Clearance (CL/F) of Fitusiran | Day 1 | 37.6 liter per hour | Standard Deviation 13.6 |
| Original Dose Regimen (SAS 1) | Apparent Total Body Clearance (CL/F) of Fitusiran | Month 12 | 143 liter per hour | — |
| AT-Based Dose Regimen (SAS 2) | Apparent Total Body Clearance (CL/F) of Fitusiran | Day 1 | 38.8 liter per hour | Standard Deviation 12.7 |
| AT-Based Dose Regimen (SAS 2) | Apparent Total Body Clearance (CL/F) of Fitusiran | Month 12 | 28.3 liter per hour | — |
Secondary
Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran
Vss/F was defined as apparent volume of distribution of study drug at steady state concentration. The non-compartmental PK analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran | Day 1 | 283 liter | Standard Deviation 155 |
| Original Dose Regimen (SAS 1) | Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran | Month 12 | 834 liter | — |
| AT-Based Dose Regimen (SAS 2) | Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran | Day 1 | 390 liter | Standard Deviation 348 |
| AT-Based Dose Regimen (SAS 2) | Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran | Month 12 | 204 liter | — |
Secondary
Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran
AUCinf was defined as area under the concentration versus time curve extrapolated to infinity. The non-compartmental PK analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran | Day 1 | 1470 ng*h/mL | Standard Deviation 441 |
| Original Dose Regimen (SAS 1) | Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran | Month 12 | 356 ng*h/mL | — |
| AT-Based Dose Regimen (SAS 2) | Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran | Month 12 | 2860 ng*h/mL | — |
| AT-Based Dose Regimen (SAS 2) | Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran | Day 1 | 2230 ng*h/mL | Standard Deviation 641 |
Secondary
Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran
AUClast was defined as area under the concentration versus time curve from time 0 to the last measurable concentration. The non-compartmental PK analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | Day 1 | 1110 ng*hour/mL | Standard Deviation 486 |
| Original Dose Regimen (SAS 1) | Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | Month 12 | 961 ng*hour/mL | Standard Deviation 551 |
| Original Dose Regimen (SAS 1) | Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | Month 24 | 935 ng*hour/mL | Standard Deviation 550 |
| AT-Based Dose Regimen (SAS 2) | Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | Day 1 | 2130 ng*hour/mL | Standard Deviation 769 |
| AT-Based Dose Regimen (SAS 2) | Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | Month 12 | 2020 ng*hour/mL | Standard Deviation 708 |
| AT-Based Dose Regimen (SAS 2) | Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | Month 24 | 2070 ng*hour/mL | Standard Deviation 917 |
Secondary
Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24
The EQ-5D-5L is a standardized and disease-generic instrument for use as a measure of quality of life (QoL) outcome. The EQ-5D-5L consists of 2 parts: EQ-5D descriptive system and EQ VAS. The EQ-5D descriptive system included questions for each of following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The VAS recorded participant's self-rated health on a vertical 20-centimeter. VAS scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The EQ-5D-5L questionnaire scores range from 0-100, where 0= worst self-perceived health and 100= best self-perceived health. Positive change from baseline indicates an improvement in QoL. Baseline refers to the last non-missing value on or before the first significant treatment in TDR14767(ALN-AT3SC-001) or LTE14762 study.
Time frame: Baseline and Month 24
Population: The FAS included all participants in SAS. Only participants analyzed at baseline and Month 24 are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 | Index score | 0.01 units on a scale | Standard Deviation 0.14 |
| Original Dose Regimen (SAS 1) | Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 | VAS score | 4.73 units on a scale | Standard Deviation 18.37 |
| AT-Based Dose Regimen (SAS 2) | Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 | Index score | 0.09 units on a scale | Standard Deviation 0.06 |
| AT-Based Dose Regimen (SAS 2) | Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 | VAS score | 16.67 units on a scale | Standard Deviation 7.64 |
Secondary
Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24
The Haem-A-QoL questionnaire is psychometrically tested QoL assessment instrument for participants with hemophilia and includes 46 items contributing to 10 QoL domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item is based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5= all the time), and the physical health and total transformed scores range from 0 to 100. Higher scores indicated greater impairment. Baseline refers to the last non-missing value on or before the first significant treatment in TDR14767(ALN-AT3SC-001) or LTE14762 study.
Time frame: Baseline and Month 24
Population: The FAS included all participants in SAS. Only participants analyzed at baseline and Month 24 are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 | Total score | -0.20 units on a scale | Standard Deviation 0.47 |
| Original Dose Regimen (SAS 1) | Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 | Physical health score | -0.14 units on a scale | Standard Deviation 0.58 |
| AT-Based Dose Regimen (SAS 2) | Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 | Total score | 0.02 units on a scale | Standard Deviation 0.34 |
| AT-Based Dose Regimen (SAS 2) | Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 | Physical health score | -0.53 units on a scale | Standard Deviation 0.61 |
Secondary
Maximum Observed Concentration (Cmax) of Fitusiran
Cmax was defined as maximum plasma concentration observed. The non-compartmental Pharmacokinetic (PK) analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24
Population: Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Maximum Observed Concentration (Cmax) of Fitusiran | Day 1 | 86.8 nanogram per milliliter (ng/mL) | Standard Deviation 44.1 |
| Original Dose Regimen (SAS 1) | Maximum Observed Concentration (Cmax) of Fitusiran | Month 12 | 75.2 nanogram per milliliter (ng/mL) | Standard Deviation 50.3 |
| Original Dose Regimen (SAS 1) | Maximum Observed Concentration (Cmax) of Fitusiran | Month 24 | 62.5 nanogram per milliliter (ng/mL) | Standard Deviation 35.3 |
| AT-Based Dose Regimen (SAS 2) | Maximum Observed Concentration (Cmax) of Fitusiran | Day 1 | 168 nanogram per milliliter (ng/mL) | Standard Deviation 74.6 |
| AT-Based Dose Regimen (SAS 2) | Maximum Observed Concentration (Cmax) of Fitusiran | Month 12 | 149 nanogram per milliliter (ng/mL) | Standard Deviation 53.2 |
| AT-Based Dose Regimen (SAS 2) | Maximum Observed Concentration (Cmax) of Fitusiran | Month 24 | 155 nanogram per milliliter (ng/mL) | Standard Deviation 87.9 |
Secondary
Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration
fe was defined as the amount of fitusiran excreted in urine in 0-24 hour. The non-compartmental PK analysis was performed.
Time frame: Postdose, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours at Month 24
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 urine sample collection post dose to determine urine concentrations of study drug. Only those participants with data available at Month 24 are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration | 10.7 percentage of study drug | Standard Deviation 4.08 |
| AT-Based Dose Regimen (SAS 2) | Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration | 12.6 percentage of study drug | Standard Deviation 4.92 |
Secondary
Terminal Half-Life (t1/2z) of Fitusiran
t1/2z associated with the terminal slope (λz) determined according to the following equation: t1/2z = 0.693/λz; where, λz is the slope of the regression line of the terminal phase of the plasma concentration versus time curve, in semi-logarithmic scale. The non-compartmental PK analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Dose Regimen (SAS 1) | Terminal Half-Life (t1/2z) of Fitusiran | Day 1 | 5.19 hour | Standard Deviation 1.61 |
| Original Dose Regimen (SAS 1) | Terminal Half-Life (t1/2z) of Fitusiran | Month 12 | 3.91 hour | — |
| AT-Based Dose Regimen (SAS 2) | Terminal Half-Life (t1/2z) of Fitusiran | Day 1 | 5.90 hour | Standard Deviation 3.83 |
| AT-Based Dose Regimen (SAS 2) | Terminal Half-Life (t1/2z) of Fitusiran | Month 12 | 4.94 hour | — |
Secondary
Thrombin Generation at the End of Treatment Regimen
The TG data was analyzed by CoagScope and assay performed using calibrated automated thrombogram method. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose.
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: The PD analysis set included all participants who received at least 1 dose of study drug and had at least 1 blood sample collection post dose to determine plasma AT and TG levels.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Thrombin Generation at the End of Treatment Regimen | 71.39 nanomoles/liter | Standard Deviation 24.67 |
| AT-Based Dose Regimen (SAS 2) | Thrombin Generation at the End of Treatment Regimen | 32.31 nanomoles/liter | Standard Deviation 20.05 |
Secondary
Time Intervals Between Bleeding Events
Bleed-free duration was defined as the time interval between 2 protocol-defined treated bleeding events, excluding events that occurred during the intercurrent periods.
Time frame: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Population: The FAS included all participants in SAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Original Dose Regimen (SAS 1) | Time Intervals Between Bleeding Events | 368.50 days |
| AT-Based Dose Regimen (SAS 2) | Time Intervals Between Bleeding Events | 249.00 days |
Secondary
Time to Reach the Maximum Concentration (Tmax) of Fitusiran
tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed.
Time frame: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24
Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Original Dose Regimen (SAS 1) | Time to Reach the Maximum Concentration (Tmax) of Fitusiran | Day 1 | 3.97 hour |
| Original Dose Regimen (SAS 1) | Time to Reach the Maximum Concentration (Tmax) of Fitusiran | Month 12 | 4.02 hour |
| Original Dose Regimen (SAS 1) | Time to Reach the Maximum Concentration (Tmax) of Fitusiran | Month 24 | 4.00 hour |
| AT-Based Dose Regimen (SAS 2) | Time to Reach the Maximum Concentration (Tmax) of Fitusiran | Day 1 | 4.00 hour |
| AT-Based Dose Regimen (SAS 2) | Time to Reach the Maximum Concentration (Tmax) of Fitusiran | Month 12 | 6.00 hour |
| AT-Based Dose Regimen (SAS 2) | Time to Reach the Maximum Concentration (Tmax) of Fitusiran | Month 24 | 7.83 hour |