Clinical Trial Results:
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
Summary
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EudraCT number |
2015-001395-21 |
Trial protocol |
GB BG |
Global end of trial date |
21 Mar 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Mar 2024
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First version publication date |
30 Mar 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
LTE14762
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02554773 | ||
WHO universal trial number (UTN) |
U1111-1251-5204 | ||
Sponsors
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Sponsor organisation name |
Genzyme Corporation
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Sponsor organisation address |
450 Water Street, Cambridge, Massachusetts, United States, 02141
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Public contact |
Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Apr 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Mar 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the long-term safety and tolerability of fitusiran in male participants with moderate or severe hemophilia A or B.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency.
Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Sep 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 15
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Country: Number of subjects enrolled |
Russian Federation: 6
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Country: Number of subjects enrolled |
Switzerland: 2
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Country: Number of subjects enrolled |
United Kingdom: 9
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Country: Number of subjects enrolled |
United States: 2
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Worldwide total number of subjects |
34
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EEA total number of subjects |
15
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
34
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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
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Screening details |
Participants were rolled over from the parent study TDR14767 (NCT02035605). SAS 1= Safety Analysis Set 1, SAS 2= Safety Analysis Set 2, and AT= Antithrombin. | ||||||||||||||||||
Period 1
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Period 1 title |
Original Dose Regimen (SAS 1)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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Original Dose Regimen (SAS 1) | ||||||||||||||||||
Arm description |
Participants received fitusiran 50 milligram (mg) or 80 mg subcutaneous (SC) injection every month (QM) under the original dose and regimen. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Fitusiran
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Investigational medicinal product code |
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Other name |
SAR439774, ALN-AT3SC
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fitusiran 50 mg or 80 mg SC injection was administered at the clinic (healthcare setting) or in a nonhealth care setting (home injection) QM under the original dose and regimen.
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Period 2
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Period 2 title |
AT-Based Dose Regimen (SAS 2)
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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AT-Based Dose Regimen (SAS 2) | ||||||||||||||||||
Arm description |
Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg every 2 months (Q2M) SC injection under recommended AT-based dose regimen. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Fitusiran
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Investigational medicinal product code |
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Other name |
SAR439774, ALN-AT3SC
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection was administered at the clinic (healthcare setting) or in a nonhealth care setting (home injection) under recommended AT-based dose regimen.
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Baseline characteristics reporting groups
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Reporting group title |
Original Dose Regimen (SAS 1)
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Reporting group description |
Participants received fitusiran 50 milligram (mg) or 80 mg subcutaneous (SC) injection every month (QM) under the original dose and regimen. | |||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Original Dose Regimen (SAS 1)
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Reporting group description |
Participants received fitusiran 50 milligram (mg) or 80 mg subcutaneous (SC) injection every month (QM) under the original dose and regimen. | ||
Reporting group title |
AT-Based Dose Regimen (SAS 2)
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Reporting group description |
Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg every 2 months (Q2M) SC injection under recommended AT-based dose regimen. | ||
Subject analysis set title |
Fitusiran 50 mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants received fitusiran 50 mg QM or Q2M SC injection under original dose regimen (SAS 1) and AT-based dose regimen (SAS 2).
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Subject analysis set title |
Fitusiran 80 mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants received fitusiran 80 mg QM SC injection under original dose regimen (SAS 1) and AT-based dose regimen (SAS 2).
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End point title |
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) [1] | ||||||||||||||||||||||||
End point description |
Adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a study drug and which does not necessarily have to have a causal relationship with treatment. 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 were considered TEAE as all participants received dose in parent study. AE 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. Results are based on safety analysis set (SAS) included all participants who received at least a partial dose of study drug.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology [2] | |||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to determine the hematology laboratory significant abnormalities. Results are based on the SAS included all participants who received at least a partial dose of study drug. Here, DFB = decrease from baseline, NB = non-black, and B = black.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry [3] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to determine the clinical chemistry laboratory abnormalities. Results are based on the SAS included all participants who received at least a partial dose of study drug. 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.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis [4] | |||||||||
End point description |
Urine samples were collected to determine the significant abnormalities in urine.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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Notes [5] - No participants were analyzed for this endpoint. [6] - No participants were analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs [7] | |||||||||||||||||||||
End point description |
Participants vital signs were examined to determine the abnormalities. Vital signs included weight, supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP). Results are based on the SAS included all participants who received at least a partial dose of study drug. Here, mmHg = millimeter of mercury, IFB = increase from baseline, and 99999 = no participants were analyzed.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) [8] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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. Results are based on the SAS included all participants who received at least a partial dose of study drug. Here, msec = milliseconds and 99999 = no participants were analyzed.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination [9] | |||||||||
End point description |
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. Results are based on the SAS included all participants who received at least a partial dose of study drug.
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End point type |
Primary
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End point timeframe |
From first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2
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Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint is descriptive in nature, no statistical analysis is provided. |
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No statistical analyses for this end point |
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End point title |
Annualized Bleeding Rate (ABR) During the Efficacy Period | ||||||||||||
End point description |
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 full analysis set 1 and the dose re-start Day 169 to the end of study visit for full analysis set 2. Results are based on the full analysis set (FAS) included all participants in SAS.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Annualized Spontaneous Bleeding Rate During the Efficacy Period | ||||||||||||
End point description |
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 full analysis set 1 and the dose re-start Day 169 to the end of study visit for full analysis set 2. Results are based on the FAS included all participants in SAS.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Annualized Joint Bleeding Rate During the Efficacy Period | ||||||||||||
End point description |
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 full analysis set 1 and the dose re-start Day 169 to the end of study visit for full analysis set 2. Results are based on the FAS included all participants in SAS.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Time Intervals Between Bleeding Events | ||||||||||||
End point description |
Bleed-free duration was defined as the time interval between 2 protocol-defined treated bleeding events, excluding events that occurred during the intercurrent periods. Results are based on the FAS included all participants in SAS.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) | ||||||||||||||||||
End point description |
Number of coagulation factor injections per bleed, weight-adjusted total dose per injection and total dose per bleed was determined. Results are based on the FAS included all participants in SAS. Here, n = number of participants analyzed for each factor.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa) | ||||||||||||
End point description |
Number of BPA injections per bleed, weight-adjusted total dose per injection and total dose per bleed was determined. Results are based on the FAS included all participants in SAS. Only participants analyzed for this endpoint are reported.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Activated Prothrombin Complex Concentrate (aPCC) | ||||||||
End point description |
Number of BPA injections per bleed, weight-adjusted total dose per injection and total dose per bleed was determined. Results are based on the FAS included all participants in SAS. Only participants analyzed for this endpoint are reported.
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End point type |
Secondary
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1
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No statistical analyses for this end point |
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End point title |
Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 | ||||||||||||||||||
End point description |
The EQ-5D-5L is a standardized and disease-generic instrument for use as a measure of quality of life (QoL) outcome. It consists of a questionnaire pertaining to 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS. The 5 dimensions questionnaire is based on 5 degrees of severity (1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, or 5= extreme problems). The EQ-5D-5L index value was calculated using the crosswalk link function and the individual responses to the EQ-5D-5L descriptive system. The VAS is a continuous score ranging from 0 to 100. Lower score indicated 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. Results are based on the FAS included all participants in SAS. Only participants analyzed at baseline and Month 24 are reported.
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End point type |
Secondary
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End point timeframe |
Baseline and Month 24
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Haemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 | ||||||||||||||||||
End point description |
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. Results are based on the FAS included all participants in SAS. Only participants analyzed at baseline and Month 24 are reported.
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End point type |
Secondary
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End point timeframe |
Baseline and Month 24
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No statistical analyses for this end point |
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End point title |
Antithrombin Activity Level Over Time | ||||||||||||
End point description |
The AT activity level was analyzed at each post-baseline visit. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose. Results are based on the 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.
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End point type |
Secondary
|
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Thrombin Generation Over Time | ||||||||||||
End point description |
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. Results are based on 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.
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End point type |
Secondary
|
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End point timeframe |
From Day 29 up to end of treatment regimen in SAS 1 and SAS 2
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No statistical analyses for this end point |
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End point title |
Maximum Observed Concentration (Cmax) of Fitusiran | |||||||||||||||||||||
End point description |
Cmax was defined as maximum plasma concentration observed. The non-compartmental Pharmacokinetic (PK) analysis was performed. Results are based on the 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. Here, n = number of participants analyzed at each specific time point.
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End point type |
Secondary
|
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End point timeframe |
At Day 1, Months 12 and 24
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No statistical analyses for this end point |
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End point title |
Time to Reach the Maximum Concentration (tmax) of Fitusiran | |||||||||||||||||||||
End point description |
tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed. Results are based on 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. Here, n = number of participants analyzed at each specific time point.
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End point type |
Secondary
|
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End point timeframe |
At Day 1, Months 12 and 24
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No statistical analyses for this end point |
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End point title |
Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran | |||||||||||||||||||||
End point description |
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. Results are based on 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. Here, n = number of participants analyzed at each specific time point.
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End point type |
Secondary
|
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End point timeframe |
At Day 1, Months 12 and 24
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No statistical analyses for this end point |
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End point title |
Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran | ||||||||||||||||||
End point description |
AUCinf was defined as area under the concentration versus time curve extrapolated to infinity. The non-compartmental PK analysis was performed. Results are based on 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. Here, n = number of participants analyzed at each specific time point and 99999 = standard deviation could not be determined when only 1 participant was analyzed.
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End point type |
Secondary
|
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End point timeframe |
At Day 1 and Month 12
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No statistical analyses for this end point |
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End point title |
Terminal Half-Life (t1/2z) of Fitusiran | ||||||||||||||||||
End point description |
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. Results are based on 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. Here, n = number of participants analyzed at each specific time point and 99999 = standard deviation could not be determined when only 1 participant was analyzed.
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End point type |
Secondary
|
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End point timeframe |
At Day 1 and Month 12
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No statistical analyses for this end point |
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End point title |
Apparent Total Body Clearance (CL/F) of Fitusiran | ||||||||||||||||||
End point description |
CL/F was defined as apparent clearance of study drug from the body. The non-compartmental PK analysis was performed. Results are based on 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. Here, n = number of participants analyzed at each specific time point and 99999 = standard deviation could not be determined when only 1 participant was analyzed.
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End point type |
Secondary
|
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End point timeframe |
At Day 1 and Month 12
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No statistical analyses for this end point |
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End point title |
Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran | ||||||||||||||||||
End point description |
Vss/F was defined as apparent volume of distribution of study drug at steady state concentration. The non-compartmental PK analysis was performed. Results are based on 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. Here, n = number of participants analyzed at each specific time point and 99999 = standard deviation could not be determined when only 1 participant was analyzed.
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End point type |
Secondary
|
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End point timeframe |
At Day 1 and Month 12
|
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No statistical analyses for this end point |
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End point title |
Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration | ||||||||||||
End point description |
fe was defined as the amount of fitusiran excreted in urine in 0-24 hour. The non-compartmental PK analysis was performed. Results are based on 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 those participants with data available at Month 24 were reported.
|
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End point type |
Secondary
|
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End point timeframe |
Postdose, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours at Month 24
|
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No statistical analyses for this end point |
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Adverse events information
|
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Timeframe for reporting adverse events |
TEAEs data was collected from first dose of study drug (Day 1) up to end of treatment regimen in SAS 1 and SAS 2.
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Adverse event reporting additional description |
Analysis was performed on the safety analysis set.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
AT-Based Dose Regimen (SAS 2)
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Reporting group description |
Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Original Dose Regimen (SAS 1)
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Reporting group description |
Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | ||||||||||
Date |
Amendment |
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30 Nov 2015 |
• Primary changes: Exclusion criterion #3, updated to permit enrollment of participants with inhibitors who have a medical history of previous thrombotic event related to permanent indwelling venous access.
• Other changes: Maximum sample size increased to N=48 and sites increased to 30; Bleed management guidelines revised for participants without inhibitors and added for participants with inhibitors; Participants may resume standard prophylaxis or on demand dosing with Factor or BPA at Investigator discretion after dosing of ALN-AT3SC has been completed and AT levels begin returning to Screening levels; Removal of contraception language; Use of fixed dose, provided that dose is no greater on a weight basis than the highest dose determined previously in the parent study (TDR14767 [ALN-AT3SC-001]) to be safe and well tolerated; Addition of the Haem-A-QoL to assess QoL; Addition of text based on Ethics Committee feedback; Clarification of overlapping study assessments (vs parent study). |
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20 Oct 2016 |
• Primary changes: Exploratory objective added for assessment of safety and hemostatic efficacy rating for operative procedures conducted in participants while on study.
• Other changes: Study duration expanded by 2 years to 4 years total; Text added to permit self-administration of study drug during non-quarterly visits from Month 3 forward; Participant activity levels assessment removed; Adverse Events of Clinical Interest section added; Body temperature method revised to include all types (oral, tympanic, axillary); Other minor corrections. |
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13 Jun 2017 |
• Primary changes: Text and table added for liver function test monitoring in participants with elevated ALT; Text added to permit direct-acting antiviral treatment for Hepatitis C virus (HCV) infected participants; FibroScan (FibroTest and aspartate aminotransferase to platelet ratio index where FibroScan unavailable) added to assess liver fibrosis/cirrhosis in HCV infected participants; added in text and to Schedule of Assessments; Clinical development status text updated; Risk-benefit text updated; New bleed management recommendations added to text and new tables added; Surgery table and footnotes updated to align with Phase 3 studies; Optional plasma PK visit and optional urine PK visit added at Month 24; Schedule of Assessments reformatted and visits adjusted where necessary per above changes; Other minor corrections applied. |
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09 Nov 2017 |
• Primary changes: Updated clinical development status text to account for a participant death, which was reported in a participant with cerebral venous sinus thrombosis in this study; Additional safety measures were implemented to mitigate risk of thrombosis in the lowered-AT setting, including updating bleed management guidelines, adding recommendations for monitoring and management of thrombotic events, clarification of definitions for bleeding episodes, revised recommendations for management of sepsis, and adding additional exploratory laboratory assessments; Frequency of visits increased in Schedule of Assessments from quarterly schedule in years 2 to 4, to a monthly schedule; Updated Benefit-Risk Assessment section accordingly with respect to the above new safety monitoring; Added Participant Education Module training to Schedule of Assessments; Clarification added that Adverse Events should include review for signs and symptoms of thrombosis at each visit; Revision of hepatic tests for hepatitis B; Clarifications added to the Perioperative Schedule of Assessments; Addition of acetaminophen restriction to <4 grams per day; Stipulation added that antifibrinolytics may be used as single agents, but may not be used in combination with factor or BPA; Addition of monthly AT monitoring visits after the final dose of ALN-AT3SC until AT activity level returns to ~60%; Addition of prothrombin activation fragment 1,2 to the coagulation panel, as exploratory marker of hemostasis; Addition of new stipulation for participants who present to the study site for management of bleed symptoms, samples were collected pre-treatment and post-treatment with factor or BPA for the exploratory purposes of characterizing TG and other coagulation parameters; Other minor corrections applied. |
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31 May 2018 |
• Clinical development and commercialization of fitusiran were granted from Alnylam Pharmaceuticals, Inc. to Genzyme Corporation, a Sanofi Company that assumed responsibility of the current clinical program. Therefore, the Alnylam logo and reference to Alnylam within the confidentiality statement were deleted from the title page. Throughout all sections of the protocol including the page headers and appendices, Alnylam had been changed to “the Sponsor” or “Sanofi Genzyme” as appropriate. In addition to change in Sponsor name, address, and contact details were also updated. The Sanofi Genzyme study code (LTE14762) has been added. The Alnylam study drug code ALN-AT3SC has also been updated to the generic drug name fitusiran. Sections regarding ‘Criteria for Study Termination’, ‘Study Drug Accountability’, ‘Guidelines for Reporting Product Complaints/Medical Device Incidents (Including Malfunctions)’, ‘Study Monitoring’, ‘Ethics’, ‘Data Handling and Record Keeping’, ‘Publication Policy’, and ‘Dissemination of Clinical Study Data’ had been created or updated to reflect the Sanofi Genzyme environment. |
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05 Mar 2019 |
• Study extension beyond 48 months: LTE14762 was an open label extension study of the long-term safety and efficacy of fitusiran in participants with hemophilia A or B, with or without inhibitory antibodies to factor VIII or IX. The primary objective of this study was the safety and tolerability assessed by incidence, severity, relatedness, and seriousness of adverse events, and laboratory assessments. This amendment, as study duration extension, was enabled participants who had completed 48 months study participation to continue to be treated and evaluated for long term safety and efficacy over 24 additional months or until fitusiran becomes commercially available, whichever occurs first.
• Prefilled syringe with safety system (PFS-S): Study drug provided in prefilled syringes either at the clinic or in a nonhealth care setting in a subset of participants receiving 80 mg monthly dose of fitusiran. The participant was trained on prefilled syringe self-administration. Participants who had missed more than 6 consecutive fitusiran dose for any reason should utilize the study drug provided as a vial and syringe for at least 3 injections prior to utilizing prefilled syringe.
• After at least a 2-year period of participation in the study, visits and assessments were adjusted with reducing frequency of routine clinical hematology/biochemistry and urinary laboratory evaluations, coagulation testing and exploratory biomarkers. The study duration of all participants has reached adequate follow-up to allow this adjustment. Based on gathered cumulative safety data during the study without any new safety concern or any new potential risk for fitusiran, the Sponsor determined that current visits and assessments frequency does not contribute additional information needed to evaluate participant’s safety beyond 2 years. This justifies the proposed visits and routine assessments frequency adjustment and was also reduce participant burden without compromising safety monitoring. |
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25 Nov 2020 |
• The main purpose of this amendment was to introduce a risk mitigation strategy for vascular thrombotic events in participants exposed to fitusiran. This strategy aims to decrease the level of antithrombin reduction via a change in the fitusiran dosing regimen. A Schedule of Assessments was added to accommodate the new dose regimen and to ensure optimal monitoring during the transition.
• Cholecystitis and symptomatic cholelithiasis were newly identified risks of fitusiran. As such, cholecystitis and cholelithiasis had been added to the protocol as AESIs.
• The amendment also included the addition of new guidance to facilitate the continuation of the study in the event of a regional or national government declared emergency such as the coronavirus disease 2019 pandemic. The guidance provided instruction on how to ensure continued dosing, monitor participants and perform assessments remotely when study participants were unable to travel to the site. |
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08 Dec 2020 |
• The main purpose of this amendment was to minimize the time between 2 AT measurements if the first AT result is <15%. |
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23 Jun 2021 |
• Antithrombin activity level was recently identified as a modifiable target for risk mitigation of vascular thrombosis in participants exposed to fitusiran and the protocol was subsequently amended to introduce a revised fitusiran dose and regimen with the aim of lessening AT reduction.
• The overall rationale for the amendment was to extend the study duration for some participants to allow all participants currently in the study to have at least an 18 calendar months period after introduction of the revised dose and regimen (regardless of whether the individual participant changed regimen) for purposes of collecting sufficient data for assessment of efficacy and safety of the revised dose and regimen. The study duration was extended for few participants who would complete the study as per current schedule before having at least 18 calendar months on study after resuming fitusiran under the new dose and regimen.
• The whole study duration (till last patient last visit) was not be impacted, and the extension was concern only some participants (those who would have completed the study before having this additional follow-up). |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | ||||||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | ||||||||||
None reported |