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| ID | Type | Description | Link |
|---|---|---|---|
| ALN-AT3SC-004 | Other Identifier | Alnylam | |
| 2016-001464-11 | EudraCT Number |
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Primary Objective:
-To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by the frequency of bleeding episodes.
Secondary Objectives:
To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by:
To determine the frequency of bleeding episodes during the onset period.
To determine the safety and tolerability of fitusiran.
The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, was up to 11 months for all participants in the factor on-demand arm and for participants in the fitusiran arm who enrolled in the extension study (LTE15174). The estimated total time on the study was up to 17 months for participants in the fitusiran treatment arm who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.
Participants who completed the study will be eligible for an open-label extension study LTE15174 (NCT03754790).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Factor On-demand | Experimental | Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months. |
|
| Fitusiran 80 mg Prophylaxis | Experimental | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| fitusiran | Drug | by SC injection |
| |
| factor concentrates |
| Measure | Description | Time Frame |
|---|---|---|
| Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of by-passing agents (BPA) or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to (<=) 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) presents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP). | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on the data collected during EP). | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Measure | Description | Time Frame |
|---|---|---|
| Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of Day 246 or last day of bleeding follow up (maximum duration of TP: from Day 1 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during TP). |
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Inclusion Criteria:
Males, >=12 years of age.
Severe hemophilia A or B without inhibitors.
Severity confirmed by a central laboratory where FVIII level was less than (<) 1 percent (%) or Factor IX (FIX) level was less than or equal to (<=) 2% at Screening.
On-demand use of factor concentrate to manage bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:
A minimum of 6 bleeding episodes requiring factor concentrate treatment within the last 6 months prior to Screening.
Willing and complied with the study requirements and to provide written informed consent and assent.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Sciences & Operations, MD | Sanofi | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Investigational Site Number 0140 | Little Rock | Arkansas | 72202 | United States | ||
| Investigational Site Number 128 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37003278 | Derived | Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, You CW, Xu W, Malan N, Frenzel L, Bagot CN, Stasyshyn O, Chang CY, Poloskey S, Qiu Z, Andersson S, Mei B, Pipe SW. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2023 May;10(5):e322-e332. doi: 10.1016/S2352-3026(23)00037-6. Epub 2023 Mar 29. | |
| 34922648 |
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Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
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120 participants were randomized in 2:1 ratio to fitusiran prophylaxis and on-demand arms by interactive response system; stratified by the number of bleeding episodes in the 6 months prior to Screening (less than or equal to [<=10] versus greater than [>]10) and by hemophilia type (hemophilia A or B).
The study was conducted at 64 centers in 19 countries. A total of 177 participants were screened between 1 March 2018 to 22 May 2020, of which 57 participants were screen failure. Screen failures were mainly due to presence of a co-existing thrombophilic disorder. In total, 120 participants were enrolled in the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Factor On-demand | Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 27, 2018 | Jan 7, 2022 |
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| Drug |
by intravenous (IV) injection |
|
| From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1- year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of TP: from Day 1 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during TP). | From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP). | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246).This OM presents observed results (i.e., descriptive statistics values based on data collected during EP). | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP). | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP). | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
| Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score at Month 9 | Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 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 was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represented greater impairment. Change from baseline in physical health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health. | Baseline (Day 1), Month 9 |
| Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 | Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 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 was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better health. Haem-A-QoL total score was average of all domain scores and ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health. | Baseline (Day 1), Month 9 |
| Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period | ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM presents estimated results (i.e., results received by applying NB regression model on data collected during onset period). | From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment-emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the factor on-demand arm. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. | From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up) |
| Gainesville |
| Florida |
| 32610 |
| United States |
| Investigational Site Number 103 | Tampa | Florida | 33607 | United States |
| Investigational Site Number 102 | Chicago | Illinois | 60612-3833 | United States |
| Investigational Site Number 119 | New Orleans | Louisiana | 70112 | United States |
| Investigational Site Number 125 | Ann Arbor | Michigan | 48109 | United States |
| Investigational Site Number 111 | Las Vegas | Nevada | 89135 | United States |
| Investigational Site Number 110 | Akron | Ohio | 44308 | United States |
| Investigational Site Number 6101 | Camperdown | 2050 | Australia |
| Investigational Site Number 6103 | Murdoch | 6961 | Australia |
| Investigational Site Number 6104 | Prahran | 3181 | Australia |
| Investigational Site Number 8604 | Beijing | 100045 | China |
| Investigational Site Number 8602 | Guangzhou | 510515 | China |
| Investigational Site Number 8605 | Hangzhou | 89147 | China |
| Investigational Site Number 8603 | Shanghai | 200025 | China |
| Investigational Site Number 8601 | Tianjin | 300020 | China |
| Investigational Site Number 4501 | Copenhagen | 2100 | Denmark |
| Investigational Site Number 3303 | Lyon | 69677 | France |
| Investigational Site Number 3305 | Paris | 75015 | France |
| Investigational Site Number 3301 | Rouen | 76038 | France |
| Investigational Site Number 4904 | Berlin | 10249 | Germany |
| Investigational Site Number 4905 | Frankfurt am Main | 60590 | Germany |
| Investigational Site Number 4906 | Leipzig | 4103 | Germany |
| Investigational Site Number 3602 | Budapest | 1134 | Hungary |
| Investigational Site Number 9102 | Bangalore | 560034 | India |
| Investigational Site Number 9104 | Jaipur | 302017 | India |
| Investigational Site Number 9106 | Lucknow | 226003 | India |
| Investigational Site Number 9109 | Mumbai | 400012 | India |
| Investigational Site Number 9108 | Mumbai | 400022 | India |
| Investigational Site Number 9111 | Mumbai | India |
| Investigational Site Number 9103 | Pune | 411001 | India |
| Investigational Site Number 9105 | Vellore | 632004 | India |
| Investigational Site Number 9701 | Ramat Gan | 52621 | Israel |
| Investigational Site Number 3904 | Padova | 35128 | Italy |
| Investigational Site Number 8105 | Isehara | Japan |
| Investigational Site Number 8104 | Saitama | Japan |
| Investigational Site Number 6004 | Ampang | 68000 | Malaysia |
| Investigational Site Number 6002 | Johor Bahru | 80100 | Malaysia |
| Investigational Site Number 6003 | Kota Kinabalu | 88586 | Malaysia |
| Investigational Site Number 2701 | Parktown | 2193 | South Africa |
| Investigational Site Number 2702 | Port Elizabeth | 6001 | South Africa |
| Investigational Site Number 8201 | Busan | 602-739 | South Korea |
| Investigational Site Number 8202 | Daejeon | 35233 | South Korea |
| Investigational Site Number 8204 | Seoul | 3722 | South Korea |
| Investigational Site Number 3402 | Madrid | 28046 | Spain |
| Investigational Site Number 8807 | Taichung | 40447 | Taiwan |
| Investigational Site Number 8805 | Taichung | 40705 | Taiwan |
| Investigational Site Number 8804 | Taipei | 100 | Taiwan |
| Investigational Site Number 8801 | Taipei | 110 | Taiwan |
| Investigational Site Number 8808 | Taoyuan | 33305 | Taiwan |
| Investigational Site Number 9002 | Adana | ?01130 | Turkey (Türkiye) |
| Investigational Site Number 9004 | Antalya | 07059 | Turkey (Türkiye) |
| Investigational Site Number 9008 | Gaziantep | 27100 | Turkey (Türkiye) |
| Investigational Site Number 9005 | Istanbul | 34093 | Turkey (Türkiye) |
| Investigational Site Number 9003 | Izmir | TR-35100 | Turkey (Türkiye) |
| Investigational Site Number 9009 | Kayseri | 38039 | Turkey (Türkiye) |
| Investigational Site Number 9006 | Samsun | 55200 | Turkey (Türkiye) |
| Investigational Site Number 8001 | Kyiv | 04060 | Ukraine |
| Investigational Site Number 8003 | Kyiv | ?01135 | Ukraine |
| Investigational Site Number 8002 | Lviv | 79044 | Ukraine |
| Investigational Site Number 8005 | Mykolaiv | 54058 | Ukraine |
| Investigational Site Number 4402 | Glasgow | G4 0SF | United Kingdom |
| Investigational Site Number 4407 | London | E1 2ES | United Kingdom |
| Investigational Site Number 4401 | London | SE1 9RT | United Kingdom |
| Derived |
| Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available. |
| Fitusiran 80 mg Prophylaxis |
Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
| Treated |
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| COMPLETED |
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| NOT COMPLETED |
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Analysis was performed on intent-to-treat (ITT) population which included all randomized participants analyzed according to the randomized arm.
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| ID | Title | Description |
|---|---|---|
| BG000 | Factor On-demand | Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months. |
| BG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
| BG002 | Total Title |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of by-passing agents (BPA) or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to (<=) 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) presents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Number | 95% Confidence Interval | episodes per participant per year | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Primary | Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on the data collected during EP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Median | Inter-Quartile Range | episodes per participant per year | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of Day 246 or last day of bleeding follow up (maximum duration of TP: from Day 1 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during TP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Number | 95% Confidence Interval | episodes per participant per year | From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1- year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of TP: from Day 1 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during TP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Median | Inter-Quartile Range | episodes per participant per year | From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Number | 95% Confidence Interval | episodes per participant per year | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246).This OM presents observed results (i.e., descriptive statistics values based on data collected during EP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Median | Inter-Quartile Range | episodes per participant per year | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or the last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Number | 95% Confidence Interval | episodes per participant per year | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of Day 246 or last day of bleeding follow up (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Median | Inter-Quartile Range | episodes per participant per year | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest |
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| Secondary | Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score at Month 9 | Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 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 was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represented greater impairment. Change from baseline in physical health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health. | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Least Squares Mean | 95% Confidence Interval | scores on a scale | Baseline (Day 1), Month 9 |
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| Secondary | Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 | Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 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 was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better health. Haem-A-QoL total score was average of all domain scores and ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health. | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Least Squares Mean | 95% Confidence Interval | scores on a scale | Baseline (Day 1), Month 9 |
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| Secondary | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period | ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM presents estimated results (i.e., results received by applying NB regression model on data collected during onset period). | Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure. | Posted | Number | 95% Confidence Interval | episodes per participant per year | From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest |
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| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment-emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the factor on-demand arm. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. | Analysis was performed on safety analysis set that included all participants who received at least 1 dose of study drug or were randomized to on-demand arm, analyzed according to the actual treatment received. | Posted | Count of Participants | Participants | From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up) |
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From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up).
Treatment-emergent AE were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the factor on-demand arm. Analysis was performed on safety analysis set.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Factor On-demand | Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months. | 0 | 40 | 5 | 40 | 8 | 40 |
| EG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. | 0 | 79 | 5 | 79 | 45 | 79 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Epidural Haemorrhage | Injury, poisoning and procedural complications | MedDRA24.0 | Systematic Assessment |
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| Humerus Fracture | Injury, poisoning and procedural complications | MedDRA24.0 | Systematic Assessment |
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| Subdural Haemorrhage | Injury, poisoning and procedural complications | MedDRA24.0 | Systematic Assessment |
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| Tibia Fracture | Injury, poisoning and procedural complications | MedDRA24.0 | Systematic Assessment |
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| Diplopia | Eye disorders | MedDRA24.0 | Systematic Assessment |
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| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA24.0 | Systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA24.0 | Systematic Assessment |
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| Lower Respiratory Tract Infection | Infections and infestations | MedDRA24.0 | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA24.0 | Systematic Assessment |
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| Suicidal Ideation | Psychiatric disorders | MedDRA24.0 | Systematic Assessment |
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| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA24.0 | Systematic Assessment |
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| Cholecystitis | Hepatobiliary disorders | MedDRA24.0 | Systematic Assessment |
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| Cholelithiasis | Hepatobiliary disorders | MedDRA24.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alanine Aminotransferase Increased | Investigations | MedDRA24.0 | Systematic Assessment |
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| Aspartate Aminotransferase Increased | Investigations | MedDRA24.0 | Systematic Assessment |
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| Blood Bilirubin Increased | Investigations | MedDRA24.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA24.0 | Systematic Assessment |
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| Abdominal Pain | Gastrointestinal disorders | MedDRA24.0 | Systematic Assessment |
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| Abdominal Pain Upper | Gastrointestinal disorders | MedDRA24.0 | Systematic Assessment |
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| Gastritis | Gastrointestinal disorders | MedDRA24.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA24.0 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA24.0 | Systematic Assessment |
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| Upper Respiratory Tract Infection | Infections and infestations | MedDRA24.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA24.0 | Systematic Assessment |
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| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA24.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA24.0 | Systematic Assessment |
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The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Trial Transparency Team | Sanofi aventis recherche & développement | 800-633-1610 | 6# | Contact-US@sanofi.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 22, 2020 | Jan 7, 2022 | SAP_001.pdf |
| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| D002836 | Hemophilia B |
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D040181 | Genetic Diseases, X-Linked |
| ID | Term |
|---|---|
| D006425 | Hemic and Lymphatic Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
Not provided
Not provided
| ID | Term |
|---|---|
| C000632624 | fitusiran |
| C025667 | prothrombin complex concentrates |
Not provided
Not provided
Not provided
| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| OG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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| OG001 |
| Fitusiran 80 mg Prophylaxis |
Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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| OG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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| OG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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| OG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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| OG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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| OG001 | Fitusiran 80 mg Prophylaxis | Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. |
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