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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03549871

Registration number

NCT03549871

Ethics application status

Date submitted

25/05/2018

Date registered

8/06/2018

Date last updated

6/02/2023

Titles & IDs

Public title

A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis

Scientific title

ATLAS-PPX: an Open-label, Multinational, Switching Study to Describe the Efficacy and Safety of Fitusiran Prophylaxis in Patients With Hemophilia A and B Previously Receiving Factor or Bypassing Agent Prophylaxis.

Secondary ID [1]

2016-004087-19

Secondary ID [2]

EFC15110

Universal Trial Number (UTN)

Trial acronym

ATLAS-PPX

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Hemophilia

Condition category

Condition code

Blood

Clotting disorders

Human Genetics and Inherited Disorders

Other human genetics and inherited disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - Fitusiran
Treatment: Drugs - BPA prophylaxis
Treatment: Drugs - Factor (FVIII or FIX) prophylaxis

Experimental: Fitusiran - Cohort A \[inhibitor\]: participants with severe hemophilia A/B and inhibitory antibodies to coagulation factor VIII (FVIII)/factor IX (FIX) previously received BPA prophylaxis. Cohort B \[non-inhibitor\]: participants with severe hemophilia A/B without inhibitory antibodies to FVIII/FIX previously received factor prophylaxis. Participants from both cohorts was enrolled into 6-month factor/BPA prophylaxis period and continued their pre-study, regularly scheduled prophylaxis regimen with factor/BPAs. This period could be skipped by subgroup of Cohort A (hemophilia B with inhibitors to FIX and historical annualized bleeding rate \[ABR\] \>=20) that started directly with fitusiran. Post completing factor/BPA prophylaxis period, participants entered 7-month fitusiran treatment period (1-month onset+6-month efficacy) followed by AT follow-up/roll-over into LTE15174 (NCT03754790). Throughout study, participants could receive on-demand treatment for breakthrough BE with factor/BPAs, as appropriate.

Treatment: Drugs: Fitusiran
Pharmaceutical form: solution for injection Route of administration: subcutaneous

Treatment: Drugs: BPA prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous

Treatment: Drugs: Factor (FVIII or FIX) prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

Estimated Annualized Bleeding Rate (ABR)

Assessment method [1]

Bleeding episodes (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/total number of days in the respective period\*365.25. Estimated data were derived by using repeated measures negative binomial (NB) regression model.

Timepoint [1]

Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

Primary outcome [2]

Observed Annualized Bleeding Rate (ABR)

Assessment method [2]

A bleeding episode (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as 1 BE towards ABR. Any bleeding that began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/number of days in the respective period \*365.25.

Timepoint [2]

Secondary outcome [1]

Estimated Annualized Spontaneous Bleeding Rate

Assessment method [1]

BE: any occurrence of hemorrhage that might require administration of factor/BPA infusion. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. Spontaneous BE: BE occurrence for no apparent/known reason, particularly into joints, muscles, and soft tissues. ABR = total number of qualifying BE/number of days in respective period \*365.25. Estimated data was derived using repeated measures NB regression model.

Timepoint [1]

Secondary outcome [2]

Observed Annualized Spontaneous Bleeding Rate

Assessment method [2]

BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Spontaneous BE: bleeding event occurred for no apparent or known reason, particularly into joints, muscles and soft tissues. ABR = total number of qualifying BE/number of days in respective period \*365.25.

Timepoint [2]

Secondary outcome [3]

Estimated Annualized Joint Bleeding Rate

Assessment method [3]

BE: any hemorrhage that required administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection to treat BE at that location was considered part of original BE; counted as 1 BE towards ABR. Bleeding after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint ("aura") + increasing swelling/warmth over joint skin, increasing pain/progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of qualifying BE/number of days in respective period \*365.25. Estimated data were derived by using repeated measures NB regression model.

Timepoint [3]

Secondary outcome [4]

Observed Annualized Joint Bleeding Rate

Assessment method [4]

BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint (aura) increasing swelling/warmth over joint skin, increasing pain or progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of joint BE/number of days in respective period\*365.25.

Timepoint [4]

Secondary outcome [5]

Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period

Assessment method [5]

Haem-A-QoL: participant-reported questionnaire for adults aged \>=17 years with hemophilia and comprised of 46 items covering 10 domains. Physical health domain (PHD) is assessed with 5 items rated on 5-point Likert scale: never, rarely, sometimes, often or all the time. Raw score for PHD were transformed to scale ranged from 0 to 100, where lower scores = better physical health. Least square (LS) mean and 95% confidence interval (CI) by mixed model for repeated measure (MMRM) analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis \& fitusiran treatment) \& Baseline score (Month -6) as fixed effects.

Timepoint [5]

Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period

Secondary outcome [6]

Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period

Assessment method [6]

Haem-A-QoL: questionnaire for adults aged \>= 17 years with hemophilia; and comprised of 46 items covering 10 domains: physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality. Items were rated on 5-point Likert scale: never, rarely, sometimes, often or all time. Domain raw score was transformed to scale ranged from 0 to 100, where lower scores=better health. LS mean \& 95% CI by MMRM analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis \& fitusiran treatment) \& Baseline score (Month -6) as fixed effects.

Timepoint [6]

Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period

Secondary outcome [7]

Estimated Annualized Bleeding Rate in the Fitusiran Onset Period

Assessment method [7]

BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Estimated ABR and 95% CI was derived by using repeated measures NB regression model with logarithm of duration (years) that each participant spends in 1-Month fitusiran onset period matching BE data being analyzed as offset variable. ABR = total number of qualifying BE/number of days in respective period \*365.25.

Timepoint [7]

Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest

Secondary outcome [8]

Observed Annualized Bleeding Rate in the Fitusiran Onset Period

Assessment method [8]

BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and was counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in the 1-month onset period \*365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in 1-month onset period and excluded any bleeding events in period of intercurrent events.

Timepoint [8]

Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest

Secondary outcome [9]

Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period

Assessment method [9]

BE: defined as any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in the period of intercurrent events. ABR = total number of qualifying BE/number of days in respective period \*365.25.

Timepoint [9]

From Day 1 up to Day 190

Secondary outcome [10]

Observed Annualized Bleeding Rate in the Fitusiran Treatment Period

Assessment method [10]

BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original bleeding event and was counted as one BE towards ABR. Any bleeding that began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in treatment period \*365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in period of intercurrent events.

Timepoint [10]

from Day 1 up to Day 190

Secondary outcome [11]

Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates)

Assessment method [11]

Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: \[Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period\]\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agent: aPCC (unit per kilogram \[U/kg\]) were reported.

Timepoint [11]

Secondary outcome [12]

Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa)

Assessment method [12]

Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: rFVIIa (unit: micrograms per kg \[mcg/kg\]) were reported. Combined data of annualized weight-adjusted BPA consumption (mcg/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure.

Timepoint [12]

Secondary outcome [13]

Cohort B: Annualized Weight-adjusted Consumption of Factor

Assessment method [13]

Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: FVIII and FIX (unit: international Units \[IU\] per kg \[IU/kg\]) were reported.

Timepoint [13]

Eligibility

Key inclusion criteria

* Males, >=12 years of age.
* Severe hemophilia A or B (as evidenced by a central laboratory measurement at screening or documented medical record evidence of FVIII less than (<) 1 percent (%) or FIX level less than or equal to (<=) 2%).
* A minimum of 2 bleeding episodes required BPA treatment within the last 6 months prior to screening for participants with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode required factor treatment within the last 12 months prior to screening for participants without inhibitory antibodies to factor VIII or factor IX (Cohort B).
* Met either the definition of inhibitor or non-inhibitor participant as below:
* Inhibitor: Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met one of the following Nijmegen-modified Bethesda assay results criteria:
* Inhibitor titer of >=0.6 Bethesda Unit per milliliter (BU/mL) at screening, or
* Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of 2 consecutive titers >=0.6 BU/mL, or
* Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of anamnestic response
* The subgroup of participants in Cohort A participants might additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period:

* Hemophilia B with inhibitory antibody to Factor IX as defined above
* Not responding adequately to BPA treatment (historical ABR >=20) prior to enrollment
* In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted.
* Non-inhibitor: Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met each of the following criterion:
* Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at screening and
* No use of BPAs to treat bleeding episodes for at least the last 6 months prior to screening and
* No history of immune tolerance induction therapy within the past 3 years prior to screening.
* Documented prophylactic treatment with factor concentrates or BPAs for the treatment of hemophilia A or B for at least 6 months prior to screening.
* Adherent to the prescribed prophylactic therapy for at least 6 months prior to screening per Investigator assessment.
* Willed and complied with the study requirements and to provide written informed consent and assent.

Minimum age

12 Years

Maximum age

No limit

Sex

Males

Can healthy volunteers participate?

Key exclusion criteria

* Known co-existing bleeding disorders other than hemophilia A or B.
* AT activity <60% at screening.
* Co-existing thrombophilic disorder.
* Clinically significant liver disease.
* Active Hepatitis C virus infection.
* Acute or chronic Hepatitis B virus infection.
* HIV positive with a CD4 count of <200 cells per microliter.
* History of arterial or venous thromboembolism.
* Inadequate renal function.
* History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine (GalNAc).
* History of intolerance to subcutaneous injection(s).
* Any other conditions or comorbidities that made the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Phase 3

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

25/07/2018

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

25/03/2022

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Investigational Site Number 6104 - Prahran

Recruitment postcode(s) [1]

3181 - Prahran

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

California

Country [2]

China

State/province [2]

Beijing

Country [3]

Denmark

State/province [3]

Copenhagen

Country [4]

France

State/province [4]

Lyon

Country [5]

Ireland

State/province [5]

Crumlin

Country [6]

Israel

State/province [6]

Ramat-Gan

Country [7]

Italy

State/province [7]

Milano

Country [8]

Japan

State/province [8]

Nagoya

Country [9]

Japan

State/province [9]

Nishinomiya

Country [10]

Japan

State/province [10]

Saitama

Country [11]

Japan

State/province [11]

Tokyo

Country [12]

Korea, Republic of

State/province [12]

Busan

Country [13]

Korea, Republic of

State/province [13]

Daejeon

Country [14]

Korea, Republic of

State/province [14]

Seoul

Country [15]

Malaysia

State/province [15]

Ampang

Country [16]

Malaysia

State/province [16]

Johor Bahru

Country [17]

Malaysia

State/province [17]

Kota Kinabalu

Country [18]

Mexico

State/province [18]

San Pablo

Country [19]

Turkey

State/province [19]

Adana

Country [20]

Turkey

State/province [20]

Ankara

Country [21]

Turkey

State/province [21]

Antalya

Country [22]

Turkey

State/province [22]

Gaziantep

Country [23]

Turkey

State/province [23]

Istanbul

Country [24]

Turkey

State/province [24]

Izmir

Country [25]

Turkey

State/province [25]

Kayseri

Country [26]

Turkey

State/province [26]

Samsun

Country [27]

Turkey

State/province [27]

Van

Country [28]

Ukraine

State/province [28]

Kyiv

Country [29]

Ukraine

State/province [29]

Lviv

Country [30]

United Kingdom

State/province [30]

Glasgow

Country [31]

United Kingdom

State/province [31]

London

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

Genzyme, a Sanofi Company

Country

Ethics approval

Ethics application status

Summary

Brief summary

Primary Objective:

To characterize the frequency of bleeding episodes (BE) while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor concentrate or bypassing agent (BPA) prophylaxis.

Secondary Objectives:

* To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis:
* the frequency of spontaneous bleeding episodes
* the frequency of joint bleeding episodes
* health related quality of life (HRQOL) in participants greater than or equal to (\>=) 17 years of age
* To characterize the frequency of bleeding episodes during the onset and treatment periods in participants receiving fitusiran.
* To characterize the safety and tolerability of fitusiran.
* To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis.

Trial website

https://clinicaltrials.gov/study/NCT03549871

Public notes

Contacts

Principal investigator

Name

Clinical Sciences & Operations

Address

Sanofi

Country

Phone

Contact person for public queries

Name

Address

Country

Phone

Contact person for scientific queries

Data sharing statement

What supporting documents are/will be available?

Type	Other Details	Attachment
Study protocol		https://cdn.clinicaltrials.gov/large-docs/71/NCT03549871/Prot_000.pdf
Statistical analysis plan		https://cdn.clinicaltrials.gov/large-docs/71/NCT03549871/SAP_001.pdf

Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT03549871

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03549871