1.3. Study Design Rationale The ATLAS-PPX trial (ALN-AT3SC-009) is a multicenter, multinational, open-label Phase 3 switching study designed to demonstrate the efficacy and safety of fitusiran in patients with hemophilia A or B, with inhibitory…
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
* Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the BPA
prophylaxis period
Secondary outcome
Secondary
* Annualized spontaneous bleeding rate in the fitusiran efficacy period and the
BPA prophylaxis period
* Annualized joint bleeding rate in the fitusiran efficacy period and the BPA
prophylaxis period
* Change in Haem-A-QOL score in the fitusiran treatment period
* ABR in the fitusiran onset period
* ABR in fitusiran treatment period
Background summary
Hemophilia is a rare bleeding problem in which blood does not clot normally.
This means that people with hemophilia may bleed for longer periods of time
after an injury or, they may develop bleeds spontaneously. This happens because
people with hemophilia have little or none of certain clotting factors.
Clotting factors are proteins in the blood that help the body to stop bleeding
by forming a blood clot.
Fitusiran may make it possible to prevent or reduce the frequency of
hemophilia-related bleeding in patients with hemophilia. Your study doctor will
explain the detailed information below about how the drug is believed to
behave.
Study objective
1.3. Study Design Rationale
The ATLAS-PPX trial (ALN-AT3SC-009) is a multicenter, multinational, open-label
Phase 3 switching study designed to demonstrate the efficacy and safety of
fitusiran in patients with hemophilia A or B, with inhibitory antibodies to
factor VIII or IX who are currently treated with
prophylactic regimens of BPAs.
The switching design allows for an intra-patient control to enable examination
of the effect of the two treatment methods through comparison of the median ABR
during the BPA prophylaxis period and the median ABR of the same patient group
when receiving fitusiran, while limiting
confounding effects of different patient bleeding phenotypes and prophylaxis
therapy variability. The onset period duration reflects modeling data that
estimates it takes approximately 28 days to reach the therapeutic target range
in the majority of patients.
Given that the study design employed is a single treatment arm, with a switch
from prophylaxis to fitusiran for each patient, the study is not blinded.
The primary endpoint of the study is ABR in the fitusiran efficacy period and
the BPA prophylaxis period. ABR is a well-established endpoint that has been
used as the primary endpoint in global approvals of factor replacement and BPA
products. Secondary endpoints
characterize annualized spontaneous and joint bleeding rates, change in
Haem-A-QoL score in patients *17 years of age, ABR in the onset period, and
overall safety profile.
Characterization of bleeding episodes is clinically relevant to assess overall
bleeding episode protection. Joint bleeding episodes result in pain and
hemarthrosis, leading to progressive joint destruction, and hence are important
to assess. Haem-A-QOL is a hemophilia-specific HRQOL
survey instrument, has been used in other hemophilia clinical trials, has been
validated, reviewed by clinicians, and is considered the most appropriate HRQOL
tool available for use in the study.
The study population will be comprised of males *12 years of age; it is
appropriate to study fitusiran in adolescents (patients *12 to <18 years of
age) because the pathophysiology of disease progression and bleeding episode
management is the same as adults and self-management of
hemophilia typically begins at 12 years of age [6].
In the event of a breakthrough bleeding episode, on-demand use of BPAs will be
permitted throughout the entire study duration.
Study design
Study Design
The ATLAS-PPX trial (ALN-AT3SC-009) is a multicenter, multinational, open
label, Phase 3 study designed to evaluate the efficacy and safety of fitusiran
in male patients, aged *12 years, with hemophilia A or B, with inhibitory
antibodies to factor VIII (FVIII) or factor IX (FIX), who have
switched from prior bypassing agent (BPA) prophylaxis.
The study has 3 periods:
* 6-Month BPA prophylaxis period in which patients will continue their
prestudy, regularly scheduled prophylaxis regimen with BPAs
* 1-Month onset period in which patients receive their first dose of 80 mg
fitusiran while continuing their BPA prophylaxis for up to 7 days
* 6-Month fitusiran efficacy period in which patients receive 80 mg fitusiran
as a once monthly prophylaxis
Together, the 1-month onset period and the 6-month fitusiran efficacy period
constitute the fitusiran treatment period.
Bleeding events and doses of BPAs administered during the conduct of the study
will be recorded in an eDiary. Safety, quality of life, pharmacodynamic, and
pharmacokinetic data will also be collected.
Following the screening and prophylaxis periods, all patients will be treated
with fitusiran for a total of 7 months and will receive 7 SC injections of
fitusiran. Because the full PD effect of fitusiran is not achieved until
approximately 28 days after receiving the first dose, efficacy will be assessed
during the final 6 months of the fitusiran treatment period (Day 29 to Month
7).
Throughout the study, patients may receive on-demand treatment for breakthrough
bleeding episodes with BPAs. An independent data monitoring committee (DMC)
will oversee the safety and overall conduct of this study. The DMC will perform
periodic reviews of data during the course of the clinical trial, and on an ad
hoc basis for review of emergent safety data, as defined in the DMC Charter for
this clinical trial.
Patients who complete the study may be eligible for participation in an
open-label extension study. For patients who do not enroll in the extension
study, AT activity level will be monitored at monthly intervals following the
final fitusiran dose until activity levels return to approximately 60% per the
central laboratory, or per Investigator discretion in consultation with the
study Medical Monitor.
Intervention
Diagnosis and Main Eligibility Criteria
This study will include males with severe hemophilia A or B with inhibitors,
aged *12 years, who have been prescribed prophylactic treatment with BPAs for
at least 6 months prior to Screening. Diagnosis of severe hemophilia A or B
will be based on a central laboratory measurement or documented medical record
evidence of FVIII level <1% or FIX level *2%. Patients with inhibitors must
have used BPAs on demand to manage bleeding episodes for at least the last 6
months prior to Screening and must meet one of the following Nijmegen-modified
Bethesda
assay results criteria: 1) Inhibitor titer of *0.6 BU/mL at Screening, OR 2)
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 2
consecutive titers *0.6 BU/mL, OR 3) Inhibitor titer of <0.6 BU/mL at Screening
with medical record evidence of anamnestic response. A minimum
of 2 bleeding episodes requiring BPA treatment within the last 6 months prior
to Screening is required.
Investigational Product, Dose and Mode of Administration
Fitusiran is a subcutaneously (SC) administered GalNAc-conjugated siRNA
targeting liver-expressed messenger RNA (mRNA) for AT.
Patients will receive open-label fitusiran 80 mg as an SC injection once
monthly, for a total of 7 months; dosing will begin on Day 1 of the fitusiran
treatment period.
Reference Therapy, Dose and Mode of Administration
During the BPA prophylaxis period, patients will continue BPA prophylaxis as
treatment for hemophilia on a regimen consistent with recommendations in the
approved prescribing information, allowing for adjustment to individual patient
response, and designed to decrease spontaneous bleeding.
Dose and mode of administration will be per Investigator discretion; bleeding
episode management should be per the local standard practice for episodic use
of BPAs and as per Investigator discretion.
Patients will continue to receive BPA prophylaxis for the first 7 days of the
onset period. Subsequently, breakthrough bleeding episodes will be treated
with on-demand BPA therapy as necessary per the bleeding episode management
guidelines.
Duration of Treatment
The duration of treatment with fitusiran is 7 months. The estimated total time
on study, inclusive of Screening, for each patient is up to 15 months for
patients who enroll in the extension study. The estimated total time on study
may be up to 21 months in patients who do not enroll in the extension
study due to the requirement for an additional 6 months of follow-up for
monitoring of AT levels.
Study burden and risks
see schedule of event in the protocol and section intervention above
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Age
Inclusion criteria
1. Males *12 years of age.
2. Severe hemophilia A or B as evidenced by:
a . A central laboratory measurement or documented medical record evidence of FVIII <1% or FIX level *2% at Screening.
3. A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months prior to Screening.
4. Must meet the definition of inhibitor patient as below:
Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet one of the following Nijmegen-modified Bethesda assay results criteria:
- Inhibitor titer of *0.6 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
5. Prescribed prophylactic treatment (documented in the medical or pharmacy records) of hemophilia with BPAs for at least 6 months prior to Screening; the regimen must be consistent with the approved prescribing information for the product or local recommendations, allowing for adjustment to individual patient response, and designed to decrease spontaneous bleeding.
6. Adherent to the prescribed prophylactic therapy for at least 6 months prior to Screening per Investigator assessment.
7. Willing and able to comply with the study requirements and to provide written informed consent and assent in the case of patients under the age of legal consent, per local and national requirements.
Exclusion criteria
1. Known co-existing bleeding disorders other than hemophilia A or B, ie, Von Willebrand*s disease, additional factor deficiencies, or platelet disorders.
2. Current participation in immune tolerance induction therapy (ITI).
3. AT activity <60% at Screening, as determined by central laboratory measurement
4. Presence of clinically significant liver disease, or as indicated by any of the conditions below:
a. INR >1.2;
b. ALT and/or AST >1.5× upper limit of normal reference range (ULN);
c. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert*s Syndrome);
d. History of portal hypertension, esophageal varices, or hepatic encephalopathy;
e. Presence of ascites by physical exam.
5. Hepatitis C virus antibody positive, except patients with a history of HCV infection who meet both conditions a. and b.:
a. Completed curative treatment at least 12 weeks prior to enrollment and attained sustained virologic response as documented by a negative HCV RNA at screening, or they have spontaneously cleared infection as documented by negative HCV RNA at Screening.
b. No evidence of cirrhosis according to one of the following assessments:
* FibroScan <12.5 kPa (where available), or
* FibroTest score <0.75 and APRI <2 (if FibroScan unavailable)
6. Presence of acute hepatitis, ie, hepatitis A, hepatitis E.
7. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or HBsAg positive).
8. Platelet count *100,000/*L.
9. Presence of acute infection at Screening.
10. Known to be HIV positive with CD4 count <200 cells/*L.
11. Estimated glomerular filtration rate *45 mL/min/1.73m2 (using the Modification of Diet in Renal Disease [MDRD] formula).
12. Co-existing thrombophilic disorder, as determined by presence of any of the below as identified at central laboratory (or via historical results, where available):
a. FV Leiden mutation (homozygous or heterozygous)
b. Protein S deficiency
c. Protein C deficiency
d. Prothrombin mutation (G20210A; homozygous and heterozygous)
13. History of antiphospholipid antibody syndrome.
14. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke. Patients who have experienced thrombosis associated with indwelling venous access may be enrolled.
15. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin that has been successfully treated.
16. Any condition (eg, medical concern), which in the opinion of the Investigator, would make the patient unsuitable for dosing on Day 1 or which could interfere with the study compliance, the patient*s safety and/or the patient*s participation in the completion of the
treatment period of the study. This includes significant active and poorly controlled (unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders unrelated to hemophilia identified by key laboratory abnormalities or medical history.
17. At Screening, anticipated need of surgery during the study or planned surgery scheduled to occur during the study.
18. Completion of a surgical procedure within 14 days prior to Screening, or currently receiving additional factor concentrate or BPA infusion for postoperative hemostasis.
19. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.
20. Inadequate venous access, as determined by the Investigator, to allow the blood draws required by the study protocol.
21. History of intolerance to SC injection(s).
22. Current or future participation in another clinical study, scheduled to occur during this study, involving an investigational product other than fitusiran or an investigational device; in order to participate in this study, patient must discontinue the investigational product or investigational device at least 30 days (or 5× the investigational product halflife, whichever is longer) prior to dosing (Day 1).
23. Current or prior participation in a gene therapy trial.
24. History of alcohol abuse within the 12 months before Screening. Alcohol abuse is defined as regular weekly intake of more than 14 units (unit: 1 glass of wine [approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = * pint of beer [approximately 284 mL]).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004087-19-NL |
| CCMO | NL63089.000.18 |