1.3. Study Design Rationale The ATLAS-INH trial (ALN-AT3SC-003) is a multicenter, multinational, randomized, openlabel Phase 3 study designed to demonstrate the efficacy and safety of fitusiran in patients with haemophilia A or B with inhibitory…
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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. Some people with hemophilia also develop *inhibitors*
against their standard factor treatment. *Inhibitors* are antibodies (a type of
protein made by your immune system) that stop your factor treatment from
working, which makes forming blood clots even more difficult.
Fitusiran may make it possible to prevent or reduce the frequency of
hemophilia-related bleeding in patients with hemophilia.
Study objective
1.3. Study Design Rationale
The ATLAS-INH trial (ALN-AT3SC-003) is a multicenter, multinational,
randomized, openlabel Phase 3 study designed to demonstrate the efficacy and
safety of fitusiran in patients with haemophilia A or B with inhibitory
antibodies to FVIII or FIX who are
Currently treated with ondemand BPAs.
The primary objective is to assess the efficacy of fitusiran on prevention or
reduction of bleeding episodes. Secondary objectives are to assess the
efficacy of fitusiran on: the number and type ofbleeding episodes; HRQOL; and
to determine the safety and tolerability of fitusiran.
Blinding is not considered feasible for this study since differences in
treatment for each study
arm cannot be blinded. The open-label, randomized study design is justified
because safety
monitoring of theoretical risks such as transaminitis or thrombosis can be
objectively verified by laboratory monitoring or objective visualization, eg,
ultrasound or CT. Therefore the safety monitoring of the studied population
does not require blinding.
The primary endpoint of the study is ABR in the fitusiran efficacy period (Day
29 to EOS).
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 ABR in
the treatment period, annualized spontaneous and joint bleeding rates, change
in Haem-A-QOL score in patients =17 years of age, ABR in the onset period, and
the 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 that has been validated
in other hemophilia clinical trials and is considered the most appropriate
HRQOL tool for this 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] A similar study in hemophilia patients without inhibitors
(ALN-AT3SC-004) is being conducted concurrently to this study.
To protect against bias, patients will be assigned to fitusiran (fitusiran
treatment arm; N=36) or on-demand BPA therapy (on-demand arm; N=18) by
stratified randomization.
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. Efficacy of fitusiran will be assessed over the remaining 8 months
of the study (Day 29 to Month 9).
In the event of a breakthrough bleeding episode, on-demand use of BPAs will be
permitted
throughout the entire study duration (see Section 6.3.1).
Study design
an open-label, multinational, switching study to describe the efficacy and
safety of fitusiran prophylaxis in patients with hemophilia A and B with
inhibitory antibodies to factor VIII or IX previously receiving bypassing agent
prophylaxis.
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.
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.
Study burden and risks
Fitusiran can increase the risk of developing blood clots by raising the
AT-level in the blood.
The use of factor or bypassing agents while fitusiran is administered can
increase the risk on developing blood clots even further. Blood clots can cause
problems in the functioning of organs (e.g. lungs, heart, brain and kidneys),
or cause swelling and pain in the arms or legs. In many cases blood clots are
treatable with blood thinning medication, but sometimes blood clots can cause
serious problems or death. In a clinical study with firusiran one patient
developed a blood clot during treatment that resulted in death, and taking
factor while receiving fitusiran may have been related to this event.
Risk on changes in liver function
As fitusiran is designed to go to the liver, there is a potential for changes
in liver function tests. Abnormal liver tests have been seen in humans treated
with fitusiran. Most of these cases have been mild and returned to normal.
Risk on bleeding
Subjects who are receiving fitusiran may be asked to use lower doses of factor
or BPA than they are used to for treating bleeding events.
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Age
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the study:
1. Males <=12 years of age.
2. Severe hemophilia A or B with inhibitors evidenced by:
a. A central laboratory measurement or documented medical record evidence of FVIII
<1% or FIX level <=2% at Screening.
b. On-demand use of bypassing agents to manage 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
3. A minimum of 6 bleeding episodes requiring bypassing agent treatment within the last
6 months prior to Screening.
4. 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
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in the study:
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. Current use of bypassing agents as regularly administered prophylaxis designed to
prevent spontaneous bleeding episodes.
4. AT activity <60% at Screening, as determined by central laboratory measurement.
5. 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
6. 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)
7. Presence of acute hepatitis, ie, hepatitis A, hepatitis E.
8. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or
HBsAg positive).
9. Platelet count =100,000/µL.
10. Presence of acute infection at Screening.
11. Known to be HIV positive with CD4 count <200 cells/µL.
12. Estimated glomerular filtration rate =45 mL/min/1.73m2 (using the Modification of Diet
in Renal Disease [MDRD] formula).
13. 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 or heterozygous)
14. History of antiphospholipid antibody syndrome.
15. 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.
16. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin
that has been successfully treated.
17. 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.
18. At Screening, anticipated need of surgery during the study or planned surgery scheduled
to occur during the study.
19. Completion of a surgical procedure within 14 days prior to Screening, or currently
receiving additional bypassing agent infusion for postoperative hemostasis.
20. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or
GalNAc.
21. Inadequate venous access, as determined by the Investigator, to allow the blood draws
required by the study protocol.
22. History of intolerance to SC injection(s).
23. 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).
24. Current or prior participation in a gene therapy trial.
25. 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 | EUCTR2016-001463-36-NL |
| ClinicalTrials.gov | NCT03417102 |
| CCMO | NL63088.000.18 |