Primary Efficacy Objective (Blinded Treatment Period)• To demonstrate the efficacy of rilzabrutinib versus placebo in participants with refractory/relapsed ITP, based on the durability of platelet response during the last12 weeks of the 24-week…
ID
Source
Brief title
Condition
- Platelet disorders
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint (Blinded Treatment Period)
• Durable platelet response defined as a proportion of participants able to
achieve platelet counts at or above 50,000/µL for >= two-thirds of at least 8
non-missing weekly scheduled platelet measurements during the last 12 weeks of
the 24 week blinded treatment period in the absence of rescue therapy, provided
that at least 2 non-missing weekly scheduled platelet measurements are at or
above 50,000/µL during the last 6 weeks of the 24-week blinded treatment
period; see Appendix 10.7 for country specific definition of durable platelet
response (EU [EEA countries] and UK).
Secondary outcome
Key Secondary Efficacy Endpoints (Blinded Treatment Period)
• Number of weeks with platelet count >=50,000/µL OR between >=30,000/µL and
<50,000/µL and at least doubled from baseline over the 24-week blinded
treatment period in the absence of rescue therapy
• Number of weeks with platelet counts >=30,000/µL and at least doubled from
baseline over the 24-week blinded treatment period in the absence of rescue
therapy
• Time to first platelet count of >=50,000/µL OR between >=30,000/µL and
<50,000/µL and doubled from baseline
• Proportion of participants requiring rescue therapy during the 24-week
blinded treatment period
• Change from baseline on Item 10 of the ITP-PAQ (ie, physical fatigue) in
adult participants (>=18 years) at Week 13
See Appendix 10.7 for EU (EEA countries) and UK specific requirements.
Other Secondary Endpoints
Efficacy Endpoint
• Stability of response defined as the proportion of participants able to
achieve stable platelet response, which is defined as no 2 scheduled visits, at
least 4 weeks apart, with a platelet count less than 50,000/µL, without an
intervening visit with a platelet count >=50,000/µL, within a period of 24 weeks
following initial achievement of the platelet response (initial platelet
response defined as platelet count >=50,000/µL within 12 weeks of initiation of
treatment with rilzabrutinib during the study)
Safety Endpoints
• Frequency and severity of TEAEs
• Frequency and severity of bleeding TEAEs
• Change from baseline in physical examination, ECG, vital signs and clinical
laboratory tests results: serum chemistry and hematology (except for platelet
counts included in the primary efficacy endpoint)
Pharmacokinetic Endpoints
• Plasma concentrations of rilzabrutinib
Quality of Life (QOL) Endpoints
• Change from baseline on the Symptoms, Bother and Activity domains of the ITP
Patient Assessment Questionnaire (ITP-PAQ) in adult participants (>=18 years)
• Change from baseline in disease-specific QoL as measured by the Kids* ITP
Tools (ITP-KIT) score in pediatric participants
Background summary
Immune Thrombocytopenia (ITP) is characterized by autoantibody-mediated
destruction of platelets and impaired platelet production, which result in
thrombocytopenia and a predisposition to bleeding associated with morbidity and
mortality.
In general, pharmacotherapy (corticosteroids [CSs], intravenous immunoglobulin
[IVIg] or Anti D) is used for symptomatic patients with low platelet counts for
reducing platelet destruction. While a majority of patients respond initially
to CSs, the rate of continued remission is low. Second line therapies include
rituximab and splenectomy and are associated with risk of sepsis and immune
suppression. Thrombopoietin (TPO) mimetics (Bussel 2007) are approved for the
treatment of patients with chronic ITP who have not had sufficient responses to
CSs, IVIg, or splenectomy. Second-line treatment with TPO-RAs have a clinical
response rate of 80%, however approximately one third of patients discontinue
TPO-RAs due to lack of response (Ghanima 2019). Novel, safe and effective, oral
treatments to maintain platelet counts in this setting would be a significant
therapeutic advantage. Thus, there remains a high unmet medical need for novel,
safe and effective oral therapies for ITP.
A BTK inhibitor such as rilzabrutinib has the potential to target multiple
pathways and cell types involved in inflammation and autoimmunity.
There is preliminary evidence to support the role of BTK inhibition in patients
with autoimmune cytopenias (Rogers 2016, Montillo 2017), where sequential
episodes of severe autoimmune hemolytic anemia and ITP ceased after initiation
of treatment with ibrutinib, a BTK/epidermal growth factor receptor
/interleukin-2-inducible T-cell kinase inhibitor, in patients with chronic
lymphatic leukemia (CLL).
Preliminary review of data from patients with ITP (Study PRN1008-010 Part A)
demonstrated a potentially favorable platelet response in the patient
population and in patients who received the 400 mg BID dose of rilzabrutinib.
Participants that failed multiple treatments for ITP were able to achieve a
rapid and durable platelet response.
Study objective
Primary Efficacy Objective (Blinded Treatment Period)
• To demonstrate the efficacy of rilzabrutinib versus placebo in participants
with refractory/relapsed ITP, based on the durability of platelet response
during the last
12 weeks of the 24-week blinded treatment period in the absence of rescue
therapy
Key Secondary Efficacy Objectives (Blinded Treatment Period)
• To evaluate the effect of rilzabrutinib versus placebo on the number of weeks
with platelet count >=50,000/µL OR between >=30,000/µL and <50,000/µL and at
least doubled
from baseline, over the 24-week blinded treatment period in the absence of
rescue therapy
• To evaluate the effect of rilzabrutinib versus placebo on the number of weeks
with platelet counts >=30,000/µL and at least doubled from baseline over the
24-week blinded
treatment period in the absence of rescue therapy
• To evaluate the effect of rilzabrutinib versus placebo on the time to first
platelet count of >=50,000/µL OR between >=30,000/µL and <50,000/µL and at least
doubled from baseline
• To evaluate the effect of rilzabrutinib versus placebo on the proportion of
participants requiring rescue therapy
• To evaluate the effect of rilzabrutinib versus placebo on the change from
baseline on Item 10 of the ITP-PAQ (ie, physical fatigue) in adult participants
(>=18 years) at Week 13
Study design
This is a global, randomized, parallel-group, double-blind, multicenter
clinical study in patients with primary ITP who had a response to either
intravenous immunoglobulin (IVIg) or corticosteroid (CS) that was not sustained.
After providing informed consent, participants will enter a 28-day screening
period. Upon completion of the screening period, participants who satisfy all
the inclusion criteria and none of the exclusion criteria of this protocol will
be randomized in a 2:1 allocation ratio to one of two study arms: rilzabrutinib
or placebo.
Randomization will be carried out separately for the two age groups. For the
adult group, stratified permuted block randomization will be implemented; for
the pediatric group, dynamic randomization algorithm (minimization) will be
implemented. The factors used for stratification (for adults) or balance (for
pediatric participants) are splenectomy status (yes/no), and by severity of
thrombocytopenia (Inclusion Criteria 3 platelet counts <15,000/µL or >=15,000/
µL).
After randomization, participants will start a blinded treatment period of up
to 24 weeks followed by an open-label period of 28 weeks during which all
participants will receive rilzabrutinib, and then a 4 week safety follow-up
period or long-term extension.
At the end of 12 weeks of treatment, participants will be assessed for
achieving a platelet response defined as:
a) platelet count of >=50,000/µL OR a platelet count between >=30,000/µL and
<50,000/µL and at least doubled from baseline at any time during the first 12
weeks and
b) absence of rescue medication in the 4 weeks prior to the elevated platelet
count that meets platelet response criteria.
Figure 1 depicts the decision process for assessing response. Baseline is
defined as the average of all the participant*s predose platelet counts
(Screening and Study Day 1).
• Participants who respond will continue the blinded treatment period for a
total of 24 weeks before entering the open label period.
• Participants who do not respond (including participants who receive rescue
medication after 8 weeks of treatment) may discontinue from the study or enter
the 28-week open label period at the end of Week 12, receiving treatment with
400 mg twice daily (BID) of rilzabrutinib. The initial study medication
assignment will remain blinded.
Concomitant ITP medications (an oral CS and/or a thrombopoietin receptor
agonist [TPO RA]) will be permitted in both treatment arms and must be
maintained at stable doses from 14 days before Study Day 1 until the last dose
of study medication. Reductions in the doses of concomitant ITP medications
will be permitted for associated safety concerns only.
The use of rescue medications (one of IVIg, high-dose CSs, platelet infusion,
or anti-D immunoglobulin infusion) intended to increase platelet counts or
prevent bleeding when platelet counts are less than 20,000/µL, or for bleeding
or wet purpura, will be allowed.
After completing the open label period, participants who demonstrate a platelet
response defined as platelet counts >=50,000/µL or >=30,000/µL and at least
doubled from baseline at >=50% of the visits without receiving rescue therapy
while on treatment during the last 8 weeks of the open label period, will be
allowed to enter the LTE.
Participant(s) may continue in the LTE until:
a) The participant is no longer responding (platelet counts <30,000/µL or less
than 20,000/µL above baseline on two consecutive visits)
b) The drug is no longer being developed by the Sponsor for ITP
c) The program is stopped for safety reasons or
d) The drug becomes commercially available in the participant*s country.
Safety Measures Due to COVID-19 Pandemic
Due to the COVID-19 pandemic, safety measures have been implemented to ensure
continued supply of study medication and safety monitoring for participants.
These measures are described in the *Guidelines to Sites for Delayed
Participant Visits or Missed Visits due to travel restrictions and any
foreseeable impacts of COVID-19.* When the COVID-19 pandemic resolves, the
measures will be repealed back to the previous state as government rules and
benefit/risk assessment allow.
Intervention
Participants will receive one 400 mg tablet of rilzabrutinib or placebo BID in
the double-blind portion of the study. Participants will receive one 400 mg
tablet of rilzabrutinib BID in the open label portion of the study and the LTE.
Tablets should be taken with (~8oz/250mL) of water and may be taken with or
without food.
Study burden and risks
Overall Risk-Benefit Assessment
Based on the review of the cumulative data, there are no important identified
risks for rilzabrutinib. There are adverse events that have been reported
during the administration of other drugs from the same therapeutic class (BTK
inhibitors) as rilzabrutinib, but primarily for oncologic indications including
B-cell malignancies (Lipsky 2020). Taken together, it is postulated that there
is a low probability of occurrence of the above-mentioned *BTK inhibitor class*
adverse events during the administration of rilzabrutinib.
ITP is associated with an increased risk of mortality due to bleeding,
thrombosis, and reduced quality of life (QoL) (Trotter and Hill 2018). The
disease burden is more significant in patients with severe and chronic
thrombocytopenia and those who are unresponsive to current therapy. Patients
with such severe thrombocytopenia have a high risk of hemorrhage which
increases with age. Intracranial hemorrhage is the major cause of death which
is reported to occur in 1.5% of adult patients (Neunert et al 2015). Besides
the high risk of bleeding, patients with chronic ITP experience significant
fatigue, cognitive impairment, fear of bleeding and a negative impact on social
and work activities (Frith et al 2012; Trotter and Hill 2018). Treatment with
rilzabrutinib may induce durable platelet response in patients not responsive
to prior therapies.
The safety of rilzabrutinib to date, and the resulting benefit risk balance
profile, supports the continued investigation in patients with ITP. The adverse
events seen with other BTK inhibitors (bleeding, cytopenia, atrial
fibrillation) will be closely monitored.
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Listed location countries
Age
Inclusion criteria
Patients may be included in the study if ALL of the following criteria are met:
1. Patients will be male and female with primary ITP with duration of >6 months
in pediatric participants aged 12 to <18 years (pediatric participants aged 10
to <12 years will be enrolled in the EU [EEA countries] only; refer to Appendix
10.2, Appendix 10.3 and Appendix 10.7 for country-specific requirements) and
duration of >3 months in adults aged >=18 years
2. Patients who had a response (achievement of platelet count >=50,000/µL) to
IVIg/anti-D or CSs that was not sustained and who have documented intolerance,
insufficient response or any contra-indication to any appropriate courses of
standard of care ITP therapy
3. An average of 2 platelet counts at least 5 days apart of <30,000/µL during
the screening period, and no single platelet count >35,000/µL within 14 days
prior to the first dose of study drug
• Pediatric participants must additionally be determined to need treatment for
ITP as per clinical assessment by the Investigator (see Appendix 10.7 for EU
[EEA countries] specific requirements).
4. Adequate hematologic, hepatic, and renal function (absolute neutrophil count
>=1.5 X 10^9/L, AST/ALT <=1.5 x upper limit of normal [ULN], albumin >=3 g/dL,
total bilirubin <=1.5 x ULN [unless the participant has documented Gilbert
syndrome], glomerular filtration rate >50 [Cockcroft and Gault method])
5. Hemoglobin >9 g/dL within 1 week prior to Study Day 1
6. All contraceptive use by men and women should be consistent with local
regulations regarding the methods of contraception for those participating in
clinical studies
A) Male participants
Male participants are eligible to participate if they agree to the following
during the intervention period and for at least 13 weeks after the last
administration of study intervention:
• Refrain from donating or cryopreserving sperm
Plus either:
- Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle (abstinent on a long term and persistent basis) and agree to remain
abstinent
OR
- Must agree to use contraception/barrier as detailed below
- A male condom; the participant should also be advised of the benefit for a
female partner to use a highly effective method of contraception (as described
in Appendix 13 Contraceptive and barrier guidance of the protocol) as a condom
may break or leak when having sexual intercourse with a woman of childbearing
potential (WOCBP) who is not currently pregnant
B) Female participants
A female participant is eligible to participate if she is not pregnant or
breastfeeding, and one of the following conditions applies:
• Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 13 of
the protocol.
OR
• Is a woman of childbearing potential (WOCBP) and agrees to use a
contraceptive method that is highly effective (with a failure rate of <1% per
year), with low user dependency, as described in Appendix 13 of the protocol,
during the study intervention period (to be effective before starting the
intervention) and for at least 4 weeks after the last administration of study
intervention AND agrees not to donate or cryopreserve eggs (ova, oocytes) for
the purpose of reproduction during this period.
• A WOCBP must have a negative highly sensitive pregnancy test (serum) as
required by local regulations) within 3 days before the first administration of
study intervention
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a
serum pregnancy test is required. In such cases, the participant must be
excluded from
participation if the serum pregnancy result is positive.
7. Patients must be able to provide written informed consent or informed assent
with corresponding informed consent obtained from the participant*s guardian
and agree to the schedule of assessments.
Exclusion criteria
Patients will be excluded from the study if any of the following criteria are
met:
1. Patients with secondary ITP
2. Pregnant or lactating women
3. Electrocardiogram (ECG) findings for participants:
o Aged >=10 and <16 years: QTcF >449 msec (males) or >457 msec (females)
o Aged >=16 and <18 years: QTcF >450 msec (males) or >460 msec (females)
o Aged >=18 years, of QTcF >450 msec (males) or >470 msec (females), poorly
controlled atrial fibrillation (ie, symptomatic participants or a ventricular
rate above 100 beats/min on ECG), or other clinically significant abnormalities
4. History (within 5 years of Study Day 1) or current, active malignancy
requiring or likely to require chemotherapeutic or surgical treatment during
the study, with the exception of non-melanoma skin cancer
5. Transfusion with blood, blood products, plasmapheresis, or use of any other
rescue medications with intent to increase platelet count within 14 days before
Study Day 1
6. Change in CS and/or TPO-RA dose within 14 days prior to Study Day 1 (more
than 10% variation from current doses)
7. Immunosuppressant drugs other than CSs within 5 times the elimination
half-life of the drug or 14 days of Study Day 1, whichever is longer
8. Treatment with rituximab or splenectomy within the 3 months prior to Study
Day 1
- Patients treated with rituximab will have normal B-cell counts prior to
enrollment
9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole
and esomeprazole (it is acceptable to change participant to histamine 2
receptor blocking drugs prior to Study Day 1)
10. Use of known strong-to-moderate inducers or inhibitors of CYP3A within 14
days or 5 half-lives (whichever is longer) of Study Day 1 and until the end of
the active treatment period
11. Planned or concomitant use of any anticoagulants and platelet aggregation
inhibiting drugs such as aspirin (except for low dose aspirin up to 100 mg per
day), nonsteroidal
anti-inflammatory drugs, and/or thienopyridines within 14 days of Study Day 1
and until the end of the active treatment period
12. Has received any investigational drug within the 30 days before receiving
the first dose of study medication, or at least 5 times elimination half-life
of the drug (whichever is longer); participant should not be using an
investigational device at the time of dosing
o Patients who previously received treatment with Bruton*s Tyrosine Kinase
(BTK) inhibitors (except rilzabrutinib) within 30 days before the first dose of
study drug are not
eligible
o Patients who previously received rilzabrutinib at any time are not eligible
13. Current drug or alcohol abuse
14. Refractory nausea and vomiting, malabsorption, external biliary shunt,
significant bowel resection, or any other condition that would preclude
adequate study drug absorption
15. History of solid organ transplant
16. Positive at Screening for human immunodeficiency virus (HIV), hepatitis B
virus (HBV) (surface and core antibodies unrelated to vaccination), or
hepatitis C virus (anti-HCV antibody confirmed with Hep C RNA)
o Patients who are hepatitis B virus surface antigen (HBsAg) positive will not
be eligible.
o Patients who are HBsAg negative and hepatitis B core antigen antibody (HBcAb)
positive will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBV
DNA is
negative and HBsAb titer is >=100 IU/L, patients may be enrolled. Monthly HBV
DNA monitoring will be required while on treatment and for 6 months after the
last dose of the
study drug. Positive HBV DNA results will be managed appropriately as per local
standard of care.
o Patients who are HBcAb positive and HBsAg negative with HBsAb titer <100 IU/L
or negative, are not eligible.
17. Positive QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus) at
Screening unless all of the following 3 conditions are true (see Appendix 10
country-specific requirements):
a) Chest X-ray does not show evidence suggestive of active tuberculosis (TB)
disease
b) There are no clinical signs and symptoms of pulmonary and/or extra-pulmonary
TB disease
c) Documented receipt of one of the following prophylactic treatment regimens:
i. Oral daily Isoniazid for 6 months or
ii. Oral daily Rifampin for 4 months or
iii. Isoniazid and Rifapentine weekly for 3 months (3HP)
On a case-by-case basis, after discussion and approval by the Sponsor, a local
TB test that is negative and is considered equivalent to 1 of the above tests
may be used for eligibility. For example, if a QuantiFERON®-TB Gold, or
QuantiFERON-TB Gold Plus (QFT Plus) is indeterminate for any reason and a local
blood test or T-Spot® TB test is negative, the patient may be enrolled using
the local result upon approval of the Sponsor.
18. History of recurring (2 or more) serious infections requiring intravenous
antibiotic, antivirals or antifungals therapy within the last 3 months before
Study Day 1 or active serious or moderate infection ongoing on the day of
randomization
19. Myelodysplastic syndrome
20. Live vaccine within 28 days prior to Study Day 1 or plan to receive one
during the study
21. Planned surgery in the time frame of the dosing period
22. Any other clinically significant disease, condition, or medical history
that, in the opinion of the Investigator or Sponsor*s medical monitor, would
interfere with participant safety, study evaluations, and/or study procedures
23. Positive SARS-CoV-2 molecular test (if COVID-19 testing required per local
guidelines to be determined for each site)
24. COVID-19 vaccine within 14 days prior to Study Day 1 or planned during the
last 12 weeks of the blinded treatment period
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 | EUCTR2020-002063-60-NL |
| ClinicalTrials.gov | NCT04562766 |
| CCMO | NL83147.078.23 |