| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immune Thrombocytopenia (ITP) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Immune Thrombocytopenia (ITP) is a chronic, autoimmune disease that is associated with bleeding risk due to low platelet levels in the blood. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074667 |
| E.1.2 | Term | Immune thrombocytopenic purpura |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To demonstrate the efficacy of rilzabrutinib vs placebo in patients with refractory/relapsed ITP, based on the proportion of adult patients able to achieve platelet counts at or above 50,000/μL for at least 8 out of the last 12 weeks of the 24-week blinded treatment period |
|
| E.2.2 | Secondary objectives of the trial |
•Evaluate effect of rilzabrutinib vs PBO on number of wks with PLT count ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline, over the 24-wk blinded treatment period in absence of rescue therapy
•Evaluate effect of rilzabrutinib vs PBO on number of wks with PLT counts between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline over the 24-wk blinded treatment period in absence of rescue therapy
•Evaluate effect of rilzabrutinib vs PBO on time to first PLT count of ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and at least doubled from baseline
•Evaluate effect of rilzabrutinib vs PBO on proportion of patients requiring rescue therapy
•Evaluate effect of rilzabrutinib vs PBO on change from baseline in ITP-BAT assessment.
•Evaluate safety and tolerability of rilzabrutinib in patients aged 12 to <18 yrs and in adult patients (≥18 yrs) with refractory/relapsed ITP
•Characterize PK of rilzabrutinib
•Evaluate effect of rilzabrutinib on QoL |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients will be men and women with primary ITP with duration of > 6 months in ages 12 to < 18 years and duration of > 3 months in ages 18 years and above
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 or insufficient response to any appropriate courses of standard of care ITP therapy
3. An average of 2 platelet counts at least 5 days apart of < 30,000µL (and no single platelet count >35,000µL) within 14 days prior to the first dose of study drug
4. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, AST/ALT ≤ 1.5 x ULN, albumin ≥ 3 g/dL, total bilirubin ≤ 1.5 x ULN, estimated GFR > 50 (Cockcroft and Gault method)
5. Hemoglobin (Hgb) > 9 g/dL prior to dosing on Study Day 1
6. Female patients who are of reproductive potential (or are likely to reach reproductive potential during the study) must agree for the duration of the study to use an effective means of contraception (e.g. hormonal contraception methods that inhibit ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner or condoms) or practice true abstinence (when this is in line with the usual and preferred lifestyle). For females considered not to have reproductive potential: Any woman of age ≥ 55 years with amenorrhea for >1 year, will be considered as having confirmed menopause and follicle-stimulating hormone (FSH) or pregnancy testing will not be needed. Postmenopausal females <55 years of age (defined as amenorrhea > 1 year) must have menopause confirmed by elevated FSH levels at Screening. Surgically sterile females do not require any further confirmation of menopause and will not be considered to have reproductive potential.
7. Patients must be able to provide written informed consent or informed assent with corresponding informed consent obtained from the patient’s guardian and agree to the schedule of assessments. |
|
| E.4 | Principal exclusion criteria |
1. Patients with secondary ITP
2. Pregnant or lactating women
3. Electrocardiogram (ECG) findings for patients:
• aged ≥ 12 and < 16: QTc > 449 msec (males) or > 457 msec (females)
• aged ≥ 16 and < 18: QTc >450 msec (males) or > 460 msec (females)
• aged ≥ 18, of QTcF > 450 msec (males) or > 470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients 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 14 days of Study Day 1
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 patient to H2 receptor blocking drugs prior to Study Day 1)
10. Use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 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 (NSAIDs), 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); patient should not be using an investigational device at the time of dosing
• Patients who previously received treatment with BTK inhibitors (except rilzabrutinib) within 30 days before the first dose of study drug are not eligible
• Patients who previously received rilzabrutinib (PRN1008) 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)
• Patients who are hepatitis B virus surface antigen (HBsAg) positive will not be eligible
• 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 HBsAb titer is >100 IU/ml, 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
• Patients who are HBcAb positive and HBsAg negative with HBsAb titer <100 IU/ml 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:
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 (RIF) 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.
18. History of recurring (2 or more) serious infections requiring intravenous antibiotic 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 patient safety, study evaluations, and/or study procedures |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients able to achieve platelet counts at or above 50,000/μL for at least 8 out of the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Efficacy (blinded period): At every visit Week 2 through Week 25 including weekly lab visits between clinic visits and early withdrawal/unscheduled visits |
|
| E.5.2 | Secondary end point(s) |
Efficacy
• 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 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
• Time to first platelet count of ≥50,000/μL OR between ≥ 30,000/μL and <50,000/μL and doubled from baseline
• Proportion of patients requiring rescue therapy
• Change from baseline in ITP Specific Bleeding Assessment Tool (ITP-BAT) assessment
Safety
• Frequency and severity of TEAEs
• Frequency and severity of bleeding TEAEs
• Change from baseline in physical examination, ECG, clinical laboratory test results, vital signs. and laboratory tests (serum chemistry, hematology (except for platelet counts included in the primary efficacy endpoint)
PK
• Plasma concentrations of rilzabrutinib
QoL
• Change from baseline on the Symptoms, Bother and Activity domains of the ITP Patient Assessment Questionnaire (ITP-PAQ) in adult patients (≥18 years)
• Change from baseline in disease-specific quality of life (QoL) as measured by the Kids’ ITP Tools (ITP-KIT) score in patients ages 12 to <18
Exploratory
• Proportion of patients able to achieve platelet counts ≥50,000/μL for 4 out of last 8 weeks of the 24-week treatment period
• Proportion of patients who have a platelet count that exceeds 250,000/μL or 450,000/µL (for patients on TPO RA’s)
• Change from baseline on the Fatigue, Psychological, Fear, Social Activity, Women’s Reproductive Health, Work, and Overall QoL domains of the ITP-PAQ in adult patients (≥18 years)
• Change from baseline in quality of life as measured by the Euro-QoL-5 Dimensions-5 Level (Euro-QoL-5D-5L) in adult patients (≥18 years)
• Change from baseline in disease-related symptom severity as measured by the Patient Global Impression of Severity (PGIS)
• Patient perception of disease-related symptom improvement as measured by Patient Global Impression of Change Scale (PGIC)
• PK parameters as assessed by population pharmacokinetic analysis
• BTK occupancy
• Changes from baseline in TPO levels, T/B/NK counts, immunoglobulin (IgG, IgG1, IgG4, IgM, IgE) levels |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy (blinded period): At every visit Week 2 through Week 25 including weekly lab visits between clinic visits and early withdrawal/unscheduled visits
Efficacy (open-label): Week 26 through Week 53 including end of study 4-weeks post last dose and early withdrawal/unscheduled visits
Safety (blinded period, open-label): At every visit
PK (blinded period): Week 1 and Week 13
PK (open-label): Week 25 and Week 53 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Czechia |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Norway |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial is defined as the point at which the last patient has completed final assessments at the last visit of the study (LPLV). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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