Study to Evaluate Rilzabrutinib in Adults and Adolescents With Persistent or Chronic Immune Thrombocytopenia (ITP)

Phase 3Active Not RecruitingNCT04562766

Principia Biopharma, a Sanofi Company232 enrolled

Overview

This was a randomized, double-blind study of rilzabrutinib in patients with persistent or chronic ITP, with an average platelet count of \<30,000/μL (and no single platelet count \>35,000/μL) on two counts at least 5 days apart in the 14 days before treatment begins. Patients received rilzabrutinib or placebo 400mg twice daily. For each patient, the study lasted up to 60 weeks from the start of the Screening Period to the End of Study (EOS) visit. This included Screening (up to 4 weeks) through a 12 to 24-week Blinded Treatment Period followed by a 28-week Open-Label Period. Followed by a 4-week post dose follow-up. For adult participants, the maximum duration of the long-term extension (LTE) period was 12 months from the date of the last adult participant to enter the LTE. For pediatric participants, the maximum duration of the LTE period was 12 months from the date of the last pediatric participant to enter the LTE.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

232

Conditions

Immune Thrombocytopenia

Interventions

Eligibility

Sex: ALLMin age: 10 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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) 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, 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 patients must additionally be determined to need treatment for ITP as per clinical assessment by the Investigator. 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 \[unless the patient has documented Gilbert syndrome\], glomerular filtration rate \>50 \[Cockcroft and Gault method for adult and Bedside Schwartz Equation for Pediatric participants\]) 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 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 Exclusion Criteria: 1. Patients with secondary ITP 2. Pregnant or lactating women 3. 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 4. 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 5. Change in CS and/or TPO-RA dose within 14 days prior to Study Day 1 (more than 10% variation from current doses) 6. 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 7. 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 8. Had 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 Bruton's Tyrosine Kinase (BTK) inhibitors (except rilzabrutinib) within 30 days before the first dose of study drug are not eligible * Patients who previously received rilzabrutinib at any time are not eligible 9. History of solid organ transplant 10. Myelodysplastic syndrome 11. Live vaccine within 28 days prior to Study Day 1 or plan to receive one during the study 12. Planned surgery in the time frame of the dosing period

Locations (155)

University of Southern California_Investigational Site Number 84024

Los Angeles, California, United States

UCSF Benioff Children's Hospital San Francisco_Investigational Site Number 84020

San Francisco, California, United States

Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center_Investigational Site Number 84037

Torrance, California, United States

The Oncology Institute of Hope and Innovation_Investigational Site Number 84031

Whittier, California, United States

Children's Hospital Colorado_Investigational Site Number 84025

Aurora, Colorado, United States

Outcomes

Primary Outcomes

DB Period: Percentage of Participants With Durable Platelet Response Per Guidance in Regions Except European Union and United Kingdom

Durable platelet response per guidance in regions except European Union and United Kingdom was defined as platelet counts at or above 50,000/mcL 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 were at or above 50,000/mcL during the last 6 weeks of the 24-week blinded treatment period.

Time frame: Up to 24 weeks

DB Period: Percentage of Participants With Durable Platelet Response Per Guidance in European Union and United Kingdom

Durable platelet response per guidance in European Union and United Kingdom was defined as platelet counts at or above 50,000/mcL for at least 8 out of the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy.

Time frame: Up to 24 weeks

Secondary Outcomes

DB Period: Number of Weeks With Platelet Count >=50,000/mcL or Between >=30,000/mcL and <50,000/mcL and at Least Doubled From Baseline in the Absence of Rescue Therapy

Number of weeks with platelet response was assessed using clinically meaningful threshold of platelet count \>=50,000/mcL or between \>=30,000/mcL and \<50,000/mcL and at least doubled from baseline over the 24-week blinded treatment period in the absence of rescue therapy.

Time frame: Up to 24 weeks

DB Period: Number of Weeks With Platelet Counts >=30,000/mcL and at Least Doubled From Baseline in the Absence of Rescue Therapy

Number of weeks with platelet response was assessed using clinically meaningful threshold of platelet counts \>=30,000/mcL and at least doubled from baseline over the 24-week blinded treatment period in the absence of rescue therapy.

Time frame: Up to 24 weeks

DB Period: Time to First Platelet Count of >=50,000/mcL or Between >=30,000/mcL and <50,000/mcL and Doubled From Baseline

Time to first platelet count of \>=50,000/mcL or between \>=30,000/mcL and \<50,000/mcL and doubled from baseline was calculated as: (date of first occurrence of platelet response - date of first study drug intake) + 1.

Time frame: Up to 24 weeks

DB Period: Percentage of Participants Who Required Rescue Therapy

Resue therapy included intravenous immunoglobulin (Ig) or high-dose corticosteroids, platelet infusion, or anti-D Ig infusion. Percentage of participants who required rescue therapy are presented.

Time frame: Up to 24 weeks

DB Period: Change From Baseline on Item 10 (Physical Fatigue) of the Immune Thrombocytopenia-Patient Assessment Questionnaire (ITP-PAQ) in Adult Participants at Week 13

ITP-PAQ:38 items and 44 items completed by male and female respondents respectively.It included 10 scales:symptoms(6 items:1-6),fatigue/sleep(4 items:7-10),bother-physical health(3 items:11-13),activity(2 items:14-15),psychological health(5 items:16-20),fear(5 items:21-25),overall quality of life(QoL)(5 items:26-30),social activity(4 items:31-34),women's reproductive health(6 items:35-40),work(4 items:41-44).Responses were recorded on 4-point(1:"strongly disagree" to 4:"strongly agree"),5-point(1:"never/not at all" to 5:"all the time/extremely") or 7-point(1:"not at all" to 7:"extremely") Likert scales.Each item score:100x(\[possible maximal item score - item score\]/range).All item scores:transformed to 0 to 100 continuum and were weighted equally to derive scale scores.Total score:0(worst) to 100(best);higher scores:better QoL.Change of positive value:improvement.Change from baseline in physical fatigue is presented.Baseline:last available value before first dose of DB study drug.

Time frame: Baseline (Day 1) and Week 13

DB Period: Change From Baseline in Idiopathic Thrombocytopenic Purpura Bleeding Scale (IBLS) Assessment in Adult Participants at Week 25 Per Guidance in European Union and United Kingdom

Per guidance in European Union and United Kingdom, ITP IBLS was a bleeding assessment system which comprised of 11 (10 for male) site-specific grades assessed at 9 anatomical sites by history (Hx) over previous period. In addition, 2 of these sites, skin and oral, were also assessed by physical examination (PE). These 11 grades included: skin (PE), skin (Hx), oral (PE), oral (Hx), epistaxis, gastrointestinal, urinary, gynecological, pulmonary, intracranial hemorrhage, and subconjunctival hemorrhage; scores ranged from 0 (none) to 2 (marked bleeding). For each participant, an IBLS score at each visit was calculated by taking average across 11 items (10 for male and postmenopausal female) at 9 sites (8 for male and postmenopausal female). Total score was calculated as mean value for all 11 grades ranging from 0 (best) to 22 (worst); higher scores indicated worse outcomes. Change of negative value indicates an improvement.Baseline:last available value before first dose of DB study drug.

Time frame: Baseline (Day 1) and Week 25

DB Period: Change From Baseline in Idiopathic Thrombocytopenic Purpura Bleeding Scale Assessment in Adolescent Participants at Week 25 Per Guidance in European Union and United Kingdom

Per guidance in European Union and United Kingdom, ITP IBLS was a bleeding assessment system which comprised of 11 (10 for male) site-specific grades assessed at 9 anatomical sites by Hx over previous period. In addition, 2 of these sites, skin and oral, were also assessed by PE. These 11 grades included: skin (PE), skin (Hx), oral (PE), oral (Hx), epistaxis, gastrointestinal, urinary, gynecological, pulmonary, intracranial hemorrhage, and subconjunctival hemorrhage; scores ranged from 0 (none) to 2 (marked bleeding). For each participant, an IBLS score at each visit was calculated by taking average across 11 items (10 for male) at 9 sites (8 for male). Total score was calculated as mean value for all 11 grades ranging from 0 (best) to 22 (worst); higher scores indicated worse outcomes. Change of negative value indicates an improvement. Baseline:last available value before first dose of DB study drug.

Time frame: Baseline (Day 1) and Week 25

DB-OL Period: Percentage of Participants With Stability of Response in Adult Participants

Stability of response was defined as the percentage of participants who were able to achieve stable platelet response defined as no 2 scheduled visits, at least 4 weeks apart, with a platelet count \<50,000/mcL, without an intervening visit with a platelet count \>=50,000/mcL, within a period of 24 weeks following initial achievement of the platelet response (initial platelet response defined as platelet count \>=50,000/mcL within 12 weeks of initiation of treatment with rilzabrutinib during the study). This endpoint was assessed from start of DB period through OL period.

Time frame: Up to 52 weeks

DB-OL Period: Percentage of Participants With Stability of Response in Adolescent Participants

Time frame: Up to 52 weeks

DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Bleeding Treatment-Emergent Adverse Events >=Grade 2

An AE was any untoward medical occurrence in a participant or clinical investigation participant, administered a study drug and which did not necessarily had a causal relationship with the study drug. An SAE was any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened or became serious during the TE period. Bleeding TEAEs Grade \>=2 (criteria mentioned in statistical analysis plan) are also presented.

Time frame: From first dose of study drug (Day 1) up to maximum DB exposure, up to 182 days (adults) and up to 175 days (adolescent)

DB Period: Plasma Concentrations of Rilzabrutinib

Blood samples were collected at specified timepoints for the analysis of plasma concentration of rilzabrutinib.

Time frame: Pre-dose at Weeks 1, 13 and 25 and 2 hours post-dose at Week 1 and 25 (adults); Pre-dose at Weeks 1, 13 and 25, 0.5, 2, 4 and 6 hours post-dose at Weeks 1 and 25 (adolescent)

DB Period: Change From Baseline in the Symptoms, Bother and Activity Domains of the Immune Thrombocytopenia-Patient Assessment Questionnaire in Adult Participants

ITP-PAQ:38 items and 44 items completed by male and female respondents respectively.It included 10 scales:symptoms(6 items:1-6),fatigue/sleep(4 items:7-10),bother-physical health(3 items:11-13),activity(2 items:14-15),psychological health(5 items:16-20),fear(5 items:21-25),overall QoL(5 items:26-30),social activity(4 items:31-34),women's reproductive health(6 items:35-40),work(4 items:41-44).Responses were recorded on 4-point(1:"strongly disagree" to 4:"strongly agree"),5-point(1:"never/not at all" to 5:"all the time/extremely") or 7-point(1:"not at all" to 7:"extremely") Likert scales.Each item score:100x(\[possible maximal item score - item score\]/range).All item scores:transformed to 0 to 100 continuum and were weighted equally to derive scale scores.Total score:0(worst) to 100(best);higher scores:better QoL.Change of positive value:improvement.Change from baseline in symptoms,bother and activity domains is presented.Baseline:last available value before first dose of DB study drug.

Time frame: Baseline (Day 1) and Week 25

DB Period: Change From Baseline in Disease-Specific Quality Of Life as Measured by the Kids' Immune Thrombocytopenia Tools (ITP-KIT) Score in Adolescent Participants

ITP-KIT was a disease-specific instrument and child self-report form designed to be completed by children \>=7 years. It comprised of total of 27 items among which 26 items were structured as Likert scales with 5 response options 1: "never", 2: "rarely", 3: "sometimes", 4: "often" and 5: "always". An additional "not applicable" option was available for items 18 to 26, which was scored as 1: the same as "never". Item 27 was a descriptive question answered "yes" or "no" which was not included in the calculation of the summary score. Instrument yielded a summary KIT score which was the summation of the items calculated as: 100 x (1- \[{sum of all valid responses - number of valid responses}/{number of valid responses\*4}\]). Scores were converted to a 0 to 100 with higher scores indicating better disease-specific QoL. Change from baseline of positive value indicated improvement. Baseline was defined as the last available value before first dose of DB study drug.

Time frame: Baseline (Day 1) and Week 25