A Study to Assess Efficacy and Safety of Eltrombopag in Combination With a Short Course of Dexamethasone in Patients With Newly Diagnosed ITP

Phase 2

Completed

Conditions: Immune Thrombocytopenia (ITP)

Interventions: Drug: Eltrombopag
Drug: Dexamethasone

Registration Number: NCT04346654

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study was to compare the ability of eltrombopag in combination with a short course of high-dose dexamethasone to induce sustained response off treatment in patients with newly-diagnosed ITP versus 1-3 cycles of dexamethasone monotherapy.

The unmet clinical need and the potential for eltrombopag when added to steroids to improve the treatment outcome and the potential to induce sustained response off treatment serve as the basis for clinical investigation of eltrombopag in first-line ITP.

Detailed Description: This is a Phase II, multicenter, 1:1 randomized, open-label study that compared the efficacy and safety of eltrombopag in combination with a short course of high-dose dexamethasone to 1-3 cycles of high-dose dexamethasone monotherapy, as first-line treatment in adult patients with newly diagnosed ITP.

Adult patients with newly diagnosed ITP who had platelet counts \< 30 × 10\^9/L and required treatment were screened, and if eligible, were randomized to either Arm A (eltrombopag in combination with a short course of dexamethasone) or Arm B (1-3 cycles of dexamethasone monotherapy).

The study was conducted in the following periods:

Screening Period: Patients were screened for 14 days based on the inclusion and exclusion criteria.

Treatment Period: Arm A: Patients were treated for 26 weeks during the treatment period. Patients who reached platelet counts ≥ 30 × 10\^9/L and maintained counts ≥ 30 × 10\^9/L during the tapering phase were eligible for treatment discontinuation. Duration of tapering before treatment discontinuation at Week 26 was 6 weeks. Arm B: Patients were treated up to 12 weeks during the treatment period. Patients who reached platelet counts ≥ 30 × 10\^9/L and maintained counts ≥ 30 × 10\^9/L after 1-3 cycles of dexamethasone treatment were eligible for treatment discontinuation. Patients with platelet counts \< 30 × 10\^9/L after 3 cycles of dexamethasone treatment were offered a course of eltrombopag treatment within the study and were discontinued from study at week 52.

Observation period: After completion of the treatment period, all patients were observed for sustained response off treatment until week 52. Only patients with sustained response at week 52 were followed for another 26 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

Inclusion Criteria

Signed informed consent must be obtained prior to participation in the study.
Men and women ≥ 18 years of age
Newly diagnosed with primary ITP (time from diagnosis within 3 months)
Platelet count < 30 × 109/L at screening and a need for treatment (per physician's discretion) Note: If pre-treatment is necessary, platelet count data performed directly before pre-treatment (can be used for study inclusion (screening value). Treatment-naïve patients will be included based on their platelet counts performed at screening

Exclusion Criteria

Previous history of treatment for ITP, except any ITP-directed therapy for a maximum of 3 days within 7 days before randomization
Patients with diagnosis of secondary thrombocytopenia
Patients who have life threatening bleeding complications per physician´s discretion
Patients with a history of thromboembolic events in the 6 months preceding enrollment or known risk factors for thromboembolism
Serum creatinine > 1.5 mg/dL
Total bilirubin (TBIL) > 1.5 × upper limit of normal (ULN)
Aspartate transaminase (AST) > 3.0 × ULN
Alanine transaminase (ALT) > 3.0 × ULN
Patients who are human immune deficiency virus (HIV),hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) positive
Patients with hepatic impairment (Child-Pugh score > 5)
Patients with known active or uncontrolled infections not responding to appropriate therapy
History of current diagnosis of cardiac disease or impaired cardiac function denoted
Patients who have active malignancy
Patients with evidence of current alcohol/drug abuse
Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance with the study procedures
Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1
Women of child-bearing potential and males unwilling to use adequate contraception during the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Eltrombopag + Dexamethasone	Eltrombopag	Patients were treated with eltrombopag in combination with a standard high-dose dexamethasone (1 cycle: 40 mg once daily (QD) from day 1-4) to induce sustained response off treatment.
Eltrombopag + Dexamethasone	Dexamethasone	Patients were treated with eltrombopag in combination with a standard high-dose dexamethasone (1 cycle: 40 mg once daily (QD) from day 1-4) to induce sustained response off treatment.
Dexamethasone	Dexamethasone	Patients were treated with a standard high-dose dexamethasone (1-3 cycles: 40 mg QD day 1-4 at 4 weeks intervals (or at 14-28 days intervals if needed) to induce sustained response off treatment.

Primary Outcome Measures

Name	Time	Method
Percentage of Patients With Sustained Response Off Treatment at 52 Weeks	Study treatment discontinuation until week 52	Sustained response off treatment at 52 weeks is defined as maintenance of platelet count ≥ 30 × 10\^9/L after treatment discontinuation until Week 52 in the absence of bleeding events ≥ Grade II or use of any rescue medication at all visits until Week 52. Bleeding events ≥ Grade II are assessed by the modified World Health Organization (WHO) Bleeding Scale; Bleeding is graded based on a 1-4 scale (1=minor bleeding to 4=severe bleeding). Characteristics of bleeding events ≥ Grade II include: epistaxis ≥30 minutes, large purpura, joint bleeding, melanotic stool, hematemesis, gross hematuria, abnormal vaginal bleeding, hemoptysis, Visible blood in body cavity fluid, retinal bleeding, bleeding at invasive sites, bleeding requiring transfusion, bleeding associated with moderate or severe hemodynamic instability, fatal bleeding, CNS bleeding.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients With Overall Response at Week 52	Study treatment discontinuation until week 52	Overall response after treatment at week 52 was defined as maintenance of platelet count ≥ 30 x 109/L and ≥ 2-fold increase of screening platelet count after treatment discontinuation in the absence of bleeding event ≥ Grade II and no rescue therapy at all visits until Week 52. Bleeding events ≥ Grade II are assessed by the modified World Health Organization (WHO) Bleeding Scale; Bleeding is graded based on a 1-4 scale (1=minor bleeding to 4=severe bleeding). Characteristics of bleeding events ≥ Grade II include: epistaxis ≥30 minutes, large purpura, joint bleeding, melanotic stool, hematemesis, gross hematuria, abnormal vaginal bleeding, hemoptysis, Visible blood in body cavity fluid, retinal bleeding, bleeding at invasive sites, bleeding requiring transfusion, bleeding associated with moderate or severe hemodynamic instability, fatal bleeding, CNS bleeding.
Duration of Sustained Response Off Treatment	from last dose of study treatment until loss of response, approx. 52 weeks	Duration of sustained response off treatment is defined as time of treatment discontinuation until platelet count \< 30 × 109/L or bleeding events ≥ Grade II or use of any rescue therapy. If sustained response remains, the interval was censored with the date of the last platelet assessment. Bleeding events ≥ Grade II are assessed by the modified World Health Organization (WHO) Bleeding Scale; Bleeding is graded based on a 1-4 scale (1=minor bleeding to 4=severe bleeding). Characteristics of bleeding events ≥ Grade II include: epistaxis ≥30 minutes, large purpura, joint bleeding, melanotic stool, hematemesis, gross hematuria, abnormal vaginal bleeding, hemoptysis, Visible blood in body cavity fluid, retinal bleeding, bleeding at invasive sites, bleeding requiring transfusion, bleeding associated with moderate or severe hemodynamic instability, fatal bleeding, CNS bleeding.
Overall Response by Week 4	By Week 4	Overall response by week 4 is defined as platelet count ≥ 30 × 109/L and ≥ 2 fold increase of screening platelet count and absence of bleeding and no rescue therapy within the first 4 weeks
Complete Response by Week 4	By Week 4	Complete Response by week 4 is defined as platelet count ≥ 100 × 109/L and absence of bleeding and no rescue therapy until week 4.
Absolute Change in Platelet Count From Pre-treatment/Screening to Baseline and to Various Time Points	Pre-treatment/screening, Week 1 (baseline), 2, 4, 13, 27, and 53	Absolute change in platelet count from pre-treatment or screening to baseline (week 1) and from pre-treatment / screening to 2, 4, 13, 27 and 53 weeks. If pre-treatment was necessary before inclusion, platelet count data performed directly before pre-treatment were used for study inclusion (screening value to be used for inclusion/exclusion check and for analysis as a covariate).
Relative Change in Platelet Count From Pre-treatment/Screening to Baseline and to Various Time Points	Pre-treatment/screening, Week 1 (baseline), 2, 4, 13, 27, and 53	Relative change in platelet count from pre-treatment or screening to baseline (week 1) and from pre-treatment or screening to 2, 4, 13, 27, and 53 weeks. If pre-treatment was necessary before inclusion, platelet count data performed directly before pre-treatment were used for study inclusion (screening value to be used for inclusion/exclusion check and for analysis as a covariate).
Time to Overall Response (TOR)	Time from starting study treatment to achievement of complete response (up to 52 weeks)	Time to overall response is defined as time from starting study treatment to time of achievement of overall response. Overall response is defined as a platelet count ≥ 30 × 10\^9/L and ≥ 2 fold increase of baseline platelet count and absence of bleeding and no rescue therapy censored with the last visit date for patients not achieving overall response. Results of TOR are reported per Kaplan-Meier estimates.
Time to Complete Response	Time from starting study treatment to achievement of complete response (up to 52 weeks)	Time to complete response is defined as time from starting study treatment to time of achievement of complete response. Complete response is defined as a platelet count ≥ 100 × 109/L and absence of bleeding and no rescue therapy. Results of time to complete response are reported per Kaplan-Meier estimates.
Duration of Overall Response (OR) and Complete Response (CR)	Achievement of overall or complete response until loss of response (up to 52 weeks)	Duration of overall or complete response (CR) is defined as time of achievement of overall or CR until loss of overall or CR. The duration of CR was calculated from the date of onset of CR until platelet count \< 100 x 109/L, or bleeding events ≥ Grade II (assessed by the modified World Health Organization (WHO) Bleeding Scale) or use of any rescue therapy, whatever was earlier. Bleeding is graded based on a 1-4 scale (1=minor bleeding to 4=severe bleeding). Characteristics of bleeding events ≥ Grade II include: epistaxis ≥30 minutes, large purpura, joint bleeding, melanotic stool, hematemesis, gross hematuria, abnormal vaginal bleeding, hemoptysis, Visible blood in body cavity fluid, retinal bleeding, bleeding at invasive sites, bleeding requiring transfusion, bleeding associated with moderate or severe hemodynamic instability, fatal bleeding, CNS bleeding. Results of duration of overall and complete response are reported per Kaplan-Meier estimates.
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Questionnaire	Baseline (Week 1), Week 2, 3, 5, 13, 27 and 53	The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) instrument is a 13-item validated tool used to measure an individual's level of fatigue during usual daily activities over the past 7 days. Items are scored on a 0-4 response scale (4=not at all to 0=very much) where the total possible score ranges from 0-52 (all items are summed up to create the total score); A score of less than 30 indicates severe fatigue. The higher scores represent better HRQoL.
Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire (Physical (PS), Mental Score (MS) and Alternative Scoring (PS-QM))	Baseline (Week 1), Week 2, 3, 5, 13, 27 and 53	SF36 questionnaire is a tool to measure health-related QoL. SF36 questionnaires (physical and mental score) were answered throughout the study and is a validated instrument with 36 questions to measure general physical and mental health status via assessment of 8 domains-Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health-over the past 4 weeks. The SF36 is scored using norm-based scoring procedures and scores ranging from 0-100; higher values indicate less impairment, a higher QoL. In addition to this SAP-planned scoring score, an alternative scoring for both the physical SF36 score and the mental SF36 were performed by QualityMetric (QM) Incorporated, an IQVIA business.
Incidence and Severity of Bleeding Events	Baseline up to 52 weeks	Incidence and severity of bleeding assessed by the modified World Health Organization (WHO) Bleeding Scale; Bleeding is graded based on a 1-4 scale (1=minor bleeding to 4=severe bleeding). Incidence of bleeding: participants had at least one bleeding event. Severity of bleeding: bleeding event is from grade 2 and higher