A Study to Assess the Ability of Eltrombopag to Induce Sustained Response Off Treatment in Subjects With ITP

Immune Thrombocytopenic Purpura (ITP) Clinical Trial

— TAPER  

Official title:

A Phase II, Open-label, Prospective, Single-arm, Study to Assess Ability of Eltrombopag to Induce Sustained Remission in Subjects With ITP Who Are Refractory or Relapsed After First-line Steroids

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03524612
• Other study ID #: CETB115J2411
• Secondary ID: 2018-000452-18
• Status: Completed
• Phase: Phase 2
• Start date: November 2, 2018
• Est. completion date: October 3, 2022

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial was to assess the ability of eltrombopag to induce sustained treatment-free remission in immune thrombocytopenia purpura (ITP) subjects who relapsed or failed to respond to an initial treatment with steroids.

Description:

Protocol Amendment 01 added a follow-up period of 12 months for patients with sustained response off treatment at month 12 to obtain further data on response duration.

The starting dose was eltrombopag 50 mg daily (25 mg daily for Asian patients and 12.5 mg daily for Japanese patients in Japan). The starting dose for this study was consistent with the dosing guidelines approved for eltrombopag use in ITP. An increase of eltrombopag dose up to 75 mg was allowed for patients who did not respond to standard-dosage treatment and to reduce the risk of bleeding. The rationale for this increased dose was to use the minimal efficacious dosage of eltrombopag in order to achieve a platelet count ≥ 100×10^9/L and maintain it around 100×10^9/L (no counts below 70×10^9/L) for 2 months in order to allow patients to start the eltrombopag tapering and withdrawal process.

Patients who reached a platelet count of >= 100 × 10^9/L and maintained counts around 100×10^9/L for 2 months with no platelet count < 70 × 10^9/L were eligible for tapering-off and treatment discontinuation, which occurred via 25 mg reduction every 2 weeks up to 25 mg on alternate days for 2 weeks until treatment discontinuation.

Patients who successfully discontinue eltrombopag and maintained platelet count >= 30 × 10^9/L in the absence of bleeding or use of rescue therapy were followed to month 12. If a relapse (defined as platelet count <30 × 10^9/L) occurred during the 12-month treatment period, they were offered a new course of eltrombopag treatment within this timeframe at the appropriate starting dose. If a patient relapsed in the post 12-month follow-up period, no further attempts for tapering and achieving sustained response off treatment were made.

The taper-off scheme followed recommendations within the current established dosing regimen for when to consider dose adjustment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: October 3, 2022
• Est. primary completion date: October 22, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study

2. Patients = 18 years old

3. Patients with a confirmed diagnosis of primary ITP, who are not responsive or in relapse after a first line of steroid therapy ± intravenous immunoglobulin (IVIG) (used as a rescue therapy)

4. Platelet count < 30×10^9/L and assessed as needing treatment (per physician's discretion

Exclusion Criteria:

1. ITP patients previously treated with any ITP second-line therapies, thrombopoietin receptor (TPO-R) agonists for ITP, except steroids / IVIG

2. Patients who relapsed more than one year after the end of first-line full course of steroid therapy

3. Patients with a diagnosis of secondary thrombocytopenia

4. Patients who have life threatening bleeding complications per investigator discretion

5. Patients who had a deep vein thrombosis or arterial thrombosis in the 6 months preceding enrollment

6. Serum creatinine = 1.5 mg/dL

7. Total bilirubin > 1.5 × upper limit of normal (ULN)

8. Aspartate transaminase (AST) > 3.0 × ULN

9. Alanine transaminase (ALT) > 3.0 × ULN

10. Patients who are human immune deficiency virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) positive

11. Patients with hepatic impairment (Child-Pugh score > 5)

12. Patients who have active malignancy

13. Patients with 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 per investigator discretion

14. History or current diagnosis of cardiac disease indicating significant risk of safety for Patients participating in the study

15. Patients with known active or uncontrolled infections not responding to appropriate therapy

16. Patients with evidence of current alcohol/drug abuse

17. Women of child-bearing potential and sexually active males unwilling to use adequate contraception during the study

18. Female Patients 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

Other protocol-defined inclusion/exclusion criteria may apply.

Related Conditions & MeSH terms

• Immune Thrombocytopenic Purpura (ITP)
• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombocytopenic, Idiopathic

Intervention

Drug:
• eltrombopag
12.5, 25, 50 and 75 mg tablets for oral use once daily

Locations

Country	Name	City	State
Austria	Novartis Investigative Site	Linz
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Sao Paulo	SP
Chile	Novartis Investigative Site	Temuco	Araucania
Chile	Novartis Investigative Site	Vina del Mar	Valparaiso
France	Novartis Investigative Site	Caen Cedex
France	Novartis Investigative Site	Pessac Cedex
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Patras
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Trieste	TS
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Mexico	Novartis Investigative Site	Ciudad de Mexico
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Oman	Novartis Investigative Site	Muscat
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St Petersburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Majadahonda	Madrid
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Murcia
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Switzerland	Novartis Investigative Site	Bern
Turkey	Novartis Investigative Site	Aydin
Turkey	Novartis Investigative Site	Edirne
Turkey	Novartis Investigative Site	Kocaeli
United Kingdom	Novartis Investigative Site	London
United States	Case Western Reserve SC - 2	Cleveland	Ohio
United States	Hematology Oncology Association of Rockland Drug Shipment	Nyack	New York

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Brazil,  Chile,  France,  Greece,  Italy,  Japan,  Mexico,  Oman,  Russian Federation,  Spain,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Sustained Response Off Treatment (SRoT) by 12 Months	Sustained response off treatment (SRoT) was defined as: reaching platelet count >= 100×10^9/L (complete response [CR]) and then maintaining platelet counts around 100×10^9/L for 2 months (no counts below 70×10^9/L), AND then tapering off the drug until treatment discontinuation while maintaining platelet count >= 30×10^9/L in the absence of bleeding (no bleeding AEs) or use of any rescue therapy until month 12.	Month 12
Secondary	Median Duration of Sustained Response Off Treatment (SRoT) After Treatment Discontinuation for Participants With Sustained Response Off Treatment	Sustained response off treatment (SRoT) was defined as: reaching platelet count >= 100×10^9/L (complete response [CR]) and then maintaining platelet counts around 100×10^9/L for 2 months (no counts below 70×10^9/L), AND then tapering off the drug until treatment discontinuation while maintaining platelet count >= 30×10^9/L in the absence of bleeding (no bleeding AEs) or use of any rescue therapy until month 12.	From last dose of eltrombopag to month 12
Secondary	Estimated Median Duration of Sustained Response Off Treatment (SRoT) for Participants With Sustained Response Off Treatment at Month 12 and Who Enter 12 Months Follow-up Period	Sustained response off treatment (SRoT) was defined as: reaching platelet count >= 100×10^9/L (complete response [CR]) and then maintaining platelet counts around 100×10^9/L for 2 months (no counts below 70×10^9/L), AND then tapering off the drug until treatment discontinuation while maintaining platelet count >= 30×10^9/L in the absence of bleeding (no bleeding AEs) or use of any rescue therapy.; Patients with SRoT until month 12 who entered follow-up and did not relapse by cut-off date/Month 24 were censored at the earliest of discontinuation date/death date/Month 24 platelet assessment date/cutoff date. Patients with SRoT until Month 12 patients who did not enter or do not yet have data in follow-up phase are censored at their Month 12 platelet assessment date.	From last dose of eltrombopag to relapse, assessed up to month 24
Secondary	Estimated Median Duration of Sustained Response Off Treatment (SRot) for All Patients	Patients who tapered and discontinued successfully, or did not relapse/die by cutoff date /month 24 were censored at the earliest of discontinuation date/death date/month 24 platelet assessment date/cutoff date.	From last dose of eltrombopag to month 24
Secondary	Percentage of Participants With Sustained Response Off Treatment Until Month 24	Sustained response off treatment is defined as reach platelet count = 100×10^9/L (complete response [CR]) and then maintain platelet counts around 100×10^9/L for 2 months (no counts below 70×10^9/L) AND then taper off the drug until treatment discontinuation while, maintain platelet count = 30×10^9/L in the absence of bleeding (no bleeding AEs) or use of any rescue therapy	Month 15, 18, 21 and 24
Secondary	Percentage of Participants With Early Response Within First Month	Early response is defined as reaching a platelet count >= 50×10^9/L at least once within the first month (month 1) without bleeding events and no rescue therapy.	By 1 month
Secondary	Percentage of Participants With Recovery Response in Case of Loss of Response During or After Tapering of Eltrombopag Until Month 24	Recovery response is defined as platelet count >=30×10^9/L after eltrombopag is re-introduced, in case of loss of response (< 30×10^9/L and/or bleeding event) without bleeding events and no rescue therapy.	Up to month 24
Secondary	Relative Change From Baseline in Platelet Count Over Time	Relative change (%) is the absolute change divided by the platelet counts at baseline and multiplied by 100.	Baseline, month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Percentage of Participants Who Maintain Platelet Counts Level Within 12 Months and Every 3 Months Until Month 24	Platelet counts level is defined as having platelet counts >=30×10^9/L without bleeding events and no rescue therapy.	From first time of reaching the level to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Questionaire	The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue©) is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities over the past 7 days. FACIT-fatigue is scored using a 4-point Likert scale. Items are scored as follows: 4 = Not At All; 3 = A Little Bit; 2 = Somewhat; 1 = Quite A Bit; 0 = Very Much, EXCEPT items #7 and #8 which are reversed scored. Score range from 0-52. A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of life (less fatigue).	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Functional Assessment of Cancer Therapy- Thrombocytopenia (FACT-Th6) Questionnaire	FACT-Th6 instrument is used to measure worry/concern about bleeding and bruising, and the impact of this worry/concern on physical and social activity (Cella 2006). FACT-Th6 is a 6-item subset of the more detailed FACT-Th, which is an 18-item subscale of the validated FACT that specifically measures concerns related to thrombocytopenia in the past 7 days. The FACT-Th6 is scored using a 5-level Likert scale (0=not at all to 4=very much) and is calculated by summing scores for the 6-items; therefore, scores can range from 0-24, with higher scores representing better HRQoL	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Bodily Pain (BP) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: General Health (GH) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Mental Health (MH) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Physical Functioning (PF) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Role Emotional (RE) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Role Physical (RP) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Social Functioning (SF) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Vitality (VT) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Physical Component Summary (PCS) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Change From Baseline in Short Form 36 Health Survey (SF-36v2) Questionnaire: Mental Component Summary (MCS) Score	The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (bodily pain (BP), general health (GH), mental health (MH), physical functioning (PF), role emotional (SE), role physical (RP), social role functioning (SF) and vitality (VT)) which can be aggregated to derive a physical-component summary (PCS) score and a mental-component score (MCS). The SF-36 is scored using norm-based scoring procedures: each sub-scale score ranges from 0 to 10, and the composite score ranges from 0 to 100. Higher scores indicative of better HRQoL.	Baseline to month 3, 6, 9, 12 (End of Treatment Visit for non-responders), 15, 18, 21 and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Percentage of Participants With Worst Post-baseline Value in Functional Assessment of Cancer Therapy-G (GP5)	The GP5 is a single question used to assess the overall bothersomeness of treatment side effects. The GP5 is scored using a 5-point rating scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; and 4 = very much), where lower scores reflect less bothersomeness from treatment side effects.	Baseline to end of treatment visit, assessed up to 12 months for non-responders and up to 24 months for responders
Secondary	Overall Change of Treatment Satisfaction Using Treatment Satisfaction Questionnaire (TSQM-9)	The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. The lowest possible score (1 for each item and 3 for all 3 subscales) was subtracted from the composite score and divided by the greatest possible score range. The greatest range was (7-1) X 3 items = 18 for the effectiveness and convenience, and (5-1) x 3 items = 12 for global satisfaction. This provided a transformed score between 0 and 1 that was then multiplied by 100. A positive change from baseline indicates improvement.	Baseline to month 12 (End of Treatment Visit for non-responders) and 24 (End of Treatment Visit for responders), assessed up to 12 months for non-responders and up to 24 months for responders

External Links

•   Patient Lay Trial Summary