The Combination of Low-dose Rituximab and ATRA as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia

The Combination of Low-dose Rituximab and All-trans Retinoic Acid as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia: a Multicenter, Randomized, Open-label Trial

Randomized, open-label, multicentre study to assess the efficacy and safety of the combination of low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.

Study Overview

• Status: Unknown
• Conditions: Immune Thrombocytopenia
• Intervention / Treatment: Drug: Rituximab; Drug: All-trans retinoic acid

Detailed Description

Immune thrombocytopenia (ITP) is a severe bleeding disorder. Approximately 2/3 of patients achieve remission from first-line therapies. However, the underlying mechanism of steroid-resistant or relapsed ITP is not well understood; thus, treatment remains a great challenge. Rituximab has been shown to partly improve the complete remission rate of ITP. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haematopoiesis, making it a possible treatment option.

A multicentre prospective study was performed in non-splenectomized ITP patients who were either resistant to a standard dose of corticosteroids or had relapsed. Patients were randomized to the low-dose rituximab+ATRA and the low-dose rituximab monotherapy groups. Platelet count, bleeding and other symptoms were evaluated before and after treatment. Interim analysis was scheduled at 50% through recruitment. Adverse events are also recorded throughout the study, in order to assess the efficacy and safety of the combination of low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100730
      • Beijing Hospital
    • Beijing, Beijing, China, 100044
      • Peking University Insititute of Hematology, Peking University People's Hospital
    • Beijing, Beijing, China
      • Beijing Tongren Hospital
    • Beijing, Beijing, China, 100048
      • Navy General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ITP confirmed by excluding other supervened causes of thrombocytopenia;
• Platelet count of less than 30×10^9/L at enrollment;
• Patients who did not achieve a sustained response to treatment with full dose corticosteroids for a minimum duration of 4 weeks or who relapsed during steroid-tapering or after its discontinuation;
• ECOG<2.

Exclusion Criteria:

• Secondary immune thrombocytopenia (e.g., patients with HIV, HCV, Helicobacter pylori infection or patients with systemic lupus erythematosus)
• Congestive heart failure
• Severe arrhythmia
• Nursing or pregnant women
• Aspartate aminotransferase and alanine transaminase levels ≥ 3×the upper limit of the normal threshold criteria
• Creatinine or serum bilirubin levels each 1•5 times or more than the normal range
• Active or previous malignancy
• Patients with other diseases were undergoing treatment with immunosuppressants
• Patients with ITP had received rituximab

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: low-dose rituximab & ATRA; rituximab 100mg once weekly for 6 weeks and oral all-trance retinoid acid 20mg/m^2 qd for 12 weeks.	Drug: Rituximab; Low-dose rituximab was used in combination with ATRA or as the monotherapy; Drug: All-trans retinoic acid; ATRA was used in combination with low-dose rituximab
Active Comparator: low-dose rituximab; rituximab 100mg once weekly for 6 weeks	Drug: Rituximab; Low-dose rituximab was used in combination with ATRA or as the monotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall response	The number of participants (responders) with platelet count >=30x10^9/L and at least a 2-fold increase in the baseline count (PR) or a platelet count >=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment.	From the start of study treatment (Day 1) up to the end of Year 1
sustained response	The number of participants that can maintain the platelet count > 30 x 109/L, an absence of bleeding events, and without requirement for any other ITP-specific treatment for 6 consecutive months after achievement of response. Interim analysis was scheduled at 50% through recruitment.	From the start of study treatment (Day 1) up to the end of Year 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
complete response	The number of participants (responders) with platelet count>=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment.	From the start of study treatment (Day 1) up to the end of Year 1
time to response	Time to response was defined as the time from starting treatment to the time to achieve the response. Interim analysis was scheduled at 50% through recruitment.	From the start of study treatment (Day 1) up to the end of Year 1
duration of response	Duration of response was measured from the achievement of response to the loss of response. Interim analysis was scheduled at 50% through recruitment.	From the start of study treatment (Day 1) up to the end of Year 1
incidence of adverse events	All patients were assessed for adverse events every week during the first 4 weeks of treatment, and at 2-weeks interval for the following 5 months, and monthly thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Interim analysis was scheduled at 50% through recruitment.	From the start of study treatment (Day 1) up to the end of Year 1
Initial response	The number of patients who achieve response at 4 weeks following treatment	From the start of study treatment (Day 1) up to the end of Week 4

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: Beijing Tongren Hospital; Beijing Hospital; Navy General Hospital, Beijing
• Investigators: Principal Investigator: Xiao-hui Zhang, Professor, Peking University Insititute of Hematology, Peking University People's Hospital

Publications and helpful links

General Publications

• Wu YJ, Liu H, Zeng QZ, Liu Y, Wang JW, Wang WS, Jia-Feng, Zhou HB, Huang QS, He Y, Fu HX, Zhu XL, Jiang Q, Jiang H, Chang YJ, Xu LP, Huang XJ, Zhang XH. All-trans retinoic acid plus low-dose rituximab vs low-dose rituximab in corticosteroid-resistant or relapsed ITP. Blood. 2022 Jan 20;139(3):333-342. doi: 10.1182/blood.2021013393.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2017
• Primary Completion (Actual): January 15, 2021
• Study Completion (Anticipated): February 28, 2021

Study Registration Dates

• First Submitted: October 3, 2017
• First Submitted That Met QC Criteria: October 3, 2017
• First Posted (Actual): October 9, 2017

Study Record Updates

• Last Update Posted (Actual): January 20, 2021
• Last Update Submitted That Met QC Criteria: January 16, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: rituximab; refractory; steroid-resistant; low-dose; all-trans retinoid acid
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Hematologic Diseases; Hemorrhage; Hemorrhagic Disorders; Blood Coagulation Disorders; Skin Manifestations; Blood Platelet Disorders; Thrombotic Microangiopathies; Purpura, Thrombocytopenic; Purpura; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Dermatologic Agents; Keratolytic Agents; Rituximab; Tretinoin
• Other Study ID Numbers: 81670116

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No