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

• ClinicalTrials.gov Identifier: NCT03304288
• Recruitment Status: Active, not recruiting
• First Posted: October 9, 2017
• Last Update Posted: January 20, 2021
• Sponsor: Peking University People's Hospital
• Collaborators: Beijing Hospital; Navy General Hospital, Beijing; Beijing Tongren Hospital
• Information provided by (Responsible Party): Xiao-hui Zhang, Peking University People's Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Immune Thrombocytopenia	Drug: Rituximab; Drug: All-trans retinoic acid	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 11, 2017
• Actual Primary Completion Date: January 15, 2021
• Estimated Study Completion Date: February 28, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. overall response [ Time Frame: From the start of study treatment (Day 1) up to the end of Year 1 ]
   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.
2. sustained response [ Time Frame: From the start of study treatment (Day 1) up to the end of Year 1 ]
   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.

Secondary Outcome Measures :

1. complete response [ Time Frame: From the start of study treatment (Day 1) up to the end of Year 1 ]
   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.
2. time to response [ Time Frame: From the start of study treatment (Day 1) up to the end of Year 1 ]
   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.
3. duration of response [ Time Frame: From the start of study treatment (Day 1) up to the end of Year 1 ]
   Duration of response was measured from the achievement of response to the loss of response. Interim analysis was scheduled at 50% through recruitment.
4. incidence of adverse events [ Time Frame: From the start of study treatment (Day 1) up to the end of Year 1 ]
   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.
5. Initial response [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 4 ]
   The number of patients who achieve response at 4 weeks following treatment

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

China, Beijing

Peking University Insititute of Hematology, Peking University People's Hospital

Beijing, Beijing, China, 100044

Navy General Hospital

Beijing, Beijing, China, 100048

Beijing Hospital

Beijing, Beijing, China, 100730

Beijing Tongren Hospital

Beijing, Beijing, China

Sponsors and Collaborators

Peking University People's Hospital

Beijing Hospital

Navy General Hospital, Beijing

Beijing Tongren Hospital

Investigators

• Principal Investigator: Xiao-hui Zhang, Professor; Peking University Insititute of Hematology, Peking University People's Hospital

More Information

• Responsible Party: Xiao-hui Zhang, Professor, Peking University People's Hospital
• ClinicalTrials.gov Identifier: NCT03304288
• Other Study ID Numbers: 81670116
• First Posted: October 9, 2017
• Last Update Posted: January 20, 2021
• Last Verified: January 2021

• 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

Keywords provided by Xiao-hui Zhang, Peking University People's Hospital:

all-trans retinoid acid; rituximab; steroid-resistant; refractory; low-dose

Additional relevant MeSH terms:

Thrombocytopenia; Purpura, Thrombocytopenic, Idiopathic; Pathologic Processes; Blood Platelet Disorders; Hematologic Diseases; Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Thrombotic Microangiopathies; Hemorrhagic Disorders; Autoimmune Diseases; Immune System Diseases; Hemorrhage; Skin Manifestations; Rituximab; Tretinoin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Keratolytic Agents; Dermatologic Agents