The Combination of ATRA and Danazol as Second-line Treatment in Adult Immune Thrombocytopenia

Autoimmune Thrombocytopenia Clinical Trial

Official title:

The Combination of Oral All-trans Retinoic Acid and Danazol vs Danazol as Second-line Treatment in Adult Immune Thrombocytopenia: a Multicenter, Randomized, Open-label Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01667263
• Other study ID #: U1111-1132-6877
• Secondary ID: Z111107058811024
• Status: Completed
• Phase: Phase 2
• First received: August 15, 2012
• Last updated: September 3, 2017
• Start date: June 1, 2012
• Est. completion date: February 1, 2017

Study information

• Verified date: April 2017
• Source: Peking University People's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Randomized, open-label, multicentre study to compare the efficacy and safety of ATRA plus danazol with danazol monotherapy in patients with corticosteroid-resistant/relapsed ITP.

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 corticosteroid-resistant or relapsed ITP is not well understood; thus, treatment remains a great challenge. 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 ATRA+danazol and danazol monotherapy group. Platelet count, bleeding and other symptoms were evaluated before and after treatment. Adverse events are also recorded throughout the study, in order to compare the efficacy and safety of ATRA plus danazol with danazol monotherapy in patients with corticosteroid-resistant/relapsed ITP.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: February 1, 2017
• Est. primary completion date: July 1, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Primary immune thrombocytopenia (ITP) confirmed by excluding other supervened causes of thrombocytopenia;

• Platelet count of less than 30×109/L at enrolment

• 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.

• 18 years older.

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

• Unable to do blood routine test for the sake of time, distance, economic issues or other reasons.

Related Conditions & MeSH terms

• Autoimmune Thrombocytopenia
• Purpura, Thrombocytopenic, Idiopathic
• Thrombocytopenia

Intervention

Drug:
• All-trans retinoic acid

• Danazol

Locations

Country	Name	City	State
China	Beijing Hospital, Ministry of Health	Beijing	Beijing
China	Beijing Tongren Hospital	Beijing	Beijing
China	Peking University People's Hospital, Peking University Insititute of Hematology	Beijing	Beijing
China	PLA Navy General Hospital	Beijing	Beijing
China	Qilu Hospital, Shandong University	Jinan	Shandong

Sponsors (6)

Lead Sponsor	Collaborator
Peking University People's Hospital	Beijing Hospital, Beijing Municipal Science & Technology Commission, Beijing Tongren Hospital, Navy General Hospital, Beijing, Qilu Hospital of Shandong University

Country where clinical trial is conducted

China, 

References & Publications (7)

LIU Wen-bin, WANG Zhao-yue, CAO Li-juan, ZHAO Xiao-juan, ZHU Ming-qing, BAI Xia, RUAN Chang-geng.Therapeutic Effect and Mechanism of All-trans-retinoic Acid Treatment in Refractory Idiopathic Thrombocytopenic Purpura.Suzhou University Journal of Medical Science.2009;3 476-479.

Nozaki Y, Tamaki C, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. All-trans-retinoic acid suppresses interferon-gamma and tumor necrosis factor-alpha; a possible therapeutic agent for rheumatoid arthritis. Rheumatol Int. 2006 Jul;26(9):810-7. Epub 2005 Nov 15. — View Citation

Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kühne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12. — View Citation

Sakakura M, Wada H, Tawara I, Nobori T, Sugiyama T, Sagawa N, Shiku H. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb Res. 2007;120(2):187-93. Epub 2006 Oct 24. — View Citation

Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008 Mar 1;111(5):2505-15. doi: 10.1182/blood-2007-07-102798. Review. — View Citation

Wing K, Larsson P, Sandström K, Lundin SB, Suri-Payer E, Rudin A. CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology. 2005 Aug;115(4):516-25. — View Citation

Zhang X, Fu H, Xu L, Liu D, Wang J, Liu K, Huang X. Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes. Biol Blood Marrow Transplant. 2011 Feb;17(2):274-80. doi: 10.1016/j.bbmt.2010.09.007. Epub 2010 Sep 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the sustained platelet response at the 12-month follow-up	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 12-month follow-up.	From the start of study treatment (Day 1) up to the end of Month 12
Secondary	overall response	The number of participants with platelet count >=30×10^9/L at least once and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy	From the start of study treatment (Day 1) up to the end of Month 12
Secondary	primary response rate at 4 weeks	The number of participants with platelet count >=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 4 of treatment	From the start of study treatment (Day 1) up to week 4 of treatment
Secondary	primary response rate at 8 weeks	The number of participants with platelet count >=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 8 of treatment	From the start of study treatment (Day 1) up to week 8 of treatment
Secondary	time to response	Time to response was defined as the time from starting treatment to the time to achieve the response.	From the start of study treatment (Day 1) up to the end of month 12
Secondary	duration of response	Duration of response was measured from the achievement of response to the loss of response.	From the start of study treatment (Day 1) up to the end of month 12
Secondary	reduction in bleeding symptoms	Changes of bleeding after treatment. Bleeding was defined in accordance with the WHO bleeding scale (0, no bleeding; 1, petechiae; 2, mild blood loss; 3, gross blood loss; and 4, debilitating blood loss).	From the start of study treatment (Day 1) up to the end of month 12
Secondary	safety	All patients were assessed for safety every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	From the start of study treatment (Day 1) up to the end of follow-up