Comparison of the Efficacy of Leflunomide and Azathioprine for the Maintenance Therapy of ANCA Associated Vasculitis (LEFAZAREM)

The Efficacy of Leflunomide for the Maintenance Therapy of ANCA Associated Vasculitis

This study is a prospective, open-labelled, randomized, controlled,multi-center clincial trial. The aim of this study is to verify that the remission rate of patients treated with Leflunomide is not inferior to that of patients treated with Azathioprine.

Study Overview

• Status: Recruiting
• Conditions: ANCA Associated Vasculitis; Maintenance Therapy
• Intervention / Treatment: Drug: Azathioprine Tablets; Drug: Leflunomide

Detailed Description

Background The basic theme of AAV is relapse and remission. The maintenance therapy of AAV aimed to reduce or prevent relapse is very challenge. Although many medications have been used for the maintenance of AAV, Leflunomide (LEF) has not studied thoroughly yet. So far, only one study tested the efficacy of LEF in the maintenance therapy for AAV. However, the sample size of this study is small, so large size clinical study is needed to clarify the role of LEF in the maintenance of AAV.

LEF is one of the most frequently prescribed DMARDs in the treatment of rheumatic diseases in China. It is cheap and widely available. Many experiences have been accumulated about its efficacy and safety in Chinese patients with rheumatic diseases. But there is no study to show its effectiveness in the reduction of the relapse of AAV in China. In this study, we try to compare the effectiveness of LEF and AZA, the gold standard for maintenance therapy, in the maintenance of AAV.

Objectives To verify that the effectiveness of LEF in reducing relapse is not inferior to AZA by comparing the relapse rate of LEF and AZA during the 18 month maintenance treatment of AAV.

Study Design This is a prospective, randomized, open-label, control, non-inferiority study.

• Study Type: Interventional
• Enrollment (Anticipated): 114
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yunjiao Yang, MD; Phone Number: 8613671313079 86-13671313079; Email: yangyunjiao81@163.com
• Study Contact Backup: Name: Hanqi Wang, RN; Phone Number: 8613691165939 86-15810927696; Email: tianxp6@126.com

Study Locations

• China
  • Beijing, China, 100032
    • Recruiting
    • Peking Union Medical College Hospital
    • Contact: Hanqi Wang, RN; Phone Number: 86-15810927696; Email: wanghanqi06@163.com
  • Anhui
    • Hefei, Anhui, China
      • Not yet recruiting
      • Anhui Provincial Hospital
  • Inner Mongolia
    • Hohhot, Inner Mongolia, China, 010050
      • Not yet recruiting
      • The Affiliated Hospital of Inner Mongolia Medical University
      • Contact: Hongbin Li, MD; Phone Number: 13948536552; Email: hongbin.li@cstar.org.cn
      • Contact: Ning Tie, MD; Phone Number: 13948610720; Email: tieting@126.com
  • Yunnan
    • Kunming, Yunnan, China, 650032
      • Not yet recruiting
      • the Affiliated Hospital of Kunming Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients age 18 to 75 years, both genders can be included.
2. Patients who are newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or EGPA in complete remission after combined treatment with glucocorticoids and pulse cyclophosphamide or Rituximab. Remission is defined as a Birmingham Vasculitis Activity Score(BVAS version 3) of 0.
3. Patients must fulfill the 1990 ACR classification criteria of GPA, EGPA and 2012 modified Chapel Hill classification criteria of MPA.
4. Patients have to be ANCA-positive at diagnosis or during the course of their disease.
5. Patients must sign the informed consent.

Exclusion Criteria:

1. Patients with TPMT gene mutation；
2. Patients who had been treated with either AZA or LEF but relapsed in the past;
3. Patients who had been treated with either AZA or LEF but had to stop due to adverse events or intolerance;
4. Patients who have planned for pregnancy in next 2 years;
5. Patients with severe liver dysfunction(defined as the elevation of liver enzyme 3 times the upper limit or Child grade III) or ESRD；
6. Patients with uncontrolled sever hypertension, diabetes, active bacteria or fungal infection;
7. Patients with active hepatitis virus infection as well as patients who have active mycobacteria infection;
8. Patients who are not eligible according to the judge of the principal investigators or site investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Azathioprine treatment arm; Patients will be treated with Azathioprine 100mg QD for 18 months combined with rednisone. The dosage of prednisone is tapered in the study period but will be maintained at 7.5mg/d to the end of the study period.All included patients will be treated with TMPco 2 tablets everyday during the study period if not contraindicated or intoleran.t	Drug: Azathioprine Tablets; Patients included into this study will be treated with Azathioprine tablets 100mg QD for 18 months.
EXPERIMENTAL: Leflunomide treatment arm; Patient will be treated with Leflunomide 30mg QD for 18 months combined with prednisone. The dosage of prednisone is tapered in the study period but will be maintained at 7.5mg/d to the end of the study period. All included patients will be treated with TMPco 2 tablets everyday during the study period if not contraindicated or intolerant.	Drug: Leflunomide; Patient will be treated with Leflunomide(Tuoshu, the commericial name) 30mg QD for 18 months; Other Names: Tuoshu for commericial name

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the percentage of patients with major relapse in 18 months follow-up time	the percentage of patients with major relapse (re-appearance or worsening of disease with a BVAS >0 and involvement of at least one major organ, a life-threatening manifestation, or both) at month 18	from inclusion to the end of the study, 18 months in total

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rate of minor relapse of the AZA and LEF treatment group in 18 months.	The rate of minor relapse (reappearance or worsening of disease with a BVAS >0, not corresponding to a major relapse but requiring mild treatment intensification) of the AZA and LEF treatment group.	from inclusion to the end of the study, 18 months in total
The rate of adverse events and their severity in both LEF and AZA treated patients during 18 months of the study period.	2. The rate of adverse events and their severity(Severe events were defined as the adverse events of grade 3 or 4, deaths caused by any cause, cancers, side effects that necessitate hospitalization) in both LEF and AZA treated patients during the study period.	from inclusion to the end of the study, 18 months in total
Patients progress to ESRD at the end of the study	Patients progress to ESRD at the end of the study	from inclusion to the end of the study, 18 months in total

Collaborators and Investigators

• Sponsor: Chinese SLE Treatment And Research Group
• Collaborators: The First Affiliated Hospital of Anhui Medical University; Shanghai Zhongshan Hospital; Second Affiliated Hospital, School of Medicine, Zhejiang University; Beijing Shijitan Hospital, Capital Medical University; The First Affiliated Hospital of Kunming Medical College; Second Affiliated Hospital of Nanchang University; The Affiliated Hospital of Inner Mongolia Medical University; Affiliated Hospital of Jilin University, Changchun,China; Sichuan Province People's Hospital
• Investigators: Principal Investigator: Xinping Tian, Peking Unione Mdecial College Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 30, 2021
• Primary Completion (ANTICIPATED): November 30, 2024
• Study Completion (ANTICIPATED): December 31, 2024

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (ACTUAL): February 3, 2021

Study Record Updates

• Last Update Posted (ACTUAL): November 30, 2021
• Last Update Submitted That Met QC Criteria: November 26, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Maintenance; Leflunomide; Azathioprine; ANCA Associated Vasculits
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Autoimmune Diseases; Systemic Vasculitis; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Leflunomide; Azathioprine
• Other Study ID Numbers: CSTAR-006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: only patient clincial information coud be released to public

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No