Effectiveness and Safety of Yisaipu Combined With Tripterygium Wilfordii for Active RA (YISTAR)

• ClinicalTrials.gov Identifier: NCT03589833
• Recruitment Status: Unknown
• First Posted: July 18, 2018
• Last Update Posted: July 19, 2018
• Sponsor: Peking Union Medical College Hospital
• Information provided by (Responsible Party): Xuan Zhang, Peking Union Medical College Hospital

Study Description

Brief Summary:

In this 24-week, multi-center, randomized, double-blind study, the investigators will evaluate the efficacy and safety profile of subcutaneously injected Yisaipu, a Tumor Necrosis Factor Receptor Fusion Protein, combined with oral Tripterygium Wilfordii for patients with active rheumatoid arthritis.

Condition or disease	Intervention/treatment	Phase
Arthritis, Rheumatoid	Drug: Tripterygium Wilfordii; Drug: Methotrexate; Drug: Yisaipu	Phase 2

Detailed Description:

This study evaluates the efficacy and safety of YISAIPU plus Tripterygium wilfordii (T2w) for the treatment of RA patients. YISAIPU is a recombinant human tumor necrosis factor receptor fusion protein, and tripterygium wilfordii is a chloroform/methanol extract of Tripterygium wilfordii Hook F.

Objectives:

1. To compare the efficacy of YISAIPU plus T2w versus MTX monotherapy for the treatment of signs and symptoms of RA.
2. To evaluate the safety of YISAIPU plus T2w in patients with RA for 24 weeks.

Design:

This is a Phase 2, randomized, 24-week, double-blind, parallel group study, and 506 patients with active RA will be randomized in a 1:1:1:1 ratio to one of the following four parallel treatment arms:

1. Methotrexate monotherapy
2. T2w monotherapy
3. YISAIPU plus methotrexate
4. YISAIPU plus T2w

Escape:

On week 12, all participants with inadequate response, defined as a <30% improvement of swollen and tender joint counts from baseline, will switch to YISAIPU plus T2w treatment throughout the study.

Endpoints :

1. ACR20, ACR50 and ACR70 response rates at 4, 12 and 24 weeks.
2. DAS 28 (CRP) and DAS 28 (ESR) at 4, 12 and 24 weeks.
3. EULAR response rates at 4, 12 and 24 weeks.
4. Health assessment questionnaire (HAQ) at 4, 12 and 24 weeks.
5. Patient assessment of arthritis pain at 4, 12 and 24 weeks.
6. Patient and physician global assessment of arthritis at 4, 12 and 24 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 504 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effectiveness and Safety of Tumor Necrosis Factor Receptor Fusion Protein(Yisaipu) Combined With Tripterygium Wilfordii for Active Rheumatoid Arthritis
• Estimated Study Start Date: July 2018
• Estimated Primary Completion Date: July 2020
• Estimated Study Completion Date: July 2020

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: MTX; Treated with oral methotrexate and two placebos.	Drug: Methotrexate; Oral methotrexate 7.5-15mg per week for 24 weeks. The starting dose was 7.5mg per week, then increased to 15mg (max 0.3mg/Kg) per week in 4 weeks. Folic acid at the dose of 5 mg per week were applied to all participants.
Placebo Comparator: Tripterygium Wilfordii; Treated with oral Tripterygium Wilfordii and two placebos.	Drug: Tripterygium Wilfordii; Oral Tripterygium Wilfordii 20mg thrice daily for 24 weeks.
Active Comparator: Yisaipu + MTX; Treated with subcutaneously injected Yisaipu, oral methotrexate and a placebo.	Drug: Methotrexate; Oral methotrexate 7.5-15mg per week for 24 weeks. The starting dose was 7.5mg per week, then increased to 15mg (max 0.3mg/Kg) per week in 4 weeks. Folic acid at the dose of 5 mg per week were applied to all participants.; Drug: Yisaipu; Yisaipu, a Tumor Necrosis Factor Receptor Fusion Protein, was subcutaneously injected at a dose of 50 mg once a week for 24 weeks.
Experimental: Yisaipu + Tripterygium Wilfordii; Treated with subcutaneously injected Yisaipu, oral methotrexate and a placebo.	Drug: Tripterygium Wilfordii; Oral Tripterygium Wilfordii 20mg thrice daily for 24 weeks.; Drug: Yisaipu; Yisaipu, a Tumor Necrosis Factor Receptor Fusion Protein, was subcutaneously injected at a dose of 50 mg once a week for 24 weeks.

Outcome Measures

Primary Outcome Measures :

1. The American College of Rheumatology 50 (ACR50) response at 12 weeks [ Time Frame: week 12 ]
   The difference of ACR50 between Arm 4 (Yisaipu + Tripterygium Wilfordii) and Arm 1 (MTX) at week 12.

Secondary Outcome Measures :

1. The American College of Rheumatology 20/70 (ACR20/ACR70) response at 12 weeks [ Time Frame: week 12 ]
   The difference of ACR20 and ACR70 between Arm 4 (Yisaipu + Tripterygium Wilfordii) and Arm 1 (MTX) at week 12.
2. The American College of Rheumatology 20/50/70 (ACR20/ACR50/ACR70) response at 24 weeks [ Time Frame: week 24 ]
   The difference of ACR20, ACR50 and ACR70 between Arm 4 (Yisaipu + Tripterygium Wilfordii) and Arm 1 (MTX) at week 24.
3. The Disease Activity Score-28 (DAS28) response at 24 weeks [ Time Frame: week 24 ]

   The change in DAS28 score from baseline to week 24 between Arm 4 (Yisaipu + Tripterygium Wilfordii) and Arm 1 (MTX).

   DAS28 ＝ 0.56*SQRT(TJC28) + 0.28*SQRT(SJC28) + 0.36*ln(CRP + 1) + 0.014*GH + 0.96

   • TJC28: The number of tender joints (0-28).
   • SJC28: The number of swollen joints (0-28).
   • CRP: The C-Reactive Protein level (in mg/l).
   • GH: The patient global health assessment (from 0=best to 100=worst).

   The 28 joint: shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and the knees.

4. The European League Against Rheumatism (EULAR) response at 12 weeks [ Time Frame: week 12 ]
   The difference of proportions of patients meeting EULAR response between Arm 4 (Yisaipu + Tripterygium Wilfordii) and Arm 1 (MTX) at week 12.
5. Health Assessment Questionnaire without Didability Index (HAQ-DI) at 12 weeks [ Time Frame: week 12 ]

   The change in HAQ-DI score from baseline to week 12 between Arm 4 (Yisaipu + Tripterygium Wilfordii) and Arm 1 (MTX).

   HAQ-DI is an index measuring the quality of life related to health, which includes 20 questions in terms of three categories:

   • from 0 to 1: mild difficulties to moderate disability,
   • from 1 to 2: disability moderate to severe,
   • from 2 to 3: severe to very severe disability.

   The mean score is recorded as the result.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age 18-65 years with informed consent
• Fulfill the 2010 ACR/EULAR classification criteria for rheumatoid arthritis
• Disease duration > 6 weeks
• Swollen joint (SJC)≥4 and tender joint count(TJC)≥4
• ESR >28 mm/hr or C-reactive protein > 1.5 ULN
• Positive RF or anti-CCP antibody on screening
• Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA
• No evidence of active or latent or inadequately treated Mycobacterium tuberculosis infection

Exclusion Criteria:

• Pregnant, lactating or further fertility requirements
• Previously received any biologic agents.
• Recently (<12 weeks) received methotrexate, leflunomide, salazosulfapyridine, azathioprine, cyclosporine, mycophenolate mofetil or Tripterygium Wilfordii.
• Active or chronic infection, including HIV, HCV, HBV, tuberculosis.
• History of any other rheumatic autoimmune disease
• History of any lymphoproliferative disorder
• Malignancy or history of malignancy.
• Abnormal laboratory tests, including: Hemoglobin <8.5 g/dL, White blood cell count <3.5 x 109/L, Platelet count <100 x 109/L, AST/ALT >1.5 ULN, and serum creatine > 1.5 mg/dL.
• Severe, progressive, or uncontrolled cardiac, pulmonary, renal, hepatic, gastrointestinal, hematologic, metabolic, endocrine or neurologic disease

Contacts and Locations

Contacts

Contact: Hua Chen, MD; +861069158795; chenhua@pumch.cn

Locations

China, Beijing

Deptment of Rheumatology, Peking Union Medical College Hospital; Recruiting

Beijing, Beijing, China, 100032

Contact: Xuan Zhang, MD

Principal Investigator: Xuan Zhang, MD

Sponsors and Collaborators

Peking Union Medical College Hospital

Investigators

• Principal Investigator: Xuan Zhang, MD; Peking Union Medical College Hospital

More Information

• Responsible Party: Xuan Zhang, Professor, Peking Union Medical College Hospital
• ClinicalTrials.gov Identifier: NCT03589833
• Other Study ID Numbers: YISTAR
• First Posted: July 18, 2018
• Last Update Posted: July 19, 2018
• Last Verified: July 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Xuan Zhang, Peking Union Medical College Hospital:

Rheumatoid Arthritis; Methotrexate; Tripterygium; TNF inhibitor

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Methotrexate; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors