Treatment of Axial Spondyloarthritis by Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc Fusion Protein

Treatment of Active Axial Spondyloarthritis by Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc Fusion Protein Injection: a Randomized, Double-blind, Multicentral Clinical Trial to Investigate the Efficacy and Safety of Yisaipu®

This is a randomized, double-blind, multicentral clinical trial to investigate the efficacy and safety of Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc fusion protein injection (Yisaipu®) in the treatment of active axial spondyloarthritis(SpA). The primary purpose is to assess the different situations in maintaining treatment programme in SpA patients with controlled inflammation by Yisaipu®. And the second purpose is to assess the eficacy and safety of Yisaipu® in axial SpAs. The trial will include 150 patients with stable NSAIDs therapy, and at the first stage they will receive 24-week full-dose of Yisaipu®. Then at the second stage the patients who achieve low disease activity (LDA, ASDAS<2.1) at 24th week will be randomizedly divided into three group: full-dose of Yisaipu® group, half-dose of Yisaipu® group and placebo group. And the blind stage will last for 48 weeks. Patients who complete the 72-week therapy or achieve disease-flare criteria during the blind stage would finish the study.

Study Overview

• Status: Completed
• Conditions: Spondyloarthritis
• Intervention / Treatment: Drug: 50mg Yisaipu; Drug: 25mg etanercept; Drug: Placebo

Detailed Description

This randomised controlled trial enrolled adult patients aged 18 years or older diagnosed with non-radiographic axial spondyloarthritis at 3 centres in China. Patients had to fulfil ASAS axial spondyloarthritis criteria but could not fulfil the modified New York radiologic criterion for ankylosing spondylitis,and had to have objective evidence of active inflammation or chronic structral change，such as bone erosion or fat metaplasia in the sacroiliac joints on MRI at screening. Active disease activity was defined as a disease activity score in ASDAS-CRP ≥2.1,or Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] ≥4 on a numerical rating scale of 0-10, and an inadequate response to more than one non-steroidal anti-inflammatory drugs (NSAIDs) for 4 weeks at least, intolerance to NSAIDs, or contraindication for NSAIDs. No change in NSAIDs dose was required from 2 weeks before screening to the end of the study. Dose stability or discontinuation was required for 4 weeks before baseline for concomitant DMARDs or corticosteroids (prednisone or equivalent at a dose of less than 10 mg/day). Chinese herbal medicine, physical therapy, or live (attenuated) vaccine, or intravenous immunoglobulin IgG, was required for discontinuation and wash period for at least 4 weeks. Patients were excluded if they had previously taken or were taking biologic treatment, any biologic Dmards such as IL-6 or CD-20 inhibitors. Patients with latent tuberculosis infection were included only when local guidelines were followed for prophylactic treatment and if treatment was initiated before Yisaipu.

All patients provided written informed consent, and the study protocol was approved by an institutional review board or independent ethics committee at each study site. The study was conducted in accordance with applicable regulations and the ethical principles of Good Clinical Practice as defined by the International Conference on Harmonisation (ICH) and the Declaration of Helsinki.

A randomized envelope was used to enrol all patients at the baseline visit and to randomly assign qualifying patients in a 1:1:1 ratio to receive either blinded Yisaipu 50 mg subcutaneously every week or 25 mg subcutaneously every week or matching placebo at week 24. All study personnel, including the sponsor (with the exception of the Sanshengguojian drug supply management team), investigator, and study site personnel, and the patient remained blinded to treatment throughout the double-blinded period from week 24 through week 72 of the study. Investigational products were provided to maintain blinding.

In the initial open-label period, enrolled patients were given subcutaneous injections of 50 mg Yisaipu every week for 36 weeks. Participants were given the dose of NSAIDs they had been receiving at screening; a dose decrease or discontinuation was allowed when the patients were intolerance to NSAIDs, or contraindication for NSAIDs. Patients who achieved clinical remission, defined as achieving ASDAS inactive or moderate disease (ASDAS score <2.1) at weeks 24, were randomly assigned to receive either blinded 50mg Yisaipu (continuation arm), 25mg Yisaipu(reduction arm) or matching placebo (withdrawal arm) for 48 weeks during the double-blind period, for a total of 72 weeks of treatment.

During the double-blind period, patients who experienced a flare (defined as an increase in BASDAI ≥2 points compare to the BASDAI score when randomization) were allocate to termination of this trial.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Department of Rheumatology, the Third Affiliated Hospital of Sun Yat-sen University

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:

• Fulfill the 2009 ASAS criteria for axial spondyloarthritis(SpA), and without bilateral more than grave 2 or unilateral more than grave 3 sacroilitis on X ray plan
• Active disease phase of SpA, defined as BASDAI≥4 or ASDAS≥2.1
• Inadequate response to NSAID≥4 week
• Application of NSAID with stable dose for no less than 2 weeks
• Stable dose of prenisone for at least four weeks at ≤10mg per day if used at screening, or stop use for at least 4 weeks.
• Stable dose of any DMARD for at least four weeks if used at screening, or stop use for at least 4 weeks
• Stop and receiving washing out for at least 4 week if receiving Chinese traditional drug for AS, physical treatment, vaccication or IVIG.
• The lab exam should achieve the criteria as below: Hb≥85g/L, 3.5×109/L≤WBC count≤10×109/L, PLT≥ lower limit of normal range, ALT≤2 fold of upper limit of normal range, serum creatine ≤upper limit of normal range.
• Negative pregnacy test for female patients. And promise to carry out contraception during the trial and 6 weeks after the trial is ended.
• Sign the informed consent.

Exclusion criteria:

• Previous application of any biologic agents.
• Allergic to any element of Yisaipu®
• Intolerance to NASID.
• History of active tubercolosis, or radiographic evidence of present or previous history of pulmonary tubercolosis, or close contact with patients with tubercolosis, or with high risk of infection of tubercolosis such as immune suppression status, or strong positive of PPD skin test with diameter ≥10mm.
• Presence of acute infection or acute onset of chronic infection at screen.
• Invasive fungal infection or conditional infection within 6 months prior to screen.
• Present or history of serious liver disease.
• History of infection on artifitial joints.
• Organ transplantation surgery within 6 months prior to screen.
• Presence of other autoimmune diseases, including IBD, psoriasis, uveitis, SLE, multiple sclerosis, etc.
• History of congestive heart failure.
• History of malignancies within 5 years prior to screen, excluding complete resection of squamous cell carcinoma, or basal cell carcinoma or cervical carcinoma in situ.
• AIDS or HIV infection.
• History of lymphoma or lymphoproliferative disorders.
• Presence of serious disorder of important organs or system.
• Presence of factors which may influence the compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 50mg etanercept; Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc Fusion Protein Injection, 50mg per week, Subcutaneous injection	Drug: 50mg Yisaipu; Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc Fusion Protein Injection, 50mg per week; Other Names: 50mg entanercept(Yisaipu)
Experimental: 25mg etanercept; Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc Fusion Protein Injectio, 25mg per week, Subcutaneous injection	Drug: 25mg etanercept; Recombinant Human Tumor Necrosis Factor-α Receptor Ⅱ IgG Fc Fusion Protein Injection, 25mg per week; Other Names: 25mg entanercept(Yisaipu)
Placebo Comparator: Placebo; Placebo, Subcutaneous injection per week	Drug: Placebo; The injection method and frequency of placebo is the same as the other arms.; Other Names: placebo arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of patients achieving ASDAS<2.1	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of patients achieving ASDAS<1.3	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
proportion of ASDAS major improvement	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
proportion of ASDAS clinically important improvement	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
ASAS 20	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
ASAS 40	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
ASAS5/6	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
ASAS PR	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
BASDAI50	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
BASDAI	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
BASFI	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
BASMI	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
spinal pain score	The unabbreviated scale title is VAS from 0 to 100mm. 100 mm mean the most severe pain	72 weeks
patient global assessment(PGA) score	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
physician global assessment(PhGA) score	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
ESR	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks
CRP	in the groups given 50 mg Yisaipu, 25mg Yisaipu compared to placebo in the double-blind period	72 weeks

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Jieruo Gu, Professor, 3rd Affiliated Hospital of Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2014
• Primary Completion (Actual): July 28, 2016
• Study Completion (Actual): August 28, 2016

Study Registration Dates

• First Submitted: February 10, 2015
• First Submitted That Met QC Criteria: February 10, 2015
• First Posted (Estimate): February 18, 2015

Study Record Updates

• Last Update Posted (Actual): December 19, 2019
• Last Update Submitted That Met QC Criteria: December 17, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: relapse; Yisaipu
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Joint Diseases; Musculoskeletal Diseases; Arthritis; Spinal Diseases; Bone Diseases; Bone Diseases, Infectious; Necrosis; Spondylitis; Spondylarthritis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Etanercept
• Other Study ID Numbers: [2013]2-21

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