ARCADIA: Phase II proof of concept study of Abatacept (Orencia) in individuals who aRe Considered At risk of Developing Inflammatory Arthritis

Phase 1

• Conditions: MedDRA version: 20.0Level: PTClassification code 10003246Term: ArthritisSystem Organ Class: 10028395 - Musculoskeletal and connective tissue disorders; Inflammatory arthritis; Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

• Registration Number: EUCTR2015-005285-38-GB
• Lead Sponsor: The University of Leeds

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-01-02
• Last Update Posted: 13 October 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

• Participant in Leeds CCP ‘Next Generation’ observational cohort who has tested positive for anti-CCP Ab in the context of a new musculoskeletal complaint.
•Age >18 years old.
•A moderate to high risk of progression to IA (see below)
•Consents to be contacted in future for an interventional study

A prediction model will be used to risk stratify individuals based on the following predictors:
a. Tenderness of =1 small joint of the hands or feet (wrists, metacarpophalangeal (MCP), proximal interphalangeal (PIP), midtarsal and/or meta-tarsophalangeal joints) defined by the physician on examination.
b. Early morning stiffness > or = 30 minutes
c. RF and/or anti-CCP Ab concentration >3x upper limit of normal.

The individual’s risk will be calculated according to the model suggested by Rakieh et al. (1). This gives 1 point each for presence of tenderness and EMS=30 mins, and 2 points for rheumatoid factor or ACPA antibody >3x upper limit of normal. Participants with a score =3 will be considered as moderate to high risk of developing IA (= 40% progression risk), therefore eligible for randomisation.

•For the intervention arm:
oRandomised to intervention arm
oConsents to commence Abatacept therapy (if not, will remain in CCP Next-generation study)
•For the control arm:
oRandomised to the control arm
oThese patients will remain in the CCP Next-generation study
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 38

Exclusion Criteria

1.Both Intervention arm and control arm
•Previous diagnosis of RA or other form of inflammatory arthritis including, but not limited to SLE, psoriatic arthritis, ankylosing spondylitis, gout or pyrophosphate arthropathy and including current treatment with DMARDs or biological therapy.
•Clinical synovitis on clinical examination by a rheumatologist.
•Presence of concomitant illness likely to require systemic glucocorticosteroid therapy during the study, in the opinion of the investigator
•Treatment with an intravenous, intramuscular, intrabursal or intraarticular corticosteroid within 12 weeks prior to randomization.
•Co-morbidities requiring chronic treatment with immunosuppressive or immune modulating therapy.
•Women in the intervention arm who get pregnant during the study will be withdrawn from treatment and followed for the duration of the pregnancy for safety purposes. All participants who get pregnant will continue to be followed up via 12-weekly visits until 96 weeks has been reached and secondary end point data collected
•Individuals with palindromic rheumatism

2.Intervention arm only
•History of acute allergic reactions to biologic therapies or immunoglobulins
•Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, whether or not related to RA and which, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
•Subjects who have at any time received treatment with any investigational drug within 28 days of the first dose of study drug.
•Subjects who test positive for Hepatitis B, C or HIV.
•Subjects with tuberculosis (TB), including those at high risk of TB, chronic viral infections, recent serious bacterial infections, subjects receiving live vaccinations within 3 months of the anticipated first dose of study medication, or those with chronic illnesses that would, in the opinion of the investigator, put the participant at risk.
•Subjects who currently abuse drugs or alcohol
•Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ.
•Scheduled for or anticipating joint replacement surgery
•Men or women unwilling to use an acceptable method of contraception to avoid pregnancy for up to 14 weeks after the last dose of trial medication (acceptable method of contraception described in section 7.1.4).
•Women of childbearing potential with positive serum or urine pregnancy test within 48 hours prior to start of investigational product. Women of child bearing potential are defined as women who have had any menstrual bleeding in the last 24 months and who have not had a hysterectomy or surgical sterilisation.
•Evidence of active or latent bacterial or viral infection at the time of potential enrolment, including human immunodeficiency or herpes zoster virus or cytomegalovirus that resolved less than 2 months prior to enrolment.
•Inadequate haematological, hepatic or renal function within 28 days of treatment:
oHaemoglobin <8.5 g/dL
oWhite blood cells <3000/mm3
oPlatelets <100,000/mm3
oSerum creatinine, ALT or AST >2 times upper limit of normal
Any other laboratory test result that, in the opinion of the study investigator, might place the participant at unacceptable risk for participation in the study

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To obtain preliminary evidence of the clinical efficacy of abatacept in reducing the incidence of inflammatory arthritis in individuals who are at-risk.<br><br>;Secondary Objective: To evaluate the ability of abatacept to influence immune, clinical and imaging biomarkers in anti-CCP positive individuals at risk of progressing to IA. To determine whether T-cell subset biomarkers are valid surrogate markers for progression to IA, and to determine if there is a response to treatment in these biomarkers.;Primary end point(s): The percentage of individuals that have developed IA at 48 weeks.;Timepoint(s) of evaluation of this end point: 48 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Joint swelling and tenderness <br>- Acute phase reactant levels<br>- Physician assessment of global disease activity<br>- Ultrasound synovitis and erosions<br>- X-ray scan measurements<br>- Patient-reported measures: Early morning stiffness, Joint pain, Functional impairment, Quality of life, General health assessment, Pain, Disease activity & Fatigue<br>- T-cell subset levels<br>- Toxicity;Timepoint(s) of evaluation of this end point: - Joint swelling and tenderness, acute phase reactant levels and physician assessment of global disease activity at weeks 12, 24, 36, 48, 60, 72, 84 and 96<br>- Ultrasound synovitis and erosions at weeks 24, 48, 72 and 96.<br>- X-ray scan measurements at weeks 48 and 96<br>- Patient-reported measures (Early morning stiffness, Joint pain, Functional impairment, Quality of life, General health assessment, Pain, Disease activity, Fatigue and Toxicity) at weeks 12, 24, 36, 48, 60, 72, 84 and 96.