Bisphosphonates for the Treatment of Seropositive Musculoskeletal Complaints

Phase 4

• Conditions: Seropositive Muskuloskeletal Complaints
• Interventions: Drug: Zoledronic Acid; Drug: Placebo

• Registration Number: NCT04115397
• Lead Sponsor: Karolinska Institutet

Brief Summary

Seropositive Rheumatoid arthritis (RA) is characterized by autoantibodies that develop prior to clinical onset, allowing identification of individuals at risk for disease development. In a unique program in Stockholm, seropositive individuals presenting with musculoskeletal complains are currently identified and followed-up in a dedicated outpatient clinical program. Despite significant disease burden and increased sick leave among these individuals, we lack today any therapeutic and preventive measures.

We aim to (1). establish a nation-wide health program, (2). develop an algorithm for disease risk estimation and (3). test a novel strategy to delay and/or prevent disease onset in seropositive at risk individuals with musculoskeletal complains. We will perform a multicentre randomised study to treat autoantibody-positive individuals at risk for developing RA presenting with pain (Population), by repurposing of bisphosphonates (Intervention) as compared to placebo (Control) to treat pain (primary Outcome) and delay/prevent RA development during 1-year follow-up (secondary Outcome)

Detailed Description

we have recently identified a novel disease-triggering pathogenic mechanism in autoantibody-positive individuals consisting in a bone-mediated induction of pain by autoantibodies. We hypothesize that specific targeting of this new mechanism, rather than using therapies developed for already established disease (where other mechanisms are active), will be able to treat pain with arthralgia and halt disease progression in seropositive at-risk individuals.

We will address this hypothesis by repurposing of bisphosphonates, currently used in clinical practice in both RA patients as well as in many individuals at risk for RA (mainly women in post-menopausal age). We will perform a multi centre, prospective, randomised, double-blind and placebo-controlled study with 2 parallel groups.

Patients will be randomised 1:1 to receive either one infusion aclasta (5 mg zolendronic acid, n=40) or placebo (n=40). The primary outcome is the VAS pain score and the study is powered to detect a 20% difference in the primary endpoint between the active and the control arm. The study is powered to detect a 20-percentage point difference in proportions between the control and the treated group. Subjects may withdraw from the trial at any time at their own or the investigators request for safety reasons.

Study Timeline

• Status Verified: 2019-10
• Study First Submitted: 2019-10-02
• Study First Submitted QC: 2019-10-03
• Last Update Submitted: 2019-10-03
• Study First Posted: 2019-10-04
• Last Update Posted: 2019-10-04
• Study Start: 2020-01
• Primary Completion: 2021-12
• Study Completion: 2022-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

Age older than 18 years Lack of arthritis as estimated by clinical and ultrasound examination of the joints ACPA positive Intermediate or high risk for RA (according to the algorithm described above) VAS score of at least 20 mm

Exclusion Criteria

A previous diagnosis of arthritis Intolerance/contraindication to any of the study medications

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bisphophonate	Zoledronic Acid	Zolendronic acid, one infusion iv
Placebo	Placebo	Placebo, one infusion iv

Primary Outcome Measures

Name	Time	Method
VAS pain	3 months	PAin on a visual analogue scale

Secondary Outcome Measures

Name	Time	Method
HAQ	3 months	Health assessment questionnaire
MRI	6 months	MRI investigation of the symptomatic joints in the hands
Rheumatoid Arthritis (RA ) diagnosis	1 year	Getting a diagnosis of RA