Efficacy Study of an Anti-Tumor Necrosis Factor (TNF) Alpha Agent in Patients With Hand Osteoarthritis (DORA)

Randomized Double Blind Placebo-controlled Trial of the Efficacy of an Anti-TNF Alpha Agent (Adalimumab, Humira®) in Patients With Incapacitating Hand Osteoarthritis Refractory to Usual Treatment

Digital osteoarthritis (DO) which affects the interphalangeal joints and the Metacarpophalangeal (MCP) of the thumb is a common disease, the prevalence of which increases with age (36% of the population aged over 70). Certain forms of DO with clinical manifestations involving inflammatory features are particularly refractory to usual treatments (analgesics, NSAIDs, braces and local injections). The mechanism of osteoarthritis involves two major cytokines: interleukin-1 beta and tumor necrosis factor alpha. TNF alpha is particularly involved in the inflammation process.

The aim of the present study is to study the efficacy of TNF alpha blockers (2 injections of adalimumab compared to placebo injections in patients with severe and refractory hand osteoarthritis.

We hope that such new therapeutic option may induce substantial pain relief.

Study Overview

• Status: Completed
• Conditions: Hand Osteoarthritis
• Intervention / Treatment: Other: Adalimumab (Humira®); Other: Placebo

Detailed Description

Objective: To demonstrate the efficacy of two subcutaneous injections of anti-TNF alpha (adalimumab) in patients with DO refractory to usual treatments (NSAIDs - analgesics).

Design: Randomized placebo-controlled multicenter (20 sites (amendment 18/12/2008)) trial

Trial duration: 6 months follow-up per patient, total trial duration: 12 months

Number of patients: 84(up)

Dose of administration: Two subcutaneous injections separated by a 2-week interval of either adalimumab or placebo. Therapeutic precautions inherent to the prescription of anti-TNF alpha are based upon those recommended in rheumatoid arthritis. With only two injections of anti-TNF alpha, the risk of complications (infectious in particular) inherent to the anti-TNF alpha appears to be extremely slight.

Patient selection: Patients with digital osteoarthritis (DIP and PIP) according to American College of Rheumatology (ACR) criteria (with a recent X-ray, less than 6 months, of the hands, showing signs of digital osteoarthritis), symptomatic for more than 3 months (at least three finger joints) and scored more than 40 mm on a pain visual analog scale (VAS) despite use of a level 1 analgesic (acetaminophen: 4 g daily) andNSAIDs. Main Exclusion criteria are contraindications to anti-TNF alpha according to international guidelines.

Methods: Patients will be seen at a screening visit, then during treatment administration (W0 and W2) and at follow-up visits: W6, 10, 14 and 26. NSAIDs will be stopped at the time of screening.

Efficacy evaluation: The efficacy endpoint is improvement in pain on a pain VAS at different times of assessment (primary endpoint at W6). A more than 50% improvement, in comparison with baseline, will be considered to be significant. Secondary endpoints are: number of tender joints, number of swollen joints, morning stiffness, global assessment of handicap by patient, global assessment of handicap by physician, the DREISER'S algofunctional index, Cochin hand index, weekly evolution of pain ( patient record), and recording of analgesic use (acetaminophen or NSAIDs).

Statistical data: Statistical analysis will be performed on the inter-group difference in the intention-to-treat population. khi-2 will be used only for criteria number 1.

Anticipated result: Significant superiority of adalimumab over placebo which would provide a therapeutic solution in difficult-to-treat patients with hand OA.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Créteil, France, 94000
    • Chu Henri Mondor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age: 40-80
• Men or women
• Digital osteoarthritis (DIP and PIP) according to ACR criteria (with recent X-ray, dating from less than 6 months, of the hands showing radiological signs of digital osteoarthritis)
• Symptomatic digital osteoarthritis for more than 3 months (at least every other day) despite taking analgesics and NSAIDs (except when there are contraindications to the latter therapeutic group)
• Osteoarthritis affecting more than three finger joints
• Pain more than 40 mm as evaluated by pain VAS (0-100 mm)
• No contraindication to anti-TNF alpha treatments
• No digital osteoarthritis surgery scheduled within the next 2 months
• Written informed consent

Exclusion Criteria:

• Pregnant women or women of reproductive potential without effective contraception
• Known hypersensitivity
• Patients having already been treated with an anti-TNF alpha
• Finger osteoarthritis secondary to inflammatory rheumatism
• Psoriasis
• Existence of painful syndrome of upper limbs likely to interfere with the monitoring of pain (cervicobrachial neuralgia, incapacitating carpal tunnel syndrome, joint disorders of the elbow or shoulder)
• Inflammatory rheumatism
• Contraindications to anti-TNF alpha agents: patients with suspected reactivation of tuberculosis (phlyctenular IDR, past history of tuberculosis, chest X-ray deemed suspect) or known leukopenia (< 3500 leukocytes), known hepatic cytolysis (transaminases more than twice normal), a history of serious allergy, concomitant infection, past history of serious systemic infection (septicemia), a history of known cancer within the past 5 years, history of multiple sclerosis
• Skin disease incompatible with subcutaneous injection
• Anticoagulant (oral) or treatment with heparin at a curative dose
• Surgery scheduled within the coming 2 months
• Finger surgery scheduled within the coming 6 months
• Local injection of a corticosteroid in a symptomatic finger joint during the previous month
• Local injection of hyaluronic acid in a symptomatic finger joint during the prior 3 months
• Treatment with a slow-acting anti-osteoarthritis agent initiated and colchicine (amendment 26/06/2008) within the previous 3 months
• Oral corticosteroids
• Psychiatric illness
• Non-controlled diabetes "mellitus"
• Known viral hepatitis B or C, HIV infection

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; 2 injections of Adalimumab (Humira®)	Other: Adalimumab (Humira®); syringes for injections under cutaneous dose = 40mg vol = 0.8 ml
Placebo Comparator: 2; 2 injection of Placebo	Other: Placebo; syringes under cutaneous vol = 8 ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Level of Pain on visual analogue scale	4 weeks following the last injection

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of tender joints	at weeks 4, 6, 10, 14, 26
Number of swollen joints	at weeks 4, 6, 10, 14, 26
Global assessment of handicap by patient	at weeks 4, 6, 10, 14, 26
Global assessment of handicap by physician	at weeks 4, 6, 10, 14, 26
Duration of morning stiffness	at weeks 4, 6, 10, 14, 26
DREISER'S algofunctional index	at weeks 4, 6, 10, 14, 26
Cochin hand index	at weeks 4, 6, 10, 14, 26
Weekly pain recording, and recording of analgesic use (acetaminophen)	at weeks 4, 6, 10, 14, 26
Percentage of non responders according to the number of patients requiring NSAIDS intake during the trial and/or rule out for lack of efficacy	from week 0 until week 26

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Abbott
• Investigators: Principal Investigator: Xavier Chevalier, PU-PH, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Chevalier X, Ravaud P, Maheu E, Baron G, Rialland A, Vergnaud P, Roux C, Maugars Y, Mulleman D, Lukas C, Wendling D, Lafforgue P, Loeuille D, Foltz V, Richette P; French section of osteoarthritis. Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial. Ann Rheum Dis. 2015 Sep;74(9):1697-705. doi: 10.1136/annrheumdis-2014-205348. Epub 2014 May 9.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: January 15, 2008
• First Submitted That Met QC Criteria: January 15, 2008
• First Posted (Estimate): January 18, 2008

Study Record Updates

• Last Update Posted (Estimate): July 26, 2012
• Last Update Submitted That Met QC Criteria: July 25, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Osteoarthritis; Hand; Biological Therapy; Tumor Necrosis Factor-alpha inhibitors
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: P 051007