Effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) on RAdiographic Damage in Ankylosing Spondylitis

Study Overview
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Brief Summary
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This is a randomised, controlled, multi-centre clinical trial on AS patients. Experimental intervention: continuous (daily) treatment with diclofenac cholestyramine 150 mg (Voltaren Resinate), divided into 75mg Voltaren twice dailyControl intervention: treatment on-demand (as needed) with diclofenac-cholestyramine 75 to 150 mg (Voltaren Resinate). The treatment strategy of the control intervention (on-demand) reflects current clinical practice in AS. Duration of intervention per patient: 2 years Follow-up per patient: safety assessment 3 months after termination of the trial.

Detailed Description
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Ankylosing spondylitis (AS) is a common chronic inflammatory rheumatic disease with a prevalence of about 0.5%. First symptoms normally occur in young adulthood. Early in its course, AS is dominated by chronic pain, fatigue and morning stiffness, later on by ankylosis and loss of function. Nonsteroidal anti-inflammatory drugs (NSAID) and tumor necrosis factor (TNF) alpha blocking agents are the only drugs with proven efficacy for signs and symptoms. It is not clear, however, whether these drugs are also capable of retarding or stopping structural damage, i.e. prevention of bony ankylosis. Earlier investigations indicated that NSAIDs have, in addition to their anti-inflammatory, also an anti-osteoproliferative effect. In this study we will investigate whether treatment with 150 mg diclofenac, a non-selective NSAID, on a daily basis (continuous treatment) over 2 years is capable to slow down the development of bony ankylosis as compared to treatment with 75-150mg diclofenac as needed according to clinical symptoms (on-demand treatment). In this national multi-centre randomized trial patients with symptomatic AS and indication for NSAID therapy will be enrolled in about 40 centres. The primary outcome parameter is the proportion of patients with radiographic progression in the spine after 2 years in each treatment arm. If continuous NSAID treatment results in less radiographic progression as compared to on-demand treatment, a true disease modifying effect of NSAID has to be assumed which will most likely change the place of NSAID treatment in AS.

Official Title
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Effects of NSAIDs on RAdiographic Damage in Ankylosing Spondylitis (ENRADAS) - a Prospective Randomised Controlled Trial

Conditions
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Ankylosing Spondylitis

Intervention / Treatment
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* Drug: diclophenac
* Drug: diclophenac


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: AS according to mod. New York criteria Patients must have radiographic damage (at least one syndesmophyte) of the spine but no complete ankylosis of the cervical and lumbar spine (these are patients at risk for further and more rapid radiographic progression) Patients must have active disease at inclusion defined as BASDAI question 2 (related to back pain) >= 4 (VAS, range 0-10) without NSAID treatment and with a clinical indication for NSAID therapy based on signs and symptoms Exclusion Criteria: No radiographic damage (syndesmophyte) of the spine at baseline Complete ankylosis of the cervical and lumbar spine Inactive disease Evidence of current or past peptic ulcer Current or past coronary heart disease Stroke or transient ischemic attack Uncontrolled hypertension Chronic renal failure (creatinine > 1.5mg/dl) Impaired liver function Pregnancy Abnormal liver function (2x upper limit of normal) Active hepatitis B or C, chronic or acute heart failure (NYHA III or IV) - History of HIV infection History of neoplastic disease (details please refer to exclusion criteria) History of abuse of hard drugs or alcoholism Concomitant treatment with steroids, TNF-blockers, other DMARDs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>continuous (daily) treatment with diclofenac cholestyramine 150 mg (Voltaren Resinate), divided into 75mg Voltaren twice daily | Drug: diclophenac<br>* continuous (daily) treatment of diclofenac cholestyramine 150 mg, divided into 75mg twice daily<br>* Other names: voltaren resinat;|
| Active Comparator: 2<br>treatment on-demand (as needed) with diclofenac-cholestyramine 75 to 150 mg (Voltaren Resinate). The treatment strategy of the control intervention (on-demand) reflects current clinical practice in AS. | Drug: diclophenac<br>* treatment on-demand (as needed) with diclofenac-cholestyramine 75 to 150 mg daily<br>* Other names: Voltaren resinate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| radiographic change (mean) of the spine after 2 years in the per-protocol population. Radiographs will be collected and centrally digitized. Scoring will be done by 2 readers who were blinded to treatment and sequence of the films |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the proportions of patients with any progression (change in the mSASSS ≥ 1) and change in the mSASSS > smallest detectable change (SDC), i.e. change in mSASSS which is greater than the measurement error. |  | 2 years | 
| ITT analysis of radiographic change. |  | 2 years | 
| Change in VAS back pain, BASDAI, BASFI, BASMI, CRP. |  | 2 years | 
| event rates of serious and non-serious adverse events will be documented and compared between the two groups. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSAIDS, ankylosing spondylitis, SpA, Spondyloarthritis, radiographic changes