Clinical trial NCT00715091: Effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) on RAdiographic Damage in Ankylosing Spondylitis
Official title: Effects of NSAIDs on RAdiographic Damage in Ankylosing Spondylitis (ENRADAS) - a Prospective Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ankylosing Spondylitis
Keywords: NSAIDS
ankylosing spondylitis
SpA
Spondyloarthritis
radiographic changes
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2008-07-15
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 2 years
Secondary outcomes:
measure: 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.
timeFrame: 2 years
measure: ITT analysis of radiographic change.
timeFrame: 2 years
measure: Change in VAS back pain, BASDAI, BASFI, BASMI, CRP.
timeFrame: 2 years
measure: event rates of serious and non-serious adverse events will be documented and compared between the two groups.
timeFrame: 2 years
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: Medizinische Universitätsklinik Innere Medizin
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Praxis Dr. Jacki
state: Baden-Württemberg
city: Bamberg
country: Germany
facility: Praxis Dr. Manger
state: Bayern
city: Bayreuth
country: Germany
facility: Praxis Dr. Ochs
state: Bayern
city: München
country: Germany
facility: Praxis Dr. Kellner
state: Bayern
city: München
country: Germany
facility: Praxiszentrum St. Bonifazius
state: Bayern
city: Passau
country: Germany
facility: Gemeinschaftspraxis Dr. Göttl
state: Bayern
city: Bad Bentheim
country: Germany
facility: Fachklinik Bad Bentheim
state: Niedersachsen
city: Goslar
country: Germany
facility: Praxis Dr. Rockwitz
state: Niedersachsen
city: Hildesheim
country: Germany
facility: Gemeinschaftspraxis Dr. von Hinüber
state: Niedersachsen
city: Osnabrück
country: Germany
facility: Gemeinschaftspraxis Dr. Gauler
state: Niedersachsen
city: Weener
country: Germany
facility: Praxis Dr. Dockhorn
state: Niedersachsen
city: Düsseldorf
country: Germany
facility: Universitätsklinikum DüsseldorfKlink für Endokrinologie, Diabetologie und Rheumatologie
state: Nordrhein-Westfalen
city: Düsseldorf
country: Germany
facility: Rheumatologische Schwerpunktpraxis
state: Nordrhein-Westfalen
city: Ratingen
country: Germany
facility: Evangelisches Krankenhaus
state: Nordrhein-Westfalen
city: Remscheid
country: Germany
facility: Praxis Dr. Kramer
state: Nordrhein-Westfalen
city: Rheine
country: Germany
facility: Praxis Dr. Schoo
state: Nordrhein-Westfalen
city: Zerbst
country: Germany
facility: Rheumatologische Praxis Dr. Spieler
state: Sachsen-Anhalt
city: Berlin
country: Germany
facility: Brandt
city: Berlin
country: Germany
facility: Praxis Mielke
city: Berlin
country: Germany
facility: Praxis Zinke
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Dr. Schwenke
city: Grafschaft bei Bad Neuenahr-Ahrweiler
country: Germany
facility: Praxis Dr. Pick
city: Haldensleben
country: Germany
facility: Praxis Dr. Kühne
city: Herne
country: Germany
facility: Rheumazentrum Ruhrgebiet, St. Josefs Krankenhaus
city: Herne
country: Germany
facility: St. Josefs-Krankenhaus, Rheumatologie
city: Hoyerswerda
country: Germany
facility: Praxis Dr. Kapelle
city: Katzhütte
country: Germany
facility: Gemeinschaftspraxis Dr. Kolitsch
city: Pirna
country: Germany
facility: Praxis Dr. Gräßler
city: Potsdam
country: Germany
facility: Praxis Bohl-Bühler
Study officials:
affiliation: Charité University, Berlin, Germany
name: Martin Rudwaleit, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité University, Berlin, Germany
name: Joachim Sieper, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rheumazentrum Ruhrgebiet, Herne, Germany
name: Jürgen Braun, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wanders A, Heijde Dv, Landewe R, Behier JM, Calin A, Olivieri I, Zeidler H, Dougados M. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 2005 Jun;52(6):1756-65. doi: 10.1002/art.21054.
citation: Hartl A, Sieper J, Syrbe U, Listing J, Hermann KG, Rudwaleit M, Poddubnyy D. Serum levels of leptin and high molecular weight adiponectin are inversely associated with radiographic spinal progression in patients with ankylosing spondylitis: results from the ENRADAS trial. Arthritis Res Ther. 2017 Jun 15;19(1):140. doi: 10.1186/s13075-017-1350-9.
citation: Sieper J, Listing J, Poddubnyy D, Song IH, Hermann KG, Callhoff J, Syrbe U, Braun J, Rudwaleit M. Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. 2016 Aug;75(8):1438-43. doi: 10.1136/annrheumdis-2015-207897. Epub 2015 Aug 4.