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

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

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.

Study Overview

• Status: Completed
• Conditions: Ankylosing Spondylitis
• Intervention / Treatment: Drug: diclophenac; Drug: diclophenac

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.

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12163
    • Brandt
  • Berlin, Germany, 12627
    • Praxis Mielke
  • Berlin, Germany, 13055
    • Praxis Zinke
  • Dresden, Germany, 01109
    • Gemeinschaftspraxis Dr. Schwenke
  • Grafschaft bei Bad Neuenahr-Ahrweiler, Germany, 53501
    • Praxis Dr. Pick
  • Haldensleben, Germany, 39340
    • Praxis Dr. Kühne
  • Herne, Germany, 44652
    • Rheumazentrum Ruhrgebiet, St. Josefs Krankenhaus
  • Herne, Germany, 44652
    • St. Josefs-Krankenhaus, Rheumatologie
  • Hoyerswerda, Germany, 02977
    • Praxis Dr. Kapelle
  • Katzhütte, Germany, 98746
    • Gemeinschaftspraxis Dr. Kolitsch
  • Pirna, Germany, 01796
    • Praxis Dr. Gräßler
  • Potsdam, Germany, 14469
    • Praxis Bohl-Bühler
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 1072076
      • Medizinische Universitätsklinik Innere Medizin
    • Tübingen, Baden-Württemberg, Germany, 72072
      • Praxis Dr. Jacki
  • Bayern
    • Bamberg, Bayern, Germany, 96047
      • Praxis Dr. Manger
    • Bayreuth, Bayern, Germany, 95445
      • Praxis Dr. Ochs
    • München, Bayern, Germany, 80639
      • Praxis Dr. Kellner
    • München, Bayern, Germany, 81541
      • Praxiszentrum St. Bonifazius
    • Passau, Bayern, Germany, 94032
      • Gemeinschaftspraxis Dr. Göttl
  • Niedersachsen
    • Bad Bentheim, Niedersachsen, Germany, 48455
      • Fachklinik Bad Bentheim
    • Goslar, Niedersachsen, Germany, 38640
      • Praxis Dr. Rockwitz
    • Hildesheim, Niedersachsen, Germany, 31134
      • Gemeinschaftspraxis Dr. von Hinüber
    • Osnabrück, Niedersachsen, Germany, 49076
      • Gemeinschaftspraxis Dr. Gauler
    • Weener, Niedersachsen, Germany, 26828
      • Praxis Dr. Dockhorn
  • Nordrhein-Westfalen
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40001
      • Universitätsklinikum DüsseldorfKlink für Endokrinologie, Diabetologie und Rheumatologie
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40217
      • Rheumatologische Schwerpunktpraxis
    • Ratingen, Nordrhein-Westfalen, Germany, 40882
      • Evangelisches Krankenhaus
    • Remscheid, Nordrhein-Westfalen, Germany, 42897
      • Praxis Dr. Kramer
    • Rheine, Nordrhein-Westfalen, Germany, 48431
      • Praxis Dr. Schoo
  • Sachsen-Anhalt
    • Zerbst, Sachsen-Anhalt, Germany, 39261
      • Rheumatologische Praxis Dr. Spieler

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; continuous (daily) treatment with diclofenac cholestyramine 150 mg (Voltaren Resinate), divided into 75mg Voltaren twice daily	Drug: diclophenac; continuous (daily) treatment of diclofenac cholestyramine 150 mg, divided into 75mg twice daily; Other Names: voltaren resinat; Drug: diclophenac; treatment on-demand (as needed) with diclofenac-cholestyramine 75 to 150 mg daily; Other Names: Voltaren resinate
Active Comparator: 2; 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; continuous (daily) treatment of diclofenac cholestyramine 150 mg, divided into 75mg twice daily; Other Names: voltaren resinat; Drug: diclophenac; treatment on-demand (as needed) with diclofenac-cholestyramine 75 to 150 mg daily; Other Names: Voltaren resinate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Investigators: Principal Investigator: Martin Rudwaleit, MD, Charite University, Berlin, Germany; Principal Investigator: Joachim Sieper, MD, Charite University, Berlin, Germany; Principal Investigator: Jürgen Braun, MD, Rheumazentrum Ruhrgebiet, Herne, Germany

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 14, 2008
• First Submitted That Met QC Criteria: July 14, 2008
• First Posted (Estimate): July 15, 2008

Study Record Updates

• Last Update Posted (Estimate): August 25, 2014
• Last Update Submitted That Met QC Criteria: August 22, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Spondyloarthritis; ankylosing spondylitis; NSAIDS; SpA; radiographic changes
• Additional Relevant MeSH Terms: Infections; Joint Diseases; Musculoskeletal Diseases; Arthritis; Spinal Diseases; Bone Diseases; Spondylarthropathies; Bone Diseases, Infectious; Ankylosis; Spondylitis; Spondylarthritis; Spondylitis, Ankylosing; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Diclofenac
• Other Study ID Numbers: ENRADAS-01; EUDA-CT: 2007-007637-39

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No