A Single Center 2-way Crossover Study to Investigate the Mechanism of Action of Etoricoxib in Subjects With Osteoarthritis Knee Pain

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
C4Pain
ClinicalTrials.gov Identifier:
NCT01619150
First received: June 7, 2012
Last updated: July 22, 2013
Last verified: July 2013
  Purpose

The purpose of this study is to investigate which pain mechanisms that can be affected by etoricoxib compared to placebo (inactive medication)in subjects with painful knee osteoarthritis af 4 weeks of treatment.


Condition Intervention Phase
Osteoarthritis
Drug: Etoricoxib, followed by placebo (matching tablet, without active ingredient)
Drug: Placebo (matching tablet, without active ingredient), followed by etoricoxib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: A Single Center, Randomized, Double-blind, Placebo-controlled 2-way Crossover Study to Investigate the Mechanism of Action of Etoricoxib in Subjects With Osteoarthritis Knee Pain.

Resource links provided by NLM:


Further study details as provided by C4Pain:

Primary Outcome Measures:
  • Change in Experimental mechanism based Pain Measures (EPMs)during two treatment periods of 4-weeks each [ Time Frame: The EPMs will be measured: at V3, prior to 1. treatment sequence w/ Medication/Placebo; at V5, after 4 weeks of treatment; at V6, prior to 2. treatment sequence w/ Medication/Placebo; at V8, after 4 weeks of treatment. ] [ Designated as safety issue: No ]

    The following EPMs will be applied:

    • Quantitative Sensory Testing (QST) of 3 knee joint pain locations
    • Spreading sensitization
    • Pain areas
    • Wind-up like pain
    • Descending noxious inhibitory control
    • Cuff evoked pain
    • Infrared thermography of both knees


Secondary Outcome Measures:
  • Change in Clinical Outcome measures during two treatment periods of 4-weeks each [ Time Frame: The Clinical Outcome measures will be measured at screening and throughout the two treatment sequences. The study period is in total 16 weeks. Some measures will be recorded daily, others only at study visits. ] [ Designated as safety issue: No ]

    Change of pain severity as measured by the daily 24-hour average pain score (APS), night pain and worst daily pain, the following questionnaires: PQAS, BPI, IGIC, PGAC, WOMAC, Dolotest® and PDQ. Furthermore time and pain intensity from a 40 m self-paced walk test and from a 11 step stair climb test.

    Fasting plasma, serum and urine samples will be collected and stored for potential further analysis of e.g. IL-6, IL-8, CTX1, CTX2, TNFα, CCL2, CO1, CO2, sCRP, CRP25, C1M, C2M, C3M, OC, MMP.



Enrollment: 39
Study Start Date: July 2012
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Etoricoxib, followed by placebo
4 weeks of treatment with etoricoxib, followed by a wash out period of at least 6 days, followed by another 4 weeks of treatment with placebo.
Drug: Etoricoxib, followed by placebo (matching tablet, without active ingredient)
Sequence 1: 1 tablet of 60 mg etoricoxib daily for 4 weeks, for oral use. Sequence 2: 1 tablet of matching placebo daily for 4 weeks, for oral use.
Other Name: Acoxia®
Placebo, followed by etoricoxib
4 weeks of treatment with placebo, followed by a wash out period of at least 6 days, followed by another 4 weeks of treatment with etoricoxib.
Drug: Placebo (matching tablet, without active ingredient), followed by etoricoxib
Sequence 1: 1 tablet of matching placebo daily for 4 weeks, for oral use. Sequence 2: 1 tablet of 60 mg etoricoxib daily for 4 weeks, for oral use.
Other Name: Acoxia®

Detailed Description:

Study Rationale: The purpose of this study is to investigate which pain mechanisms in subjects with painful knee osteoarthritis can be affected by the peripheral and central actions of etoricoxib as compared to placebo during a 4 week treatment therapy period.

The present study will utilize a set of quantitative mechanism based pain biomarkers to assess peripheral and central pain manifestations in OA and the influence of etoricoxib on those individual manifestations in an attempt to understand and explain clinical pain alleviation.

Study Treatment: Subjects will be randomized to one of the 2 sequences of treatment: Sequence 1 (60 mg/day etoricoxib followed by placebo) or Sequence 2 (placebo followed by 60 mg/day etoricoxib). The two treatment periods of 4 weeks each are separated by a washout period of at least 6 days.

Primary Objective: To assess which pain mechanisms are modulated by 60 mg daily administration of etoricoxib compared to placebo in subjects with osteoarthritic (OA) knee pain during two treatment periods of 4-weeks each.

Secondary Objectives: To evaluate if changes in any of the mechanism based experimental pain assessment parameters can explain changes in clinical outcome parameters.

To profile drug responders- versus non-responders based on pain mechanisms involved.

To investigate if change in inflammatory, bone and cartilage related bio-chemical biomarkers can explain changes in either experimental or clinical pain parameters.

  Eligibility

Ages Eligible for Study:   40 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent (IRB/IEC specific) has been obtained prior to initiation of any protocol required procedures.
  2. Male or female between 40 and 75 years of age. Females of childbearing potential must have a negative urine pregnancy test at screening.
  3. Body weight >40 kg and <150 kg with a body mass index (BMI) between 19-40 kg/m2 inclusive.
  4. Idiopathic osteoarthritic knee pain diagnosed in accordance with the American College of Rheumatology modified clinical classification criteria (Altman et al, 1986) and verified radiologically as Kellgren-Lawrence grade I, II or III (Kellgren and Lawrence, 1957) at the index knee. The clinical diagnosis of OA will be confirmed by the ACR clinical and radiographic criteria for classification of idiopathic OA based upon the following criteria (index knee):

    1. Knee pain for at least 14 days per month for the 3 months before study entry.
    2. Osteophytes (with radiographic evidence).
    3. And at least 1 of the following 3 conditions: Age >50, or morning stiffness <30 minutes, or crepitus.
    4. X-ray images of the knee joints are available confirming OA. X-ray images older than12 months cannot be used. New photos are needed to confirm the diagnostic criteria for OA.
  5. For the index knee, the average of the worst daily pain score over the last 14 days prior to day 0 must be 4.0 to 9.0. The 14-day average score will be derived from worst daily pain scores recorded in a diary for the index knee.
  6. Discontinued use of all analgesic medications (including over-the-counter analgesics/ Non-Steroidal Anti-Inflammatory Drug at least 3 days prior to visit 2 (subjects are allowed limited use of analgesic medications).
  7. Have agreed to maintain the same activity level throughout the course of the study.

Exclusion Criteria:

  1. Have a history of recurrent seizures other than febrile seizures.
  2. Have a history of frequent and/or severe allergic reactions with multiple medications.
  3. Have a current or recent history, as determined by the investigator or his delegates, of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, psychiatric or cerebral disease which could interfere with the subject's participation in the study.
  4. At screening, have an abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the risks associated with participation in the study. In addition, subjects with following findings will be excluded:

    1. Confirmed Bazett's corrected QT (QTcB) interval > 450 msec for men and > 470 msec for women at screening. If QTcB is prolonged a second ECG will be taken to confirm the finding; (additional ECGs may be performed if required),
    2. Bundle branch blocks and other conduction abnormalities other than mild first degree atrio-ventricular block, left anterior hemi block due to left axis deviation and right bundle branch block of benign origin i.e. not caused by other cardiac disease,
    3. Irregular rhythms other than sinus arrhythmia or occasional supraventricular or ventricular ectopic beats,
    4. History of unexplained syncope,
    5. Family history of unexplained sudden death or sudden death due to long QT syndrome,
    6. T-wave configurations are not of sufficient quality for assessing QT interval determination, as assessed by the investigator.
  5. Have an alanine aminotransaminase > 2.5 times Upper Limit of Normal (ULN) at screening, based on reference ranges of the local laboratory. Moderate or greater hepatic impairment.
  6. Have prior renal transplant, current renal dialysis or severe renal insufficiency (determined by a derived glomerular filtration rate using Cockcroft Gault formula of ≤30 ml/min/1,73m² calculated by the local lab), or serum creatinine laboratory value >1.5 times ULN, based on the reference ranges of the local laboratory.
  7. Have active peptic ulcer or gastrointestinal bleeding.
  8. Have known inflammatory intestinal disease.
  9. Subject with ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
  10. Subject with congestive heart failure (NYHA II-IV).
  11. Subject with uncontrolled arterial hypertension (>160/90).
  12. Subject with diabetes mellitus and documented atherosclerosis.
  13. History of bronchospasms, acute rhinitis, nasal polyps, angioneurotic edema, urticaria or other type of allergic reaction after having used acetylic acid or NSAID, inclusive COX-2 inhibitors.
  14. Is allergic to the active ingredient of etoricoxib or one or more of the excipients.
  15. Pregnant female, breast feeding or planning a pregnancy during the study period. Females of child-bearing potential, not using a reliable means of contraception.
  16. Subject with an active malignancy of any type or a history of malignancy within the last 5 years (except basal cell carcinoma of the skin that has been excised prior to study start).
  17. Are taking any excluded medications (analgesic medications) that cannot be discontinued during the screening period (3 days prior to visit 2).
  18. Subject in treatment with anticoagulants (with the exception of acetylsalicylic acid), methotrexate or rifampicin or antihypertensives (with the exception of Ca+-antagonists).
  19. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at Visit 1.
  20. Have a history of substance abuse or dependence within the past year, excluding nicotine and caffeine.
  21. Subject at a high risk of infection (e.g. leg ulcers, indwelling urinary catheter and persistent or recurrent chest infections and subjects who are permanently bed ridden or wheelchair bound).
  22. Subject with a history of, or suspected, demyelinating disease of the central nervous system (e.g. multiple sclerosis or optic neuritis).
  23. Have an autoimmune disorder (not including psoriasis).
  24. Subject that do not fully understand the EPM procedures according to investigator experience.
  25. Investigator site personnel directly affiliated with this study and/or their immediate family cannot participate. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
  26. Subject diagnosed with any condition suggestive of a secondary cause of knee OA including but not limited to knee trauma, septic arthritis, inflammatory joint disease, articular fracture, major dysplasia or congenital abnormality, ochronosis, acromegaly, hemochromatosis, Wilson's disease, or primary osteochondromatosis.
  27. History of surgery (including arthroscopy) in the index knee within 3 months prior to visit 1 or already planned surgery of the index knee at any time.
  28. History of significant prior injury to the index knee within 12 months prior to visit 1.
  29. Subject diagnosed with Kellgren and Lawrence grade IV at the index knee.
  30. Use of lower extremity assistive devices other than a knee brace or 'shoe lift'. Use of a cane in the hand opposite to the index knee is acceptable.
  31. History of prior synovial fluid analysis showing a White Blood Cell count ≥ 2000 mm3 that is indicative of a diagnosis other than OA at the index knee.
  32. Have a confounding painful condition that may interfere with assessment of the index knee joint. (Knee pain should be the predominant pain. Mild OA of the hands is allowed, for instance).
  33. History of any other musculoskeletal or arthritic condition that may affect the interpretation of clinical efficacy and/or safety data or otherwise contraindicates participation in this clinical study (i.e., currently symptomatic fractures or any concurrent rheumatic disease such as but not limited to fibromyalgia, rheumatoid arthritis, gout, pseudo-gout or Paget's disease and Reiter's syndrome are excluded).
  34. Have used corticosteroids prior to baseline:

    1. Intra-articular injection of steroids into the index knee or into any other site than the index knee within the previous 3 months,
    2. Intra-muscular corticosteroid injections within the previous 3 months,
    3. Oral corticosteroids within the previous 1 month.
  35. Have initiated or changed their established physiotherapy program within the last 14 day prior to visit 3.
  36. Have not recorded a minimum of 10 days of diary data of the last 14 days immediately preceding visit 3.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01619150

Locations
Denmark
CCBR A/S
Aalborg, Denmark, 9000
Sponsors and Collaborators
C4Pain
Merck Sharp & Dohme Corp.
Investigators
Study Director: Hans Christian Hoeck, MD PhD C4Pain
  More Information

Publications:
Jansen JP et al. Cost effectiveness of etoricoxib versus celecoxib and non-selective NSAIDS in the treatment of ankylosing spondylitis. Pharmacoeconomics. 2010;28(4):323-44
Trelle S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011 Jan 11;342, in press.
Van Spil WE et al. Serum and urinary biochemical markers for knee and hip-osteoarthritis: a systematic review applying the Consensus BIPED criteria. Osteoarthritis and Cartilage 2010:18:605-612.

Responsible Party: C4Pain
ClinicalTrials.gov Identifier: NCT01619150     History of Changes
Other Study ID Numbers: OSKNEEPA02
Study First Received: June 7, 2012
Last Updated: July 22, 2013
Health Authority: Denmark: Danish Dataprotection Agency
Denmark: Danish Medicines Agency
Denmark: Ethics Committee

Keywords provided by C4Pain:
knee
osteoarthritis
central sensitization
mechanical detection
pain threshold
quantitative sensory testing
pain biomarkers
COX-2 inhibitors
etoricoxib.

Additional relevant MeSH terms:
Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Etoricoxib
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antirheumatic Agents
Central Nervous System Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014