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Discontinuing NSAIDs

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ClinicalTrials.gov Identifier: NCT01799213
Recruitment Status : Active, not recruiting
First Posted : February 26, 2013
Last Update Posted : November 5, 2018
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
Knee osteoarthritis (OA) is now recognized as a major health problem. It is the number one cause of lower extremity disability and has significant deleterious effects on quality of life. While there are numerous therapies available for knee OA, most have limited efficacy. Of particular concern, is the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) for this disorder. Veterans, as a group, are at high risk for both gastrointestinal and cardiovascular NSAID-induced complications. In this study the investigators propose to examine whether replacing NSAIDs with cognitive behavioral therapy delivered by telephone is an effective strategy for Veterans with knee OA. Telephone-administered therapy is particularly appealing since Veterans with knee OA are more likely to have limited mobility. If successful, this program may result in significant cost-savings for both Veterans (decreased co-pays and transportation costs) and the VA (decreased hospitalizations due to NSAID induced toxicity).

Condition or disease Intervention/treatment Phase
Knee Osteoarthritis Drug: Meloxicam 15 mg po QD Behavioral: Cognitive Behavioral Therapy Phase 2

Detailed Description:

Knee osteoarthritis (OA) is a major cause of disability among Veterans and is the primary indication of knee replacement in the VA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications for knee OA. Though short-term studies have demonstrated that NSAIDs are more effective than placebo and acetaminophen, there are no long-term data supporting their use. This is of concern, because long-term use of NSAIDs is associated with significant morbidity and mortality. Guidelines have been published to improve safe use of NSAIDs; however, adherence to these evidence-based recommendations is low in the VA. There is therefore an important need to determine if the long-term use of NSAIDs offers any incremental benefit over safer alternatives. This is especially true for Veterans, a population at high risk for NSAID-induced toxicity.

Cognitive behavioral therapy (CBT) is an effective and safe treatment alternative for OA. This modality is becoming increasingly available in the VA for treatment of chronic pain as well as other chronic disorders such as depression, post-traumatic stress disorder and insomnia. CBT can be successfully administered over the telephone and thus stands to benefit Veterans living in more remote areas with limited access to hospital or community-based outpatient clinics.

In this study, the investigators propose to conduct a 2-phase randomized withdrawal trial (RWT). The trial will focus on recruiting Veterans with knee OA who have been using NSAIDs for at least 3 months.

In the first phase of the study, 544 Veterans with knee OA will be randomized to continue NSAIDs or to placebo for 4 weeks. This double-blind phase will enable us to infer whether placebo is non-inferior to continued NSAID use. In the second phase, subjects in the NSAIDs group will continue NSAIDs and those on placebo will stop taking the placebo and participate in a 10-week CBT program. The second, single-blind, phase will allow us to infer whether CBT is non-inferior to NSAIDs. All study data will be collected over the telephone thus enabling Veterans who have difficulty arranging transportation to the VA to participate.

The investigators will test for between-group differences in knee pain measured using the well-validated Western Ontario and McMaster Universities Osteoarthritis Index (primary outcome) at 4 and 14 weeks. The investigators will also test for between group differences in lower extremity disability, subjects' global impression of change and use of co-therapies (secondary outcomes). As recommended for non-inferiority trials, the investigators will perform both an intent to treat and per protocol analysis. Lastly, the investigators will estimate the potential cost-effectiveness of the CBT protocol compared with continued NSAID use.

Though it would be ideal for subjects randomized to the active study drug to continue their current NSAID, having the VA pharmacy formulate multiple different active drugs and maintaining the blind is not possible. Therefore, the investigators will include a 2-week run-in period where study subjects will replace their NSAID with meloxicam. Meloxicam was chosen as the study drug because it is the most commonly prescribed at the investigators' center and has a favorable safety profile compared to other NSAIDS.

If successful, the trial will improve the quality of care delivered to Veterans with chronic knee pain due to OA. The proposed strategy is particularly appealing because it replaces the widespread use of NSAIDs with a safer alternative, enables delivery of care to Veterans with limited access, and is likely to be cost saving.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 680 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Discontinuing NSAIDs in Veterans With Knee Osteoarthritis
Actual Study Start Date : September 2, 2013
Actual Primary Completion Date : October 5, 2018
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis
Drug Information available for: Meloxicam

Arm Intervention/treatment
Experimental: Active Treatment
Eligible subjects will be randomized to Meloxicam 15 mg po QD vs placebo
Drug: Meloxicam 15 mg po QD
Eligible subjects will be take Meloxicam 15 mg po QD

Placebo Comparator: Placebo
Eligible subjects will be randomized to Meloxicam 15 mg po QD vs placebo
Behavioral: Cognitive Behavioral Therapy
Subjects originally assigned to placebo will receive cognitive behavioral therapy for 10 weeks




Primary Outcome Measures :
  1. The primary endpoint will be between-group differences in the WOMAC pain score (Likert Scale version) measured at 4 weeks. [ Time Frame: 4 Weeks ]
    The WOMAC pain scale consists of 5 questions that ask about pain during walking, stair use, lying in bed at night, sitting, and standing. Each question is scored on a 5-point scale, where 0 = None, 1 = Mild pain, 2 = Moderate pain, 3 = Severe pain, and 4 = Very severe pain. Total pain scores range from 0 to 20 with higher scores reflecting worse pain. The WOMAC also includes a lower extremity disability scale. Both the pain scale and disability scale (17 items) can be analyzed separately.


Secondary Outcome Measures :
  1. Area under the curve (AUC) of the WOMAC pain scale score over the observation period: AUC will be measured in order to capture the variability in pain that is characteristic of knee OA . [ Time Frame: 14 Weeks ]
    As above

  2. Intermittent vs. Constant Pain [ Time Frame: Weekly ]
    Measure of Intermittent and Constant Osteoarthritis Pain will be used to evaluate the subject's pain experience, including pain intensity, frequency, as well as impact on mood, sleep, and quality of life. This 11-item scale asks subjects to rate their "constant knee pain" and their "knee pain that comes and goes" over the past week. Each item is scored on a scale from 0 to 4, with higher scores indicating a worse pain experience. The Intermittent and Constant Osteoarthritis Pain (ICOAP) complements the WOMAC given that the latter focuses on the impact of pain on physical functioning.

  3. Lower extremity disability [ Time Frame: 4 and 14 weeks ]
    Lower extremity disability: Lower extremity functional outcomes will be measured using the WOMAC disability scale. The physical disability scale contains 17 items that assess the amount of difficulty subjects say they have with climbing stairs, rising from a chair, walking, and other activities of daily living. Responses are measured and scored in the same way as the pain scale.

  4. Global impression of change [ Time Frame: 4 and 14 weeks ]
    A balanced 5-point scale (1 = Much better to 5 = Much worse) asking subjects to rate their change (if any) in pain since starting the study.

  5. Adherence to study medication and use of co-therapies [ Time Frame: Weekly ]
    • Over the past week, how many days did you use the study drug for your knee pain?
    • Over the past week, how many days did you use Tylenol or acetaminophen for your knee pain?
    • Over the past week, how many days did you use other medications that were prescribed by one of your doctors for your knee pain?
    • Over the past week, how many days did you use other medications, creams or supplements that you got without a prescription for your knee pain?
    • Over the past week, how many days did you use any medications for a different problem or type of pain (e.g. headache)?



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects will include those for whom a discontinuation trial of NSAIDs is most appropriate: 1) Veterans with knee pain despite NSAID use and/or 2) Veterans at relatively higher risk of NSAID toxicity 55-59 as ascertained by meeting 1 or more of the following 4 criteria:

  • Answer affirmatively to the question: "Do you have some knee pain on most days over the past 3 months?"
  • Have 1 or more risk factors for NSAID-induced nephrotoxicity (age greater than 60 years, atherosclerotic cardiovascular disease, current diuretic use, chronic renal insufficiency, congestive heart failure (New York Heart Association class I-II. Note, Class III and IV are excluded).
  • Have 1 or more risk factors for NSAID-induced gastrointestinal toxicity (history of peptic ulcer disease, age > 65 years, concurrent use of daily ASA or corticosteroids), and are currently on a gastro-protective agent.
  • Have 1 or more risk factors for NSAID-induced cardiovascular toxicity (prevalent cardiovascular disease, hypertension, hypercholesterolemia, diabetes, smoking, family history of early heart disease or age greater than 55 years for women).

In addition, subjects must:

  • Be age 20 years or older. While the usual cut off for knee OA is approximately 40 years, the investigators chose to lower the age cutoff as younger Veterans have a higher than expected risk of OA (see B.1).
  • Have radiographic evidence of knee OA reported in the VistA electronic system.
  • Be using an NSAID (other than daily ASA) for knee pain on most days of the month for at least the past 3 months.
  • Be able to understand and speak English and have a telephone.
  • Be willing to engage in a CBT program, to discontinue (or replace) their NSAID, and to restrict co-therapies to acetaminophen for 14 weeks.

Exclusion Criteria:

  • Subjects desiring escalation of analgesics for their current level of knee pain as determined by endorsement of the following statement: "Is your knee pain bad enough that you want to talk to your doctor about taking stronger pain medications?"
  • Current use of opioids and/or Celebrex.
  • Current use of an NSAID (not including ASA) for a painful condition in addition to knee OA.
  • Contraindications to chronic NSAID use: current use of warfarin or antiplatelet agent other than ASA, allergy to any NSAID, active upper gastrointestinal ulceration in the previous 30 days, upper gastrointestinal bleeding in the past year, history of gastroduodenal perforation or obstruction, cardiovascular event within the past 6 months (myocardial infarction, cerebrovascular event, coronary-artery bypass graft, invasive coronary revascularisation, or new-onset angina), severe congestive heart failure (New York Heart Association class III-IV), evidence of serious anemia, hepatic, renal (including nephrotic syndrome), or blood coagulation disorders, and pregnancy.

***Though the investigators are proposing a RWT - and thus will not be initiating NSAID therapy - it would not be appropriate to continue NSAIDs (even when prescribed) in high-risk patients. The investigators acknowledge that these exclusion criteria limit generalizability, but the investigators feel justified to ensure subjects' safety.***

  • Previous hyaluronic acid knee injections (within 6 months) or corticosteroid knee injections (within 3 months).
  • Scheduled knee hyaluronic acid or corticosteroid injections, arthroscopy, or knee surgery.
  • Co-morbid conditions that include the following: known other causes of arthritis (infectious arthritis, rheumatoid arthritis, connective tissue disease, or psoriatic arthritis), gout or pseudogout attack within the last 12 months, peripheral neuropathy or cardiopulmonary disease that limits walking more than knee pain, bone metastases or Paget's disease involving the lower extremities, and history of drug or alcohol abuse within the past 2 years, bilateral knee replacements or knee pain in the replaced knee only.
  • Current involvement in litigation or receiving workmen's compensation.
  • Hearing, cognitive impairment or mental illness, as determined by chart review that would preclude participation in a CBT program.
  • For Women of Childbearing Age: Must not currently be pregnant, agree to avoid getting pregnant during the course of the study and should inform the study team if pregnancy occurs at any time during study participation.
  • Previous meloxicam use discontinued due to lack of effective symptom relief
  • Contraindications to prolonged NSAID use, per PI discretion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01799213


Locations
United States, Connecticut
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, United States, 06516
United States, Florida
North Florida/South Georgia Veterans Health System, Gainesville, FL
Gainesville, Florida, United States, 32608
United States, Massachusetts
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Boston, Massachusetts, United States, 02130
United States, Rhode Island
Providence VA Medical Center, Providence, RI
Providence, Rhode Island, United States, 02908
Sponsors and Collaborators
VA Office of Research and Development
Investigators
Principal Investigator: Liana Fraenkel, MD MPH FRCPC VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT01799213     History of Changes
Other Study ID Numbers: IIR 11-113
First Posted: February 26, 2013    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by VA Office of Research and Development:
Knee Osteoarthritis
NSAID
Cognitive Behavioral Therapy

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