Efficacy and Safety of Rofecoxib 12.5 Versus Nabumetone 1,000 mg
Objectives: To evaluate the use of starting doses of rofecoxib and nabumetone in patients with osteoarthritis (OA) of the knee.
Design: A 6-week, randomized, parallel-group, double-blind, placebo-controlled study.
Setting: One hundred thirteen outpatient sites in the United States.
Participants: A total of 1,042 male and female patients aged 40 and older with OA of the knee (>6 months).
Interventions: Rofecoxib 12.5 mg once a day (n=424), nabumetone 1,000 mg once a day (n=410), or placebo (n=208) for 6 weeks.
Measurements: The primary efficacy endpoint was patient global assessment of response to therapy (PGART) over 6 weeks, which was also specifically evaluated over the first 6 days. The main safety measure was adverse events during the 6 weeks of treatment.
Results: The percentage of patients with a good or excellent response to therapy as assessed using PGART at Week 6 was significantly higher with rofecoxib (55.4%) than nabumetone (47.5%; P =.018) or placebo (26.7%; P <.001 vs rofecoxib or nabumetone). Median time to first report of a good or excellent PGART response was significantly shorter in patients treated with rofecoxib (2 days) than with nabumetone (4 days, P =.002) and placebo (>5 days, P <.001) (nabumetone vs placebo; P =.007). The safety profiles of rofecoxib and nabumetone were generally similar, including gastrointestinal, hypertensive, and renal adverse events.
Conclusion: Rofecoxib 12.5 mg daily demonstrated better efficacy over 6 weeks of treatment and quicker onset of OA efficacy over the first 6 days than nabumetone 1,000 mg daily. Both therapies were generally well tolerated.
Osteoarthritis (OA) is the most common joint disorder in the United States, affecting more than 21 million Americans. The structural development of OA is generally gradual over a lifespan, with radiographic evidence of the disorder present in up to 80% of the population of the United States by age 65 and virtually everyone aged 75 and older. Because there is no available disease-modifying treatment for OA, therapy currently focuses on the management of symptoms, dominated by pain that can be acute and chronic. Nonsteroidal antiinflammatory drugs (NSAIDs) are among the agents available for symptomatic relief of pain, as well as of stiffness and inflammation, which, in aggregate, can limit function and negatively affect quality of life of OA patients. Despite their effectiveness, NSAIDs have a side-effect profile that must be considered in monitoring treatment response.
Gastrointestinal-related morbidity and mortality can occur in patients receiving chronic therapy with NSAIDs, particularly patients with additional risk factors such as prior peptic ulcer disease, advanced age, high doses of NSAIDs, corticosteroid and anticoagulant use, and comorbidities that are associated with higher risk of gastrointestinal bleeding. Moreover, increases in blood pressure and development of edema can be observed in predisposed patients treated with NSAIDs and selective cyclooxygenase (COX)-2 inhibitors. Therefore, published guidelines recommend prescribing NSAID therapy at lowest doses to provide symptomatic relief.
Nabumetone, a dual COX-1/COX-2 inhibiting member of the NSAID class, is a prodrug that does not inhibit locally the gastroprotective prostaglandin E2 as do other NSAIDs; its primary metabolite, 6-methoxy-2-naphthylacetic acid, produced after hepatic metabolism, is responsible for its analgesic and antiinflammatory activity. Rofecoxib is a specific inhibitor of COX-2 and COX-2-mediated production of proinflammatory prostanoids that spares COX-1-mediated production of gastroprotective prostaglandins that are inhibited by dual COX-1/COX-2-inhibiting NSAIDs. Efficacy has been demonstrated in the treatment of the symptoms of OA that is comparable with high doses of NSAIDs such as diclofenac 50 mg three times a day and ibuprofen 800 mg three times a day.
Published consensus approaches to the conduct of clinical trials have suggested the identification of a single study joint and use of a variety of endpoints in evaluating response to therapy in OA, including evaluations of pain (as a single question or using a battery of questions), physical function, and global assessments, with one of these endpoints chosen as the primary objective of the study. The purpose of this placebo-controlled trial was to compare clinical responses of patients with OA of the knee to starting doses of rofecoxib and nabumetone. The primary hypothesis was that rofecoxib would be superior to nabumetone, as assessed by the primary endpoint: percentage of patients with a good or excellent response over 6 weeks of treatment on patient global response to therapy (PGART) questionnaire, a suggested categorical questionnaire with high face validity in quantifying effect of study medication in this disease. Other prespecified endpoints included evaluation of degree of pain walking on a flat surface (The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Question 1), particularly relevant for the study of OA of the knee; application of the Multiple Outcomes Study (MOS) Short-Form 36 (SF-36), a measure of quality of life that includes functional assessments; and investigator global assessment of response to therapy (IGART). The safety and tolerability of rofecoxib and nabumetone were also assessed and summarized.
Objectives: To evaluate the use of starting doses of rofecoxib and nabumetone in patients with osteoarthritis (OA) of the knee.
Design: A 6-week, randomized, parallel-group, double-blind, placebo-controlled study.
Setting: One hundred thirteen outpatient sites in the United States.
Participants: A total of 1,042 male and female patients aged 40 and older with OA of the knee (>6 months).
Interventions: Rofecoxib 12.5 mg once a day (n=424), nabumetone 1,000 mg once a day (n=410), or placebo (n=208) for 6 weeks.
Measurements: The primary efficacy endpoint was patient global assessment of response to therapy (PGART) over 6 weeks, which was also specifically evaluated over the first 6 days. The main safety measure was adverse events during the 6 weeks of treatment.
Results: The percentage of patients with a good or excellent response to therapy as assessed using PGART at Week 6 was significantly higher with rofecoxib (55.4%) than nabumetone (47.5%; P =.018) or placebo (26.7%; P <.001 vs rofecoxib or nabumetone). Median time to first report of a good or excellent PGART response was significantly shorter in patients treated with rofecoxib (2 days) than with nabumetone (4 days, P =.002) and placebo (>5 days, P <.001) (nabumetone vs placebo; P =.007). The safety profiles of rofecoxib and nabumetone were generally similar, including gastrointestinal, hypertensive, and renal adverse events.
Conclusion: Rofecoxib 12.5 mg daily demonstrated better efficacy over 6 weeks of treatment and quicker onset of OA efficacy over the first 6 days than nabumetone 1,000 mg daily. Both therapies were generally well tolerated.
Osteoarthritis (OA) is the most common joint disorder in the United States, affecting more than 21 million Americans. The structural development of OA is generally gradual over a lifespan, with radiographic evidence of the disorder present in up to 80% of the population of the United States by age 65 and virtually everyone aged 75 and older. Because there is no available disease-modifying treatment for OA, therapy currently focuses on the management of symptoms, dominated by pain that can be acute and chronic. Nonsteroidal antiinflammatory drugs (NSAIDs) are among the agents available for symptomatic relief of pain, as well as of stiffness and inflammation, which, in aggregate, can limit function and negatively affect quality of life of OA patients. Despite their effectiveness, NSAIDs have a side-effect profile that must be considered in monitoring treatment response.
Gastrointestinal-related morbidity and mortality can occur in patients receiving chronic therapy with NSAIDs, particularly patients with additional risk factors such as prior peptic ulcer disease, advanced age, high doses of NSAIDs, corticosteroid and anticoagulant use, and comorbidities that are associated with higher risk of gastrointestinal bleeding. Moreover, increases in blood pressure and development of edema can be observed in predisposed patients treated with NSAIDs and selective cyclooxygenase (COX)-2 inhibitors. Therefore, published guidelines recommend prescribing NSAID therapy at lowest doses to provide symptomatic relief.
Nabumetone, a dual COX-1/COX-2 inhibiting member of the NSAID class, is a prodrug that does not inhibit locally the gastroprotective prostaglandin E2 as do other NSAIDs; its primary metabolite, 6-methoxy-2-naphthylacetic acid, produced after hepatic metabolism, is responsible for its analgesic and antiinflammatory activity. Rofecoxib is a specific inhibitor of COX-2 and COX-2-mediated production of proinflammatory prostanoids that spares COX-1-mediated production of gastroprotective prostaglandins that are inhibited by dual COX-1/COX-2-inhibiting NSAIDs. Efficacy has been demonstrated in the treatment of the symptoms of OA that is comparable with high doses of NSAIDs such as diclofenac 50 mg three times a day and ibuprofen 800 mg three times a day.
Published consensus approaches to the conduct of clinical trials have suggested the identification of a single study joint and use of a variety of endpoints in evaluating response to therapy in OA, including evaluations of pain (as a single question or using a battery of questions), physical function, and global assessments, with one of these endpoints chosen as the primary objective of the study. The purpose of this placebo-controlled trial was to compare clinical responses of patients with OA of the knee to starting doses of rofecoxib and nabumetone. The primary hypothesis was that rofecoxib would be superior to nabumetone, as assessed by the primary endpoint: percentage of patients with a good or excellent response over 6 weeks of treatment on patient global response to therapy (PGART) questionnaire, a suggested categorical questionnaire with high face validity in quantifying effect of study medication in this disease. Other prespecified endpoints included evaluation of degree of pain walking on a flat surface (The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Question 1), particularly relevant for the study of OA of the knee; application of the Multiple Outcomes Study (MOS) Short-Form 36 (SF-36), a measure of quality of life that includes functional assessments; and investigator global assessment of response to therapy (IGART). The safety and tolerability of rofecoxib and nabumetone were also assessed and summarized.