Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. METHODS: We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. RESULTS: A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. CONCLUSIONS: Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.).

Tofacitinib versus methotrexate in rheumatoid arthritis.

BACKGROUND: Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. METHODS: We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). RESULTS: Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. CONCLUSIONS: In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis.

OBJECTIVE: To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX. METHODS: In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep). RESULTS: At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ⩾minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ⩾minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab. CONCLUSION: Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo.

Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.

BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. METHODS: In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). RESULTS: At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. CONCLUSIONS: In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).

Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial.

BACKGROUND: Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. METHODS: We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28<2·6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440. FINDINGS: At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06-28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45-34·92]; p<0·0001) for tofacitinib 10 mg twice a day versus 24·4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0·43 ([-0·36 to -0·15]; p<0·0001) for 5 mg twice a day and -0·46 ([-0·38 to -0·17]; p<0·0001) for 10 mg twice a day tofacitinib versus -0·18 for placebo; DAS28<2·6 rates were 6·7% (eight of 119; [0-10·10]; p=0·0496) for 5 mg twice a day tofacitinib and 8·8% (11 of 125 [1·66-12·60]; p=0·0105) for 10 mg twice a day tofacitinib versus 1·7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4·9%), nasopharyngitis (11 of 267; 4·1%), headache (11 of 267; 4·1%), and urinary tract infection (eight of 267; 3·0%) across tofacitinib groups, and nausea (nine of 132; 6·8%) in the placebo group. INTERPRETATION: In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. FUNDING: Pfizer.

Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial.

BACKGROUND: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN: 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING: 114 centers in 19 countries. PATIENTS: 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE: Pfizer.

Methods for integrating medication compliance and persistence in pharmacoeconomic evaluations.

OBJECTIVES: Suboptimal compliance and failure to persist with drug treatments are important determinants of therapeutic nonresponse and are of potential economic significance. The present article aims to describe the methodologies that may be appropriate for integrating noncompliance and nonpersistence in economic evaluations. METHODS: MEDLINE and NHS-EED were searched for economic evaluations published in the period between 1997 and 2005. Articles were included if they explored the dependence of cost-effectiveness results on varying levels of some form of compliance-related measure. The different methodologies used were reviewed and articles were appraised critically. Alternative methodological approaches are proposed, illustrated by an example of the impact of different persistence rates on a treatment's cost-effectiveness. RESULTS: Ten articles were selected for inclusion. These were generally scant on detail relating to how compliance/persistence was assessed and what the impact was on health outcomes. The methods used included Markov models and decision analyses. Markov models allow for persistence to be included directly in the analysis, as patients transit during each cycle. Net-benefit regression models are well suited for analyzing prospective and retrospective studies where patient-level data are available, whereas discrete event simulations have the potential to offer more flexibility. CONCLUSIONS: Compliance and/or persistence are not included routinely in pharmacoeconomic analyses, despite their potential impact. Where compliance and/or persistence are included, a lack of methodological rigor and consistency in definitions often limits the usefulness of the analyses. The analytical techniques discussed in this article should serve as a basis for developing guidelines on appropriate methodology.

Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.

Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial.

OBJECTIVES: To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. METHODS: In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]). RESULTS: PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F. CONCLUSIONS: Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier. TRIAL REGISTRATION NUMBER: NCT01039688.

[Economic evaluation of population-based mass screening for the early detection of cancer: a systematic review]. / Daganatos betegségek korai felismerésére irányuló populációs szintû szûrôprogramok egészség-gazdaságtani elemzése - rendszerezett irodalmi áttekintés.

PURPOSE: The increasing premature mortality due to cancer has made population based screening programs for cervical,breast and colorectal cancers inevitable in Hungary. However, when confronted with limited resources, the aim is that, within the budget constrain, the greatest possible health gain should be "produced". METHODS: The authors made a systematic review of the international literature concerning the cost-effectiveness of screening programs for the above tumours. RESULTS: In case of cervical cancer the Papanicolaou test, in case of breast cancer the mammography meet the WHO criteria for population-based mass screening. The well-designed organised screening programs are more cost-effective than the opportunistic screening. Among sexually active women, according to structure the mobile screening buses, according to age group screening of the 30-39 years old women seems the most favourable. For breast cancer, screening the 60-70 years old population every second year is the reference strategy from a health economic perspective. The cost-effectiveness results of either increasing the frequency of screening, extending the program for other age groups, or selecting a high-risk population are contradictory. In case of colorectal cancer there is no screening method, which would meet the WHO criteria. The two-day FOBT seems the most favourable, followed by colonoscopy for positive results, in the 55-74 years old population every second year. CONCLUSION: In addition to fulfilling requirements for a population-based screening method, the cost-effectiveness perspective should be taken into account.

Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient's perspective.

OBJECTIVE: Health measurements used to evaluate the effectiveness of rheumatoid arthritis (RA) therapies often fail to reflect patients' priorities, despite recommendations towards more patient-centered assessments. The goals of the current review are: (1) to present guidelines, tools, and required steps for successful implementation of patient-reported outcome (PRO) measurement in RA clinical trials; and (2) to identify gaps between recommendations and current practices. METHODS: The first objective was addressed by reviewing existing frameworks for assessment of health-related quality of life among patients with RA and guidelines on the evaluation of PRO instruments, with a focus on evidence required to demonstrate the adequacy of PRO-based labeling claims. The second goal was addressed by conducting an empirical investigation of the overlap between patients' perspectives and current practices regarding PROs in RA studies, elaborated from systematic literature searches. The first search identified qualitative studies that reported direct input from patients with RA, while the second identified the main health outcomes measured in RA trials, with a focus on biologic therapy. RESULTS: Our review revealed a set of outcomes that have thus far not been widely used to assess treatment benefit in RA, despite evidence of their importance to patients. The psychometric properties of PRO instruments used to evaluate commonly assessed domains are presented, as are recommendations for PRO tools that assess domains less often measured in RA studies. CONCLUSIONS: Although the validity of some PRO tools among patients with RA is well established, further work needs to be done in several health domains which have traditionally received insufficient attention.

Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors.

INTRODUCTION: The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor α (TNF-α) inhibitors. METHODS: A systematic search was undertaken to identify published, peer-reviewed articles that reported clinical outcomes of biologic treatment among RA patients with an inadequate response to TNF-α inhibitors. Data were systematically abstracted. Efficacy rates were estimated for groups of patients who differed in the number of prior TNF-α inhibitors used. End points included American College of Rheumatology (ACR)-, European League Against Rheumatism (EULAR)- and Disease Activity Score 28 (DAS28)-based response criteria. RESULTS: The literature search identified 41 publications, of which 28 reported biologic treatment outcomes for RA patients with prior exposure to TNF-α inhibitors. Seven publications reported outcomes obtained in randomized clinical trials, while the remaining consisted of observational studies. The likelihood of responding to a subsequent biologic treatment decreased as the number of previous treatments with TNF-α inhibitors increased for six of the seven response criteria examined. CONCLUSIONS: For patients with prior exposure to TNF-α inhibitors, the likelihood of response to subsequent treatment with biologic agents declines with the increasing number of previous treatments with TNF-α inhibitors.

Adherence to biologic DMARD therapies in rheumatoid arthritis.

IMPORTANCE OF THE FIELD: The efficacy of the biologic disease-modifying antirheumatic drugs (DMARDs) shown in clinical trials may be jeopardized due to prevalent poor patient adherence. AREAS COVERED IN THIS REVIEW: Patient adherence including compliance and persistence with biologic DMARDs in rheumatoid arthritis. WHAT THE READER WILL GAIN: This is a comprehensive review of the literature. The various definitions and methodologies of measurement used in adherence research are reviewed and data are presented by separating compliance and persistence. Differences in compliance rates were mainly based on numerical trends. There was evidence for and against greater persistence with infliximab versus adalimumab and etanercept. There was a trend in favour of greater compliance and lower persistence with TNF-alpha inhibitor monotherapy versus in combination therapy with methotrexate. TAKE HOME MESSAGE: The evidence suggests that adherence to biologic DMARDs is suboptimal. When further research is applied in the field, agreed definitions and methodology need to be used to allow for cross-study comparisons. In addition, adherence should be assessed in conjunction with clinical outcomes and not on its own so that it can be better understood what levels of adherence provide the required clinical outcomes.

Analgesic effectiveness of celecoxib and diclofenac in patients with osteoarthritis of the hip requiring joint replacement surgery: a 12-week, multicenter, randomized, double-blind, parallel-group, double-dummy, noninferiority study.

BACKGROUND: The hip is the second most common large joint that is affected by osteoarthritis (OA), with prevalence ranging from 3% to 11% in patients aged > or = 35 years. OA is often associated with significant pain, disability, and impaired quality of life. Treatment should be tailored according to the level of pain, disability, and handicap. Pharmacologic treatment options for hip OA include acetaminophen (recommended by the European League Against Rheumatism as a first-line treatment), NSAIDs such as diclofenac, and cyclooxygenase-2-selective NSAIDs such as celecoxib. OBJECTIVE: The purpose of this study was to determine whether celecoxib 200 mg QD is noninferior to diclofenac 50 mg TID in the treatment of OA of the hip. METHODS: This was a 12-week, randomized, double-blind, parallel-group, double-dummy, noninferiority study conducted at 40 centers in the United Kingdom. Patients with OA flare at baseline (determined by visual analog scale [VAS] measurement of > or = 40 to < 90 mm and patient's and physician's global assessments of arthritis ratings of "poor" or "very poor") and awaiting joint replacement surgery were randomized to receive celecoxib QD or diclofenac TID. Patients were excluded if surgery was anticipated within 8 weeks. The United Kingdom National Health Service initiatives on waiting-list times caused a reduction in the number of potential patients available for participation. Therefore, the study protocol was amended such that change from baseline to week 6 (as opposed to week 12) in the patient's assessment of arthritis pain on walking, measured by VAS (0-100 mm), was the primary outcome. Primary analysis was carried out on the evaluable population (subjects with baseline and week 6 arthritis pain on walking VAS scores and no major protocol deviations). Celecoxib was declared noninferior to diclofenac if the upper limit of the 2-sided 95% CI of the treatment difference (celecoxib vs diclofenac) in the mean change from baseline in VAS did not exceed 10 mm. Tolerability was assessed by the documentation of observed and volunteered adverse events (AEs), physical examination findings, sitting blood pressure, and pulse at screening and at the end of the study (week 12 or early withdrawal). RESULTS: A total of 249 patients aged > or = 45 years were randomized to treatment. There were 126 patients in the celecoxib group and 123 patients in the diclofenac group. One patient in the celecoxib group did not receive any treatment and was excluded from analysis. Additionally, 54 patients in the celecoxib group and 45 patients in the diclofenac group discontinued treatment due to AEs and/or lack of treatment effectiveness. Therefore, 71 patients in the celecoxib group and 78 patients in the diclofenac group completed the study. No significant differences in demographic characteristics were observed between treatment groups. The mean (SD) age was 64.0 (9.0) years, 53.9% (76/141) of the patients were men and 46.1% (65/141) were women, and 99.3% (140/141) were white. At weeks 6 and 12, the patient's assessment of arthritis pain on walking (VAS) improved in both groups (-20.0 [23.6] mm in the celecoxib group and -35 [27.0] mm in the diclofenac group [mean treatment difference, 14.4 mm; 95% CI, 6.1 to 22.7]). However, treatment differences in change from baseline favored diclofenac at week 6 (14.4 mm; 95% CI, 6.1 to 22.7) and week 12 (12.2 mm; 95% CI, 2.2 to 22.1). A post hoc analysis, performed after unblinding due to an imbalance in the numbers of patients previously receiving NSAIDs, found a greater treatment difference at week 6 between celecoxib and diclofenac in arthritis pain, favoring diclofenac, in previous nonusers of NSAIDs (n = 49, 18.6 mm; 95% CI, 4.5 to 32.8) compared with previous NSAID users (n = 92, 9.5 mm; 95% CI, -0.4 to 19.3). Celecoxib and diclofenac were generally well tolerated. A similar proportion of patients in both treatment groups experienced AEs (all causality): 67/125 of celecoxib-treated patients (53.6%) compared with 66/123 of diclofenac-treated patients (53.7%). CONCLUSION: This study did not demonstrate noninferiority of celecoxib 200 mg QD to diclofenac 50 mg TID in treating arthritis pain in patients with OA of the hip requiring joint replacement.