Calculation of Phase 2 dose-finding study sample size for reliable Phase 3 dose selection.

Sample sizes of Phase 2 dose-finding studies, usually determined based on a power requirement to detect a significant dose-response relationship, will generally not provide adequate precision for Phase 3 target dose selection. We propose to calculate the sample size of a dose-finding study based on the probability of successfully identifying the target dose within an acceptable range (e.g., 80%-120% of the target) using the multiple comparison and modeling procedure (MCP-Mod). With the proposed approach, different design options for the Phase 2 dose-finding study can also be compared. Due to inherent uncertainty around an assumed true dose-response relationship, sensitivity analyses to assess the robustness of the sample size calculations to deviations from modeling assumptions are recommended. Planning for a hypothetical Phase 2 dose-finding study is used to illustrate the main points. Codes for the proposed approach is available at https://github.com/happysundae/posMCPMod.

Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial.

BACKGROUND: Raltegravir is an integrase inhibitor approved for use in adults and children with HIV-1 infection, but there are no data on the long-term use of this medication in children. We aimed to assess the long-term safety, tolerability, pharmacokinetics, and efficacy of multiple raltegravir formulations in children aged 4 weeks to 18 years with HIV-1 infection. METHODS: In this phase 1/2 open-label multicentre trial (IMPAACT P1066), done in 43 IMPAACT network sites in the USA, South Africa, Brazil, Botswana, and Argentina, eligible participants were children aged 4 weeks to 18 years with HIV-1 infection who had previously received antiretroviral therapy (ART), had HIV-1 RNA higher than 1000 copies per mL, and no exposure to integrase inhibitors. Participants were separated into five age groups and enrolled in six cohorts. Three formulations of open-label raltegravir-adult tablets, chewable tablets, and granules for oral suspension-were added to individualised optimised background therapy, according to the age and weight of participants. The primary outcome at 48 weeks has been previously reported. In the 240-week follow-up, outcomes of interest included graded clinical and laboratory safety of raltegravir formulations during the study and virological efficacy (with virological success defined as HIV-1 RNA reduction of >1 log10 from baseline or HIV-1 RNA <400 copies per mL) at week 240. The primary analysis group for safety and efficacy comprised patients treated only with the final selected dose of raltegravir. This trial is registered with ClinicalTrials.gov, number NCT00485264. FINDINGS: Between August, 2007, and December, 2012, 220 patients were assessed for eligibility, and 153 were enrolled and treated. Of these patients, 122 received only the final selected dose of raltegravir (63 received adult tablets, 33 chewable tablets, and 26 oral granules), and one was not treated. There were few serious clinical or laboratory safety events noted, with two patients having a drug-related adverse event (skin rash), which led one patient to discontinue the study treatment. The addition of raltegravir to an individually optimised ART regimen resulted in virological success at week 240 in 19 (44·2%, 95% CI 29·1-60·1) of 43 patients receiving 400 mg tablets, 24 (77·4%, 58·9-90·4) of 31 patients receiving the chewable tablets, and 13 (86·7%, 59·5-98·3) of 15 patients receiving oral granules. Among patients with virological failure, raltegravir resistance was noted in 19 (38%) of 50 patients who had virological rebound after initial suppression and had samples at virological failure available for testing. INTERPRETATION: Our study suggests that raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who had previous extensive antiretroviral therapy. FUNDING: National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, and Merck.

Influence of Sex/Gender and Race on Responses to Raltegravir Combined With Tenofovir-Emtricitabine in Treatment-Naive Human Immunodeficiency Virus-1 Infected Patients: Pooled Analyses of the STARTMRK and QDMRK Studies.

BACKGROUND: Antiretroviral therapy in human immunodeficiency virus (HIV)-infected women and blacks merits particular scrutiny because these groups have been underrepresented in clinical trials. METHODS: To document the effects of raltegravir across sex and racial lines, we conducted a pooled subgroup analysis of the efficacy and safety of raltegravir 400 mg BID plus tenofovir-emtricitabine by sex (women vs men) and self-identified race (black vs non-black) using phase 3 studies in treatment-naive patients. RESULTS: Study participants included 42 black women, 102 non-black women, 48 black men, and 477 non-black men. Clade B infections were less common in women (43.8%) than men (84.6%) and in blacks (45.6%) than non-blacks (80.5%). Baseline CD4 counts were ≤200 cells/µL in 52.2% of blacks and 31.6% of non-blacks. Black men had the largest proportion of patients with baseline CD4 counts <50 cells/µL and the highest nontreatment-related discontinuation rate among the 4 sex-by-race subgroups. Human immunodeficiency virus-ribonucleic acid levels <50 copies/mL were achieved at week 48 in 92.7% (95% confidence interval [CI], 80.1-98.5) of black women, 93.6% (95% CI, 86.6-97.6) of non-black women, 82.9% (95% CI, 67.9-92.8) of black men, and 91.4% (95% CI, 88.4-93.8) of non-black men. Serious clinical adverse events were reported in 9.0% of women versus 8.8% of men and in 11.1% of blacks versus 8.5% of non-blacks. CONCLUSIONS: In this post hoc analysis of patients with previously untreated HIV-1 infection receiving raltegravir plus tenofovir-emtricitabine, generally comparable results were achieved across sex and racial subgroups. However, black men had a lower response rate than either black women or non-black men, partially attributable to lower baseline CD4 counts and higher discontinuation rates.

Different impact of raltegravir versus efavirenz on CD4/CD8 ratio recovery in HIV-infected patients.

OBJECTIVES: A low CD4/CD8 ratio during treated HIV identifies individuals with heightened immunoactivation and excess mortality. Whether ART regimens elicit distinct CD4/CD8 ratio recovery remains unknown. We aimed to compare the efficacy of an integrase inhibitor versus a non-nucleoside to normalize the CD4/CD8 ratio. METHODS: We conducted a post hoc analysis of the STARTMRK study, a randomized, blinded, double-dummy Phase III trial of raltegravir versus efavirenz, and each in combination with tenofovir/emtricitabine, in treatment-naive HIV-infected adults. Blinding was maintained for the entire 5 year duration of the study. Kaplan-Meier methods for time-dependent variables were used to calculate the rates of CD4/CD8 normalization at different cut-offs and cumulative probabilities. Cox proportional hazard models were used to compare probabilities of CD4/CD8 normalization by treatment arm. RESULTS: A total of 563 patients were analysed; 81% were males and the mean age (SD) was 37 (10) years. Raltegravir was associated with higher rates of CD4/CD8 ratio normalization at the >0.4 cut-off (median time to normalization = 56 versus 84 days; P = 0.048 by log-rank test). A Cox proportional hazard model stratified based on baseline CD4 counts showed an association between raltegravir and higher rates of CD4/CD8 ratio normalization (HR = 1.23; P = 0.02). CONCLUSIONS: We herein show that normalization of the CD4/CD8 ratio above a clinically meaningful threshold may be dependent on the drug class used. Raltegravir showed faster CD4/CD8 ratio normalization compared with efavirenz, a finding with potential clinical implications. Whether other integrase inhibitors have a similar impact for this outcome remains to be explored.

Association between first-year virological response to raltegravir and long-term outcomes in treatment-experienced patients with HIV-1 infection.

BACKGROUND: We explored the relationship between virological response in the first year of treatment and long-term outcomes in the BENCHMRK studies. METHODS: Patients failing antiretroviral treatment with 3-class resistant HIV-1 received double-blinded raltegravir (or placebo) with optimized background therapy (OBT) until week 156, followed by open-label raltegravir with OBT up to week 240. In this exploratory analysis of patients randomized to raltegravir, virological response over weeks 16-48 was categorized as continuous suppression (CS; viral RNA [vRNA] always <50 copies/ml), low-level viraemia (LLV; vRNA always <400 copies/ml, >50 copies/ml at least once), or not suppressed (NS; vRNA >400 copies/ml at least once). The association between these first-year vRNA response categories and baseline factors was analysed with univariate and multivariate models. Virological and immunological outcomes for years 2-5 were assessed by first-year vRNA response category (observed failure approach). RESULTS: Baseline vRNA, baseline CD4(+) T-cell count and rapid viral decay (vRNA <50 copies/ml between weeks 2-12) correlated with first-year vRNA response (P<0.001); only rapid viral decay remained significant by multiple regression. Virological response rates were similar in the LLV and CS groups and lowest in the NS group. CD4(+) T-cell count increased through week 240 in the CS and LLV groups. Time to loss of virological response (confirmed vRNA ≥400 copies/ml) through week 240 did not support as strong a difference between the LLV and CS groups (log-rank P=0.11) as previously reported through weeks 156 and 192 (P<0.05). CONCLUSIONS: Treatment-experienced patients on a raltegravir-based regimen with early LLV may have long-term virological and immunological benefit when their therapy is maintained.

Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK.

BACKGROUND: STARTMRK, a phase III noninferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naive patients, remained blinded until its conclusion at 5 years. We now report the final study results. METHODS: Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary end points stipulated at weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with viral RNA (vRNA) levels <50 copies per milliliter counting noncompleters as failures (NC=F). Changes from baseline CD4 count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at week 240. RESULTS: Overall, 71 of 281 raltegravir recipients (25%) and 98 of 282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the primary NC=F efficacy analysis at week 240, 198 of 279 (71.0%) raltegravir recipients and 171 of 279 (61.3%) efavirenz recipients had vRNA levels <50 copies per milliliter, yielding a treatment difference {Δ [95% confidence interval (CI)] = 9.5 (1.7 to 17.3)}. Generally comparable between-treatment differences were seen in both the protocol-stipulated sensitivity analyses and the prespecified subgroup analyses. The mean (95% CI) increments in baseline CD4 counts at week 240 were 374 and 312 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Δ(95% CI) = 62 (22 to 102)]. Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric side effects (39.1% vs 64.2%, P < 0.001) or drug-related clinical adverse events (52.0% vs 80.1%, P < 0.001). CONCLUSIONS: In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine seemed to have superior efficacy compared with efavirenz/tenofovir/emtricitabine.

Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK.

We compared 4 years of antiretroviral therapy with tenofovir/emtricitabine and either raltegravir or efavirenz from the ongoing STARTMRK study of treatment-naïve HIV-infected patients. Through 192 weeks, raltegravir produced durable and consistent viral suppression and immune restoration compared with efavirenz irrespective of baseline demographic and prognostic factors, including in patients with high viral loads.

Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial.

BACKGROUND: Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. METHODS: In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823. FINDINGS: From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per µL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. INTERPRETATION: Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. FUNDING: Merck.

Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK.

BACKGROUND: We compared 3 years of antiretroviral therapy with raltegravir or efavirenz as part of a combination regimen in the ongoing STARTMRK study of treatment-naive patients infected with human immunodeficiency virus (HIV). METHODS: Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies/mL and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind, noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Outcomes included viral suppression, adverse events, and changes from baseline metabolic parameters. Dual energy X-ray absorptiometry scans were obtained on a convenience sample of patients at prespecified time points to assess changes in body fat composition. RESULTS: At week 156 counting noncompleters as failures, 212 (75.4%) of 281 versus 192 (68.1%) of 282 had vRNA levels <50 copies/mL in the raltegravir and efavirenz groups, respectively [Δ (95% CI) = 7.3% (-0.2, 14.7), noninferiority P < .001]. Mean changes from baseline CD4 count were 332 and 295 cells/mm³ in the raltegravir and efavirenz arms, respectively [Δ (95% CI) = 37 (4, 69)]. Consistent virologic and immunologic efficacy was maintained across prespecified demographic and baseline prognostic subgroups for both treatment groups. Fewer drug-related clinical adverse events (49% vs 80%; P < .001) occurred in raltegravir than efavirenz recipients, with discontinuations due to adverse events in 5% and 7%, respectively. Elevations in fasting lipid levels (including LDL- and HDL-cholesterol) were consistently lower in the raltegravir than efavirenz group (P < .005). Fat gain was 19% in 25 raltegravir recipients and 31% in 32 efavirenz recipients at week 156. CONCLUSIONS: When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir produced durable viral suppression and immune restoration that was at least equivalent to efavirenz through 156 weeks of therapy. Both regimens were well tolerated, but raltegravir was associated with fewer drug-related clinical adverse events and smaller elevations in lipid levels. Clinical Trials Registration. NCT00369941.

Total migraine freedom, a potential primary endpoint to assess acute treatment in migraine: comparison to the current FDA requirement using the complete rizatriptan study database.

OBJECTIVE: To examine total migraine freedom (TMF), defined as pain freedom and absence of associated symptoms, using rizatriptan clinical trial data and to explore advantages of TMF as a single primary composite efficacy endpoint. BACKGROUND: The FDA has set a higher regulatory hurdle for registration of new migraine agents requiring both pain freedom (or relief) and absence of each associated symptom (phonophobia, photophobia, and nausea). METHODS: Twelve studies representing phase III + efficacy/safety studies of rizatriptan 10 mg in adults treating migraine were included in the meta-analysis. The percentage of patients achieving TMF at 2 hours by study and combined by treatment group was summarized by treatment paradigm (early/mild pain, moderate/severe, menstrual migraine). To demonstrate the impact of the strict migraine regulatory hurdle on clinical trial design and to compare it to TMF, simulation via bootstrap sampling was used. RESULTS: Odds ratios (rizatriptan vs placebo, all P < .001) for TMF were 6.2 (95% CI: [4.9, 7.7]) for moderate/severe, 2.7 (95% CI: [1.8, 4.0]) for menstrual, and 3.1 (95% CI: [2.4, 4.0]) for early/mild. Most with moderate/severe migraine reported photophobia and/or phonophobia at baseline, but only half had nausea. Simulation results showed a substantial loss of power analyzing absence of pain and each symptom compared with the composite TMF endpoint across all treatment paradigms. CONCLUSION: Rizatriptan 10 mg was superior to placebo in achieving TMF at 2 hours post-dose across all treatment paradigms. Given that the majority of patients with migraine do not exhibit all 3 associated symptoms, the TMF endpoint has significant advantages vs establishing efficacy on pain and each symptom individually.

Raltegravir versus Efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses.

BACKGROUND: We analyzed the 96-week results in the overall population and in prespecified subgroups from the ongoing STARTMRK study of treatment-naive HIV-infected patients. METHODS: Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies per milliliter and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. RESULTS: At week 96 counting noncompleters as failures, 81% versus 79% achieved vRNA levels <50 copies per milliliter in the raltegravir and efavirenz groups, respectively [Delta (95% confidence interval) = 2% (-4 to 9), noninferiority P < 0.001]. Mean change in baseline CD4 count was 240 and 225 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Delta (95% confidence interval) = 15 (-13 to 42)]. Treatment effects were consistent across prespecified baseline demographic and prognostic subgroups. Fewer drug-related clinical adverse events (47% versus 78%; P < 0.001) occurred in raltegravir than efavirenz recipients. Both regimens had modest effects on serum lipids and glucose levels and on body fat composition. CONCLUSIONS: When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir exhibited durable antiretroviral activity that was noninferior to the efficacy of efavirenz through 96 weeks of therapy. Subgroup analyses were generally consistent with the overall findings. Both regimens were well tolerated.

Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials.

BACKGROUND: To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy. METHODS: The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729. FINDINGS: 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group. INTERPRETATION: Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir. FUNDING: Merck.

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial.

BACKGROUND: Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. METHODS: Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941. FINDINGS: 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. INTERPRETATION: Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. FUNDING: Merck.

The efficacy of rofecoxib 50 mg and hydrocodone/acetaminophen 7.5/750 mg in patients with post-arthroscopic pain.

OBJECTIVE: To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5 mg/750 mg (H/A) and placebo in treating pain after arthroscopy of the knee. METHODS: A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50 mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24 h. The primary endpoint was total pain relief at 6 h for rofecoxib 50 mg compared with placebo. RESULTS: H/A (p = 0.003), but not rofecoxib (p = 0.256) was significantly more effective than placebo for total pain relief at 6 h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (p < 0.01, p < 0.05, respectively) and placebo (p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (p < 0.001) over 24 h. Rofecoxib also provided better Brief Pain Inventory Severity (p = 0.008) and Interference Domain (p = 0.045) scores at 24 h compared to placebo and had lower 24-h Pain Severity scores than H/A (p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups. CONCLUSIONS: Rofecoxib 50 mg did not provide significantly different pain relief than placebo at 6 h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24 h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model.