Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study.

BACKGROUND: The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. METHODS: In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18-61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103, 3 × 104, 3 × 105, or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106, 9 × 106, 2 × 107, or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov, number NCT02314923. FINDINGS: Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 [n=64], 3 × 104 [n=64], 3 × 105 [n=64], or 3 × 106 PFU [n=64]) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 [n=20], 9 × 106 [n=47], 2 × 107 [n=47], or 1 × 108 PFU [n=48]) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% [27 of 47] vs 7·4% [seven of 94]) and local tenderness (59·6% [28 of 47] vs 8·5% [eight of 94]). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% [22 of 47] vs 27·7% [26 of 94]), fatigue (38·3% [18 of 47] vs 19·1% [18 of 94]), myalgia (34·0% [16 of 47] vs 10·6% [10 of 94]), subjective fever (29·8% [14 of 47] vs 2·1% [two of 94]), shivering or chills (27·7% [13 of 47] vs 7·4% [seven of 94]), sweats (23·4% [11 of 47] vs 3·2% [three of 94]), joint aches and pain (19·1% [nine of 47] vs 7·4% [seven of 94]), objective fever (14·9% [seven of 47] vs 1·1% [one of 94]), and joint tenderness or swelling (14·9% [seven of 47] vs 2·1% [two of 94]). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days [IQR 10-14]; median duration 8·0 days [6-15]) versus 3·2% (three of 94) of controls (median onset 15·0 days [6-20]; median duration 47·0 days [37-339]), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days [IQR 2-12]; median duration 7·0 days [4-9]) versus 3·2% (three of 94) of controls (median onset 5·0 days [3-53]; median duration 33·0 days [5-370]). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test [PRNT60] by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146-2302) and seroconversion was 95·7% (95% CI 85·5-98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176-355) and seroconversion was 95·7% (85·5-98·8). These robust immunological responses were sustained for 1 year. INTERPRETATION: rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. FUNDING: Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.

Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised, placebo-controlled phase 1/2 study.

BACKGROUND: A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. METHODS: In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18-64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). RESULTS: A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11-15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. CONCLUSIONS: Single-dose vaccination of SA4Ag in healthy adults aged 18-64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. TRIAL REGISTRATION NUMBER: NCT01364571.

Safety, tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: Results of a randomised trial.

BACKGROUND: The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18-64years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted. METHODS: In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65-85years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays. RESULTS: The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels. CONCLUSIONS: Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65-85years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85years. TRIAL REGISTRATION NUMBER: NCT01643941.

Immune response and reactogenicity of intradermal administration versus subcutaneous administration of varicella-zoster virus vaccine: an exploratory, randomised, partly blinded trial.

BACKGROUND: The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. METHODS: In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50-59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01385566. FINDINGS: Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48-2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68-3·94; p<0·0001), which also remained high at 18 months. An apparent dose-response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 [90% CI 1·36-1·99], 1/3 dose intradermal 2·58 (2·13-3·13), 1/10 dose intradermal 2·22 [1·83-2·69], and 1/27 dose intradermal 1·64 [1·35-2·00]). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). INTERPRETATION: Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. FUNDING: Merck & Co Inc.

Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults.

AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax(®) (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1-2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2-4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (≥0.56) to be ≥40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine.

Immunogenicity of a quadrivalent Ann Arbor strain live attenuated influenza vaccine delivered using a blow-fill-seal device in adults: a randomized, active-controlled study*.

BACKGROUND: Influenza B strains from two distinct lineages (Yamagata and Victoria) have cocirculated over recent years. Current seasonal vaccines contain a single B lineage resulting in frequent mismatches between the vaccine strain and the circulating strain. An Ann Arbor strain quadrivalent live attenuated influenza vaccine (Q/LAIV) containing B strains from both lineages is being developed to address this issue. OBJECTIVES: The goal of this study was to evaluate whether Q/LAIV administered intranasally as a single dose to a single nostril, using a blow-fill-seal (BFS) delivery system had a similar immunogenicity and safety profile compared with the licensed trivalent vaccine delivered using the Accuspray device. PATIENTS/METHODS: Adults aged 18-49 years were randomized to receive one intranasal dose of Q/LAIV delivered using a BFS device (Q/LAIV-BFS; n=1202) or one of two trivalent live attenuated influenza vaccines (T/LAIV) containing one of the corresponding B strains (total T/LAIV, n=598). Primary endpoints were the post-vaccination strain-specific serum hemagglutination inhibition antibody geometric mean titers for each strain. Secondary immunogenicity endpoints, safety, and acceptability of the BFS device were also assessed. RESULTS: Q/LAIV was immunogenically non-inferior to T/LAIV for all four influenza strains. Secondary immunogenicity outcomes were consistent with the primary endpoint. Solicited symptoms and AEs were comparable in both groups. Subjects considered the BFS device to be acceptable. CONCLUSIONS: Immune responses to vaccination with Ann Arbor strain Q/LAIV-BFS were non-inferior to those with T/LAIV. Q/LAIV may confer broader protection against seasonal influenza B by targeting both major influenza B lineages.

A phase 1, randomized, open-label, active-controlled trial to assess the safety of a meningococcal serogroup B bivalent rLP2086 vaccine in healthy adults.

Neisseria meningitidis serogroup B (MnB) is a significant cause of invasive meningococcal disease, but no broadly protective vaccine is yet approved. We assessed the safety and immunogenicity of a bivalent MnB vaccine composed of lipidated subfamily A and B variants of recombinant LP2086 (rLP2086, also known as factor H binding protein, fHBP). Forty-eight adults, ages 18-40 y, were randomized to receive 60, 120 or 200 µg of the bivalent rLP2086 vaccine or control at 0, 2 and 6 mo. Immunogenicity was assessed by rLP2086-specific immunoglobulin G (IgG) geometric mean titers for subfamily A and B proteins. Safety was determined by laboratory assessments of blood and urine and by reporting of solicited and unsolicited adverse events (AEs). The bivalent rLP2086 vaccine elicited high IgG titers following the second and third vaccination at all dose levels. In each of the four study arms, 11 of the 12 participating subjects reported ≥ 1 AE, and no serious AEs were reported. Local and systemic reactions were mainly mild to moderate. Laboratory abnormalities (including increased sodium, decreased neutrophils, and proteinuria) were not associated with clinical events and were not considered to be related to the study vaccine. Vaccinations were generally well-tolerated. Strong IgG antibody responses and the absence of clinically significant laboratory abnormalities support further development of the bivalent rLP2086 vaccine (www.clinicaltrials.gov; identifier: NCT00879814).

Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response.

BACKGROUND: We evaluated the safety and immunogenicity profiles of 3 novel influenza vaccine constructs consisting of the globular head of the HA1 domain of the Novel H1N1 genetically fused to the TLR5 ligand, flagellin. HA1 was fused to the C-terminus of flagellin in VAX128A, replaced the D3 domain of flagellin in VAX128B and was fused in both positions in VAX128C. METHODS: In a dose escalation trial, 112 healthy subjects 18-49 and 100 adults ≥65 years old were enrolled in a double blind, placebo controlled clinical trial at two centers. Vaccines were administered IM at doses ranging from 0.5 to 20 µg. VAX128C was selected for second study performed in 100 subjects 18-64 years old comparing 1.25 and 2.5 µg doses. All subjects were followed for safety and sera collected pre- and post-vaccination were tested by hemagglutination-inhibition (HAI). Serum C-reactive protein and cytokine levels were also measured. CONCLUSIONS: In the first study high HAI titers and high seroconversion and seroprotection rates were observed at doses ≥2.5 µg in adults 18-49. In adults ≥65 years, the vaccines doses of ≥4 µg were required to induce a ≥4-fold rise in HAI titer, 50% seroconversion and 70% seroprotection. Based on safety, VAX128A was tested up to 8 µg, VAX128B to 16 µg and VAX128C to 20 µg. Dose escalation for VAX128A was stopped at 8 µg because one subject had temperature 101.6°F associated with a high CRP response, VAX128B was stopped at 16 µg because of a severe AE associated with a high CRP and IL-6 response. VAX128C was not stopped before reaching the 20 µg dose. In the second study VAX128C was well tolerated among 100 subjects who received 1.25 or 2.5 µg. The peak GMT was 385 (95%CI 272-546), 79% (71-87%) seroconversion and 92% (84-96%) seroprotection. DISCUSSION: Flagellin adjuvanted vaccines can be designed to minimize reactogenicity and retain immunogenicity, thereby representing a promising next generation vaccine technology.

Correlation of measures of pain, function, and overall response: results pooled from two identical studies of etoricoxib in chronic low back pain.

STUDY DESIGN: Assessment of correlation of measures of low back pain (LBP) using data pooled from 2 identical studies. OBJECTIVE: To assess the relative responsiveness of and correlation between various measures of LBP, including the Roland-Morris Disability Questionnaire (RMDQ), the LBP intensity (LBPI) visual analog scale (VAS), and patient's global assessment of response to therapy (PGART). SUMMARY OF BACKGROUND DATA: Several tools are available to measure pain, functional limitation, and response to therapy for LBP. Studies have shown varying degrees of responsiveness and correlation. METHODS: This was a pooled subgroup analysis of patients with chronic LBP from 2 identical studies comparing etoricoxib 60 mg, 90 mg, and placebo. LBP was assessed by the time-weighted average change from baseline over 12 weeks as measured by RMDQ, LBPI VAS, and PGART. Correlation was calculated using Pearson's correlation coefficient. RESULTS: The correlation (r) between LBPI and RMDQ changes ranged from 0.657 and 0.703; correlations between LBPI and PGART changes ranged from 0.677 and 0.738. Cutpoints separating responders from nonresponders for all 3 measures fell near the 66.7th percentile of response and were consistent with minimal clinically significant changes identified in the literature. CONCLUSION: In this study, the RMDQ, LBPI VAS, and PGART showed a high degree of correlation in measuring response to therapy in LBP, suggesting clinicians may be able to simplify assessments.

Comparison of the effectiveness and tolerability of lidocaine patch 5% versus celecoxib for osteoarthritis-related knee pain: post hoc analysis of a 12 week, prospective, randomized, active-controlled, open-label, parallel-group trial in adults.

BACKGROUND: Cyclooxygenase-2 (COX-2) selective inhibitors and nonselective NSAIDs are commonly used to treat osteoarthritis (OA) of the knee. OBJECTIVE: The aim of this study was to compare the effectiveness of the lidocaine patch 5% with that of celecoxib 200 mg/d in the treatment of OA-related knee pain; however, the study was terminated prematurely by the sponsor because of tolerability concerns regarding the class of COX-2 selective inhibitors. A post hoc analysis of the available data is presented here. METHODS: This multicenter, randomized, open-label, active-controlled, parallel-group study included patients >or=18 years of age with unilateral or bilateral moderate to severe OA of the knee. Patients were randomized to receive treatment with either the lidocaine patch 5% or celecoxib 200 mg/d. The primary efficacy end point was change from baseline to 12 weeks in the Western Ontario and McMaster Universities (WOMAC) OA Index pain subscale. Secondary end points included additional WOMAC subscales and Brief Pain Inventory (BPI) measures. Because this trial was prematurely terminated, a post hoc analysis was performed using a random pattern-mixture model of all observed cases of the intent-to-treat population. RESULTS: A total of 143 patients were randomized to treatment (lidocaine patch 5%, 69 patients; mean [SD] age, 60.2 [11.4] years; 65.2% female; 66.7% white; weight, 94.1 [23.3] kg) or celecoxib 200 mg/d (74 patients; age, 58.2 [12.1] years; 63.5% female; 68.9% white; weight, 94.3 [22.5] kg). Baseline pain WOMAC OA subscale scores (lidocaine patch 5%, 12.087; celecoxib 200 mg/d, 12.514) and mean rates of change over time (baseline to week 2, -1.5916 vs -1.6513 per week; weeks 2-6, -0.0168 vs -0.119 per week; weeks 6-12, -0.1818 vs -0.1579 per week) were not significantly different between the 2 groups. Improvement in additional WOMAC subscales and in several BPI measures were not significantly different between the 2 groups. Treatment-related adverse events were reported in 8 patients in each treatment group (11.6% in the lidocaine patch 5% group and 10.8% in the celecoxib 200-mg/d group) and were considered mild or moderate in severity. CONCLUSION: Statistically significant differences in effectiveness and tolerability were not found between these 2 treatments in these patients with OA knee pain.

Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To directly compare the efficacy and safety of etoricoxib, 30 mg once daily, ibuprofen, 800 mg 3 times daily, and placebo for treatment of osteoarthritis (OA) of the hip and knee. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled trial of patients with OA of the knee or hip was performed between February 2003 and November 2003 in 61 medical centers in the United States. Qualified patients aged 40 to 89 years were randomized to receive placebo, etoricoxib, 30 mg once daily, or ibuprofen, 800 mg 3 times daily, for 12 weeks. Primary efficacy end points Included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales and Patient Global Assessment of Disease Status. Response to treatment was assessed by the time-weighted average change from baseline over 12 weeks. RESULTS: In 528 patients, baseline values for the 3 primary end points ranged from 67.78 to 72.60 mm (0-100 mm visual analog scale). Near-maximal efficacy was achieved by week 2 with both active treatments and sustained over the course of the trial. During the 12-week period, least squares mean changes in the primary end points (Western Ontario and McMaster Universities Osteoarthritis Index and Patient Global Assessment of Disease Status subscales) ranged from -16.53 to -13.55 mm, -27.89 to -23.68 mm, and -26.53 to -22.97 mm in the placebo, etoricoxib, and Ibuprofen groups, respectively. Both etoricoxib and ibuprofen were more effective (P<.001) than placebo for all primary end points. Etoricoxib and ibuprofen treatment responses for the primary end points were determined to be comparable with use of prespecified comparability criteria. Results for all other efficacy end points were consistent with responses observed for the primary end points. Etoricoxib and ibuprofen generally were well tolerated. CONCLUSION: For patients with OA, treatment with etoricoxib, 30 mg/d, is well tolerated and provides sustained clinical effectiveness that is superior to placebo and comparable to ibuprofen, 2400 mg/d.

Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability--a randomized, placebo-controlled, 3-month trial.

We evaluated etoricoxib, a novel COX-2-specific inhibitor, in 319 patients with chronic low back pain (LBP) in this double-blind, placebo-controlled trial. Patients were randomized to a 60 mg dose (n = 103) or 90 mg dose (n = 107) of etoricoxib, or placebo (n = 109), daily for 12 weeks. The primary endpoint was low back pain intensity scale (Visual Analog Scale of 0- to 100-mm) time-weighted average change from baseline over 4 weeks. Other endpoints included evaluation over 3 months of low back pain intensity scale, Roland-Morris Disability Questionnaire (RMDQ), low back pain bothersomeness scale, patient- and investigator-global assessments, Patient Health Survey (MOS SF-12), rescue acetaminophen use, and discontinuation due to lack of efficacy. Etoricoxib provided significant improvement from baseline versus placebo in pain intensity (4 weeks: 12.9 mm and 10.3 mm for 60-mg and 90-mg doses, P <.001 for each; 12 weeks: 10.5 mm and 7.5 mm for 60-mg and 90-mg doses, P =.001 and.018, respectively). Etoricoxib at either dose led to significant improvement in other endpoints, including RMDQ scores, bothersomeness scores and global assessments. Etoricoxib given once daily provided significant relief of symptoms, and disability associated with chronic LBP that was observed 1 week after initiating therapy, was maximal at 4 weeks, and was maintained over 3 months.