Jeffery Robbins

Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease

Background/Aims: Cyclooxygenase-2 (COX-2) may play an important role in the neuropathology of Alzheimer’s disease (AD). The efficacy and safety of celecoxib (200 mg bid), a COX-2 selective inhibitor, were assessed in patients ≧50 years with established mild-to-moderate AD to determine whether treatment was effective in retarding deterioration of cognitive function. Methods: This was a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The primary efficacy end points were the change from baseline to week 52 in the Alzheimer’s Disease Assessment Scale-Cognitive Behavior (ADAS-cog) composite score and the week 52 Clinician’s Interview-Based Impression of Change Plus (CIBIC+). Results: At 52 weeks, change in ADAS-cog scores from baseline was similar for placebo and celecoxib 200 mg bid groups (5.00 and 4.39, respectively). CIBIC+ scores were also similar (4.83 and 4.92). Two extension studies were conducted but were terminated early based on these efficacy results. Safety data from all 3 studies indicated that celecoxib was generally well-tolerated. Conclusion: Celecoxib 200 mg bid did not slow the progression of AD in this study, and the occurrence of adverse events was as expected for an elderly population with a complex chronic medical condition.

A Prospective Study Comparing Celecoxib with Naproxen in Children with Juvenile Rheumatoid Arthritis

Objective To compare the efficacy and safety of celecoxib and naproxen in children with juvenile rheumatoid arthritis (JRA). Methods In this multicenter, randomized, double-blind, noninferiority study, subjects with JRA were randomized to receive a target dose of celecoxib 3 mg/kg bid or 6 mg/kg bid, or a target dose of naproxen 7.5 mg/kg bid for 12 weeks (maximum allowed dose = 600 mg total daily dose). The primary efficacy measure was the percentage of responders at Week 12 attaining the American College of Rheumatology pediatric 30% improvement criterion (ACR Pediatric-30). Results Both celecoxib doses were at least as effective as naproxen at Week 12 [ACR Pediatric-30 treatment differences: celecoxib 3 mg/kg bid – naproxen = 1.36% (95% CI –13.08 to 15.80); celecoxib 6 mg/kg bid – naproxen = 13.02% (95% CI –0.22 to 26.25)]. Celecoxib 6 mg/kg bid had a numerically higher response rate than celecoxib 3 mg/kg bid at all postrandomization visits and a numerically higher response rate than naproxen 7.5 mg/kg bid at Weeks 4, 8, and 12. Improvement in each ACR Pediatric-30 core set measure was comparable to or numerically higher for celecoxib 6 mg/kg bid than naproxen or celecoxib 3 mg/kg bid. Adverse event rates were similar for all treatment groups, except that gastrointestinal adverse events were more common in the naproxen group, although the difference was not statistically significant. Conclusion Celecoxib 3 mg/kg bid and 6 mg/kg bid were at least as effective as naproxen 7.5 mg/kg bid in treating the signs and symptoms of JRA over 12 weeks. All treatments were generally well tolerated.

Celecoxib in the Treatment of Primary Dysmenorrhea: Results From Two Randomized, Double-Blind, Active-and Placebo-Controlled, Crossover Studies

BACKGROUND Celecoxib, a cyclooxygenase-2 inhibitor, has established analgesic efficacy for the treatment of acute pain resulting from a variety of causes. OBJECTIVE This article describes 2 studies designed to assess the efficacy and tolerability of celecoxib in patients with primary dysmenorrhea. METHODS Two identical, 3-day, multiple-dose, randomized, double-blind, active- and placebo-controlled, crossover studies were carried out in women aged 18 to 44 years with primary dysmenorrhea (studies 1 and 2). The studies employed a 6-sequence, 3-period, complete-block crossover design over 3 menstrual cycles. Patients received celecoxib 400 mg, followed by celecoxib 200 mg no sooner than 12 hours after first dose (day 1), then celecoxib 200 mg q12h as necessary (days 2 and 3); naproxen sodium 550 mg followed by naproxen sodium 550 mg no sooner than 12 hours after first dose (day 1), then naproxen sodium 550 mg q12h as necessary (days 2 and 3); or placebo. Primary efficacy measures were time-weighted sum of total pain relief and time-weighted sum of pain intensity difference at 8 hours after administration of the first dose of study medication (TOTPAR[8] and SPID[8], respectively). Tolerability was assessed using routine physical examination, including vital sign measurements, and clinical laboratory analyses at screening and end of study. RESULTS In total, 149 and 154 patients were randomized to 1 of the 6 treatment sequences in studies 1 and 2, respectively. Across treatment sequences, mean age ranges were 23.4 to 26.9 years (study 1) and 28.3 to 34.1 years (study 2). Mean weight ranges were 62.7 to 74.5 kg (study 1) and 69.2 to 86.7 kg (study 2). Most patients (96.6% in study 1, 80.5% in study 2) were white. Mean TOTPAR[8] values with celecoxib (study 1/study 2, 18.28/17.98) and naproxen sodium (20.59/21.27) were significantly greater than with placebo (12.82/12.98) (all, P < 0.001). Mean SPID[8] values were significantly greater with celecoxib (10.06/9.60) and naproxen sodium (11.48/11.71) than with placebo (5.96/6.41) (all, P < 0.001). Naproxen sodium was significantly different from celecoxib in TOTPAR[8] (study 2 only) and SPID[8] (both studies) (all, P < 0.001). In both studies, the adverse-events (AEs) profile was not significantly different between treatments, with the majority of AEs being related to primary dysmenorrhea and not medication. Less than 10% of patients experienced severe AEs in any treatment period. CONCLUSIONS In these 2 identically designed studies in women aged 18 to 44 years, celecoxib 400 mg (followed by 200 mg q12h) was more effective, as measured using pain scores, in the treatment of primary dysmenorrhea compared with placebo. In each study, the primary efficacy measures-TOTPAR[8] and SPID[8] scores-were significantly improved with celecoxib and naproxen sodium compared with placebo. SPID[8] in both studies and TOTPAR[8] in study 2 were significantly improved with naproxen sodium compared with celecoxib. Both celecoxib and naproxen sodium were well tolerated and provided relief from menstrual pain within 1 hour of administration.

Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial

Background The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP. Methods and Findings A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28–42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination. Conclusions IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria. Trial Registration ClinicalTrials.gov (NCT01103063).

Dosing Celecoxib in Pediatric Patients With Juvenile Rheumatoid Arthritis

The objective was to derive dosing recommendations for the use of celecoxib in patients with juvenile rheumatoid arthritis (JRA) using pharmacokinetic (PK) and exposure‐response data. PK and efficacy data from a randomized, double‐blind, 12‐week study of celecoxib dosed at 3 and 6 mg/kg twice a day (bid) as an investigational suspension formulation in 152 JRA patients aged 2 to 17 years, PK data from 36 adult RA patients, and relative bioavailability data in healthy adults comparing suspension or capsule sprinkles with the commercial capsule were analyzed. Typical oral clearance (L/h) values were 40% and 24% lower in patients weighing 10 and 25 kg, respectively, compared with a 70‐kg patient. Longitudinal, logistic pharmacodynamic models incorporating linear effects of dose/area under the plasma concentration—time curve (AUC) over 0 to 12 hours (AUC0–12) suggested that the percentage of responders increased with celecoxib exposure. Systemic exposures (AUC) were similar for the suspension, capsule sprinkles, and intact capsule. Administration of a 50‐mg bid capsule (or sprinkles) for patients weighing 10 to 25 kg and 100 mg bid for patients >25 kg was predicted to yield similar exposures and response rates as those observed in the JRA trial. Doses and dosage forms not studied in the JRA trial were approved based on the results of this analysis.

Parasitological Clearance Rates and Drug Concentrations of a Fixed Dose Combination of Azithromycin-Chloroquine in Asymptomatic Pregnant Women with Plasmodium Falciparum Parasitemia: An Open-Label, Non-Comparative Study in Sub-Saharan Africa.

Background Malaria remains one of the most important causes of morbidity and mortality in pregnant women and their newborn babies in sub-Saharan Africa. Intermittent preventive treatment in pregnancy (IPTp) is recommended by the World Health Organization (WHO) to reduce the burden of disease and improve maternal and neonatal survival and general health. Due to the growing resistance to sulfadoxine-pyrimethamine (SP), the current WHO-recommended drug for IPTp, identification of new and effective drugs is an urgent priority. Methods and Findings This was an open-label, non-comparative study (NCT01103713) in 5 countries in East and sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) to assess parasitological response and drug concentrations of a single, 3-day course of four tablets of a fixed-dose combination of azithromycin-chloroquine (AZCQ) 250/155 mg given during the second or third trimester to women with asymptomatic Plasmodium falciparum parasitemia in their first or second pregnancy. Parasitemia was determined by microscopy and molecular genotyping was performed to characterize parasites relative to the baseline infection. Weekly follow-up visits took place until day 42 after first dose and additional follow-up occurred after delivery. Systemic concentrations of azithromycin (AZ), chloroquine (CQ), and the CQ metabolite, desethyl CQ (DECQ) were evaluated at Day 0 (pre-dose), at Day 2 (pre-dose, 2 and 8 hours) and randomly at Days 7 and 14. Systemic concentrations of CQ and DECQ were also measured randomly at Day 21 and Day 28. In total, 404 women were screened for eligibility and 168 were treated, 155 of whom completed the study. PCR-adjusted parasitological response in the modified intent-to-treat population at day 28 (the primary efficacy endpoint) was estimated by the Kaplan-Meier method as 99.35% (95% confidence interval [CI]: 97.76, 100.00). PCR-adjusted parasitological response remained high at day 42 (95.19%; 95% CI: 91.35, 99.03). In general, the mean concentrations of serum AZ, plasma CQ, and plasma DECQ showed large CV% values (ranges of 33–156%, 42–228%, and 57–109%, respectively). There were 157 live births, three stillbirths, and eight pregnancies of unknown outcome: 7 due to withdrawal of participant consent and 1 lost to follow-up. The most frequent treatment-emergent adverse events were vomiting (20.8%) and dizziness (19.6%). Conclusions These results suggest that a 3-day course of AZCQ can lead to an adequate 28-day parasitological response.

Trial duration and follow-up

The design of most add-on registration trials for anti epileptic drugs (AEDs) usually results in a calculated compromise regarding size, scope, cost, and duration. Appropriate trial duration incorporates issues such as efficacy, safety, and regulatory constraints and is dependent on sample size, titration usage, time to onset, and magnitude of treatment effect. Two phases are usually evaluated in these trials: baseline and treatment. Typical duration for add-on epilepsy registration trials range from 4 to 12 weeks of baseline evaluation followed by 12 to 18 weeks of double-blind treatment. Trials with shorter baseline and/or shorter double-blind periods would likely be less costly, more timely, and result in improved enrollment and retention rates. Data from large dose-response trial of 3 AEDs were retrospectively analyzed previously (Sahlroot and Pledger, 1998) to examine the effect of trial duration on the primary efficacy parameter. 2. Methods