Fesoterodine treatment of pediatric patients with neurogenic detrusor overactivity: A 24-week, randomized, open-label, phase 3 study.

BACKGROUND: Neurogenic detrusor overactivity (NDO) can damage the upper urinary tract leading to chronic renal impairment. Antimuscarinic therapy is used to improve urinary incontinence and protect the upper urinary tract in patients with NDO. OBJECTIVE: This study investigated safety and efficacy of fesoterodine, a muscarinic receptor antagonist, in 6‒<18-year-old patients with NDO (NCT01557244). STUDY DESIGN: This open-label phase 3 study included 2 pediatric cohorts. Patients in Cohort 1 (bodyweight >25 kg) were randomized to fesoterodine 4 or 8 mg extended-release tablets or oxybutynin XL tablets administered over the 12-week active comparator-controlled phase. The safety extension phase evaluated fesoterodine 4 and 8 mg for a further 12 weeks, with patients in the oxybutynin arm allocated to fesoterodine 4 or 8 mg. Patients in Cohort 2 (bodyweight ≤25 kg) were randomized to fesoterodine 2 or 4 mg extended-release beads-in-capsule (BIC) administered over a 12-week efficacy phase and 12-week safety extension phase. Patients with stable neurologic disease and clinically or urodynamically proven NDO were included. The primary endpoint was change from baseline to Week 12 in maximum cystometric bladder capacity (MCC). Secondary efficacy endpoints included detrusor pressure at maximum bladder capacity, bladder volume at first involuntary detrusor contraction, bladder compliance, and incontinence episodes. Safety endpoints included adverse event incidence, and specific assessments of cognition, behavior and vision. The pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT; fesoterodine's active metabolite) was determined using population-pharmacokinetic analysis. RESULTS: In Cohort 1 (n = 124), fesoterodine 4 and 8 mg treatment resulted in significant increases from baseline in the primary endpoint of MCC at Week 12. In Cohort 2 (n = 57), fesoterodine 2 and 4 mg BIC treatment resulted in improvements in MCC from baseline. Fesoterodine 4 and 8 mg and fesoterodine 4 mg BIC led to improvements in some secondary efficacy endpoints. The most common treatment-related adverse reactions were gastrointestinal effects, such as dry mouth, which occurred more frequently with oxybutynin than fesoterodine. No detrimental effects on visual accommodation or acuity, or on cognitive function or behavior were observed. DISCUSSION: These safety and efficacy results are consistent with limited published data on fesoterodine treatment in pediatric populations with overactive bladder or NDO. Study limitations include the lack of placebo control and the small sample size, which limits the ability to make formal efficacy comparisons and detect rare adverse reactions. CONCLUSION: Fesoterodine has a favorable benefit-risk profile in 6‒<18-year-old patients with NDO and may represent an additional option for pediatric NDO treatment.

Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs.

BACKGROUND: Gastrointestinal (GI) tolerability is an important treatment consideration for physicians when choosing a nonselective nonsteroidal anti-inflammatory drug (NSAID) for their elderly arthritis patients. The objective of this study was to compare the GI tolerability of the cyclooxygenase-2 selective NSAID celecoxib and nonselective NSAIDs in elderly patients with arthritis aged 65 years or older. METHODS: This was a retrospective, pooled analysis of patients aged 65 years or older with osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS) from randomized, parallel-group trials. Selected trials had a duration of ≥2 weeks and at least one celecoxib 200-400 mg/day and one nonselective NSAID (naproxen, ibuprofen, or diclofenac) arm. Patient-level data from the safety populations of the trials were pooled. Analysis included the combined incidence of the GI intolerability adverse events (AEs) (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea) and incidence and time to trial discontinuation due to these intolerability AEs. RESULTS: A total of 21 trials were selected involving 9461 elderly patients (mean age 71.9 years). Of these, 5872 received celecoxib, 1104 naproxen, 151 ibuprofen, and 2334 diclofenac. The combined incidence of GI intolerability AEs were reported by significantly fewer patients treated with celecoxib (16.7%) than naproxen (29.4%; p < 0.0001), ibuprofen (26.5%; p = 0.0016), or diclofenac (21.0%; p < 0.0001). The discontinuation rate due to GI intolerability AEs was significantly lower for celecoxib (4.0%) versus naproxen (8.1%; p < 0.0001) and ibuprofen (7.3%; p < 0.05), but not diclofenac (4.2%; p = 0.75). CONCLUSIONS: Among elderly arthritis patients, the incidence of GI intolerability AEs was lower with celecoxib than with naproxen, ibuprofen, or diclofenac. Fewer elderly patients discontinued due to GI intolerability AEs with celecoxib than with either naproxen or ibuprofen.

Pooled analysis of GI tolerability of 21 randomized controlled trials of celecoxib and nonselective NSAIDs.

OBJECTIVE: To compare the gastrointestinal (GI) tolerability of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at approved doses in patients with common musculoskeletal conditions. RESEARCH DESIGN AND METHODS: This was a retrospective, pooled analysis of studies selected from the Pfizer Corporate Clinical Trials Registry. Study selection criteria were: (1) Data available as of October 31, 2004; (2) Randomized, parallel-group study design and planned treatment duration of >or= 2 weeks; (3) At least one nonselective NSAID (naproxen, ibuprofen, or diclofenac) as a comparator; (4) At least one arm with 200 mg or 400 mg celecoxib per day; (5) Patients with osteoarthritis (OA), adult rheumatoid arthritis (RA), or ankylosing spondylitis (AS). Data were pooled by treatment and by subject from the safety analysis population of each included study. Joint primary end points were the combined incidence of tolerability-related GI adverse events (AEs) (abdominal pain, dyspepsia, nausea, diarrhea, and flatulence), and time to study discontinuation due to any GI AE. RESULTS: In all, 21 studies met the selection criteria. Across the safety analysis populations of the included studies, 7797 patients received celecoxib total daily dose 200 mg/day, 6653 received celecoxib total daily dose 400 mg/day, 2953 received naproxen, 499 received ibuprofen, and 5643 received diclofenac. Tolerability-related GI AEs were reported by significantly fewer celecoxib-treated patients (16.0%) than by those treated with naproxen (24.3%), ibuprofen (24.2%), or diclofenac (19.9%) (p < 0.0001 vs. each comparator). Time to study discontinuation due to any GI AE was significantly longer for celecoxib than for naproxen (p < 0.0001), ibuprofen (p = 0.002), or diclofenac (p = 0.048). In the RA subpopulation (n = 2857), there was no significant difference between the celecoxib and naproxen or ibuprofen groups in incidence of tolerability-related GI AEs and GI AEs. LIMITATIONS: The limitations are inherent to the retrospective analysis design. CONCLUSIONS: In this pooled analysis of celecoxib at approved doses in OA, RA, and AS, fewer celecoxib-treated patients in the overall population had tolerability-related GI AEs than patients treated with naproxen, ibuprofen, or diclofenac. In addition, celecoxib-treated patients had a significantly longer time to study discontinuation due to GI AEs.

A double-blind placebo-controlled study evaluating the onset of action of doxazosin gastrointestinal therapeutic system in the treatment of benign prostatic hyperplasia.

OBJECTIVE: To determine the onset of improvement in benign prostatic hyperplasia symptoms in patients after treatment with doxazosin gastrointestinal therapeutic system (DOX GITS) versus placebo. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, baseline values, including International Prostate Symptom Score (IPSS) and maximum urine flow rate (Q(max)), were determined following a 2-week placebo run-in. Patients received DOX GITS 4 mg/d (n = 108) or placebo (n = 105) for 14 days. IPSS was measured on Days 3, 7, and 14; Q(max) on Days 1, 3, 7, and 14; and the patients' perception of improvement was measured on Days 1 and 2 in the evening at home and in the office on Day 14. RESULTS: Significantly more patients treated with DOX GITS than placebo perceived improvement after Day 1 (60.6% vs. 41.9%) through Day 14 (84.3% vs. 64.1%). On Day 1, improvement in Q(max) with DOX GITS was not significantly different compared with placebo. On Day 3 of the trial (1) IPSS improvement was significantly greater with DOX GITS than with placebo; (2) proportion of patients with > or =30% improvement in IPSS was significantly greater with DOX GITS (49.5%) than placebo (28.4%) and remained so through Day 14; (3) improvement in Q(max) was significantly greater with DOX GITS (3.7 mL/s) than placebo (1.9 mL/s) and remained so through Day 14; (4) proportion of patients with > or =3 mL/s increase in Q(max) was statistically greater with DOX GITS (54.4%) versus placebo (30.8%) and remained so through Day 14. CONCLUSIONS: DOX GITS significantly improved IPSS and Q(max) by Day 3 of treatment, and these changes were maintained through Day 14. More patients receiving DOX GITS than placebo perceived improvement in symptoms as early as Day 1.