Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension.

BACKGROUND & AIMS: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2). METHODS: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 µg twice daily (BID) and 24 µg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/wk vs baseline and ≥3 SBMs/wk for ≥9 weeks, including 3 of the final 4 weeks). RESULTS: 606 patients were randomized to treatment (placebo: n = 202; lubiprostone: n = 404) in study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P = .2245). Both the 12-µg BID and 24-µg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies. CONCLUSIONS: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC but did demonstrate a safety profile similar to that in adults. (ClinicalTrials.gov: Number: NCT02042183; Number: NCT02138136).

Capsule and Sprinkle Formulations of Lubiprostone Are Not Biologically Similar in Patients with Functional Constipation.

INTRODUCTION: Lubiprostone capsules are approved for managing three different chronic constipation conditions. A "sprinkle" formulation may facilitate use in individuals with difficulty swallowing capsules. Our objective was to evaluate the bioequivalence, pharmacokinetics (PK), and bioavailability of lubiprostone sprinkles vs lubiprostone capsules, compared with placebo. METHODS: A 1-week randomized, placebo-controlled, double-blinded, bioequivalence study (study 302) and a single-dose PK and bioavailability crossover study (study 304) were conducted. In study 302, 522 subjects with chronic constipation were randomized to lubiprostone sprinkle 24 µg twice daily (BID), lubiprostone capsule 24 µg BID, or placebo. The primary efficacy endpoint was observed spontaneous bowel movement (SBM) counts (equivalence defined as showing the 90% confidence interval [CI] of the "between-group SBM ratio" to be contained within 0.8-1.25). Study 304 included two cohorts of healthy volunteers randomized to a single 48-µg lubiprostone dose, sprinkle, or capsule (n = 35) or to a single 48-µg sprinkle dose, in fed or fasted state (n = 14). RESULTS: Both lubiprostone formulations significantly improved SBM count (sprinkle, 4.82 ± 3.66, P = 0.002; capsule, 5.74 ± 3.79, P < 0.0001) vs placebo (3.68 ± 2.16), but equivalent efficacy was not demonstrated, with a 90% CI for the SBM count ratio of 0.69-0.95. Quantifiable PK data on lubiprostone were limited; however, overall exposure to the M3 metabolite was approximately 44% higher with sprinkles vs capsules under fasted conditions (geometric mean ratio 1.441 [90% CI, 1.166, 1.782]), and exposure with the sprinkle formulation was 11% lower in the fed state vs the fasted state (geometric mean ratio 0.888 [90% CI, 0.675, 1.168]). Both formulations were generally well tolerated. CONCLUSION: Despite the significant improvement in SBM counts vs placebo, the sprinkle formulation did not demonstrate bioequivalence to the capsule formulation in either pharmacodynamic or PK key parameters. TRIAL REGISTRATION: Study 302: ClinicalTrials.gov identifier, NCT03097861; https://www.clinicaltrials.gov/ct2/show/NCT03097861 ; Study 304: ClinicalTrials.gov identifier, NCT03010631; https://www.clinicaltrials.gov/ct2/show/NCT03010631 .

Efficacy of Lubiprostone for the Treatment of Opioid-Induced Constipation, Analyzed by Opioid Class.

Objectives: To examine the efficacy and safety of lubiprostone for the treatment of opioid-induced constipation (OIC) in patients by opioid class received. Design: Data were pooled from three phase III, randomized, double-blind, placebo-controlled studies. Subjects/Setting: Adults with chronic noncancer pain receiving opioid therapy for 30 or more days and diagnosed with OIC. Methods: Overall mean change from baseline in spontaneous bowel movement (SBM) frequency, overall treatment response (≥1 SBM/week improvement over baseline SBM frequency in all treatment weeks with available data and ≥3 SBMs/week for ≥9 of the 12 weeks of treatment), and OIC-related symptoms were examined in patients taking opioids. Data were pooled and analyzed by opioid group. Results: In patients receiving phenanthrene opioids (e.g., oxycodone; N = 1,159), lubiprostone significantly increased overall mean changes in SBM frequency from baseline (P = 0.0001), increased overall response rate (P = 0.0024), and improved OIC symptoms (P ≤ 0.0229) vs placebo. Patients receiving phenylpiperidine opioids (e.g., fentanyl; N = 137) had significant improvement in SBM frequency (P = 0.0129) and favorable trends in response rates (21.4% vs 9.8%; P = 0.0723) and OIC symptoms vs placebo. Efficacy was not observed in overall analyses of patients receiving diphenylheptane opioids (e.g., methadone), although an increase in SBM frequency was observed in patients who received a morphine-equivalent daily dose of 200 or fewer mg, suggesting a dose-dependent negative interference of this opioid class on lubiprostone effects. For all groups, the lubiprostone adverse event profile was similar; the most common treatment-emergent adverse events were nausea and diarrhea. Conclusions: In patients using commonly prescribed opioids, lubiprostone is effective and generally well tolerated for the treatment of OIC.

Efficacy and Safety of Lubiprostone in Patients with Opioid-Induced Constipation: Phase 3 Study Results and Pooled Analysis of the Effect of Concomitant Methadone Use on Clinical Outcomes.

Objective: The efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain were evaluated in a randomized, double-blind, placebo-controlled study. These data were also pooled with those from two similar phase 3 studies to explore the effects of methadone on treatment response. Methods: In the primary study, adults with OIC (fewer than three spontaneous bowel movements [SBMs] per week) were randomized to receive lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary end point was a change from baseline in the frequency of SBMs at week 8 in patients without a prior dose reduction. For the pooled analysis, the efficacy of lubiprostone was compared with placebo in patients receiving methadone or nonmethadone opioids. Responders were defined as patients with nine or more weeks of nonmissing SBM data who had one or more additional SBMs per week from baseline for each week that data were available and three or more SBMs per week for nine or more weeks. Results: In the primary study, the change from baseline at week 8 in SBM frequency was similar in the lubiprostone and placebo groups (P = 0.842). In the pooled analysis, the response rate was significantly higher with lubiprostone treatment vs placebo for patients receiving nonmethadone opioids (P = 0.002) but was similar between lubiprostone treatment and placebo in patients receiving methadone (P = 0.692). The safety profile of lubiprostone was unaffected by methadone use. Conclusions: The phase 3 study did not meet its primary efficacy end point. However, analysis of pooled data from all phase 3 studies in the OIC clinical development program, stratified by methadone opioid usage, confirmed that lubiprostone is effective for treatment of OIC in patients taking nonmethadone opioids; no safety concerns were identified based on the type of opioid used.

Lubiprostone for Opioid-Induced Constipation Does Not Interfere with Opioid Analgesia in Patients with Chronic Noncancer Pain.

OBJECTIVE: To determine whether lubiprostone 24 µg twice daily (BID), administered to relieve opioid-induced constipation (OIC), affects opioid analgesia in patients with chronic noncancer pain. METHODS: Data were pooled from 3 randomized, double-blind, placebo-controlled trials of lubiprostone in adults with chronic noncancer pain receiving stable opioid analgesia and who had documented OIC. In each study, lubiprostone 24 µg BID or placebo was administered for 12 weeks for relief of OIC using a common protocol. The Brief Pain Inventory short form (BPI-SF) was administered, and opioid use (expressed as morphine-equivalent daily dose [MEDD]) was recorded at baseline and months 1, 2, and 3. The BPI-SF provided patient scores for pain severity, the worst pain experienced in the past 24 hours, and pain interference with daily life. RESULTS: The pooled patient population (N = 1300) was predominately female (62.5%) and white (82.1%), with a mean age of 50.5 years. The MEDD was 97.5 mg (range, 5 to 3656 mg) in patients receiving placebo and 112.5 mg (range, 4 to 7605 mg) in patients treated with lubiprostone. Lubiprostone 24 µg BID treatment did not appear to affect opioid use or pain scores; changes from baseline were not significantly different with placebo vs. lubiprostone 24 µg BID at months 1, 2, and 3 for MEDD (P ≥ 0.435) and for BPI-SF scores for pain interference, pain severity, and worst pain (P ≥ 0.402). DISCUSSION: Lubiprostone 24 µg BID administered for relief of OIC in patients with chronic noncancer pain does not interfere with opioid analgesia.