Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.

BACKGROUND: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. METHODS: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 µg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 µg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. FINDINGS: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 µmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 µmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 µmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. INTERPRETATION: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. FUNDING: Mirum Pharmaceuticals.

The effects of intravaginal clindamycin and metronidazole therapy on vaginal mobiluncus morphotypes in patients with bacterial vaginosis.

OBJECTIVE: The objective of this study was to compare the effects of treatments for bacterial vaginosis (BV) on vaginal Mobiluncus morphotypes. STUDY DESIGN: Analyses were performed on Mobiluncus scores from similarly conducted studies evaluating clindamycin vaginal single-dose cream (CVSDC) or metronidazole vaginal gel (MVG) in 55 patients with BV and with Mobiluncus morphotypes at baseline. RESULTS: Both treatment groups demonstrated significant reductions in Mobiluncus score. However, the Mobiluncus score at test-of-cure was lower in the CVSDC than in the MVG group (P=0.0471). More patients in the CVSDC group than in the MVG group achieved microbiologic (57.5% vs. 26.7%; P=0.04), clinical (57.5% vs. 26.7%; P=0.04), and therapeutic cures of BV (45.0% vs. 20.0%; P=0.09). CONCLUSION: Clindamycin reduces vaginal Mobiluncus morphotypes to a greater extent than metronidazole in patients with BV; this correlates with a higher BV cure rate.

The effects of intravaginal clindamycin and metronidazole therapy on vaginal lactobacilli in patients with bacterial vaginosis.

OBJECTIVE: The purpose of this study was to determine the effects of 3 intravaginal antibacterial treatments on vaginal lactobacilli in patients with bacterial vaginosis (BV). STUDY DESIGN: Retrospective analyses were performed on Lactobacillus scores from 3 similar studies evaluating 2 2% clindamycin vaginal creams and 0.75% metronidazole gel at baseline and at 21 to 30 days in 408 patients with BV. Scores were compared using a 1-way global F test and McNemar's test. RESULTS: All groups had similar mean Lactobacillus scores at baseline (P = 0.37) and at 21 to 30 days (P = .71). The 3 groups were also comparable at both visits with respect to the distributions of scores within each group. In all groups, there was significant improvement in the percentages of patients with no lactobacilli present at 21 to 30 days compared with baseline (P < .0001 for all comparisons). CONCLUSION: Clindamycin and metronidazole promoted similar levels of restoration of vaginal lactobacilli at 21 to 30 days.

An open-label, two-period, crossover study of the systemic bioavailability in healthy women of clindamycin phosphate from two vaginal cream formulations.

BACKGROUND: A clindamycin phosphate 2% single-dose vaginal cream (CSDVC) formulation has been designed to provide release of clindamycin equivalent to 7 daily doses of a conventional clindamycin phosphate 2% vaginal cream (CVC). OBJECTIVE: The purpose of this study was to compare the systemic bioavailability of clindamycin from 1 dose of CSDVC with that from 1 dose from a 7-day regimen of CVC in healthy women. METHODS: This was a single-center, open-label, randomized, 2-period, 2-sequence crossover study that enrolled healthy, nonpregnant, adult women. Subjects were randomly assigned to receive a single 5-g intravaginal dose of CSDVC or CVC. Blood samples were then collected for 96 hours after study medication administration. Subjects were crossed over after a 14-day washout period, and received a single dose of the other medication. Blood samples were then collected for 96 hours after administration of the second drug. The plasma clindamycin pharmacokinetic profiles were determined, using a validated assay with a lower limit of detection of 0.2 ng/mL, and compared between treatments. RESULTS: The median age of women was 43.5 years(range, 18-66 years), the median weight was 65.0 kg (range, 47.7-91.8 kg), and the median body mass index was 25.4 kg/m2 (range, 19.2-34.7 kg/m(2)). AUC from time 0 to the last detectable concentration (AUCO(0-t)) and from time 0 to infinity (AUCO(0-infinity)) and C(max) were significantly lower with CSDVC than with CVC (geometric means of 98.61 vs 794.21 ng . h/mL for AUCO(0-t), 100.33 vs 809.14 ng . h/mL for AUC(0-infinity), and 3.18 vs 42.27 ng/mL for C(max); all comparisons, P < 0.001 between formulations). Overall bioavailability of clindamycin from CSDVC was approximately 12% of that from CVC, as measured by AUC. The arithmetic mean T(max) was significantly longer with CSDVC (26.4 vs 9.8 hours; P < 0.007). There were 18 adverse events reported during this study. The most common adverse event with each formulation was headache (CSDVC, 10%; CVC, 25%). CONCLUSIONS: Systemic bioavailability of clindamycin was significantly lower and systemic absorption was significantly slower with the CSDVC formulation than with the single dose of 7-day CVC formulation in these healthy volunteers.