200-μg Group Research Articles

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10–90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10–90-μg dose groups ranged from −10.7 to −16.5 U l−1 versus placebo (−7.8 U l−1) and tropifexor 140- and 200-μg groups were −18.0 U l−1 and −23.0 U l−1, respectively, versus placebo (−8.3 U l−1)) and % HFF (tropifexor 10–90-μg dose groups ranged from −7.48% to −15.04% versus placebo (−6.19%) and tropifexor 140- and 200-μg groups were −19.07% and −39.41%, respectively, versus placebo (−10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164

EFFECTS OF SUBLINGUAL MISOPROSTOL AS ADJUNCT TO OXYTOCIN FOR ACTIVE MANAGEMENT OF THIRD STAGE OF LABOUR IN PATURIENTS AT RISK OF POST-PARTUM HAEMORRHAGE IN ABAKALIKI : A COMPARISON OF 200 VERSUS 400 MICROGRAMS

Background: Postpartum Haemorrhage (PPH) still remains a major cause of maternal mortality despite adequate knowledge of its causes and treatment. Oxytocin administration is one of the major components of active management of third stage of labour (AMTSL). Evidence suggest benefit of misoprostol as an adjunct however optimal dose is yet to be determine considering the dose depended side effect profile of misoprostol. . Objective: This study evaluated the efficacy and side effect profile of 200µg versus 400µg of prophylactic sublingual misoprostol as adjunct to AMTSL among parturient at risk for PPH. Methods: This was a double blinded, single centre, randomized controlled trial involving two hundred and forty parturient with 2.1% drop out rate , thus 235 of them were analyzed; 117 (48.8%) and 118(49.2%) for 200 and 400 microgram group respectively. Data was analyzed using Statistical Package for Social Science (IBM SPSS) software (version 24, Chicago II, USA). Continuous variables were presented as mean and standard deviation (Mean ± 2SD), while categorical variables were presented as numbers and percentages. Chi-square test (X2) was used for comparison between groups for qualitative variables while t-test was used for comparison between groups for quantitative variables. A difference with a P value <0.05 was considered statistically significant. Results: The mean blood loss was similar between the 200µg and 400µg groups of the study with 280.68±179.40mls and 253.86±169.80mls for the 200µg and 400µg groups respectively and p=0.240. The occurrence of primary postpartum haemorrhage (PPH) was equally similar between the two groups with incidence of 9.4% and 7.6% for the 200µg and 400µg groups respectively, p=0.7997. The risk ratio (RR) for developing PPH was 0.888 (95% CI; 0.537-1.467). The need for additional oxytocics to control bleeding was equally the same between the study groups with p=0.132. However, more participants in the 400µg group had one or more of the side effects of sublingual misoprostol compared to the participants in the 200µg group with RR 1.5759 (95% CI; 1.239-2.004), p<0.001. Shivering and fever were the side effects with significant difference between the two groups with p-values of 0.015 and 0.023 for shivering and fever respectively. Conclusion: Sublingual misoprostol as an adjuvant to AMTSL in the doses of 200µg and 400µg are equally effective in reducing blood loss and the incidence of primary PPH, among women at increased risk for PPH. However, misoprostol induced side effects were significantly higher with 400µg.

A phase 1 randomized study assessing safety and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in healthy older Japanese adults

BackgroundClostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B. MethodsHealthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 μg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A– and toxin B–specific neutralizing antibody levels in human sera. ResultsLocal reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-μg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-μg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-μg group, peaked at month 7, and remained elevated at month 12. ConclusionsThe C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI.ClinicalTrials.gov identifier: NCT02725437.

Optimal Dose of Vaginal Misoprostol for Cervical Ripening before Hysteroscopy: A Randomized Double-Blind Study

Study ObjectiveTo evaluate the optimal dose of vaginal misoprostol (200 and 400 µg) for cervical priming before operative hysteroscopy. DesignA randomized, controlled, double-blind trial (Canadian Task Force classification I). SettingA university hospital. PatientsSixty-eight patients undergoing operative hysteroscopy. InterventionsPatients were randomized to receive a low (200 µg) or high (400 µg) dose of misoprostol administered vaginally 8 hours before operative hysteroscopy. Measurements and Main ResultsThe primary outcome was perioperative dilatation time, and the secondary outcome measurements included the subjective difficulty of cervical dilatation assessed by the surgeon, operative time, self-reported adverse events after vaginal administration and before the start of the operation, and complications during the procedure. A comparison of the 200-µg (n = 34) and 400-µg (n = 34) misoprostol cohorts revealed similarities when comparing time with cervical dilatation, operative difficulty, result, and time. Misoprostol-related adverse events were significantly lower in the 200-µg cohort than the 400-µg cohort (58.8% vs 85.3%, p = .015). Abdominal pain was the most common adverse event and was higher in the 400-µg cohort compared with the 200-µg cohort (73.5% vs 50.0%, p = .046). However, there were no operative delays resulting from adverse events, and all individuals reported the procedure to be tolerable and recovered without medication or treatment. ConclusionBoth 200 µg and 400 µg vaginally administered misoprostol are effective for cervical dilatation, and we recommend vaginal administration of 200 µg misoprostol for cervical dilatation 8 hours before operative hysteroscopy because of lower adverse events in the 200-µg group as well as similar efficacy between cohorts.

Efficacy of the novel nasal steroid S0597 tested in an environmental exposure unit

BackgroundS0597 is a novel glucocorticosteroid that was formulated as an intranasal spray to treat seasonal allergic rhinitis (SAR). In a previous phase 2 study, doses of 100 to 400 μg twice daily were well tolerated and more effective than placebo for improving nasal symptoms induced by grass pollen. ObjectiveTo assess the clinical efficacy and safety of a once-daily S0597 nasal spray for treatment of SAR induced by ragweed pollen in an environmental exposure unit (EEU). MethodsA single-center, phase 2, randomized, double-blind study in 222 adults with SAR and a positive skin prick test result to short ragweed. Participants underwent ragweed pollen challenge in the EEU at the screening or priming visit and on days 1, 7, and 14 and received 50, 200, or 400 μg of S0597 or placebo in the evening for 13 days. The primary efficacy end point was change in total nasal symptom score (TNSS) from baseline to day 14. ResultsImprovement in TNSS from baseline to day 14 was statistically significant in all S0597 groups compared with placebo. Least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200-, and 400-μg/d S0597 groups, respectively (P < .05). The 200-μg group demonstrated statistically significant improvements in all TNSS subscales (rhinorrhea, nasal congestion, sneezing, nasal itching) compared with placebo at days 7 and 14. ConclusionTreatment with 50 to 400 μg of S0597 once daily was well tolerated and significantly more effective than placebo in relieving nasal symptoms of SAR associated with ragweed pollen. Trial Registrationclinicaltrials.gov Identifier: NCT01940146.

Randomized controlled trial comparing 200μg and 400μg sublingual misoprostol for prevention of primary postpartum hemorrhage.

To compare efficacy and adverse effects of 200μg and 400μg misoprostol for prevention of postpartum hemorrhage (PPH). In a randomized control trial, women with term singleton pregnancies in active labor attending University College Hospital, Ibadan, Nigeria, were enrolled between July 2011 and February 2012. Participants were randomly assigned using random numbers (block size four) to receive 200μg or 400μg sublingual misoprostol after delivery of the anterior shoulder, alongside intravenous oxytocin. Investigators were masked to group assignment, but participants were not. The primary outcomes were blood loss up to 1h after delivery, PPH (blood loss ≥500mL), and adverse effects. Overall, 62 patients were assigned to each group. No significant differences between the 200-μg and 400-μg groups were recorded in mean peripartum blood loss (307±145mL vs 296±151mL; P=0.679) and PPH occurrence (5 [8.1%] vs 6 [9.7%] women; P=0.752). Noticeable adverse effects were reported by 16 (25.8%) women in the 200-μg group and 42 (67.7%) in the 400-μg group (P<0.001). Risk of shivering was significantly lower with 200μg than 400μg (relative risk 0.33, 95% confidence interval 0.19-0.58). Blood loss and PPH occurrence did not differ by misoprostol dose, but a 200-μg dose was associated with a reduction in adverse effects. Pan Africa Clinical Trials Registry: PACTR201505001107182.

Randomized trial to determine optimal dose of vaginal misoprostol for preabortion cervical priming

Objective: To determine the optimal dosage of vaginal misoprostol for cervical priming before vacuum aspiration abortion. Methods: One hundred twenty women were assigned randomly to receive 200, 400, 600, or 800 μg of misoprostol given vaginally. Vacuum aspiration was performed 3–4 hours after the insertion of misoprostol tablets. The degree of cervical dilation before operation was measured with a Hegar dilator. Preoperative and intraoperative blood loss and associated side effects also were assessed. Results: Twenty-nine (96.7%) women in the 400-μg group and all in the 600-μg and 800-μg groups achieved cervical dilation of at least 8 mm. The success rate for the 200-μg group was only 23.3%, significantly less efficacious than the 400-μg dose (odds ratio 95.3; 95% confidence interval 10.9, 830.9; P < .001). There was no significant difference among the 400-, 600-, and 800-μg groups ( P = .364) with respect to achieving cervical dilation at least 8 mm. However, 800 μg was associated with significantly more side effects than 600 μg (preoperative and intraoperative blood loss, P < .001; abdominal pain, P = .005; products of conception at os, P < .001; fever higher than 38.0C, P = .002). When 400 μg and 600 μg were compared, we found that the higher dose also was associated with significantly more side effects. The 600-μg group was used twice in the comparison, but all P values remained significant even after the Bonferroni adjustment for multiple comparisons. Conclusion: Vaginal application of 400 μg of misoprostol is the optimal dose for vacuum aspiration preabortion cervical dilation in first-trimester nulliparas.

Randomized Trial to Determine Optimal Dose of Vaginal Misoprostol for Preabortion Cervical Priming

In Brief Objective To determine the optimal dosage of vaginal misoprostol for cervical priming before vacuum aspiration abortion. Methods One hundred twenty women were assigned randomly to receive 200, 400, 600, or 800 μg of misoprostol given vaginally. Vacuum aspiration was performed 3–4 hours after the insertion of misoprostol tablets. The degree of cervical dilation before operation was measured with a Hegar dilator. Preoperative and intraoperative blood loss and associated side effects also were assessed. Results Twenty-nine (96.7%) women in the 400-μg group and all in the 600-μg and 800-μg groups achieved cervical dilation of at least 8 mm. The success rate for the 200-μg group was only 23.3%, significantly less efficacious than the 400-μg dose (odds ratio 95.3; 95% confidence interval 10.9, 830.9; P < .001). There was no significant difference among the 400-, 600-, and 800-μg groups (P = .364) with respect to achieving cervical dilation at least 8 mm. However, 800 μg was associated with significantly more side effects than 600 μg (preoperative and intraoperative blood loss, P < .001; abdominal pain, P = .005; products of conception at os, P < .001; fever higher than 38.0C, P = .002). When 400 μg and 600 μg were compared, we found that the higher dose also was associated with significantly more side effects. The 600-μg group was used twice in the comparison, but all P values remained significant even after the Bonferroni adjustment for multiple comparisons. Conclusion Vaginal application of 400 μg of misoprostol is the optimal dose for vacuum aspiration preabortion cervical dilation in first-trimester nulliparas. A dose of 400 μg is optimal for misoprostol preabortion cervical priming in first-trimester nulliparas.

Controlled Study of Linear Growth in Asthmatic Children During Treatment With Inhaled Glucocorticosteroids

Linear growth was investigated with weekly knemometry in a population of 43 schoolchildren with mild asthma treated with inhaled budesonide. The design was a randomized, double-blind, parallel group study with three dose groups of 200, 400, and 800 micrograms of budesonide per day. Each dose group received budesonide for 8 consecutive weeks. Placebo was given for either 4 weeks before or after budesonide treatment. Twelve children in the 200-micrograms group, 14 in the 400-micrograms group, and 12 in the 800-micrograms group completed the 12-week study period. There was no significant difference in mean growth velocity among the three dose groups during placebo treatment. Compared with placebo (growth velocity: 0.39 mm/wk), mean lower leg growth velocity was reduced with 0.26 mm/wk (P less than .001, t = 5.0, df = 11; 95% confidence interval 0.14 to 0.37 mm/wk) in children treated with 800 micrograms of budesonide. There was no statistically significant difference in growth velocity between 200- or 400-micrograms budesonide treatments and placebo. These data indicate that inhaled budesonide can be safely used in doses up to 400 micrograms/d in schoolchildren with asthma.