Placebo Phase Research Articles

Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4–5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial

In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. Merck Sharp & Dohme.

A Systematic Review and Pooled Analysis of Select Safety Parameters Among Normal Healthy Volunteers Taking Placebo in Phase 1 Clinical Trials.

A systematic review of the Bristol‐Myers Squibb normal healthy volunteers (NHVs) database identified phase 1 trials that included NHVs administered placebo with the aim of characterizing normal inter‐ and intraindividual safety parameter variability. Twenty‐five single and multiple ascending dose studies, median duration 28 (2 to 63) days, were included in the pooled analysis (355 NHVs). Laboratory evaluations, vital signs, electrocardiograms, and adverse events were assessed. The most commonly occurring adverse event was headache (28 [7.9%] NHVs; 519.5 events/100 person‐years). During the dosing period (on placebo), evaluations showed 5.1 events/100 measures of alanine aminotransferase and 7.3 events/100 measures of creatine kinase 1× above the upper limit of normal. Alanine aminotransferase and creatine kinase elevations occurred in 28 (7.9%) and 39 (11.0%) NHVs, respectively; 105 (30.3%) NHVs had low and 46 (13.3%) had high diastolic blood pressure. This analysis may inform future study designs and provide a context for interpretation of safety signals in early phase clinical trials.

The Impact of Nitrate Supplementation on the Peripheral Chemoreceptor Reflex to Hypoxia in Older Adults

Peripheral chemoreceptors located within the carotid bodies activate cardiorespiratory reflexes in response to hypoxia. Carotid body chemoreceptor activity has been shown to be enhanced in conditions such as congestive heart failure, hypertension, and possibly aging. Nitric oxide (NO) has been proposed as an inhibitory modulator of carotid body chemosensitivity in response to hypoxia. Additionally, NO bioavailability is often reduced with cardiovascular risk factors such as aging. In the present study, we tested the hypothesis that increasing NO bioavailability via dietary nitrate (NO3) supplementation would reduce cardiorespiratory responses to hypoxia in older adults. A double‐blind, randomized, placebo‐controlled, cross‐over study design was used to evaluate minute ventilation (VE) and heart rate (HR) responses to acute hypoxia in 7 older adults (66±2 years; 5M/2F) before and after 4 weeks of NO3 supplementation (beetroot powder) and placebo (beetroot powder devoid of NO3). On each study visit, subjects underwent two separate isocapnic hypoxic tests (self‐regulating, partial rebreathing system with 10% O2). Subjects remained on 10% O2 until SpO2 reached ≤80%. The hypoxic exposures were separated by a 15‐minute washout period with the subjects breathing room air. VE, HR, and SpO2 were continuously monitored throughout each hypoxic exposure. Data were grouped together using a 7‐breath average with the slope of the linear regression line for each dependent variable (VE and HR) versus SpO2 serving as a measure of peripheral chemosensitivity. The slopes for the two hypoxia tests on each study visit were averaged and used for statistical comparisons. On study day one (true baseline) acute hypoxia increased both VE and HR (P<0.05 for both). Four weeks of NO3 supplementation reduced the hypoxic ventilatory response (−0.16 ± −0.05 vs. −0.06 ± −0.03 L/minute/%SpO2, P<0.05), whereas no change was observed following the placebo phase of the study (−0.14 ± −0.07 vs. −0.14 ± −0.08 L/minute/%SpO2, P=0.67). Additionally, the heart rate responses to acute hypoxia were also reduced following NO3 supplementation (−0.49 ± −0.08 vs. −0.30 ± −0.05 beats/minute/%SpO2, P<0.05), but not with placebo (−0.54 ± −0.11 vs. −0.45 ± −0.08 beats/minute/%SpO2, P=0.21). Our preliminary findings suggest that supplementation of NO3 to boost NO bioavailability in older adults blunts the cardiorespiratory responses to hypoxia. Future studies should examine the therapeutic potential of NO3 in patient populations exhibiting exaggerated peripheral chemosensitivity.Support or Funding InformationResearch supported by Neogenis Inc.

A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation

BackgroundThe sodium–glucose cotransporter 2 inhibitor, dapagliflozin, has been shown to improve diabetic control and reduce blood pressure in patients with type 2 diabetes mellitus. Its effects on micro- and macrovascular structure and function have not yet been reported.MethodsThis was a prospective, single-centre, placebo-controlled, double-blind, randomised crossover phase IIIb study conducted between March 2014 and February 2015. After a 4-week run-in/washout phase, patients (N = 59) received 6 weeks of either dapagliflozin 10 mg or placebo once daily. They then underwent a 1-week washout before crossing over to the other treatment. Changes in retinal capillary flow (RCF) and arteriole remodelling were evaluated using scanning laser Doppler flowmetry, while micro- and macrovascular parameters in the systemic circulation were assessed using pulse wave analysis.ResultsSix weeks of dapagliflozin treatment resulted in improvements in diabetes control, including blood glucose and insulin resistance, and reduced office and 24-h ambulatory blood pressure values. RCF decreased from 324 AU at baseline to 308 AU after treatment with dapagliflozin (p = 0.028), while there was little difference after the placebo (318 AU; p = 0.334). Furthermore, the arteriole remodelling that was seen after the placebo phase was not evident after the dapagliflozin phase. Central systolic and diastolic blood pressure values were significantly lower after 6 weeks of dapagliflozin, by 3.0 and 2.2 mmHg, respectively (p = 0.035 and 0.020, respectively vs. baseline).ConclusionsSix weeks of dapagliflozin treatment resulted in numerous beneficial effects. In addition to achieving superior diabetes control and blood pressure, parameters associated with the early stages of vascular remodelling were also improved.Trial registrationhttp://www.clinicaltrials.gov (NCT02383238)

Reevaluating the Efficacy and Predictability of Antidepressant Treatments

Depressive severity is typically measured according to total scores on questionnaires that include a diverse range of symptoms despite convincing evidence that depression is not a unitary construct. When evaluated according to aggregate measurements, treatment efficacy is generally modest and differences in efficacy between antidepressant therapies are small. To determine the efficacy of antidepressant treatments on empirically defined groups of symptoms and examine the replicability of these groups. Patient-reported data on patients with depression from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (n = 4039) were used to identify clusters of symptoms in a depressive symptom checklist. The findings were then replicated using the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n = 640). Mixed-effects regression analysis was then performed to determine whether observed symptom clusters have differential response trajectories using intent-to-treat data from both trials (n = 4706) along with 7 additional placebo and active-comparator phase 3 trials of duloxetine (n = 2515). Finally, outcomes for each cluster were estimated separately using machine-learning approaches. The study was conducted from October 28, 2014, to May 19, 2016. Twelve items from the self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR) scale and 14 items from the clinician-rated Hamilton Depression (HAM-D) rating scale. Higher scores on the measures indicate greater severity of the symptoms. Of the 4706 patients included in the first analysis, 1722 (36.6%) were male; mean (SD) age was 41.2 (13.3) years. Of the 2515 patients included in the second analysis, 855 (34.0%) were male; mean age was 42.65 (12.17) years. Three symptom clusters in the QIDS-SR scale were identified at baseline in STAR*D. This 3-cluster solution was replicated in CO-MED and was similar for the HAM-D scale. Antidepressants in general (8 of 9 treatments) were more effective for core emotional symptoms than for sleep or atypical symptoms. Differences in efficacy between drugs were often greater than the difference in efficacy between treatments and placebo. For example, high-dose duloxetine outperformed escitalopram in treating core emotional symptoms (effect size, 2.3 HAM-D points during 8 weeks, 95% CI, 1.6 to 3.1; P < .001), but escitalopram was not significantly different from placebo (effect size, 0.03 HAM-D points; 95% CI, -0.7 to 0.8; P = .94). Two common checklists used to measure depressive severity can produce statistically reliable clusters of symptoms. These clusters differ in their responsiveness to treatment both within and across different antidepressant medications. Selecting the best drug for a given cluster may have a bigger benefit than that gained by use of an active compound vs a placebo.

Are you a doctor? … Are you a doctor? I’m not a doctor! A reappraisal of mitigated echolalia in aphasia with evaluation of neural correlates and treatment approaches

ABSTRACTBackground: Mitigated echolalia (ME) is a symptom of aphasia which refers to a seemingly deliberate repetition of just-heard words and phrase fragments. ME has historically been viewed as a compensatory strategy aimed to strengthen auditory comprehension. Nevertheless, this hypothesis and other possible functional deficits underlying ME have not been evaluated so far.Aims: This study aimed to (a) reappraise ME in the frame of modern neuroscience; (b) report the effects of Constraint-Induced Aphasia Therapy (CIAT) and a cognition-enhancing drug (memantine) on detrimental ME in a patient (CCR) with fluent aphasia; and (c) analyse the functional and structural brain correlates of ME in CCR with multimodal neuroimaging.Methods & Procedure: Tasks tapping verbal expression and auditory comprehension were administered to CCR to evaluate ME. After baseline testing, evaluations were performed under placebo alone (weeks 0–16), combined placebo with CIAT (weeks 16–18), placebo treatment alone (weeks 18–20), washout (weeks 20–24) and memantine (weeks 24–48). Instructions to reduce ME during CIAT were provided to CCR. Language evaluation and multimodal neuroimaging were also performed 10 years after ending treatment.Outcomes & Results: At baseline, ME occurred in spontaneous speech and in difficult-to-understand single words, indicating impaired meaning access. However, more instances of ME were heard in sentence comprehension, reflecting additional impairment in short-term memory. ME also occurred in words that were correctly defined and understood to the extent that even after accessing word meaning successfully, CCR repeated the same word several times, suggesting impaired inhibitory response control. In comparison with baseline, analysis of auditory sentence comprehension under treatment revealed significant decrements of ME just after ending CIAT and 2 weeks later. These gains were maintained under memantine 6 months later. No changes in ME were found during both placebo and washout phases. Instructions to constrain ME reduced the time to complete a sentence comprehension task 2 weeks after CIAT. ME returned to baseline levels 10 years later. Multimodal imaging suggested that ME in CCR resulted from residual activity of remnants of the left dorsal stream and the intact right white matter tracts after extensive damage to the left ventral stream.Conclusions: ME in CCR interfered with functional communication, and it may be attributed to deficits in sound-meaning mapping, auditory short-term memory, attentional control, and inhibition of repetition mechanisms. Our preliminary evidence suggests that ME, in patients like CCR, may be modulated with specific instructions during aphasia therapy and drugs.

Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II

Mucopolysaccharidosis I and II are lysosomal storage disorders that, despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT), continue to cause significant skeletal abnormalities leading to pain, stiffness, physical dysfunction, and short stature. Tumor necrosis factor – alpha (TNF-α) is elevated in individuals with MPS I and II and associated with pain and physical dysfunction. Therefore, we evaluated the safety and effects of the TNF-α inhibitor adalimumab in patients with MPS I and II in a 32-week, randomized, double blind, placebo-controlled, crossover study of adalimumab at a dose of 20mg (weight 15–<30kg) or 40mg (weight ≥30kg) administered subcutaneously every other week or saline placebo for 16weeks. Participants were evaluated at baseline, week 16, and week 32 with the Children's Health Questionnaire – Parent Form 50 (CHQ-PF50), the Pediatric Pain Questionnaire (PPQ), range-of-motion (ROM) measurements, anthropometry, six-minute walk test (6MWT), hand dynamometer, and laboratory evaluations for safety. The primary outcome was safety and primary efficacy outcome was bodily pain (BP) measured by the CHQ-PF50. Two subjects, one with MPS I and one with MPS II, completed the study. Adalimumab was well tolerated and there were no serious adverse events. Standardized BP scores for age and gender were higher (i.e. less pain) at the end of the treatment versus placebo phase for both subjects. Subject #1 became unblinded during treatment due to skin erythema. Behavior measured by both CHQ-PF50 and parental report improved during treatment compared to placebo in both subjects. ROM improved by >5° in seven of eight joints in Subject #1 and five of eight joints in Subject #2 (range 7.0° to 52.8°). There was no change in the PPQ, 6MWT, or hand dynamometer. Data from this small pilot study suggest that treatment with adalimumab is safe, tolerable, and may improve ROM, physical function, and possibly pain, in children with MPS I or II. However, additional clinical trials are needed before this therapy should be recommended as part of clinical care.

Efficacy and Safety of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Virus Infection and Inherited Blood Disorders: Final Data from the C-Edge Ibld Study

Efficacy and Safety of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Virus Infection and Inherited Blood Disorders: Final Data from the C-Edge Ibld Study

Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

We tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. In this prospective, double-blind, crossover study, 19 healthy female volunteers (21-40 years) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 minutes, after which QT intervals were recorded and blood samples collected for 12 hours. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QTcI). Fifteen subjects completed all study phases. Maximum serum ibutilide concentrations in the progesterone and placebo phases were similar (1247±770 vs 1172±709 pg/mL, p=0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2±11.0 vs 1.2±1.0 ng/mL, p<0.0001), while serum estradiol concentrations in the two phases were similar (89.3±62.8 vs 71.8±31.7 pg/mL, p=0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412±15 vs 419±14 ms, p=0.04). Maximum ibutilide-associated QTcI (443±17 vs 458±19 ms, p=0.003), maximum percent increase in QTcI from pretreatment value (7.5±2.4 vs 9.3±3.4%, p=0.02) and area under the effect (QTcI) curve during the first hour post-ibutilide (497±13 vs 510±16 ms-hr, p=0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Oral progesterone administration attenuates drug-induced QTcI lengthening.

Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects.

Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first‐pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four‐session paired cross‐over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6‐mg (placebo phase) or 0.8‐mg (rifampicin phase) buprenorphine sublingually on day 7. In the second part of the study, subjects received 0.4‐mg buprenorphine intravenously. Plasma concentrations of buprenorphine and urine concentrations of buprenorphine and its primary metabolite norbuprenorphine were measured over 18 h. Adverse effects were recorded. Rifampicin decreased the mean area under the dose‐corrected plasma concentration–time curve (AUC 0–18) of sublingual buprenorphine by 25% (geometric mean ratio (GMR): 0.75; 90% confidence interval (CI) of GMR: 0.60, 0.93) and tended to decrease the bioavailability of sublingual buprenorphine, from 22% to 16% (P = 0.31). Plasma concentrations of intravenously administered buprenorphine were not influenced by rifampicin. The amount of norbuprenorphine excreted in the urine was decreased by 65% (P < 0.001) and 52% (P < 0.001) after sublingual and intravenous administration, respectively, by rifampicin. Adverse effects were frequent. Rifampicin decreases the exposure to sublingual but not intravenous buprenorphine. This can be mainly explained by an enhancement of CYP3A‐mediated first‐pass metabolism, which sublingual buprenorphine only partially bypasses. Concomitant use of rifampicin and low‐dose sublingual buprenorphine may compromise the analgesic effect of buprenorphine.

Hormone phase influences sympathetic responses to high levels of lower body negative pressure in young healthy women.

We tested the hypothesis that sympathetic responses to baroreceptor unloading may be affected by circulating sex hormones. During lower body negative pressure at -30, -60, and -80 mmHg, muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were recorded in women who were taking (n = 8) or not taking (n = 9) hormonal contraceptives. All women were tested twice, once during the low-hormone phase (i.e., the early follicular phase of the menstrual cycle and the placebo phase of hormonal contraceptive use), and again during the high-hormone phase (i.e., the midluteal phase of the menstrual cycle and active phase of contraceptive use). During baroreceptor unloading, the reductions in stroke volume and resultant increases in MSNA and total peripheral resistance were greater in high-hormone than low-hormone phases in both groups. When normalized to the fall in stroke volume, increases in MSNA were no longer different between hormone phases. While stroke volume and sympathetic responses were similar between women taking and not taking hormonal contraceptives, mean arterial pressure was maintained during baroreceptor unloading in women not taking hormonal contraceptives but not in women using hormonal contraceptives. These data suggest that differences in sympathetic activation between hormone phases, as elicited by lower body negative pressure, are the result of hormonally mediated changes in the hemodynamic consequences of negative pressure, rather than centrally driven alterations to sympathetic regulation.

OP.8E.07] MIDDLE-TERM DIETARY SUPPLEMENTATION WITH RED YEAST RICE PLUS COENZYME Q10 IMPROVES LIPID PATTERN, ENDOTHELIAL REACTIVITY AND ARTERIAL STIFFNESS IN MODERATELY HYPERCHOLESTEROLEMICS

Objective: Red yeast rice is a well-known lipid-lowering nutraceutical. The aim of this double-blind, randomized, placebo-controlled, clinical trial was to investigate if the known benefits on lipid pattern of a 6-month treatment with 10 mg monacolins could be also associated to changes in endothelial function and arterial stiffness. Design and method: This double blind, placebo-controlled, randomized clinical trial was carried out on 40 moderately hypercholesterolemic subjects, non smokers, pharmacologically untreated, in primary prevention for cardiovascular diseases (Clinicaltrial.gov ID NCT02492464). After 4 weeks of diet and physical activity, patients were allocated to treatment with an indistinguishable pill of placebo or with an active product containing 10 mg monacolins from Monascus purpureus and 50 mg coenzyme Q10 to be assumed for 6 months. Endothelial reactivity and arterial stiffness have been measured through the validated Vicorder® device. Results: When compared to the placebo phase, during monacolin treatment patients experienced a more favorable percentage change in LDL-cholesterol (LDL after monacolin treatment: −27.7%; LDL after placebo treatment: +5.0%, p < 0.05). As it regards the vascular parameters, endothelial reactivity (pulse volume displacement after monacolin treatment: +6.0%; pulse volume displacement after placebo treatment: +0.5%, p < 0.05), and arterial stiffness (pulse wave velocity after monacolin treatment: −0.4%; pulse wave velocity after placebo: +0.1%, p < 0.05) also significantly improved after monacolin treatment only. Conclusions: Based on our data, the long-term assumption of a red yeast rice dietary supplement containing 10 mg monakolins per daily dose seems to be associated to an improvement of LDL-cholesterolemia, endothelial reactivity and pulse wave velocity in moderately hypercholesterolemic subjects

Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.

This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4mg (0.6mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400mg twice daily on the first day and 200mg twice daily thereafter or (iii) posaconazole 400mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18h and pharmacological effects were measured. Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC0-∞) of buprenorphine 1.80-fold (90% confidence interval 1.45-2.24; P<0.001), its peak concentration (Cmax) 1.37-fold (P<0.013) and half-life (t ½ ) 1.37-fold (P<0.001). Posaconazole increased the AUC00-∞ of buprenorphine 1.25-fold (P<0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90% confidence interval 1.18-2.12; P<0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

Greater Beta-Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives.

Background: β-adrenergic receptors play an important role in mitigating the pressor effects of sympathetic nervous system activity in young women. Based on recent data showing oral contraceptive use in women abolishes the relationship between muscle sympathetic nervous system activity and blood pressure, we hypothesized forearm blood flow responses to a β-adrenergic receptor agonist would be greater in young women currently using oral contraceptives (OC+, n = 13) when compared to those not using oral contraceptives (OC–, n = 10).Methods: Women (18–35 years) were studied during the early follicular phase of the menstrual cycle (days 1–5) or placebo phase of oral contraceptive use. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured at baseline and during graded brachial artery infusion of the β-adrenergic receptor agonist, Isoproterenol (ISO), as well as Acetylcholine (ACH, endothelium-dependent vasodilation) and Nitroprusside (NTP, endothelium-independent vasodilation). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100 mmHg) and the rise in FVC from baseline during infusion quantified vasodilation (ΔFVC = FVCinfusion − FVCbaseline).Results: ISO increased FVC in both groups (p < 0.01) and ISO-mediated ΔFVC was greater in OC+ compared to OC– (Main effect of group, p = 0.02). Expressing data as FVC and FBF resulted in similar conclusions. FVC responses to both ACH and NTP were also greater in OC+ compared to OC–.Conclusions: These data are the first to demonstrate greater β-adrenergic receptor-mediated vasodilation in the forearm of women currently using oral contraceptives (placebo phase) when compared to those not using oral contraceptives (early follicular phase), and suggest oral contraceptive use influences neurovascular control.

Efficacy and safety of Ayurvedic herbs in diarrhoea-predominant irritable bowel syndrome: A randomised controlled crossover trial

ObjectiveHerbal medicines have been used widely for the treatment of irritable bowel syndrome (IBS) patients. The aim of this study is to investigate efficacy and safety of an Ayurvedic herbal compound preparation made from: Murraya koenigii (curry), Punica granatum (pomegranate) and Curcuma longa (turmeric), compared to a placebo in patients with diarrhoea predominant IBS. Material and methodsThis trial was conducted as a randomised placebo-controlled crossover trial with randomised sequence of verum and placebo for each patient. Verum and placebo were provided as ground powders and delivered in sealed containers. Patients and outcome assessors were blinded. Patients were advised to ingest the decoction twice daily for 4 weeks. The primary outcome measure was IBS symptom intensity; secondary outcomes included: quality of life, anxiety and depression, compliance and safety. Results32 IBS patients were included in the trial (19 females, mean age 50.3±11.9years). Eleven people dropped out during the trial resulting in 37 complete verum and 35 complete placebo phases. No group differences were found between verum and placebo for IBS symptom intensity (difference 24.10; 95% CI: −17.12; 65.32, p=0.26). The same was true for secondary outcomes. Compliance was satisfactory to good and the preparation appeared to be safe, but one third of the patients registered at least one minor adverse event that might be related to the study interventions. ConclusionAn Ayurvedic herbal preparation made from Murraya koenigii, Punica granatum and Curcuma longa appeared to be no more effective in improving diarrhoea predominant irritable bowel symptoms than placebo.

Effect of ETC-1002 on Serum Low-Density Lipoprotein Cholesterol in Hypercholesterolemic Patients Receiving Statin Therapy

ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia. This phase 2b, multicenter, double-blind trial (NCT02072161) randomized 134 hypercholesterolemic patients (LDL-C, 115 to 220mg/dl) on stable background statin therapy to 12weeks of add-on treatment with ETC-1002 120mg, ETC-1002 180mg, or placebo. The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12. For LDL-C, the least-squares mean percent change ± standard error from baseline to week 12 was significantly greater with ETC-1002 120mg (-17 ± 4%, p= 0.0055) and ETC-1002 180 mg (-24 ± 4%, p <0.0001) than placebo (-4 ± 4%). ETC-1002 also dose dependently reduced apolipoprotein B by 15% to 17%, non-high-density lipoprotein cholesterol by 14% to 17%, total cholesterol by 13% to 15%, and LDL particle number by 17% to 21%. All these reductions in ETC-1002-treated cohorts were significantly greater than those with placebo. Rates of adverse events (AEs), muscle-related AEs, and discontinuations for AEs with ETC-1002 were similar to placebo. In conclusion, ETC-1002 120mg or 180mg added to stable statin therapy significantly reduced LDL-C compared to placebo and has a similar tolerability profile.

Predicting Overall Vaccine Efficacy in a New Setting by Re-Calibrating Baseline Covariate and Intermediate Response Endpoint Effect Modifiers of Type-Specific Vaccine Efficacy.

We develop a transport formula for predicting overall cumulative vaccine efficacy through time t (VE(t)) to prevent clinically significant infection with a genetically diverse pathogen (e.g., HIV infection) in a new setting for which a Phase III preventive vaccine efficacy trial that would directly estimate VE(t) has not yet been conducted. The formula integrates data from (1) a previous Phase III trial, (2) a Phase I/II immune response biomarker endpoint trial in the new setting where a follow-up Phase III trial is planned, (3) epidemiological data on background HIV infection incidence in the new setting; and (4) genomic epidemiological data on HIV sequence distributions in the previous and new settings. For (1), the randomized vaccine versus placebo Phase III trial yields estimates of vaccine efficacy to prevent particular genotypes of HIV in participant subgroups defined by baseline covariates X and immune responses to vaccination S(1) measured at a fixed time point τ (potential outcomes if assigned vaccine); often one or more immune responses to vaccination are available that modify genotype-specific vaccine efficacy. The formula focuses on subgroups defined by X and S(1) and being at-risk for HIV infection at τ under both the vaccine and placebo treatment assignments. For (2), the Phase I/II trial tests the same vaccine in a new setting, or a refined new vaccine in the same or new setting, and measures the same baseline covariates and immune responses as the original Phase III trial. For (3), epidemiological data in the new setting are used to project overall background HIV infection rates in the baseline covariate subgroups in the planned Phase III trial, hence re-calibrating for HIV incidence differences in the two settings; whereas for (4), data bases of HIV sequences measured from HIV infected individuals are used to re-calibrate for differences in the distributions of the circulating HIV genotypes in the two settings. The transport formula incorporates a user-specified bridging assumption function that measures differences in HIV genotype-specific conditional biological-susceptibility vaccine efficacies in the two settings, facilitating a sensitivity analysis. We illustrate the transport formula with application to HIV Vaccine Trials Network (HVTN) research. One application of the transport formula is to use predicted VE(t) as a rational criterion for ranking a set of candidate vaccines being studied in Phase I/II trials for their priority for down-selection into the follow-up Phase III trial.

Development and validation of a HPLC-UV method for 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in humans: providing in vivo evidence of CYP3A4-mediated CPHP formation

We developed a high-performance liquid chromatographic procedure for the determination of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in human. Chromatographic analysis was performed on a reverse-phase C18 column with a mobile phase containing 50 mM potassium phosphate buffer/acetonitrile (75:25, vol/vol) using UV detection with a wavelength of 220 nm. The limits of detection for CPHP were 1 ng/ml in urine and the assay was linear over the concentration range of 2-500 ng/ml for urine. This analytical method was applied to measure CPHP in human. Nineteen healthy subjects were enrolled and all subjects received a single oral dose of 5 mg haloperidol following a treatment of placebo or itraconazole at 200 mg/day for 10 days in a randomized crossover manner. CPHP was detected in urine samples and average recovered amount of CPHP was 81.31 μg/24 hr in the placebo phase and it was significantly reduced to 30.34 μg/24 hr after itraconazole treatment. The finding provides in vivo evidence that CPHP is an in vivo metabolite of haloperidol in human and its formation is mediated by CYP3A4.

Efficacy of Duloxetine in Chronic Low Back Pain with a Neuropathic Component: A Randomized, Double-blind, Placebo-controlled Crossover Trial.

Among patients with chronic low back pain (CLBP), approximately 37% show signs of a neuropathic pain component (radicular pain). Treatment of this condition remains challenging. Therefore, the current study aimed to investigate the efficacy of duloxetine in the treatment of CLBP patients with neuropathic leg pain. The study was conducted as a prospective, randomized, placebo-controlled, double-blind crossover trial. CLBP with a visual analog scale (VAS) score greater than 5 and a neuropathic component that was assessed clinically and by the painDETECT questionnaire (score > 12) were required for inclusion. Patients were randomly assigned to either duloxetine or placebo for 4 weeks followed by a 2-week washout period before they crossed over to the alternate phase that lasted another 4 weeks. Duloxetine was titrated up to 120 mg/day. The primary outcome parameter was mean VAS score during the last week of treatment in each phase (VAS(week4)). Of 41 patients, 21 patients completed both treatment phases. In the intention-to-treat analysis (n = 25), VAS(week4) was significantly lower in the duloxetine phase compared with placebo (4.1 ± 2.9 vs. 6.0 ± 2.7; P = 0.001), corresponding to an average pain reduction of 32%. The painDETECT score at the end of each treatment phase was significantly lower in the duloxetine phase compared with placebo (17.7 ± 5.7 vs. 21.3 ± 3.6 points; P = 0.0023). Adverse events were distributed equally between the duloxetine (65%) and placebo phases (62%) (P = 0.5). In this crossover study, duloxetine proved to be superior to placebo for the treatment of CLBP with a neuropathic leg pain.

Thromboelastography Identifies Cyclic Haemostatic Variations in Healthy Women Using Oral Contraceptives

Using thromboelastography (TEG) and standard laboratory haemostatic tests we examined the influence of the menstrual cycle and monophasic oral contraceptive (OC) use on haemostasis in healthy women. Tests were performed on citrated whole-blood and plasma (respectively) collected from 33 healthy non-pregnant women (18 non-OC users and 15 OC users) during menses, the follicular phase and the luteal phase of non-OC users, and the placebo, early-medicated phase, and late-medicated phase of OC users. Results for various coagulation parameters determined by TEG and standard laboratory haemostatic tests were compared within and between groups. TEG detected significantly increased coagulability in OC users during the late-medicated phase when compared to the placebo and early-medicated phases, whereas standard laboratory haemostatic tests failed to reveal significant differences in haemostasis within the OC steroid medication cycle. Neither TEG nor standard laboratory haemostatic tests detected significant differences in haemostasis within the menstrual cycle in non-OC users. When compared to non-OC users, TEG revealed that OC users had significantly increased coagulability only during the late-medicated phase; whereas standard laboratory haemostatic tests detected significant differences between all individual phases of the steroid medication cycle of OC users and the combined phases of the menstrual cycle in non-OC users. In conclusion, TEG provides additional insight into haemostatic function not identifiable using standard laboratory haemostatic tests.