Immunogenicity and Safety of a Purified Vero Rabies Vaccine-Serum Free, Compared With 2 Licensed Vaccines, in a Simulated Rabies Post-Exposure Regimen in Healthy Adults in France: A Randomized, Controlled, Phase 3 Trial.

BACKGROUND: A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®). METHODS: This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection. RESULTS: Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines. CONCLUSIONS: In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines. CLINICAL TRIALS REGISTRATION: NCT03965962.

Determination of the Optimal Single Dose Treatment for Acoziborole, a Novel Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Study.

BACKGROUND AND OBJECTIVES: Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT. METHODS: Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored. RESULTS: Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached tmax between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg. CONCLUSIONS: This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov: NCT01533961.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 µg auto-injector in healthy volunteers.

AIMS: Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 µg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 µg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females. METHODS: In this exploratory open-label, single-centre study, 54 healthy volunteers aged 18-50 years received a single 500 µg adrenaline injection (Anapen auto-injector) in the thigh (antero-lateral middle third [18 males] or antero-inferior third [36 females]). Assessments included depot depth (ultrasonography), plasma adrenaline levels (liquid chromatography-tandem mass spectrometry) and heart rate (HR; ECG Holter monitor). RESULTS: Ultrasonography showed that 82.4% of normal weight males received intramuscular injections; all overweight and obese females received subcutaneous injections. Anapen injection produced rapid increases in circulating adrenaline levels and significant increases in systolic blood pressure (SBP) and HR. Second peak plasma adrenaline concentrations (Cmax2 ) were reduced, and time to Cmax2 increased in overweight and obese females compared with males with normal body mass index; area under the curve (0-240 min) (AUC(0-240) ) was increased in overweight and obese females. Obese females had reduced maximal SBP values compared with normal weight males or overweight females; overweight and obese females had markedly different HR time courses compared with normal weight males. CONCLUSION: A 500 µg adrenaline injection via Anapen produced rapid PK/PD changes in normal weight, overweight and obese subjects, irrespective of intramuscular or subcutaneous injection, and was well tolerated.

Bifidobacterium animalis subsp. lactis Bi-07 supports lactose digestion in vitro and in randomized, placebo- and lactase-controlled clinical trials.

BACKGROUND: Probiotics may alleviate lactose maldigestion. OBJECTIVES: The objective was to select a probiotic with high lactase activity and compare it with lactase and placebo in clinical trials. METHODS: Bacterial cultures were screened for lactase activity in a model of the upper gastrointestinal (GI) tract. Bifidobacterium animalis subsp. lactis Bi-07 (Bi-07) counts were adjusted in subsequent experiments to correspond to 4500 Food Chemicals Codex (FCC) units of lactase, the amount in the European Food Safety Authority (EFSA)-approved health claim. Two crossover clinical trials, Booster Alpha and Booster Omega, were performed in participants with lactose intolerance, where 2 × 1012 CFUs Bi-07, 4662 FCC lactase, or placebo was consumed simultaneously with a lactose challenge, with 1-wk washouts between challenges. The trial designs were identical except for the source of lactose. Breath hydrogen concentration (BHC) was measured to assess the effect of the investigational products on lactose digestion, for which incremental area under the curve (iAUC) was the primary outcome. Peak BHC, cumulative BHC, and GI symptoms were secondary outcomes. RESULTS: Bi-07 was superior to placebo in reducing BHC [iAUC, parts per million (ppm) ∙ h] in both trials (Booster Alpha: geometric least square mean ratio: 0.462; 95% CI: 0.249, 0.859; P = 0.016; Booster Omega: 0.227; 95% CI: 0.095, 0.543; P = 0.001). Lactase was superior to placebo in Booster Alpha (0.190; 95% CI: 0.102, 0.365; P < 0.001) but not Booster Omega (0.493; 95% CI: 0.210, 1.156; P = 0.102). Noninferiority of Bi-07 compared with lactase was observed in Booster Omega (0.460; 95% CI: 0.193, 1.096; P = 0.079; CI upper limit < 1.25 noninferiority margin). Odds of abdominal pain (compared with placebo: 0.32, P = 0.036) and flatulence (compared with placebo: 0.25, P = 0.007) were lower with lactase in Booster Alpha. Increased odds of nausea were seen with Bi-07 (compared with placebo: 4.0, P = 0.005) in Booster Omega. CONCLUSIONS: Bi-07 has high lactase activity, and in 2 clinical trials, it supported lactose digestion in individuals with lactose intolerance.These trials were registered at clinicaltrials.gov as NCT03659747 (Booster Alpha) and NCT03814668 (Booster Omega).

The New First-in-Human EMA Guideline: Disruptive or Constructive? Outcomes From the First EUFEMED Discussion Forum.

The European Federation for Exploratory Medicines Development (EUFEMED) organized a meeting in Leuven, Belgium entitled 'The new FIH EMA guideline: Disruptive or constructive?' to provide a forum for stakeholders to discuss the guideline's operational impact. The revised EMA Guideline on strategies to identify and mitigate risks for first-in-human (FIH) and early clinical trials with investigational products was published on 20 July 2017. The revision gave guidance on sentinel dosing/staggering of subjects within a multiple-ascending dose (MAD) clinical trial, permissible maximum exposure/investigation of supra-therapeutic doses and dose escalations above the no-observed adverse effect level. As the guidelines came into operation on 1 February, 2018 it was assumed that by the date of the meeting many early phase stakeholders had gathered sufficient first-hand experience of working within the guideline to discuss their thoughts on its impact. The concluding part of the meeting focused on the possible differences between European countries in handling the revised FIH guideline and ways of achieving harmonization. Information on current industry practice was gathered by online polling during the meeting, where perception of the revised guideline as either 'disruptive' or 'constructive' was explored at the start and at the end of the Forum along with recommendations on reducing future regulatory discordance. It was generally agreed that the necessary changes encompassed by new guidelines included both constructive and disruptive aspects. The final vote on whether the new FIH guideline is disruptive or constructive was taken by 69 delegates: 51% stated that it was both constructive and disruptive, 48% decided on constructive, none on disruptive and 1% were still undecided. It was generally accepted that stakeholders need to continue in a process of stakeholder engagement and discussion, particularly on critical safety issues. Such an approach allows partners to adopt a proactive approach to sharing best practice. For example, attendees agreed that a 'Question and Answer' document harmonized between the European agencies is required for the sentinel approach and for the selection of supratherapeutic doses.

Bioavailability and Cardiovascular Effects of Adrenaline Administered by Anapen Autoinjector in Healthy Volunteers.

BACKGROUND: The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability. OBJECTIVE: To assess the adequacy of Anapen, which has a relatively short needle length (10.5 mm), through a comparison of the depot localization, plasma pharmacokinetics, and cardiovascular responses of adrenaline delivered via Anapen versus a prefilled syringe with a 25.4-mm needle, which is generally used for intramuscular injections. METHODS: This randomized, open-label, crossover study compared the impact of adrenaline administration at 2 sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, we studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline level was evaluated by ultra performance liquid chromatography-mass spectrometry (UPLC-MS), and heart rates were measured using a Holter monitor. RESULTS: Intramuscular injections were given with both devices at both thigh sites in nonobese men, but not in overweight women. Adrenaline levels showed a double peak, with parallel changes in the heart rate. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 minutes postinjection, with maximum concentration and area under the curve significantly higher with Anapen than with prefilled syringes; the magnitude of the second peak did not differ among the various conditions. Unexpectedly, in overweight women treated with Anapen, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous, and the overall bioavailability was enhanced. CONCLUSIONS: Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis.

Safety, immunogenicity, and lot-to-lot consistency of a split-virion quadrivalent influenza vaccine in younger and older adults: A phase III randomized, double-blind clinical trial.

Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014-2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18-60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

Effects of 28-day Bifidobacterium animalis subsp. lactis HN019 supplementation on colonic transit time and gastrointestinal symptoms in adults with functional constipation: A double-blind, randomized, placebo-controlled, and dose-ranging trial.

Bifidobacterium animalis subsp. lactis HN019 (HN019) ameliorates chronic idiopathic constipation. Our aim was to determine the efficacy and safety of 28-day supplementation with 1 × 109 or 1 × 1010 CFU of HN019/day for constipation. A total of 228 adults who were diagnosed with functional constipation according to the Rome III criteria were randomized in a double-blind and placebo-controlled trial. Colonic transit time (CTT), the primary outcome, and secondary outcomes that were measured using inventories-patient assessment of constipation symptoms (PAC-SYM) and quality of life (PAC-QoL), bowel function index (BFI), bowel movement frequency (BMF), stool consistency, degree of straining, bowel emptying, bloating, and pain severity-were assessed. Ancillary parameters and harms were also evaluated. There were no statistically significant differences in the primary or secondary outcomes between interventions. A post hoc analysis of 65 participants with fewer than 3 bowel movements per week (BMF ≤ 3/week) showed a physiologically relevant increase in weekly BMF in the high- (+2.0) and low-dose (+1.7) HN019 groups-by RMANOVA, the HN019 groups with BMF ≤ 3/week, pooled together, had a higher BMF versus placebo (P value = 0.01). Thus, improving low stool frequency could be a target of future interventions with HN019. High-dose HN019 also decreased the degree of straining at Day 28 versus placebo in those with BMF ≤ 3/week (P value = 0.02). Three unlikely related AEs-2 with low-dose HN019 and 1 with placebo-were followed until full recovery. In conclusion, although there were no differences in the primary analysis, HN019 is well tolerated and improves BMF in adults with low stool frequency.

Pain relief of sore throat with a new anti-inflammatory throat lozenge, ibuprofen 25 mg: A randomised, double-blind, placebo-controlled, international phase III study.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of a new oromucosal ibuprofen form, ibuprofen 25 mg lozenge, in single and repeat dosing for up to 4 days, to the matched placebo, in the treatment of acute sore throat pain in adults. METHODS: In this randomised, double-blind, placebo-controlled trial, adult patients with non-streptococcal sore throat and signs of moderate-to-severe associated pain (≥5 on the objective Tonsillo-Pharyngitis Assessment 21-point scale and ≥60 mm on the subjective 0-100 mm visual analogue Sore Throat Pain Intensity Scale [STPIS]) were assigned ibuprofen 25 mg (n=194) or matching placebo (n=191) lozenge treatment. Efficacy was assessed (at the investigating centre up to 2 hours after first dosing, then on an ambulatory basis) by parameters derived from patient's scores on scales of pain relief, pain intensity, and global efficacy assessment. The primary efficacy end-point was the time-weighted TOTal PAin Relief (TOTPAR) over 2 hours after first dosing using the Sore Throat Relief Scale (STRS). Safety and local tolerability were assessed. RESULTS: Ibuprofen 25 mg was superior to placebo on numerous pain relief parameters; TOTPAR was significantly higher with ibuprofen 25 mg over 2 hours after first dosing (P<.05), the effect being apparent from the first evaluation at 15 minutes (P<.05). The STPIS reduction in favour of ibuprofen 25 mg was not significant vs placebo. Mean STRS scores and patient's global efficacy assessment both reflected a higher efficacy of ibuprofen 25 mg over the 4-day treatment period with tests of statistical significance up to day 1 evening (P<.05), and, in patients with still clinically significant pain (n=128), after an average 4 days (P<.01). Ibuprofen 25 mg lozenge was well tolerated with a safety profile similar to placebo. CONCLUSION: Low-dose ibuprofen 25 mg lozenge in repeat dosing provides in adults more efficacious and rapid relief of sore throat pain and is as well tolerated as placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01785862.

Immunogenicity and safety of the Southern Hemisphere 2015 formulation of Vaxigrip®.

An inactivated split-virion trivalent influenza vaccine (IIV3; Vaxigrip®, Sanofi Pasteur) has been available globally since 1968. Here, we describe the results of an open-label, post-licensure trial (EudraCT no. 2014-005078-12) to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of IIV3. Adults 18-60 years of age and > 60 years of age (60 per age group) received a single 0.5-ml intramuscular injection of IIV3. Between baseline and day 21 after vaccination, hemagglutination inhibition (HAI) titers for each strain in IIV3 increased, on average, by at least 11-fold for younger adults and at least 5-fold for older adults. After vaccination, 89%-100% of the younger adult participants and 90%-98% of the older adult participants attained seroprotection (HAI titer ≥ 40) for each strain. Also, 66%-81% of younger adults and 45%-63% of older adults seroconverted or had a significant increase in HAI titer for each strain. For both age groups, these post-vaccination immune responses exceeded the criteria of the Committee for Human Medicinal Products former Note for Guidance for influenza vaccines. No serious adverse events were reported, and no new safety signals were detected. In conclusion, this study confirmed that the Southern Hemisphere 2015 formulation of IIV3 was well tolerated, highly immunogenic, and met the criteria for influenza vaccine efficacy and safety.

A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects.

PURPOSE: In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. METHODS: This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 µg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. RESULTS: The C max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, selexipag, and the combination was safe and well tolerated. CONCLUSION: Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with selexipag.

EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management.

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/.

Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome.

BACKGROUND AND PURPOSE: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). METHODS: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. RESULTS: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). CONCLUSION: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.

First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity.

Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200- and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an ex vivo bioassay with P. falciparum. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (Cmax) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng/ml and 100.6 ng·h/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the Cmax was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.).

Digestive Symptoms in Healthy People and Subjects With Irritable Bowel Syndrome: Validation of Symptom Frequency Questionnaire.

GOALS: The aim of this study was to validate the ability of symptom frequency questionnaire to differentiate between irritable bowel syndrome (IBS) patients and healthy subjects. BACKGROUND: A digestive symptom frequency questionnaire (DSFQ) was previously used in a food efficacy trial in a non-IBS population with mild gastrointestinal symptoms. STUDY: We compared 2 well-defined populations: 100 IBS patients fulfilling Rome III criteria (mean age 32 y; range, 18 to 59 y), and 100 sex-matched and age-matched healthy subjects. Frequency of individual digestive symptoms (abdominal pain/discomfort, bloating, flatulence, borborygmi) was assessed using a 5-point Likert scale (from none to everyday of the week) and the IBS severity with the IBS-SSS questionnaire. Health-Related Quality of life (HRQoL) was assessed with the Food and Benefits Assessment (FBA) and Functional Digestive Disorders Quality of Life (FDDQL) questionnaires. The digestive (dis)comfort dimension of these questionnaires was considered as the main dimension for HRQoL. RESULTS: The DSFQ discriminated IBS from healthy subjects with a significant difference (P<0.001) between groups (estimated mean difference=5.58; 95% CI, 4.91-6.28). On the basis of the ROC curve (AUC=0.9479), a cutoff value of 5 gives a sensitivity of 92% and a specificity of 84%, with a positive likelihood ratio of 5.75. Composite score of symptoms correlated strongly (P<0.0001) with digestive discomfort measured by FDDQL (-0.816), digestive comfort measured by FBA (-0.789), and the IBS-SSS score (0.762). CONCLUSIONS: Measurement of digestive symptom frequency by means of the DSFQ can differentiate IBS from healthy subjects, and shows a good correlation with other validated questionnaires (clinical trial #NCT01457378).

Effect on blood lipids of two daily servings of Camembert cheese. An intervention trial in mildly hypercholesterolemic subjects.

As a concentrated source of saturated fat, cheese consumption is considered to be associated with increased cholesterolemia and generally forbidden in dietary guidelines for adults with hypercholesterolemia. The aim of this study was to evaluate the impact of saturated fatty acids on lipid parameters and blood pressure with regards to different types of dairy products: Camembert and full-fat yoghurt. One-hundred and fifty-nine moderate hypercholesterolemic subjects without treatment were instructed to consume two full-fat yoghurts (2 × 125 g) per day for 3 weeks (run-in period) and then for a further period of 5 weeks, either two full-fat yoghurts or two 30 g servings of Camembert cheese per day. We observed that over the 5-week daily consumption of two servings of Camembert cheese, blood pressure and serum lipids did not change in moderate hypercholesterolemic subjects. These results suggest that fermented cheese such as Camembert could be consumed daily without affecting serum lipids or blood pressure.

Evaluation of the effects of therapeutic and supratherapeutic doses of agomelatine on the QT/QTc interval: a phase I, randomized, double-blind, placebo-controlled and positive-controlled, crossover thorough QT/QTc study conducted in healthy volunteers.

: The effects of the antidepressant agomelatine up to a supratherapeutic dose (400 mg, single dose) on the QT corrected (QTc) interval were assessed in a randomized, double-blind, placebo- and positive-controlled, crossover thorough QT/QTc study in young healthy volunteers (29 males and 31 females). The primary criterion was the study of male or female population-derived QT-corrected interval (QTcP). The main analysis on the QTcP demonstrated that among the 10 postdose measurement times planned, the largest 1-sided 95% confidence interval upper bound of the difference between agomelatine 50 mg and placebo-adjusted means, and 1 of the differences between agomelatine 400 mg and placebo-adjusted means were both strictly inferior to the 10 millisecond upper-bound threshold of regulatory concern. The assay sensitivity was established with the positive control moxifloxacin (400 mg) and detected an effect on the mean QTcP interval that is around the threshold of regulatory concern (5 milliseconds). No relationship between QTcP and plasma concentrations of agomelatine was observed. In conclusion, agomelatine up to 400 mg has no effect on the QTc interval as demonstrated in the present regulatory thorough QT/QTc study.

ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. PRIMARY OBJECTIVE: To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray. METHODOLOGY: Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg. RESULTS: A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study. CONCLUSION: Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier #NCT01507480.

Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial.

BACKGROUND: Although reperfusion injury has been shown to be responsible for cardiomyocytes death after an acute myocardial infarction, there is currently no drug on the market that reduces this type of injury. TRO40303 is a new cardioprotective compound that was shown to inhibit the opening of the mitochondrial permeability transition pore and reduce infarct size after ischemia-reperfusion in a rat model of cardiac ischemia-reperfusion injury. METHODS: In the rat model, the therapeutic window and the dose effect relationship were investigated in order to select the proper dose and design for clinical investigations. To evaluate post-ischemic functional recovery, TRO40303 was tested in a model of isolated rat heart. Additionally, TRO40303 was investigated in a Phase I randomized, double-blind, placebo controlled study to assess the safety, tolerability and pharmacokinetics of single intravenous ascending doses of the compound (0.5 to 13 mg/kg) in 72 healthy male, post-menopausal and hysterectomized female subjects at flow rates from 0.04 to 35 mL/min (EudraCT number: 2010-021453-39). This work was supported in part by the French Agence Nationale de la Recherche. RESULTS: In the vivo model, TRO40303 reduced infarct size by 40% at 1 mg/kg and by 50% at 3 and 10 mg/kg given by intravenous bolus and was only active when administered before reperfusion. Additionally, TRO40303 provided functional recovery and reduced oxidative stress in the isolated rat heart model.These results, together with pharmacokinetic based allometry to human and non-clinical toxicology data, were used to design the Phase I trial. All the tested doses and flow rates were well tolerated clinically. There were no serious adverse events reported. No relevant changes in vital signs, electrocardiogram parameters, laboratory tests or physical examinations were observed at any time in any dose group. Pharmacokinetics was linear up to 6 mg/kg and slightly ~1.5-fold, hyper-proportional from 6 to 13 mg/kg. CONCLUSIONS: These data demonstrated that TRO40303 can be safely administered by the intravenous route in humans at doses expected to be pharmacologically active. These results allowed evaluating the expected active dose in human at 6 mg/kg, used in a Phase II proof-of-concept study currently ongoing.