Publications by authors named "Jörg Täubel"

45 Publications

Comparing the consistency of electrocardiogram interval measurements by resting ECG versus 12-lead Holter.

Ann Noninvasive Electrocardiol 2021 May 4:e12851. Epub 2021 May 4.

Richmond Research Institute, St George's University of London, London, UK.

In clinical trials, traditionally only a limited number of 12-lead resting electrocardiograms (ECGs) can be recorded and, thus, long intervals may elapse between assessment timepoints and valuable information may be missed during times when patients' cardiac electrical activity is not being monitored. These limitations have led to the increasing use of Holter recorders which provide continuous data registrations while reducing the burden on patients and freeing up time for clinical trial staff to perform other tasks. However, there is a shortage of data comparing the two approaches. In this study, data from a randomized, double-blind, four-period, crossover thorough QT study in 40 healthy subjects were used to compare continuous 12-lead Holter recordings to standard 12-lead resting ECGs which were recorded in parallel. Heart rate and QT interval data were estimated by averaging three consecutive heartbeats. Values exceeding the sample average by more than 5% were tagged as outliers and excluded from the analysis. Visual comparisons of the ECG waveforms of the Holter signal showed a good correlation with resting ECGs at matching timepoints. Resting ECG data revealed sex differences that Holter data did not show. Specifically, women were found to have a longer QTcF of 20 ms, while men had a lower heart rate. We found that continuous recordings provided a more accurate reflection of changes in cardiac electrical activity over 24 hr. However, manual adjudication is still required to ensure the quality and accuracy of ECG data, and that only artifacts are removed thereby avoiding loss of true signals.
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http://dx.doi.org/10.1111/anec.12851DOI Listing
May 2021

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Clin Pharmacol Drug Dev 2021 Jun 3;10(6):572-581. Epub 2021 May 3.

St George's, University of London, London, United Kingdom.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.
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http://dx.doi.org/10.1002/cpdd.935DOI Listing
June 2021

Confirmation of the cardiac safety of nolasiban in a randomised cohort of healthy female volunteers.

Sci Rep 2021 Mar 18;11(1):6404. Epub 2021 Mar 18.

ObsEva SA, Geneva, Switzerland.

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean C for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.
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http://dx.doi.org/10.1038/s41598-021-85650-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973531PMC
March 2021

Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial.

Eur J Heart Fail 2021 Feb 23. Epub 2021 Feb 23.

BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK.

Aims: Nitroxyl provokes vasodilatation and inotropic and lusitropic effects in animals via post-translational modification of thiols. We aimed to compare effects of the nitroxyl donor cimlanod (BMS-986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF).

Methods And Results: In a randomized, multicentre, double-blind, crossover trial, 45 patients with stable HFrEF were given a 5 h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index derived from the left ventricular outflow tract at the end of each infusion period. Stroke volume index with placebo was 30 ± 7 mL/m and was lower with cimlanod (29 ± 9 mL/m ; P = 0.03) and NTG (28 ± 8 mL/m ; P = 0.02). Transmitral E-wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e' (P = 0.006) and E/A ratio (P = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo.

Conclusion: In patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure.
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http://dx.doi.org/10.1002/ejhf.2138DOI Listing
February 2021

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting October 2019: Impending Change, Innovation, and Future Challenges.

Front Pharmacol 2020 19;11:580560. Epub 2020 Nov 19.

Niche Science & Technology Ltd., Richmond, United Kingdom.

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on impending change, innovation, and future challenges facing early phase drug development as we move into the second decade of the 21th century. The meeting opened with discussion around the technical revolution in pharmaceutical medicine over the 4 decades since the AHPPI was founded and how transformative technologies have accompanied the introduction of processes such as physiologically based pharmacokinetic modeling. During the meeting examples were presented of how in terms of the development of new therapies, the classic phases of clinical drug development are becoming a thing of the past and the lines between the phases have begun to blur, particularly in the field of oncology. The contribution that monoclonal antibodies have made to medicine and the next chapter in their design and use was also discussed. A representative of the UK's Medicine and Healthcare Products Regulatory Agency discussed the increasing numbers of requests to approve complex innovative design trials, how novel trial designs are impacting on the traditional linear "phase" approach to drug development and the common pitfalls associated with them. Guidance was provided from a regulator's viewpoint on what was meant by the term "novel design" and how to submit successful trial applications for such complex trials. In an Oxford-style debate, the audience discussed the motion that "there is no longer a need to include placebo subjects in early clinical trials." The keynote speaker focused on delivering change in complex environments such as the field of drug development. The afternoon session included presentations on the challenges associated with drug product design, the complexities within non-oral dosage forms and proposed new methods of formulations for drug delivery. Presentations were also given on advances in mechanistic and computational pharmacokinetic modeling and how they have proved to be valuable tools to rationalize and facilitate the process of drug development.
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http://dx.doi.org/10.3389/fphar.2020.580560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751735PMC
November 2020

Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study.

Eur Heart J 2021 01;42(2):178-188

Cardior Pharmaceuticals GmbH, Hannover Medical School Campus, Feodor-Lynen-Straße 15, Hannover 30625, Germany.

Aims: Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405).

Methods And Results: Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers.

Conclusion: This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF.
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http://dx.doi.org/10.1093/eurheartj/ehaa898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954267PMC
January 2021

Safety, Tolerability, and Dose Proportionality of a Novel Transdermal Fentanyl Matrix Patch and Bioequivalence With a Matrix Fentanyl Patch: Two Phase 1 Single-Center Open-Label, Randomized Crossover Studies in Healthy Japanese Volunteers.

Clin Pharmacol Drug Dev 2021 Mar 3;10(3):260-271. Epub 2020 Aug 3.

Richmond Pharmacology Ltd., St George's University London, London, UK.

Two open-label, single-dose, randomized crossover studies were conducted in healthy Japanesemen to (1) assess dose proportionality of 5 doses (1.38, 2.75, 5.5, 8.25, and 11.0 mg) of Lafenta, a novel matrix-type transdermal fentanyl patch with a rate-controlling membrane; and (2) compare patch bioequivalence (11.0 mg) with a commercially available reference patch (Durotep MT Patch [16.8 mg]). Pharmacokinetics, adhesion performance, residual fentanyl, and safety parameters were assessed. Increases in mean AUC and C after application of the test patch were dose proportional. The test patch (11.0 mg) was bioequivalent to the 16.8-mg reference patch in terms of mean AUC , AUC , and C . Residual fentanyl levels 72 hours postapplication were lower in the test than in the reference patch. Differences in adhesion performance between the test and the reference patch did not affect delivery efficacy and reliability of the novel matrix patch. Safety findings were in line with previous experiences with fentanyl. Both studies showed low variation in fentanyl exposure and delivery via the test patch. The test patch provided equivalent fentanyl exposure at a lower dose than the reference patch formulation with lower variability and the potential to lower medicinal waste.
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http://dx.doi.org/10.1002/cpdd.846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984375PMC
March 2021

Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials.

Front Pharmacol 2020 13;11:314. Epub 2020 Mar 13.

Richmond Pharmacology, London, United Kingdom.

Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials could call into question the validity of a trial's findings or limit its scientific applications and ability to accurately observe drug effects upon WBC parameters. This study pools data from multiple phase I trials, assesses the effects of race and time of day on WBC count, and compares it to the existing literature to establish race and time-specific RIs. A total 13,332 venous blood samples obtained from 7,157 healthy male and female volunteers at the time of screening or admission (predosing) who took part in 35 phase I trials over a period of seven years were pooled and the data were analyzed using generalised estimating equation models. Adjusted RI of total WBC count and its individual parameters were then calculated according to time of day (morning vs. evening) for both black and nonblack populations. This study indicates that black individuals on average had lower total WBC, neutrophil, monocyte, eosinophil, and basophil counts than individuals from nonblack racial groups. Black volunteers had higher mean lymphocyte counts relative to their nonblack counterparts. These differences were deemed statistically significant. Statistically significant increases in total WBC, neutrophil, lymphocyte, and monocyte counts were also observed over the course of daily sampling. Eosinophil counts decreased during this time period, but this finding was only statistically significant in the nonblack population. Despite an observed mild diurnal increase in basophil count in both populations, this was not considered statistically significant. This high-powered study adds significant weight to the known evidence for diurnal and racial variation in WBC parameters. Importantly, it proposes specific RIs that more precisely reflect race and time of day. These could ensure increased participation of black volunteers in clinical trials for improved population representation. Furthermore, the proposed RIs allow for more accurate postdose safety monitoring and reporting, and ensure improved monitoring of postdose WBC count changes.
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http://dx.doi.org/10.3389/fphar.2020.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082321PMC
March 2020

Efficient Design of Integrated and Adaptively Interlinked Protocols for Early-Phase Drug Development Programs.

Ther Innov Regul Sci 2020 01 6;54(1):184-194. Epub 2020 Jan 6.

Richmond Pharmacology Ltd, St Georges University of London, SW17 0RE, London, United Kingdom.

Background: Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design and implementation of trial protocols. Previously published work by the authors include a retrospective analysis of time savings using adaptive design and a systematic, 3- step methodology for writing early-phase adaptive integrated protocols.

Methods: This article builds on the authors' published work demonstrating the practical implementation of the adaptive protocol writing methodology and discussing the challenges and efficiencies. It describes the integration of an early development program of OBE022, a novel, oral, selective prostaglandin F2a receptor antagonist, intended as a treatment for preterm labor, using 2 interdependent, adaptive trial protocols. The program consisted of first-in-human single and multiple ascending dose parts with assessments of food effect, cardiac safety, proof of concept, and interactions of OBE022 with 4 standard of care medicines.

Results: The manuscript shows how the trials were tailored to OBE022's pharmacokinetic and pharmacodynamic characteristics and its therapeutic indication. The use of 2 large interdependent, adaptive protocols was facilitated by the United Kingdom's (UK's) regulatory environment and its acceptance of a rules-guided progression through the program. Changes to the planned trial conduct could be made without impacting on timelines, because they used predefined adaptive options within their authorized boundaries, and could therefore be made as nonsubstantial amendments. The program was successful and achieved its objectives. It was efficient and fast: it required a small number of participants (n=83) and completed from start of protocol writing to first draft of the clinical study report in just 11 months.

Conclusions: This program included all key elements of early drug development in 2 interlinked protocols: the assessment of single and multiple ascending doses, food effect, cardiac safety and proof of concept. The approach described in this article demonstrates how early-phase programs can be designed to be performed, analyzed and reported time- and cost-efficiently.
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http://dx.doi.org/10.1007/s43441-019-00044-yDOI Listing
January 2020

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone.

Br J Clin Pharmacol 2019 07 11;85(7):1516-1527. Epub 2019 May 11.

Richmond Pharmacology, St. George's University London, UK.

Aims: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development.

Methods: Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13).

Results: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [C ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (C  + 18%, AUC +27%) and OBE002 exposure (C  + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (C  + 29%, AUC +24%) and markedly increased nifedipine exposure (C by 2-fold and AUC by 2-fold), which may be clinically significant.

Conclusions: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.
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http://dx.doi.org/10.1111/bcp.13925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595366PMC
July 2019

The Cardiovascular Effects of a Meal: J-T and T -T Assessment and Further Insights Into the Physiological Effects.

J Clin Pharmacol 2019 06 11;59(6):799-810. Epub 2019 Jan 11.

Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.

Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-T , and T -T intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-T and T -T intervals. Our findings demonstrate that a standardized meal significantly shortened J-T for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the T -T and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on T -T beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca currents. An effect on mainly Ca aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction.
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http://dx.doi.org/10.1002/jcph.1374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590239PMC
June 2019

Practical risk management in early phase clinical trials.

Eur J Clin Pharmacol 2019 Apr 19;75(4):483-496. Epub 2018 Dec 19.

Richmond Pharmacology, St George's University, Cranmer Terrace, London, SW17 0RE, UK.

Purpose: Stopping rules are an essential part of risk management in early phase clinical trials. As well as being necessary for ensuring the safety of participants on clinical trials, they are also a requirement under the revision to the European Medicine Agency's first-in-human and early clinical trial guideline. The increasing complexity and size of modern trial designs (e.g. integrated trials) raise potential issues with risk management, which, if also too complex, presents challenges for both regulators and investigators to implement. Therefore, there is a clear need for a standard, template, or algorithm-based approach to risk management, in particular rules concerning adverse reactions. The purpose of this manuscript is to present template stopping (or adverse reaction, AR) rules that fulfil regulatory requirements and that can be adapted, taking into account trial design, nature of the investigational medicinal product, and anticipated effects.

Methods: The template AR rules that use a systematic, objective and consistent process were developed, taking into account severity (using an objective grading system), seriousness, frequency and reversibility of ARs. These rules control decisions relating to individual trial participants, dosing regimens and dose escalation and/or progression to successive trial parts. For ease of use, the template rules consist of a single, one-page table.

Results: The template AR rules have been successfully applied to many early phase adaptive integrated trials that received regulatory authorisation and were performed in the UK. This manuscript presents the template rule table and case studies of some trial-specific adaptations.

Conclusions: This work demonstrates how a systematic, objective and consistent approach to risk management of large integrated trials can be simple yet robust, facilitating effective decision making and trial progression whilst safeguarding participant safety.
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http://dx.doi.org/10.1007/s00228-018-02607-8DOI Listing
April 2019

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting 2018: Brexit and Other Challenges in Early Phase Drug Development.

Front Pharmacol 2018 19;9:1301. Epub 2018 Nov 19.

Niche Science & Technology Ltd., Richmond, United Kingdom.

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on the changing face of early phase drug development and opened with a keynote speech concerning the revolution in pharmaceutical medicine over the last 30 years and the impact this has had on the way patients are treated. Examples were presented of how translational pharmaceutics is being used to tackle the high drug candidate failure rate and is improving productivity when moving drug candidates from the laboratory through to clinical proof of concept. The European Medicines Agency revised 2007 Risk Mitigation guideline on first in human (FIH) clinical trials was discussed. The focus of the revised guideline, which came into force in February 2018, is on risk mitigation and promotion of safety and will assist drug sponsors with the design and performance of early clinical studies. The use of integrated adaptive protocol designs in early clinical development was discussed in relation to the challenges involved when running early phase clinical trials in patients. The Health Regulatory Authority presented its strategies to ensure that following Brexit, the United Kingdom remains an attractive place to conduct Phase I clinical trials. The Medicines and Healthcare products Regulatory Agency confirmed that in the event of a "no deal" Brexit, it is well placed to implement and influence many provisions of the new EU CTR. The meeting provided an opportunity to discuss the changing regulatory environment and the opportunities and challenges facing the United Kingdom following Brexit with invited speakers from a range of disciplines including drug development, clinical trials and research organizations, government science policy and regulatory agencies.
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http://dx.doi.org/10.3389/fphar.2018.01301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252346PMC
November 2018

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration.

J Clin Pharmacol 2019 01 24;59(1):35-44. Epub 2018 Jul 24.

Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects.
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http://dx.doi.org/10.1002/jcph.1283DOI Listing
January 2019

Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first-in-human trial in healthy postmenopausal women.

Br J Clin Pharmacol 2018 08 5;84(8):1839-1855. Epub 2018 Jun 5.

Richmond Pharmacology Ltd., St George's University of London, London, UK.

Aims: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F receptor antagonists under development for treating preterm labour.

Methods: We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day ; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated.

Results: Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half-life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22-29 h after multiple doses.

Conclusions: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients.
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http://dx.doi.org/10.1111/bcp.13622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046484PMC
August 2018

Confirmation of the Cardiac Safety of PGF Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments.

Clin Pharmacol Drug Dev 2018 11 28;7(8):889-900. Epub 2018 Feb 28.

ObsEva SA, Geneva, Switzerland.

OBE022, a new orally active prostaglandin F  receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean C  for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.
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http://dx.doi.org/10.1002/cpdd.447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221050PMC
November 2018

Efficacy and Safety of MED2005, a Topical Glyceryl Trinitrate Formulation, in the Treatment of Erectile Dysfunction: A Randomized Crossover Study.

J Sex Med 2018 02 3;15(2):167-175. Epub 2018 Jan 3.

Futura Medical Developments plc, Guildford, UK.

Background: Current treatments for erectile dysfunction (ED) have some limitations.

Aim: This study evaluated the efficacy and tolerability of MED2005, a 0.2% glyceryl trinitrate topical gel, formulated into an enhanced absorption topical delivery system (DermaSys), administered on demand, in the treatment of ED.

Methods: This randomized, double-blinded, placebo-controlled, phase II crossover trial involved 232 men with ED (231 treated, 230 assessed for efficacy) and their partners. After a 4-week run-in period, patients were randomized to 1 of 2 treatment sequences, MED2005-placebo or placebo-MED2005. Each treatment was given for 4 weeks, separated by a 1-week washout interval. Efficacy was assessed by the International Index of Erectile Function (IIEF), the Sexual Encounter Profile, a Global Assessment Questionnaire (GAQ), and specific questions about the onset and offset of action and treatment preferences (patients and partners).

Outcomes: The primary outcome measure was the IIEF erectile function domain (IIEF-EF) score. Other efficacy assessments were secondary outcomes.

Results: The mean baseline IIEF-EF score was 17.1 (SD = 5.7), and this increased to 19.6 (SD = 7.5) after MED2005 treatment and 18.5 (SD = 6.7) after placebo (P = .0132). Overall, 23.1% of patients showed a clinically relevant (≥4-point) increase in IIEF-EF scores after treatment with MED2005 only compared with 14.5% who responded after MED2005 and placebo, 14.0% who responded after placebo only, and 48.4% who did not respond after either treatment (P = .0272). MED2005 also was associated with significant improvements compared with placebo in the other IIEF domains, and this was consistent with patients' and partners' responses to the GAQ. For all assessments, significant effects of MED2005 were seen primarily in patients with mild ED. The start of erection was noticed within 5 and 10 minutes in 44.2% and 69.5%, respectively, of all intercourse attempts with MED2005. Patients and partners showed significant preferences for MED2005 over placebo. The most commonly reported adverse events during MED2005 treatment were headache (patients, n = 18 [7.9%]; partners, n = 3 [1.3%]) and nasopharyngitis (patients, n = 13 [5.7%]; partners, n = 2 [0.9%]).

Clinical Implications: These findings suggest that topical glyceryl trinitrate could be a useful treatment option in ED.

Strengths And Limitations: Strengths of this study include the use of a validated outcome measure. Limitations include the use of only 1 dosage.

Conclusion: Further studies are warranted to investigate the efficacy of topical glyceryl trinitrate to include higher doses, thereby improving clinical significance, especially in cases of moderate and severe ED. Ralph DJ, Eardley I, Taubel J, et al. Efficacy and Safety of MED2005, a Topical Glyceryl Trinitrate Formulation, in the Treatment of Erectile Dysfunction: A Randomized Crossover Study. J Sex Med 2018;15:167-175.
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http://dx.doi.org/10.1016/j.jsxm.2017.12.003DOI Listing
February 2018

Estimation of the Power of the Food Effect on QTc to Show Assay Sensitivity.

J Clin Pharmacol 2018 Jan 17;58(1):81-88. Epub 2017 Aug 17.

Richmond Pharmacology Ltd, London, UK.

The most recent International Conference on Harmonisation E14 Q&A document states that a separate positive control would not be necessary provided sufficiently high exposures are achieved in the early-phase studies. Realistically, a phase 1 study is unlikely to include a pharmacological positive control, and in cases in which plasma levels of the drug exceeding therapeutic levels are not achieved, the lack of a positive control can constitute a limitation when excluding an effect of regulatory concern. It has been proposed to use the effect of a standardized meal on the estimate of the diurnal time course of QTc to show assay sensitivity. We conducted simulations by subsampling subjects from a 3 different studies and could show that the effect on food on QTc can be reliably prove assay sensitivity for sample sizes as low as 3 × 6 subjects with a power greater than 80%.
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http://dx.doi.org/10.1002/jcph.975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763401PMC
January 2018

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9.

N Engl J Med 2017 01 13;376(1):41-51. Epub 2016 Nov 13.

From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).

Background: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.

Methods: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.

Results: The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).

Conclusions: In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442 .).
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http://dx.doi.org/10.1056/NEJMoa1609243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778873PMC
January 2017

Comparison of Digital 12-Lead ECG and Digital 12-Lead Holter ECG Recordings in Healthy Male Subjects: Results from a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

Ann Noninvasive Electrocardiol 2016 Nov 28;21(6):588-594. Epub 2016 Mar 28.

Richmond Pharmacology, St. George's University of London, London, United Kingdom.

Background: Electrocardiogram (ECG) variability is greatly affected by the ECG recording method. This study aims to compare Holter and standard ECG recording methods in terms of central locations and variations of ECG data.

Methods: We used the ECG data from a double-blinded, placebo-controlled, randomized clinical trial and used a mixed model approach to assess the agreement between two methods in central locations and variations of eight ECG parameters (Heart Rate, PR, QRS, QT, RR, QTcB, QTcF, and QTcI intervals).

Results: A total of 34 heathy male subjects with mean age of 25.7 ± 4.78 years were randomized to receive either active drug or placebo. Digital 12-lead ECG and digital 12-lead Holter ECG recordings were performed to assess ECG variability. There are no significant differences in least square mean between the Holter and the standard method for all ECG parameters. The total variance is consistently higher for the Holter method than the standard method for all ECG parameters except for QRS. The intraclass correlation coefficient (ICC) values for the Holter method are consistently lower than those for the standard method for all ECG parameters except for QRS, in particular, the ICC for QTcF is reduced from 0.86 for the standard method to 0.67 for the Holter method.

Conclusions: This study suggests that Holter ECGs recorded in a controlled environment are not significantly different but more variable than those from the standard method.
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http://dx.doi.org/10.1111/anec.12363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931472PMC
November 2016

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.

Br J Clin Pharmacol 2017 02 21;83(2):339-348. Epub 2016 Oct 21.

Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.

Aim: The D /D antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT).

Methods: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period.

Results: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5).

Conclusions: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.
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http://dx.doi.org/10.1111/bcp.13128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237697PMC
February 2017

Pharmacokinetics, Safety and Cognitive Function Profile of Rupatadine 10, 20 and 40 mg in Healthy Japanese Subjects: A Randomised Placebo-Controlled Trial.

PLoS One 2016 15;11(9):e0163020. Epub 2016 Sep 15.

J. Uriach y Compañía, S.A., Avda. Camí Reial, Barcelona, Spain.

Introduction: Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine in healthy Japanese subjects after single and multiple oral doses.

Methods: In this randomised, double-blind, placebo-controlled study, 27 male and female healthy Japanese subjects were administered single and multiple escalating rupatadine dose of 10, 20 and 40 mg or placebo. Blood samples were collected at different time points for PK measurements and subjects were assessed for safety and tolerability. The effect of rupatadine on cognitive functioning was evaluated by means of computerized cognitive tests: rapid visual information processing (RVP), reaction time (RT), spatial working memory (SWM) and visual analogue scales (VAS).

Results: Exposure to rupatadine as measured by Cmax and AUC was found to increase in a dose dependent manner over the dose range of 10-40 mg for both single and multiple dose administration. The safety assessments showed that all treatment related side effects were of mild intensity and there were no serious adverse events (SAEs) or withdrawals due to treatment-emergent adverse events (TEAEs) in this study. The therapeutic dose of rupatadine did not show any CNS impairment in any of the cognitive tests.

Conclusions: This study demonstrated that rupatadine is safe and well tolerated by Japanese healthy subjects. The PK-PD profile confirmed previous experience with rupatadine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163020PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025135PMC
August 2017

Stability of the Effect of a Standardized Meal on QTc.

Ann Noninvasive Electrocardiol 2017 Jan 28;22(1). Epub 2016 May 28.

Statistik Georg Ferber GmbH, Riehen, Switzerland.

Background: The assessment of QTc changes after the intake of a standardized meal has been proposed as an alternative approach to prove assay sensitivity when the proarrhythimic potential of a drug is to be excluded in either TQT or intensive Phase I QT studies.

Methods: In this article, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method.

Results: The results show that the time-effect attributed to food is stable over different study periods demonstrating consistency of the physiological response triggered by food.

Conclusions: Stability and reproducibility of the effect is comparable with moxifloxacin.
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http://dx.doi.org/10.1111/anec.12371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931674PMC
January 2017

Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects.

J Atheroscler Thromb 2016 May 18;23(5):606-20. Epub 2015 Dec 18.

Richmond Pharmacology Limited, Cranmer Terrace, Tooting.

Aims: Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolaemia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Caucasian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses.

Methods: In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥110 mg/dL were administered an escalating lomitapide dose range of 10-60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels.

Results: Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10-60 mg for both single- and multiple-dose administration. The correlation between AUC0-t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomitapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders.

Conclusions: Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.
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http://dx.doi.org/10.5551/jat.30452DOI Listing
May 2016

The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study.

Biomed Res Int 2015 5;2015:293564. Epub 2015 Oct 5.

Richmond Pharmacology Ltd., St George's, University of London, Cranmer Terrace, London SW17 0RE, UK ; Cardiovascular and Cell Sciences Research Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.

Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around t max are missed.
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http://dx.doi.org/10.1155/2015/293564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609768PMC
September 2016

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

PLoS One 2015 20;10(8):e0136369. Epub 2015 Aug 20.

Cardiovascular and Cell Sciences Research Institute, St George's University of London, Cranmer Terrace, London, United Kingdom.

Background: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.

Methods: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).

Results: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.

Conclusion: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.

Trial Registration: EU Clinical Trials Register EudraCT 2010 020343 13.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136369PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546378PMC
May 2016

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Rising TAK-438 (Vonoprazan) Doses in Healthy Male Japanese/non-Japanese Subjects.

Clin Transl Gastroenterol 2015 Jun 25;6:e94. Epub 2015 Jun 25.

1] Richmond Pharmacology Ltd, London, UK [2] St George's University of London, London, UK.

Objectives: To evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 (vonoprazan, a potassium-competitive acid blocker) in healthy male subjects.

Methods: In two phase I, randomized, double-blind, placebo-controlled, single rising-dose studies, healthy male subjects (Japan N=84; UK N=63) received a single TAK-438 dose (1-120 mg in Japan and 1-40 mg in the UK). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (intragastric pH).

Results: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax up to 2 h). Estimated mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional. No clear difference in TAK-438 pharmacokinetics was observed between Japanese and non-Japanese subjects. Acid suppression was dose dependent and similar in both studies. The 24-h intragastric pH ≥4 holding time ratio with 40 mg TAK-438 was 92% in Japan and 87% in the UK. TAK-438 was well tolerated, with no adverse events reported in Japanese subjects; 10 of 63 UK subjects experienced 12 treatment-emergent adverse events (non-serious). Increases in serum gastrin and pepsinogen I and II concentrations were observed at doses ≥10 mg, but there were no changes in alanine aminotransferase concentrations.

Conclusions: Single oral doses of TAK-438 20-120 mg caused rapid, profound, and 24-h suppression of gastric acid secretion in healthy male subjects, regardless of geographical region, and TAK-438 was well tolerated at all doses studied, making it a potential alternative to proton pump inhibitors for the treatment of acid-related disorders.
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http://dx.doi.org/10.1038/ctg.2015.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816246PMC
June 2015

The reproducibility of QTc changes after meal intake.

J Electrocardiol 2015 Mar-Apr;48(2):274-5. Epub 2014 Nov 15.

Statistik Georg Ferber GmbH, Cagliostrostrasse 14, 4125 Riehen, Switzerland.

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http://dx.doi.org/10.1016/j.jelectrocard.2014.11.006DOI Listing
October 2015

Three steps to writing adaptive study protocols in the early phase clinical development of new medicines.

BMC Med Res Methodol 2014 Jun 30;14:84. Epub 2014 Jun 30.

Richmond Pharmacology Ltd, St, George's University of London, Cranmer Terrace, London, UK.

This article attempts to define terminology and to describe a process for writing adaptive, early phase study protocols which are transparent, self-intuitive and uniform. It provides a step by step guide, giving templates from projects which received regulatory authorisation and were successfully performed in the UK. During adaptive studies evolving data is used to modify the trial design and conduct within the protocol-defined remit. Adaptations within that remit are documented using non-substantial protocol amendments which do not require regulatory or ethical review. This concept is efficient in gathering relevant data in exploratory early phase studies, ethical and time- and cost-effective.
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http://dx.doi.org/10.1186/1471-2288-14-84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096541PMC
June 2014

Concentration-effect modeling based on change from baseline to assess the prolonging effect of drugs on QTc together with an estimate of the circadian time course.

J Clin Pharmacol 2014 Dec 27;54(12):1400-6. Epub 2014 Jun 27.

Statistik Georg Ferber GmbH, Cagliostrostrasse 14, Riehen, Switzerland.

As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time-matched difference between (baseline corrected) QTcF or QTcI under the supra-therapeutic dose and placebo. A study is considered negative, if the two-sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration-response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo-corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration-response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect.
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http://dx.doi.org/10.1002/jcph.347DOI Listing
December 2014