The Africa non-communicable diseases (NCD) Open Lab: Impact of a portfolio of clinical studies to deepen the understanding of NCDs in sub-Saharan Africa.

Background: Clinical research in sub-Saharan Africa (SSA) has often focussed on communicable diseases. However, with the increasing burden of non-communicable diseases (NCDs), there is a need for Africa-specific NCD research. Methods: GSK established the Africa NCD Open Lab in 2014. Three calls for proposals were advertised through various media channels. An external independent scientific advisory board, predominantly representing African scientists and NCD experts, reviewed and selected projects to receive funding. An additional programme in the Africa NCD Open Lab was designed to build statistical capability by supporting training initiatives. We assessed the impact of the Africa NCD Open Lab in three ways: scientific quality with impact; research training and professional development; and research environments. We captured metrics through regular reports/interactions with researchers; via a final report; and through exit interviews with principal investigators. Results: Twenty projects in 11 African countries were funded; reports from 18 completed projects are available (data capture is ongoing). Overall, 139 articles have been published in peer-reviewed journals and other data have been presented at conferences and other forums. Most completed projects led to positive outcomes, such as further research, informing policy, or positively impacting clinical care, including three projects that saw changes to regional or national practice guidelines: the CREOLE study in Nigeria; the African Severe Asthma Program in Uganda; and the African Prospective Study on the Early Detection and Identification of Cardiovascular Disease and Hypertension in South Africa. Participation in the Africa NCD Open Lab led to the award of 34 grants related to or influenced by increased research capacity or experience. Significant professional development related to the projects also occurred with higher-level degrees being awarded, including 30 MScs, 30 PhDs, and nine postdoctoral fellowships. Through these projects, research capacity was strengthened across the region by equipping core research facilities, training research staff, strengthening research support services, and supporting the expansion of investigator networks. Conclusions: The completed Africa NCD Open Lab projects demonstrate high-quality research outcomes addressing important health challenges with potential benefits to African populations. Based on the success of the Africa NCD Open Lab, additional funding has been secured to extend the Open Lab initiative.

First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.

Academia and industry agreement on a feasibility tool for first-time-in-human clinical trial units.

First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working.

A randomized, fixed-dose, dose-response study of ropinirole prolonged release in advanced Parkinson's disease.

AIM: This Phase IV, double-blind, randomized, parallel-group study characterized the dose-response and tolerability of fixed doses of ropinirole prolonged release (PR) in subjects with advanced Parkinson's disease. PATIENTS & METHODS: Subjects receiving concomitant l-dopa received once-daily ropinirole PR 4, 8, 12, 16 or 24 mg, or placebo, up-titrated for 13 weeks, maintained for 4 weeks. RESULTS: At maintenance period week 4, ropinirole PR significantly reduced total awake 'Off-time' (16 mg; p = 0.027); increased absolute awake time spent 'On' without troublesome dyskinesia from baseline versus placebo (8 mg; p = 0.036); improved Unified Parkinson's Disease Rating Scale motor scores versus placebo (all doses; p = 0.005-0.016). Incidence of adverse events was similar between treatment groups; no dose-related trends were observed. CONCLUSION: Ropinirole PR (16 mg) reduced 'Off-time' with 8 mg the likely lowest maximally effective dose, and the safety profile was consistent with previous studies.

Human Kinetic Modeling of the 5HT6 PET Radioligand 11C-GSK215083 and Its Utility for Determining Occupancy at Both 5HT6 and 5HT2A Receptors by SB742457 as a Potential Therapeutic Mechanism of Action in Alzheimer Disease.

UNLABELLED: Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d). METHODS: In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457. RESULTS: Kinetic analysis of (11)C-GSK215083 uptake in the human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacologic dissection of the in vivo (11)C-GSK215083-specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457 but not by the selective 5-hydroxytryptamine-2A (5HT2A) antagonist ketanserin) and the 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15, and 35 mg/d) saturated the 5HT6 receptors at all doses. In the cortex, 5HT2A receptor occupancy was 24% ± 6% (3 mg/d), 35% ± 4% (15 mg/d), and 58% ± 19% (35 mg/d; mean ± SD), suggesting a progressive engagement of 5HT2A as the dose increased. CONCLUSION: Collectively, these data support the use of (11)C-GSK215083 as a 5HT6 clinical imaging tool and suggest that blocking both the 5HT6 and the 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD.

Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.

PURPOSE: Coadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tolerability. METHODS: This randomized, double-blind, 3-treatment crossover study included nonelderly, healthy male subjects. The study subjects received (in random order and with a minimum 7-day washout between treatments) the following: morphine placebo + GEn 600 mg; morphine 60 mg + GEn 600 mg; and morphine 60 mg + GEn placebo. Morphine/morphine placebo was administered in fasted conditions, and GEn/GEn placebo was administered 2 hours later with food. The primary end points were AUC and C(max) for gabapentin, morphine, and morphine-6-glucuronide. Pharmacodynamic measures were limited to subject assessment of somnolence, dizziness, and nausea conducted by using a visual analog scale (VAS). Safety monitoring included adverse event reporting, clinical laboratory tests, vital signs, pulse oximetry, and 12-lead ECGs. FINDINGS: Of the 18 enrolled subjects (mean age, 36 years), 15 (83%) completed the study. Sixteen received GEn, 15 received morphine, and 18 received the combination. Compared with the single treatments, the 90% CIs for the ratio of the geometric means for both AUC and C(max) were all within 0.8 to 1.25, the accepted range for bioequivalence. Ratios of geometric mean (90% CIs) values were as follows: gabapentin, AUC of 1.10 (1.035-1.162) and C(max) of 1.02 (0.920-1.126); morphine, AUC of 1.06 (1.014-1.098) and C(max) of 1.05 (0.967-1.134); and morphine-6-glucuronide, AUC of 0.992 (0.929-1.058) and C(max) of 0.953 (0.855-1.062). Mean changes from predose VAS scores were generally small and suggested a slight increase in dizziness after GEn and slight increases in dizziness, somnolence, and nausea after morphine. Trends were noted suggesting slightly greater score changes from predose with the combination treatment than with either drug given alone for somnolence and dizziness. Adverse events were generally mild; there were no serious adverse events or subject withdrawals due to adverse events. Headache and nausea were among the most commonly reported events for the combination and morphine treatments (headache, 27% and 28%; nausea, 13% and 11%, respectively). There were fewer adverse events with GEn alone than with either of the combination regimens. IMPLICATIONS: No significant pharmacokinetic interaction between the 2 drugs was seen in this study. The VAS data suggest that the potential exists for increased adverse effects when GEn and morphine are coadministered. ClinicalTrials.gov identifier: NCT01476124.

Cardiac repolarization with Gabapentin enacarbil in a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

BACKGROUND: Gabapentin enacarbil (GEn) is a prodrug of gabapentin and is approved in the United States in adults for the management of postherpetic neuralgia and in the United States and Japan for the treatment of moderate-to-severe primary restless legs syndrome. OBJECTIVE: This study examined the lack of effect of GEn on cardiac repolarization in accordance with International Conference on Harmonisation E14 guidance. METHODS: This was a randomized, double-blind, double-dummy, placebo- and active- controlled, crossover study in healthy adults (age range, 18-50 years). Study participants received the following in randomized order with a minimum 7-day washout period between treatments: placebo at 0 hours and GEn 1200 mg at 2 hours (GEn 1200 mg group), placebo at 0 hours and GEn 6000 mg at 2 hours (GEn 6000 mg group), placebo at 0 and 2 hours (placebo group), moxifloxacin 400 mg (active control group) at 0 hours, and placebo at 2 hours (moxifloxacin group). Dose offsetting permitted moxifloxacin to be administered in the fasted state and GEn to be administered in the fed state. Assessments included continuous ECG monitoring, pharmacokinetic parameters, and safety and tolerability profiles. The primary end point was the change from baseline in the Fridericia corrected QT interval, at each time point, for the GEn 6000 mg and placebo groups. RESULTS: Of 52 adults enrolled (mean [SD] age, 30.8 [8.55] years; 50% women), 44 adults (85%) completed the study. Forty-nine adults received GEn 1200 mg, 47 received GEn 6000 mg, 48 received placebo, and 47 received moxifloxacin. The highest estimated (upper limit of the 95% CI) model-adjusted difference in mean change from baseline in the Fridericia corrected QT interval between GEn and placebo was 3.55 (5.66) msec for 1200 mg and 1.20 (3.32) msec for 6000 mg. Assay sensitivity was confirmed with moxifloxacin 400 mg. The geometric mean (%CV) Cmax (between-subject coefficient of variation) was 7.49 (21.2) µg/mL for GEn 1200 mg, 32.46 (23.9) µg/mL for GEn 6000 mg, and 2.08 (24.5) µg/mL for moxifloxacin 400 mg. The most frequently reported adverse events with GEn 6000 mg were dizziness (30%), feeling drunk (26%), nausea (15%), headache (13%), and vomiting (13%). CONCLUSION: Single doses of GEn, up to 6000 mg, had no effect on cardiac repolarization in this thorough-QT study and are unlikely to cause clinically relevant QT prolongation in clinical use. Assay sensitivity was confirmed with moxifloxacin as an active control. ClinicalTrials.gov identifier: NCT01516372.