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.

A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial.

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281 .

Safety and Outcomes in Infants Born to Mothers Participating in Retosiban Treatment Trials: ARIOS Follow-up Study.

OBJECTIVE: Retosiban, an oxytocin receptor antagonist, was developed for treating spontaneous preterm labor (sPTL) in women with intact membranes. This ARIOS follow-up study aimed to characterize clinical safety, morbidity, and mortality of infants exposed to retosiban or comparator over 2 years. STUDY DESIGN: ARIOS prospectively assessed outcomes in infants whose mothers received at least one dose of retosiban or comparator (placebo/atosiban) in two Phase 3 sPTL trials. Both trials were terminated prematurely owing to poor enrolment. Infants could be enrolled into ARIOS from 28 days after estimated due date until hospital discharge or up to 9 months (corrected age). An internally developed questionnaire detailing medical conditions, mortality and resource use (Child Health Inventory; CHI), Ages and Stages Questionnaire-3 (ASQ-3), Modified Checklist for Autism in Toddlers-Revised with Follow-Up, and Child Behavior Checklist for Ages 1.5 to 5 were completed remotely by parents or legal guardians at prespecified intervals. Serious adverse events (SAEs) were primarily captured via CHI. No comparative statistical analysis was conducted between treatment arms. RESULTS: A total of 49 (86%) infants who had received retosiban and 49 (78%) infants who had received a comparator were enrolled in ARIOS. No deaths occurred during the study. Nine infants experienced SAEs: 6/49 (12.2%) infants in the comparators group and 3/49 (6.1%) in the retosiban group. Of the nine SAEs, seven were due to infections, three, and four in the retosiban and comparators groups, respectively. Based on ASQ-3 score, the incidence of neurodevelopmental delay at 18 and 24 months were 0/18 (0%) and 2/25 (8%) with retosiban and 7/22 (31.8%) and 3/21 (14.3%) with comparator, respectively. CONCLUSION: The current study showed no unexpected adverse outcome or impairment with retosiban based on safety monitoring and neurodevelopment assessments. No further follow-up is intended owing to the discontinuation of clinical development of retosiban. KEY POINTS: · There is a need for an effective and safe treatment for sPTL.. · ARIOS was a follow-up study of two Phase 3 trials in sPTL.. · There were no safety concerns with retosiban treatment.. · Slow recruitment led to termination of the Phase 3 trials..

Clinical pharmacology of albiglutide, a GLP-1 receptor agonist.

UNLABELLED: Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7-36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, ß-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; α-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials. TRIAL REGISTRATION: NCT00938158, NCT01406262, NCT00537719, NCT01077505, NCT01147731, NCT01147718, NCT01147692, NCT00354536, NCT00394030, NCT00530309, NCT01357889, NCT00518115, NCT01098461, NCT01475734, NCT00849017, NCT00838916, NCT00839527, NCT01098539.

Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.

OBJECTIVE: To evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and/or oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: In this phase III, randomized, double-blind, multicenter, 52-week study, the primary study end point was HbA1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and categorized as mild, moderate, or severe (≥60 to ≤89, ≥30 to ≤59, and ≥15 to ≤29 mL/min/1.73 m(2), respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety. RESULTS: Baseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m(2), HbA1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (-0.83% vs. -0.52%, P = 0.0003). Decreases in HbA1c, FPG, and weight were seen through week 52. Time to hyperglycemic rescue through week 52 was significantly longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments were similar between groups, and most adverse events (AEs) were mild or moderate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and vomiting, 1.6%, 1.2%, respectively. CONCLUSIONS: Once-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy.

Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study.

BACKGROUND: As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs. METHODS: We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894. FINDINGS: 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0·78% (95% CI -0·87 to -0·69) in the albigludite group and -0·99% (-1·08 to -0·90) in the liraglutide group; treatment difference was 0·21% (0·08-0·34; non-inferiority p value=0·0846). Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide (12·9% vs 5·4%; treatment difference 7·5% [95% CI 3·6-11·4]; p=0·0002), whereas the opposite was the case for gastrointestinal events, which occurred in 49·0% of patients in the liraglutide group versus 35·9% in the albiglutide group (treatment difference -13·1% [95% CI -19·9 to -6·4]; p=0·00013). INTERPRETATION: Patients who received once-daily liraglutide had greater reductions in HbA1c than did those who received once-weekly albiglutide. Participants in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than did those in the liraglutide group. FUNDING: GlaxoSmithKline.

Helping the clinician help me: towards listening in cancer care.

Despite global support for the ideal of shared decision making, its enactment remains difficult in practice. The UK charity, Macmillan Cancer Support, attempted to incorporate the principles of shared decision making within a programme of distress management in Scotland. Distress management begins by completing the Distress Thermometer (DT). Although the DT is a screening tool, its function in this programme was extended to facilitate collaborative communication within a consultation. The aim of this grounded theory was to analyse the patient experience of the process. Nineteen people underwent semi-structured interviews focused on their experience of distress management. Participants were a mixed-cancer cohort aged 40-79 years. Findings were discussed in a structured manner with a further 14 service users and carers, and 19 clinical specialists in cancer. Constant comparison of all data revealed that the process of positive distress management could best be explained by reference to the core category: 'helping the clinician help me'. The emergence of this core category is detailed by situating its development within the iterative nature of the grounded theory method.

Effects of multiple doses of albiglutide on the pharmacokinetics, pharmacodynamics, and safety of digoxin, warfarin, or a low-dose oral contraceptive.

AIMS: Albiglutide is a glucagon-like peptide-1 analog that is currently under investigation for the treatment of type 2 diabetes mellitus as a once-weekly injection. Three open-label phase 1 studies were conducted in healthy human participants to investigate potential pharmacokinetic (PK) and/or pharmacodynamic (PD) interactions between albiglutide and medications that may be used concomitantly. METHODS: Digoxin 0.5 mg, warfarin 25 mg, or a standard, low-dose oral contraceptive containing norethindrone (NE) 0.5 mg and ethinyl estradiol (EE) 0.035 mg were administered alone and after steady-state albiglutide exposure (50 mg weekly for 4-5 weeks). The lack of a drug-drug interaction was concluded if the 90% CIs of geometric least-squares means ratio of area under the curve and maximum concentration were fully contained within 0.80 to 1.25. The effects of albiglutide on the PD of warfarin (international normalized ratio) and on the PD of a low-dose oral contraceptive (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and progesterone) were assessed. Safety and tolerability were also assessed. RESULTS: Overall, the PK profiles of digoxin, warfarin, NE, and EE were unaffected by albiglutide administration; standard bioequivalence criteria were met with a few exceptions that were not considered clinically relevant. Warfarin international normalized ratio was unaffected by albiglutide administration. No clinically meaningful differences in LH, FSH, or progesterone were observed. Most treatment-emergent adverse events were mild, and all resolved by study end. CONCLUSION: Based on tolerability and the lack of clinically significant PK or PD interactions, no dose adjustments should be required when albiglutide is administered concomitantly with these medications.

The clinical utility of the distress thermometer: a review.

The Distress Thermometer (DT) is a well validated screening tool, demonstrably sensitive and reasonably specific to the construct of distress in cancer. Its brevity makes it ideal to incorporate into a system of distress management. To ascertain how far this idea has been developed in practice, and to support future research, a literature review was undertaken. Medline, CINAHL, PsycINFO, Embase, ASSIA, British Nursing Index, AMED, CCTR, and HMIC were systematically searched. Forty studies were reviewed that examined the function of the DT alone, together with the problem list (PL), and/or other validated measures. The majority of studies validated the DT against other robust measures of distress in order to establish 'caseness' in these populations, and establish factors associated with distress. Many of the studies recommended that further research should test their findings in clinical practice. A small section of the literature focused on the clinical utility of the DT as a facilitator of consultations, and found it to have potential in this regard. It is concluded that there is enough validation research, and in line with the majority of these studies' recommendations, future research should focus on the utility of DT as part of a structured distress management programme.