Sponsorship in non-commercial clinical trials: definitions, challenges and the role of Good Clinical Practices guidelines.

BACKGROUND: Non-commercial clinical research plays an increasingly essential role for global health. Multiple partners join in international consortia that operate under the limited timeframe of a specific funding period. One organisation (the sponsor) designs and carries out the trial in collaboration with research partners, and is ultimately responsible for the trial's scientific, ethical, regulatory and legal aspects, while another organization, generally in the North (the funder), provides the external funding and sets funding conditions. Even if external funding mechanisms are key for most non-commercial research, the dependence on an external funder's policies may heavily influence the choices of a sponsor. In addition, the competition for accessing the available external funds is great, and non-commercial sponsors may not be in a position to discuss or refuse standard conditions set by a funder. To see whether the current definitions adequately address the intricacies of sponsorship in externally-funded trials, we looked at how a "sponsor" of clinical trials is defined in selected international guidelines, with particular focus on international Good Clinical Practices codes, and in selected European and African regulations/legislations. DISCUSSION: Our limited analysis suggests that the sponsors definition from the 1995 WHO Good Clinical Practices code has been integrated as such into many legislations, guidelines and regulations, and that it is not adequate to cover today's reality of funding arrangements in global health, where the legal responsibility and the funding source are de facto split. In agreement with other groups, we suggest that the international Good Clinical Practices codes should be updated to reflect the reality of non-commercial clinical research. In particular, they should explicitly include the distinction between commercial and non-commercial sponsors, and provide guidance to non-commercial sponsors for negotiating with external funding agencies and other research counterparts. Non-commercial sponsors of clinical trials should surely invest in the development of adequate legal, administrative and management skills. By acknowledging their role and specificities, and by providing them with adapted guidance, the international Good Clinical Practices codes would provide valuable guidance and support to non-commercial clinical research, whose relevance for global health is increasingly evident

Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients coinfected with HIV

Abstract Background Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment. Methods Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set. Findings Distinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75–1.00). Interpretation A simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients. Funding Project funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7)

Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients coinfected with HIV

Abstract Background Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment. Methods Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set. Findings Distinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75–1.00). Interpretation A simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients. Funding Project funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7)

Efficacy and safety of a single-dose mebendazole 500 mg chewable, rapidly-disintegrating tablet for Ascaris lumbricoides and Trichuris trichiura infection treatment in pediatric patients : a double-blind, randomized, placebo-controlled, phase 3 study

This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of a new chewable, rapidly-disintegrating mebendazole (MBZ) 500 mg tablet for Ascaris lumbricoides and Trichuris trichiura infection treatment. Pediatric patients (1-15 years; N = 295; from Ethiopia and Rwanda) excreting A. lumbricoides and/or T. trichiura eggs were enrolled. The study had a screening phase (3 days), a double-blind treatment phase (DBP, 19 days), and an open-label phase (OLP, 7 days). Patients received MBZ or placebo on day 1 of DBP and open-label MBZ on day 19 +/- 2 after stool sample collection. Cure rates (primary endpoint), defined as species-specific egg count of 0 at the end of DBP, were significantly higher in the MBZ group than placebo for A. lumbricoides (83.7% [72/86; 95% CI: 74.2%; 90.8%] versus 11.1% [9/81; 95% CI: 5.2%; 20.1%], P < 0.001) and for T. trichiura (33.9% [42/124; 95% CI: 25.6%; 42.9%] versus 7.6% [9/119; 95% CI: 3.5%; 13.9%], P < 0.001). Egg reduction rates (secondary endpoint) were significantly higher in the MBZ group than placebo for A. lumbricoides (97.9% [95% CI: 94.4; 99.9] versus 19.2% [95% CI: -5.9; 41.5]; P < 0.001) and T. trichiura (59.7% [95% CI: 33.9; 78.8] versus 10.5% [95% CI: -16.8; 32.9]; P = 0.003). Treatment-emergent adverse events (TEAEs) in MBZ group occurred in 6.3% (9/144) of patients during DBP and 2.5% (7/278) during OLP. No deaths, serious TEAEs, or TEAEs leading to discontinuations were reported. A 500 mg chewable MBZ tablet was more efficacious than placebo for the treatment of A. lumbricoides and T. trichiura infections in pediatric patients, and no safety concerns were identified

Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection

<p>Abstract</p> <p>Background</p> <p>Nitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO).</p> <p>Methods</p> <p>In a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia.</p> <p>Results</p> <p>The proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate.</p> <p>Conclusion</p> <p>In both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.</p

Acute kidney injury risk factor recognition in three teaching hospitals in Ethiopia

Background. A key objective of the Nephrology Sister Centre Programme between the renal units in Cardiff and Addis Ababa, sponsored by the International Society of Nephrology, is to facilitate development of the local clinical service in Ethiopia specifically focused on the management of acute kidney injury (AKI). Objectives. To examine the relationship between AKI risk factor recognition and monitoring of renal function in three hospitals in Ethiopia. Methods. Cross-sectional data were gathered regarding renal function monitoring, recording the presence of AKI risk-associated comorbidities and prescription of nephrotoxic medications across the disciplines of medicine, surgery, obstetrics and gynaecology. Results. Patients were more likely to have their renal function checked at the hospital with specialist services. Across all centres, the highest proportion of patients who had renal function measurements were those admitted to a medical ward. There was a positive relationship between documented comorbidities and the measurement of renal function but not between the prescription of nephrotoxic drugs and measurement of renal function. Conclusion. There was great variability in the extent to which doctors recognised the presence of risk factors for the development of AKI. Failure to identify these risk factors represents a lost opportunity to identify patients at high risk of developing renal injury who would benefit from renal function monitoring

Acute kidney injury risk factor recognition in three teaching hospitals in Ethiopia

Background. A key objective of the Nephrology Sister Centre Programme between the renal units in Cardiff and Addis Ababa, sponsored by the International Society of Nephrology, is to facilitate development of the local clinical service in Ethiopia specifically focused on the management of acute kidney injury (AKI). Objectives. To examine the relationship between AKI risk factor recognition and monitoring of renal function in three hospitals in Ethiopia. Methods. Cross-sectional data were gathered regarding renal function monitoring, recording the presence of AKI risk-associated comorbidities and prescription of nephrotoxic medications across the disciplines of medicine, surgery, obstetrics and gynaecology. Results. Patients were more likely to have their renal function checked at the hospital with specialist services. Across all centres, the highest proportion of patients who had renal function measurements were those admitted to a medical ward. There was a positive relationship between documented comorbidities and the measurement of renal function but not between the prescription of nephrotoxic drugs and measurement of renal function. Conclusion. There was great variability in the extent to which doctors recognised the presence of risk factors for the development of AKI. Failure to identify these risk factors represents a lost opportunity to identify patients at high risk of developing renal injury who would benefit from renal function monitoring