Impact of population based indoor residual spraying in combination with mass drug administration on malaria incidence and test positivity in a high transmission setting in north eastern Uganda.

BACKGROUND: Mass drug administration (MDA) and indoor residual spraying (IRS) are potent malaria burden reduction tools. The impact of combining MDA and IRS is not well documented. We evaluated the impact of MDA + IRS compared to IRS alone at a high transmission site in Eastern Uganda. METHODS: A quasi-experimental study was implemented in Toroma and Kapujan subcounties in north eastern Uganda. Both subcounties received four rounds of IRS using primiphos-methyl (Acttellic SC300) 6-8 months apart from December 2016 to December 2018. Eligible residents of Kapujan simultaneously received MDA using dihydroartemesinin-piperaquine (DHA-PQ). Health facility data was used to monitor malaria case incidence rate and test positivity rates. RESULTS: In the MDA + IRS arm, malaria incidence dropped by 83% (IRR: 0·17 (0.16-0.18); p < 0.001) in children under 5 year and by 78% (IRR: 0·22 (0.22-0.23); p < 0.001) in persons aged ≥ 5 years from the pre-intervention to the intervention period. In the IRS arm malaria incidence dropped by 47% (IRR: 0.53 (0.51, 0.56); p < 0.001) in children under 5 years and by 71% 0.29 (0.28, 0.30); p < 0.001) in persons aged ≥ 5 years. A drastic drop occurred immediately after the intervention after which cases slowly increased in both arms. Malaria test positivity rate (TPR) dropped at a rate of 21 (p = 0.003) percentage points per 1000 persons in the MDA + IRS arm compared to the IRS arm. There was a mean decrease of 60 (p-value, 0.040) malaria cases among children under five years and a mean decrease in TPR of 16·16 (p-value, 0.001) in the MDA + IRS arm compared to IRS arm. INTERPRETATION: MDA significantly reduced malaria burden among children < 5 years however the duration of this impact needs to be further investigated.

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.

African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker.

BACKGROUND: Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. METHODS: Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. RESULTS: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%). CONCLUSIONS: These findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa. Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist= . FSFV: 23-Jul-2014; LSLV: 09-Oct-2015.

Factors associated with willingness to take up indoor residual spraying to prevent malaria in Tororo district, Uganda: a cross-sectional study.

BACKGROUND: Indoor residual spraying (IRS) is an efficient method of preventing malaria in homes, and community willingness to take up IRS is critical to its success. The first phase of IRS was conducted in Tororo district, Uganda between December 2014 and January 2015. High coverage rates (90%) were attained in the district. However, Mulanda sub-county had the lowest coverage of 78%, in the first round. This study assessed willingness and associated factors of IRS uptake among household heads for the next IRS campaign in Mulanda sub-county, Tororo district. METHODS: A household survey was conducted in all three parishes of Mulanda sub-county. A multistage sampling technique involving the village and household as the first and second sampling levels, respectively, was used to identify 640 households Household heads were interviewed using standard questionnaire. Seven key informants were also conducted to explore the impact of community IRS-perceptions on uptake. Bi-variable and multi-variable logistic regression analyses were used to identify factors associated with willingness to take up IRS. Qualitative data was analysed by thematic content analysis method. RESULTS: Most (79.9%) respondents were willing to take up repeat IRS. However this was below the target of 85%. Fear of insecticide adverse effects (62%) was the most common reason mentioned by 134 (21%) household heads who were not willing to take up IRS. Factors associated with to take up IRS were; age ≥ 35 years (AOR 1.9; 95% CI 1.08-3.51), higher socio-economic status (AOR 0.4; 95% CI 0.27-0.98), not taking IRS in previous round (AOR 0.1; 95% CI 0.06-0.23), not knowing reason for conducting IRS (AOR 0.4; 95% CI 0.24-0.78) and having an iron sheet roof (AOR 2.2; 95% CI 1.03-4.73). Community and religious leaders were the preferred sources of IRS information. CONCLUSIONS: The level of willingness to take up IRS was low (79%) compared to the targeted 85%. Involvement of community and religious leaders in community sensitization on the efficacy and safety of the chemicals could increase uptake of IRS.

A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages. METHODS: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42-63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure-response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children < 5 years of age. RESULTS: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13-79.19), 68.4% (59.13-76.66) and 78.6% (70.09-85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively. ACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55-76.62 and 74.5%; 68.81-79.68) respectively. Within the African population, efficacy was lowest in the youngest age group of ≥ 0.5 to ≤ 2 years, 52.7% (38.80-66.35). Initial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13 mutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability finding was vomiting (28.8%). CONCLUSIONS: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms reached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02083380 . Registered on 7 March 2014.

Prevalence and factors associated with anaemia among children aged 6 to 59 months in Namutumba district, Uganda: a cross- sectional study.

BACKGROUND: Anaemia is one of the major causes of death among children under five years in Africa, with a prevalence of 64.6% among pre-school children. In 2014, we conducted a cross-sectional study in Namutumba district in East-central Uganda to determine the prevalence and factors associated with anaemia among children aged 6 to 59 months. METHODS: We conducted a household survey in 376 randomly selected households. One child aged 6 to 59 months was randomly sampled from each selected household. A structured questionnaire administered to an adult caregiver was used to collect household data. Blood was collected by finger or heel prick to estimate the haemoglobin level using a portable haemocue analyser. Anthropometric data including age, weight and height was collected for each child. A modified poisson regression model was used to determine the correlates of anaemia, prevalence ratios and their 95% confidence intervals (CI). RESULTS: The prevalence of anaemia was high (58.8%) and was highest among children aged 12 to 23 months (68.5%) and males (61.3%). About 27.7% children were stunted. Children aged 6-11 and 12-23 months were more likely to be anaemic (APR = 1.12; 95% CI: 1.05-1.19 and APR = 1.12; 95% CI: 1.00-1.24 respectively), Resident of Magada and Namutumba (urban areas) were less likely to be anaemic (APR = 0.89; 95% CI: 0.87-0.91and APR = 0.86; 95% CI: 0. 85-0.88 respectively). Children of caretakers of a big family size (seven or more children) and with any formal education were less likely to be anaemic (APR = 0.94; 95% CI: 0.89-0.99 and APR = 0.93; 95% CI: 0.87-0.99). Stunting (HAZ scores) was a predictor of anaemia (APR = 1.07; 95% CI: 1.02-1.12). CONCLUSION: Anaemia is highly prevalent among children and there is need to invest in measures to prevent anaemia, especially among children in the rural areas.

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.

Challenges of non-commercial multicentre North-South collaborative clinical trials.

The last decade has witnessed a substantial increase of multi-centre, public health-oriented clinical trials in poor countries. However, non-commercial research groups have less staff and financial resources than traditional commercial sponsors, so the trial teams have to be creative to comply with Good Clinical Practices (GCP) requirements. According to the recent experience of a large multicentre trial on antimalarials, major challenges result from the complexity of multiple ethical review, the costs of in-depth monitoring at several sites, setting up an adequate Good Clinical Laboratory Practices (GCLP) framework, lack of insurers in host countries, and lack of adequate non-commercial data management software. Public research funding agencies need to consider these challenges in their funding policies. They also could support common spaces where North-South collaborative research groups may share critical information, such as on research insurance and open-source, GCP-compliant software. WHO should update its GCP guidelines, which date back to 1995, to incorporate the perspectives and needs of non-commercial clinical research.

Long lasting insecticidal bed nets ownership, access and use in a high malaria transmission setting before and after a mass distribution campaign in Uganda.

INTRODUCTION: Uganda is conducting a second mass LLIN distribution campaign and Katakwi district recently received LLINs as part of this activity. This study was conducted to measure the success of the campaign in this setting, an area of high transmission, with the objectives to estimate LLIN ownership, access and use pre and post campaign implementation. METHODS: Two identical cross sectional surveys, based on the Malaria Indicator Survey methodology, were conducted in three sub-counties in this district (Kapujan, Magoro and Toroma), six months apart, one before and another after the mass distribution campaign. Data on three main LLIN indicators including; household LLIN ownership, population with access to an LLIN and use were collected using a household and a women's questionnaire identical to the Malaria Indicator Survey. RESULTS: A total of 601 and 607 households were randomly selected in survey one and two respectively. At baseline, 60.57% (56.53-64.50) of households owned at least one net for every two persons who stayed in the household the night before the survey which significantly increased to 70.35% (66.54-73.96) after the campaign (p = 0.001). Similarly, the percentage of the household population with access to an LLIN significantly increased from 84.76% (82.99-86.52) to 91.57% (90.33-92.81), p = 0.001 and the percentage of household population that slept under an LLIN the night before the survey also significantly increased from 56.85% (55.06-58.82) to 81.72% (76.75-83.21), p = 0.001. CONCLUSION: The LLIN mass campaign successfully achieved the national target of over eighty-five percent of the population with access to an LLIN in this setting, however, universal household coverage and use were fourteen and three percent points less than the national target respectively. This is useful for malaria programs to consider during the planning of future campaigns by tailoring efforts around deficient areas like mechanisms to increase universal coverage and behavior change communication.