Efficacy of Artesunate + Sulfamethoxypyrazine/Pyrimethamine versus Praziquantel in the Treatment of Schistosoma haematobium in Children

BACKGROUND:This study was conducted to determine the efficacy of the antimalarial artemisinin-based combination therapy (ACT) artesunate +sulfamethoxypyrazine/pyrimethamine (As+SMP), administered in doses used for malaria, to treat Schistosoma haematobium in school aged children. METHODOLOGY/PRINCIPAL FINDINGS:The study was conducted in Djalakorodji, a peri-urban area of Bamako, Mali, using a double blind setup in which As+SMP was compared with praziquantel (PZQ). Urine samples were examined for Schistosoma haematobium on days -1, 0, 28 and 29. Detection of haematuria, and haematological and biochemical exams were conducted on day 0 and day 28. Clinical exams were performed on days 0, 1, 2, and 28. A total of 800 children were included in the trial. The cure rate obtained without viability testing was 43.9% in the As+SMP group versus 53% in the PZQ group (Chi(2) = 6.44, p = 0.011). Egg reduction rates were 95.6% with PZQ in comparison with 92.8% with As+SMP, p = 0.096. The proportion of participants who experienced adverse events related to the medication was 0.5% (2/400) in As+SMP treated children compared to 2.3% (9/399) in the PZQ group (p = 0.033). Abdominal pain and vomiting were the most frequent adverse events in both treatment arms. All adverse events were categorized as mild. CONCLUSIONS/SIGNIFICANCE:The study demonstrates that PZQ was more effective than As+SMP for treating Schistosoma haematobium. However, the safety and tolerability profile of As+SMP was similar to that seen with PZQ. Our findings suggest that further investigations seem justifiable to determine the dose/efficacy/safety pattern of As+SMP in the treatment of Schistosoma infections. TRIAL REGISTRATION:ClinicalTrials.gov NCT00510159

Engaging diverse communities participating in clinical trials: case examples from across Africa

<p>Abstract</p> <p>Background</p> <p>In the advent of increasing international collaborative research involving participants drawn from populations with diverse cultural backgrounds, community engagement becomes very critical for the smooth conduction of the research. The African Malaria Network Trust (AMANET) is a pan-African non-governmental organization that sponsors and technically supports malaria vaccine trials in various African countries.</p> <p>Case description</p> <p>AMANET sponsored phase Ib or IIb clinical trials of several malaria vaccine candidates in various Africa countries. In Burkina Faso, Mali and Tanzania trials of the merozoite surface protein 3 -- in its Long Synthetic Peptide configuration (MSP3 LSP) -- were conducted. In Mali, the apical membrane antigen 1 (AMA1) was tested, while a hybrid of glutamate rich protein (GLURP) and MSP3 (GMZ2) was tested in Gabon. AMANET recognizes the importance of engaging with the communities from which trial participants are drawn, hence community engagement was given priority in all project activities conducted in the various countries.</p> <p>Discussion and evaluation</p> <p>Existing local social systems were used to engage the communities from which clinical trial participants were drawn. This article focuses on community engagement activities employed at various AMANET-supported clinical trial sites in different countries, highlighting subtle differences in the approaches used. The paper also gives some general pros and cons of community engagement.</p> <p>Conclusions</p> <p>Community engagement enables two-way sharing of accurate information and ideas between researchers and researched communities, which helps to create an environment conducive to smooth research activities with enhanced sense of research ownership by the communities.</p

Acceptability and efficacy of intra-rectal quinine alkaloids as a pre-transfer treatment of non-per os malaria in peripheral health care facilities in Mopti, Mali

<p>Abstract</p> <p>Background</p> <p>The acceptability and efficacy of a new kit with a new formulation of quinine alkaloids designed for the intra-rectal administration in the treatment of non-per os malaria was assessed in the peripheral health care system of Mopti, Mali.</p> <p>Methods</p> <p>A single-arm trial was conducted from August 2003 to January 2004. An initial dose of diluted quinine alkaloids (20 mg/kg Quinimax^®) was administered by the intra-rectal route to children with presumptive non per-os malaria at six peripheral heath care centres. The children were then referred to two referral hospitals where standard inpatient care including intravenous route were routinely provided. A malaria thick smear was done at inclusion and a second malaria thick smear after arrival at the referral facility, where a more complete clinical examination and laboratory testing was done to confirm diagnosis. Confirmed cases of severe malaria or others diseases were treated according to national treatment guidelines. Cases of non per-os malaria received a second dose of intra rectal quinine alkaloids. Primary outcome was acceptability of the intra rectal route by children and their parents as well as the ease to handle the kit by health care workers.</p> <p>Results</p> <p>The study included 134 children with a median age of 33 months and 53.7% were male. Most of the children (67%) and 92% of parents or guardians readily accepted the intra-rectal route; 84% of health care workers found the kit easy to use. At the peripheral health care centres, 32% of children had a coma score ≤ 3 and this was reduced to 10% at the referral hospital, following one dose of intra-rectal quinine alkaloids (IRQA). The mean time to availability of oral route treatment was 1.8 ± 1.1 days. Overall, 73% of cases were confirmed severe malaria and for those the case fatality rate was 7.2%.</p> <p>Conclusion</p> <p>IRQA was well accepted by children, their parents/guardians and by the health workers at peripheral health facilities in Mopti, Mali. There was also a quick recovery from deep coma and a reduced case fatality rate in severe malaria.</p

Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown that intermittent preventive malaria treatment (IPT) in infants in areas of stable malaria transmission reduces malaria and severe anaemia incidence. However in most areas malaria morbidity and mortality remain high in older children.</p> <p>Methods</p> <p>To evaluate the effect of seasonal IPT with sulphadoxine pyrimethamine (SP) on incidence of malaria disease in area of seasonal transmission, 262 children 6 months-10 years in Kambila, Mali were randomized to receive either IPT with SP twice at eight weeks interval or no IPT during the transmission season of 2002 and were followed up for 12 months. Subjects were also followed during the subsequent transmission season in 2003 to assess possible rebound effect. Clinical malaria cases were treated with SP and followed to assess the <it>in vivo </it>response during both periods.</p> <p>Results</p> <p>The incidence rate of malaria disease per 1,000 person-months during the first 12 months was 3.2 episodes in the treatment group vs. 5.8 episodes in the control group with age-adjusted Protective Efficacy (PE) of 42.5%; [95% CI 28.6%–53.8%]. When the first 16 weeks of follow up is considered age-adjusted PE was 67.5% [95% CI 55.3% – 76.6%]. During the subsequent transmission season, the incidence of clinical malaria per 1000 persons-days was similar between the two groups (23.0 vs 21.5 episodes, age-adjusted IRR = 1.07 [95% CI, 0.90–1.27]). No significant difference was detected in <it>in vivo </it>response between the groups during both periods.</p> <p>Conclusion</p> <p>Two malaria intermittent treatments targeting the peak transmission season reduced the annual incidence rate of clinical malaria by 42.5% in an area with intense seasonal transmission. This simple strategy is likely to be one of the most effectives in reducing malaria burden in such areas.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov NCT00623155</p

Safety and Immunogenicity of an AMA-1 Malaria Vaccine in Malian Adults: Results of a Phase 1 Randomized Controlled Trial

The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria.A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen-1 (AMA-1) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). Sixty healthy, malaria-experienced adults aged 18-55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 microg/AS02A 0.25 mL or FMP2.1 50 microg/AS02A 0.5 mL) or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively.The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site

Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine

<p>Abstract</p> <p>Background</p> <p>A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons.</p> <p>Methods</p> <p>To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis.</p> <p>Results</p> <p>A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect.</p> <p>Conclusions</p> <p>While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations.</p

Increase in EPI vaccines coverage after implementation of intermittent preventive treatment of malaria in infant with Sulfadoxine -pyrimethamine in the district of Kolokani, Mali: Results from a cluster randomized control trial

<p>Abstract</p> <p>Background</p> <p>Even though the efficacy of Intermittent Preventive Treatment in infants (IPTi) with Sulfadoxine-Pyrimethamine (SP) against clinical disease and the absence of its interaction with routine vaccines of the Expanded Immunization Programme (EPI) have been established, there are still some concerns regarding the addition of IPTi, which may increase the work burden and disrupt the routine EPI services especially in Africa where the target immunization coverage remains to be met. However IPTi may also increase the adherence of the community to EPI services and improve EPI coverage, once the benefice of strategy is perceived.</p> <p>Methods</p> <p>To assess the impact of IPTi implementation on the coverage of EPI vaccines, 22 health areas of the district of Kolokani were randomized at a 1:1 ratio to either receive IPTi-SP or to serve as a control. The EPI vaccines coverage was assessed using cross-sectional surveys at baseline in November 2006 and after one year of IPTi pilot-implementation in December 2007.</p> <p>Results</p> <p>At baseline, the proportion of children of 9-23 months who were completely vaccinated (defined as children who received BGG, 3 doses of DTP/Polio, measles and yellow fever vaccines) was 36.7% (95% CI 25.3% -48.0%). After one year of implementation of IPTi-SP using routine health services, the proportion of children completely vaccinated rose to 53.8% in the non intervention zone and 69.5% in the IPTi intervention zone (P <0.001).</p> <p>The proportion of children in the target age groups who received IPTi with each of the 3 vaccinations DTP2, DTP3 and Measles, were 89.2% (95% CI 85.9%-92.0%), 91.0% (95% CI 87.6% -93.7%) and 77.4% (95% CI 70.7%-83.2%) respectively. The corresponding figures in non intervention zone were 2.3% (95% CI 0.9% -4.7%), 2.6% (95% CI 1.0% -5.6%) and 1.7% (95% CI 0.4% - 4.9%).</p> <p>Conclusion</p> <p>This study shows that high coverage of the IPTi can be obtained when the strategy is implemented using routine health services and implementation results in a significant increase in coverage of EPI vaccines in the district of Kolokani, Mali.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00766662">NCT00766662</a></p