Publications

" Our main objective is to develop and maintain over time a good expertise and infrastructure ensuring high quality training and clinical research."
Prof Halidou TINTO, PharmD, Msc, PhD Head of the CRUN

2024
Journal Articles
	Mehreen S. Datoo, Alassane Dicko, Halidou Tinto, Jean Bosco Ouédraogo, Mainga Hamaluba, Ally Olotu, Emma Beaumont, Fernando Ramos Lopez, Hamtandi Magloire Natama, Sophie Weston, Mwajuma Chemba, Yves Daniel Compaore, Djibrilla Issiaka, Diallo Salou, Athanase M. Some, Sharon Omenda, Alison Lawrie, Philip Bejon, Harish Rao, Daniel Chandramohan, Rachel Roberts, Sandesh Bharati, Lisa Stockdale, Sunil Gairola, Brian M. Greenwood, Katie J. Ewer, John Bradley, Prasad S. Kulkarni, Umesh Shaligram, Adrian V. S. Hill, Almahamoudou Mahamar, Koualy Sanogo, Youssoufa Sidibe, Kalifa Diarra, Mamoudou Samassekou, Oumar Attaher, Amadou Tapily, Makonon Diallo, Oumar Mohamed Dicko, Mahamadou Kaya, Seydina Oumar Maguiraga, Yaya Sankare, Hama Yalcouye, Soumaila Diarra, Sidi Mohamed Niambele, Ismaila Thera, Issaka Sagara, Mala Sylla, Amagana Dolo, Nsajigwa Misidai, Sylvester Simando, Hania Msami, Omary Juma, Nicolaus Gutapaka, Rose Paul, Sarah Mswata, Ibrahim Sasamalo, Kasmir Johaness, Mwantumu Sultan, Annastazia Alexander, Isaac Kimaro, Kauye Lwanga, Mwajuma Mtungwe, Kassim Khamis, Lighton Rugarabam, Wilmina Kalinga, Mohammed Mohammed, Janeth Kamange, Jubilate Msangi, Batuli Mwaijande, Ivanny Mtaka, Matilda Mhapa, Tarsis Mlaganile, Thabit Mbaga, Rakiswende Serge Yerbanga, Wendkouni Samtouma, Abdoul Aziz Sienou, Zachari Kabre, Wendinpui Jedida Muriel Ouedraogo, G. Armel Bienvenu Yarbanga, Issaka Zongo, Hamade Savadogo, Joseph Sanon, Judicael Compaore, Idrissa Kere, Ferdinand Lionel Yoni, Tewende Martine Sanre, Seydou Bienvenu Ouattara, Samuel Provstgaard-Morys, Danielle Woods, Robert W. Snow, Nyaguara Amek, Caroline J. Ngetsa, Lynette Isabella Ochola-Oyier, Jennifer Musyoki, Marianne Munene, Noni Mumba, Uche Jane Adetifa, Charles Mwangi Muiruri, Jimmy Shangala Mwawaka, Mwatasa Hussein Mwaganyuma, Martha Njeri Ndichu, Joseph Ochieng Weya, Kelvin Njogu, Jane Grant, Jayne Webster, Anand Lakhkar, N. Félix André Ido, Ousmane Traore, Marc Christian Tahita, Massa Achille Bonko, Toussaint Rouamba, D. Florence Ouedraogo, Rachidatou Soma, Aida Millogo, Edouard Ouedraogo, Faizatou Sorgho, Fabé Konate, Innocent Valea Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial Journal Article In: Lancet (London, England), vol. 403, iss. 10426, pp. 533-544, 2024, ISSN: 1474-547X. Abstract \| BibTeX \| Tags: {Alassane Dicko, Antibodies, Burkina Faso, Child, Clinical Trial, Double-Blind Method, Female, Humans, Immunization, Infant, Malaria Vaccines* / adverse effects, Malaria* / drug therapy, Male, MEDLINE, Mehreen S Datoo, Multicenter Study, Nanoparticles, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase III, Preschool, PubMed Abstract, Randomized controlled trial, Research Support, Saponins \| Links: Close Close @article{Datoo2024, title = {Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial}, author = {Mehreen S. Datoo and Alassane Dicko and Halidou Tinto and Jean Bosco Ou\'{e}draogo and Mainga Hamaluba and Ally Olotu and Emma Beaumont and Fernando Ramos Lopez and Hamtandi Magloire Natama and Sophie Weston and Mwajuma Chemba and Yves Daniel Compaore and Djibrilla Issiaka and Diallo Salou and Athanase M. Some and Sharon Omenda and Alison Lawrie and Philip Bejon and Harish Rao and Daniel Chandramohan and Rachel Roberts and Sandesh Bharati and Lisa Stockdale and Sunil Gairola and Brian M. Greenwood and Katie J. Ewer and John Bradley and Prasad S. Kulkarni and Umesh Shaligram and Adrian V. S. Hill and Almahamoudou Mahamar and Koualy Sanogo and Youssoufa Sidibe and Kalifa Diarra and Mamoudou Samassekou and Oumar Attaher and Amadou Tapily and Makonon Diallo and Oumar Mohamed Dicko and Mahamadou Kaya and Seydina Oumar Maguiraga and Yaya Sankare and Hama Yalcouye and Soumaila Diarra and Sidi Mohamed Niambele and Ismaila Thera and Issaka Sagara and Mala Sylla and Amagana Dolo and Nsajigwa Misidai and Sylvester Simando and Hania Msami and Omary Juma and Nicolaus Gutapaka and Rose Paul and Sarah Mswata and Ibrahim Sasamalo and Kasmir Johaness and Mwantumu Sultan and Annastazia Alexander and Isaac Kimaro and Kauye Lwanga and Mwajuma Mtungwe and Kassim Khamis and Lighton Rugarabam and Wilmina Kalinga and Mohammed Mohammed and Janeth Kamange and Jubilate Msangi and Batuli Mwaijande and Ivanny Mtaka and Matilda Mhapa and Tarsis Mlaganile and Thabit Mbaga and Rakiswende Serge Yerbanga and Wendkouni Samtouma and Abdoul Aziz Sienou and Zachari Kabre and Wendinpui Jedida Muriel Ouedraogo and G. Armel Bienvenu Yarbanga and Issaka Zongo and Hamade Savadogo and Joseph Sanon and Judicael Compaore and Idrissa Kere and Ferdinand Lionel Yoni and Tewende Martine Sanre and Seydou Bienvenu Ouattara and Samuel Provstgaard-Morys and Danielle Woods and Robert W. Snow and Nyaguara Amek and Caroline J. Ngetsa and Lynette Isabella Ochola-Oyier and Jennifer Musyoki and Marianne Munene and Noni Mumba and Uche Jane Adetifa and Charles Mwangi Muiruri and Jimmy Shangala Mwawaka and Mwatasa Hussein Mwaganyuma and Martha Njeri Ndichu and Joseph Ochieng Weya and Kelvin Njogu and Jane Grant and Jayne Webster and Anand Lakhkar and N. F\'{e}lix Andr\'{e} Ido and Ousmane Traore and Marc Christian Tahita and Massa Achille Bonko and Toussaint Rouamba and D. Florence Ouedraogo and Rachidatou Soma and Aida Millogo and Edouard Ouedraogo and Faizatou Sorgho and Fab\'{e} Konate and Innocent Valea}, url = {https://pubmed.ncbi.nlm.nih.gov/38310910/}, doi = {10.1016/S0140-6736(23)02511-4}, issn = {1474-547X}, year = {2024}, date = {2024-01-01}, journal = {Lancet (London, England)}, volume = {403}, issue = {10426}, pages = {533-544}, publisher = {Lancet}, abstract = {Background: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. Methods: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5\textendash36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. Findings: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71\textendash79; p\<0·0001) at the seasonal sites and 68% (61\textendash74; p\<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71\textendash78; p\<0·0001) at the seasonal sites and 67% (59\textendash73; p\<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762\textendash974) cases per 1000 children-years at seasonal sites and 296 (231\textendash362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5\textendash17 month age group compared with 18\textendash36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73\textendash84]; p\<0·001) and standard (75% [65\textendash83]; p\<0·001) sites. Interpretation: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. Funding: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.}, keywords = {{Alassane Dicko, Antibodies, Burkina Faso, Child, Clinical Trial, Double-Blind Method, Female, Humans, Immunization, Infant, Malaria Vaccines* / adverse effects, Malaria* / drug therapy, Male, MEDLINE, Mehreen S Datoo, Multicenter Study, Nanoparticles, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase III, Preschool, PubMed Abstract, Randomized controlled trial, Research Support, Saponins}, pubstate = {published}, tppubtype = {article} } Close Background: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. Methods: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5–36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. Findings: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71–79; p<0·0001) at the seasonal sites and 68% (61–74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71–78; p<0·0001) at the seasonal sites and 67% (59–73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762–974) cases per 1000 children-years at seasonal sites and 296 (231–362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5–17 month age group compared with 18–36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73–84]; p<0·001) and standard (75% [65–83]; p<0·001) sites. Interpretation: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. Funding: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy. Close
2023
Journal Articles
	Adama Gansane, Moussa Lingani, Adoke Yeka, Alain Nahum, Marielle Bouyou-Akotet, Ghyslain Mombo-Ngoma, Grace Kaguthi, Catalina Barceló, Bart Laurijssens, Cathy Cantalloube, Fiona Macintyre, Elhadj Djeriou, Andreas Jessel, Raphaël Bejuit, Helen Demarest, Anne Claire Marrast, Siaka Debe, Halidou Tinto, Afizi Kibuuka, Diolinda Nahum, Denise Patricia Mawili-Mboumba, Rella Zoleko-Manego, Irene Mugenya, Frederick Olewe, Stephan Duparc, Bernhards Ogutu Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria Journal Article In: Malaria journal, vol. 22, iss. 1, 2023, ISSN: 1475-2875. Abstract \| BibTeX \| Tags: Adama Gansane, Aminoquinolines / therapeutic use, Antimalarials* / pharmacology, Bernhards Ogutu, Clinical Trial, doi:10.1186/s12936-022-04420-2, Drug Combinations, Falciparum* / drug therapy, Falciparum* / parasitology, Humans, Malaria, MEDLINE, Moussa Lingani, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Phase II, Plasmodium falciparum, PMC9809015, pmid:36597076, PubMed Abstract, Randomized controlled trial, Treatment Outcome \| Links: Close Close @article{Gansane2023, title = {Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria}, author = {Adama Gansane and Moussa Lingani and Adoke Yeka and Alain Nahum and Marielle Bouyou-Akotet and Ghyslain Mombo-Ngoma and Grace Kaguthi and Catalina Barcel\'{o} and Bart Laurijssens and Cathy Cantalloube and Fiona Macintyre and Elhadj Djeriou and Andreas Jessel and Rapha\"{e}l Bejuit and Helen Demarest and Anne Claire Marrast and Siaka Debe and Halidou Tinto and Afizi Kibuuka and Diolinda Nahum and Denise Patricia Mawili-Mboumba and Rella Zoleko-Manego and Irene Mugenya and Frederick Olewe and Stephan Duparc and Bernhards Ogutu}, url = {https://pubmed.ncbi.nlm.nih.gov/36597076/}, doi = {10.1186/S12936-022-04420-2}, issn = {1475-2875}, year = {2023}, date = {2023-01-01}, journal = {Malaria journal}, volume = {22}, issue = {1}, publisher = {Malar J}, abstract = {Background: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. Methods: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14\textendash69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. Results: The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0\textendash∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0\textendashd28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan\textendashMeier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or \> 60 ms from baseline. Conclusion: The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. Trial registration: ClinicalTrials.gov, NCT03660839 (7 September, 2018).}, keywords = {Adama Gansane, Aminoquinolines / therapeutic use, Antimalarials* / pharmacology, Bernhards Ogutu, Clinical Trial, doi:10.1186/s12936-022-04420-2, Drug Combinations, Falciparum* / drug therapy, Falciparum* / parasitology, Humans, Malaria, MEDLINE, Moussa Lingani, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Phase II, Plasmodium falciparum, PMC9809015, pmid:36597076, PubMed Abstract, Randomized controlled trial, Treatment Outcome}, pubstate = {published}, tppubtype = {article} } Close Background: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. Methods: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14–69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. Results: The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0–∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0–d28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan–Meier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or > 60 ms from baseline. Conclusion: The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. Trial registration: ClinicalTrials.gov, NCT03660839 (7 September, 2018). Close
	Oumou Camara, Mamadou Camara, Laura Cristina Falzon, Hamidou Ilboudo, Jacques Kaboré, Charlie Franck Alfred Compaoré, Eric Maurice Fèvre, Philippe Büscher, Bruno Bucheton, Veerle Lejon Performance of clinical signs and symptoms, rapid and reference laboratory diagnostic tests for diagnosis of human African trypanosomiasis by passive screening in Guinea: a prospective diagnostic accuracy study Journal Article In: Infectious diseases of poverty, vol. 12, iss. 1, 2023, ISSN: 2049-9957. Abstract \| BibTeX \| Tags: African, Animals, Clinical Trial, Diagnostic Tests, doi:10.1186/s40249-023-01076-1, Guinea, Humans, Mamadou Camara, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Oumou Camara, PMC10026442, pmid:36941656, Prospective Studies, PubMed Abstract, Routine, Sensitivity and Specificity, Trypanosomiasis, Veerle Lejon \| Links: Close Close @article{Camara2023, title = {Performance of clinical signs and symptoms, rapid and reference laboratory diagnostic tests for diagnosis of human African trypanosomiasis by passive screening in Guinea: a prospective diagnostic accuracy study}, author = {Oumou Camara and Mamadou Camara and Laura Cristina Falzon and Hamidou Ilboudo and Jacques Kabor\'{e} and Charlie Franck Alfred Compaor\'{e} and Eric Maurice F\`{e}vre and Philippe B\"{u}scher and Bruno Bucheton and Veerle Lejon}, url = {https://pubmed.ncbi.nlm.nih.gov/36941656/}, doi = {10.1186/S40249-023-01076-1}, issn = {2049-9957}, year = {2023}, date = {2023-01-01}, journal = {Infectious diseases of poverty}, volume = {12}, issue = {1}, publisher = {Infect Dis Poverty}, abstract = {Background: Passive diagnosis of human African trypanosomiasis (HAT) at the health facility level is a major component of HAT control in Guinea. We examined which clinical signs and symptoms are associated with HAT, and assessed the performance of selected clinical presentations, of rapid diagnostic tests (RDT), and of reference laboratory tests on dried blood spots (DBS) for diagnosing HAT in Guinea. Method: The study took place in 14 health facilities in Guinea, where 2345 clinical suspects were tested with RDTs (HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT). Seropositives underwent parasitological examination (reference test) to confirm HAT and their DBS were tested in indirect enzyme-linked immunoassay (ELISA)/Trypanosoma brucei gambiense, trypanolysis, Loopamp Trypanosoma brucei Detection kit (LAMP) and m18S quantitative PCR (qPCR). Multivariable regression analysis assessed association of clinical presentation with HAT. Sensitivity, specificity, positive and negative predictive values of key clinical presentations, of the RDTs and of the DBS tests for HAT diagnosis were determined. Results: The HAT prevalence, as confirmed parasitologically, was 2.0% (48/2345, 95% CI: 1.5\textendash2.7%). Odds ratios (OR) for HAT were increased for participants with swollen lymph nodes (OR = 96.7, 95% CI: 20.7\textendash452.0), important weight loss (OR = 20.4, 95% CI: 7.05\textendash58.9), severe itching (OR = 45.9, 95% CI: 7.3\textendash288.7) or motor disorders (OR = 4.5, 95% CI: 0.89\textendash22.5). Presence of at least one of these clinical presentations was 75.6% (95% CI: 73.8\textendash77.4%) specific and 97.9% (95% CI: 88.9\textendash99.9%) sensitive for HAT. HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT were respectively 97.5% (95% CI: 96.8\textendash98.1%), 99.4% (95% CI: 99.0\textendash99.7%) and 97.9% (95% CI: 97.2\textendash98.4%) specific, and 100% (95% CI: 92.5\textendash100.0%), 59.6% (95% CI: 44.3\textendash73.3%) and 93.8% (95% CI: 82.8\textendash98.7%) sensitive for HAT. The RDT’s positive and negative predictive values ranged from 45.2\textendash66.7% and 99.2\textendash100% respectively. All DBS tests had specificities ≥ 92.9%. While LAMP and m18S qPCR sensitivities were below 50%, trypanolysis and ELISA/T.b. gambiense had sensitivities of 85.3% (95% CI: 68.9\textendash95.0%) and 67.6% (95% CI: 49.5\textendash82.6%). Conclusions: Presence of swollen lymph nodes, important weight loss, severe itching or motor disorders are simple but accurate clinical criteria for HAT referral in HAT endemic areas in Guinea. Diagnostic performances of HAT Sero-K-Set and SD Bioline HAT are sufficient for referring positives to microscopy. Trypanolysis on DBS may discriminate HAT patients from false RDT positives. Trial registration The trial was registered under NCT03356665 in clinicaltrials.gov (November 29, 2017, retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03356665) Graphical Abstract: [Figure not available: see fulltext.].}, keywords = {African, Animals, Clinical Trial, Diagnostic Tests, doi:10.1186/s40249-023-01076-1, Guinea, Humans, Mamadou Camara, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Oumou Camara, PMC10026442, pmid:36941656, Prospective Studies, PubMed Abstract, Routine, Sensitivity and Specificity, Trypanosomiasis, Veerle Lejon}, pubstate = {published}, tppubtype = {article} } Close Background: Passive diagnosis of human African trypanosomiasis (HAT) at the health facility level is a major component of HAT control in Guinea. We examined which clinical signs and symptoms are associated with HAT, and assessed the performance of selected clinical presentations, of rapid diagnostic tests (RDT), and of reference laboratory tests on dried blood spots (DBS) for diagnosing HAT in Guinea. Method: The study took place in 14 health facilities in Guinea, where 2345 clinical suspects were tested with RDTs (HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT). Seropositives underwent parasitological examination (reference test) to confirm HAT and their DBS were tested in indirect enzyme-linked immunoassay (ELISA)/Trypanosoma brucei gambiense, trypanolysis, Loopamp Trypanosoma brucei Detection kit (LAMP) and m18S quantitative PCR (qPCR). Multivariable regression analysis assessed association of clinical presentation with HAT. Sensitivity, specificity, positive and negative predictive values of key clinical presentations, of the RDTs and of the DBS tests for HAT diagnosis were determined. Results: The HAT prevalence, as confirmed parasitologically, was 2.0% (48/2345, 95% CI: 1.5–2.7%). Odds ratios (OR) for HAT were increased for participants with swollen lymph nodes (OR = 96.7, 95% CI: 20.7–452.0), important weight loss (OR = 20.4, 95% CI: 7.05–58.9), severe itching (OR = 45.9, 95% CI: 7.3–288.7) or motor disorders (OR = 4.5, 95% CI: 0.89–22.5). Presence of at least one of these clinical presentations was 75.6% (95% CI: 73.8–77.4%) specific and 97.9% (95% CI: 88.9–99.9%) sensitive for HAT. HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT were respectively 97.5% (95% CI: 96.8–98.1%), 99.4% (95% CI: 99.0–99.7%) and 97.9% (95% CI: 97.2–98.4%) specific, and 100% (95% CI: 92.5–100.0%), 59.6% (95% CI: 44.3–73.3%) and 93.8% (95% CI: 82.8–98.7%) sensitive for HAT. The RDT’s positive and negative predictive values ranged from 45.2–66.7% and 99.2–100% respectively. All DBS tests had specificities ≥ 92.9%. While LAMP and m18S qPCR sensitivities were below 50%, trypanolysis and ELISA/T.b. gambiense had sensitivities of 85.3% (95% CI: 68.9–95.0%) and 67.6% (95% CI: 49.5–82.6%). Conclusions: Presence of swollen lymph nodes, important weight loss, severe itching or motor disorders are simple but accurate clinical criteria for HAT referral in HAT endemic areas in Guinea. Diagnostic performances of HAT Sero-K-Set and SD Bioline HAT are sufficient for referring positives to microscopy. Trypanolysis on DBS may discriminate HAT patients from false RDT positives. Trial registration The trial was registered under NCT03356665 in clinicaltrials.gov (November 29, 2017, retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03356665) Graphical Abstract: [Figure not available: see fulltext.]. Close
	Adelaïde Compaore, Deborah Ekusai-Sebatta, David Kaawa-Mafigiri, Vida Kukula, Selase Odopey, James Kapisi, Heidi Hopkins, François Kiemde, Halidou Tinto, Rita Baiden, Piero Olliaro, Juvenal Nkeramahame, Sabine Dittrich, Philip Horgan Viewpoint: Antimicrobial Resistance Diagnostics Use Accelerator: Qualitative Research on Adherence to Prescriptions Journal Article In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, vol. 77, iss. Suppl 2, pp. S206-S210, 2023, ISSN: 1537-6591. Abstract \| BibTeX \| Tags: {Adélaïde Compaoré, Anti-Bacterial Agents* / therapeutic use, Author(firstnames='Adélaïde', Author(firstnames='Alexander', Author(firstnames='Asadu', Author(firstnames='Daniel', Author(firstnames='David', Author(firstnames='Deborah', Author(firstnames='Elizeus', Author(firstnames='François', Author(firstnames='Freddy Eric', Author(firstnames='Halidou', Author(firstnames='Heidi', Author(firstnames='James', Author(firstnames='Rita', Author(firstnames='Vida', Bacterial, Clinical Trial, CollabAuthor(name='ADIP study group', Communication, Deborah Ekusai-Sebatta, Drug Resistance, Humans, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, PMC10368411, Prescriptions, PubMed Abstract, Qualitative research, Research Support \| Links: Close Close @article{Compaore2023, title = {Viewpoint: Antimicrobial Resistance Diagnostics Use Accelerator: Qualitative Research on Adherence to Prescriptions}, author = {Adela\"{i}de Compaore and Deborah Ekusai-Sebatta and David Kaawa-Mafigiri and Vida Kukula and Selase Odopey and James Kapisi and Heidi Hopkins and Fran\c{c}ois Kiemde and Halidou Tinto and Rita Baiden and Piero Olliaro and Juvenal Nkeramahame and Sabine Dittrich and Philip Horgan}, url = {https://pubmed.ncbi.nlm.nih.gov/37490738/}, doi = {10.1093/CID/CIAD323}, issn = {1537-6591}, year = {2023}, date = {2023-01-01}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {77}, issue = {Suppl 2}, pages = {S206-S210}, publisher = {Clin Infect Dis}, abstract = {In this Viewpoint, the authors explore the determinants of patients' prescription adherence behaviors as part of FIND's Advancing Access to Diagnostic Innovation essential for Universal Health Coverage and AMR Prevention (ADIP) trials (ClinicalTrials.gov identifier: NCT04081051). Research findings from Burkina Faso, Ghana, and Uganda show that basic knowledge and understanding of prescription instructions are essential for adherence and can be improved through better communication. However, there are a range of other factors that influence adherence, some of which can be influenced through tailored communication messages from healthcare workers. These messages may contribute to changes in adherence behavior but may require other reinforcing interventions to be effective. Finally, there are some drivers of nonadherence centered around costs and time pressure that require other forms of intervention.}, keywords = {{Ad\'{e}la\"{i}de Compaor\'{e}, Anti-Bacterial Agents / therapeutic use, Author(firstnames='Ad\'{e}la\"{i}de', Author(firstnames='Alexander', Author(firstnames='Asadu', Author(firstnames='Daniel', Author(firstnames='David', Author(firstnames='Deborah', Author(firstnames='Elizeus', Author(firstnames='Fran\c{c}ois', Author(firstnames='Freddy Eric', Author(firstnames='Halidou', Author(firstnames='Heidi', Author(firstnames='James', Author(firstnames='Rita', Author(firstnames='Vida', Bacterial*, Clinical Trial, CollabAuthor(name='ADIP study group', Communication, Deborah Ekusai-Sebatta, Drug Resistance, Humans, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, PMC10368411, Prescriptions, PubMed Abstract, Qualitative research, Research Support}, pubstate = {published}, tppubtype = {article} } Close In this Viewpoint, the authors explore the determinants of patients' prescription adherence behaviors as part of FIND's Advancing Access to Diagnostic Innovation essential for Universal Health Coverage and AMR Prevention (ADIP) trials (ClinicalTrials.gov identifier: NCT04081051). Research findings from Burkina Faso, Ghana, and Uganda show that basic knowledge and understanding of prescription instructions are essential for adherence and can be improved through better communication. However, there are a range of other factors that influence adherence, some of which can be influenced through tailored communication messages from healthcare workers. These messages may contribute to changes in adherence behavior but may require other reinforcing interventions to be effective. Finally, there are some drivers of nonadherence centered around costs and time pressure that require other forms of intervention. Close
	Selidji T. Agnandji, Mario Recker, Benjamin Mordmüller, Stephan Glöckner, Akim A. Adegnika, Bertrand Lell, Lucas Otieno, Walter Otieno, Seth Owusu-Agyei, Kwaku P. Asante, Tsiri Agbenyega, Daniel Ansong, Eusebio Macete, Pedro Aide, Hermann Sorgho, Halidou Tinto, Neema Mturi, John P. A. Lusingu, Samwel Gesase, Irving Hoffman, Nahya Salim Masoud, Charles R. Newton, Kalifa Bojang, Gérard Krause, Peter Gottfried Kremsner Prostration and the prognosis of death in African children with severe malaria Journal Article In: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, vol. 134, pp. 240-247, 2023, ISSN: 1878-3511. Abstract \| BibTeX \| Tags: Anemia, Child, Clinical Trial, Coma, doi:10.1016/j.ijid.2023.06.022, Falciparum / drug therapy, Humans, Infant, Malaria, Malaria* / complications, Malaria* / diagnosis, Mario Recker, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Peter Gottfried Kremsner, Phase III, pmid:37414210, Prognosis, PubMed Abstract, Randomized controlled trial, Selidji T Agnandji \| Links: Close Close @article{Agnandji2023, title = {Prostration and the prognosis of death in African children with severe malaria}, author = {Selidji T. Agnandji and Mario Recker and Benjamin Mordm\"{u}ller and Stephan Gl\"{o}ckner and Akim A. Adegnika and Bertrand Lell and Lucas Otieno and Walter Otieno and Seth Owusu-Agyei and Kwaku P. Asante and Tsiri Agbenyega and Daniel Ansong and Eusebio Macete and Pedro Aide and Hermann Sorgho and Halidou Tinto and Neema Mturi and John P. A. Lusingu and Samwel Gesase and Irving Hoffman and Nahya Salim Masoud and Charles R. Newton and Kalifa Bojang and G\'{e}rard Krause and Peter Gottfried Kremsner}, url = {https://pubmed.ncbi.nlm.nih.gov/37414210/}, doi = {10.1016/J.IJID.2023.06.022}, issn = {1878-3511}, year = {2023}, date = {2023-01-01}, journal = {International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases}, volume = {134}, pages = {240-247}, publisher = {Int J Infect Dis}, abstract = {Objectives: Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. Methods: Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. Results: Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P \<0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambar\'{e}n\'{e} Organ Dysfunction Score. Conclusion: Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes.}, keywords = {Anemia, Child, Clinical Trial, Coma, doi:10.1016/j.ijid.2023.06.022, Falciparum / drug therapy, Humans, Infant, Malaria, Malaria* / complications, Malaria* / diagnosis, Mario Recker, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Peter Gottfried Kremsner, Phase III, pmid:37414210, Prognosis, PubMed Abstract, Randomized controlled trial, Selidji T Agnandji}, pubstate = {published}, tppubtype = {article} } Close Objectives: Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. Methods: Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. Results: Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P <0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambaréné Organ Dysfunction Score. Conclusion: Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes. Close
	Bernhards Ogutu, Adoke Yeka, Sylvia Kusemererwa, Ricardo Thompson, Halidou Tinto, Andre Offianan Toure, Chirapong Uthaisin, Amar Verma, Afizi Kibuuka, Moussa Lingani, Carlos Lourenço, Ghyslain Mombo-Ngoma, Videlis Nduba, Tiacoh Landry N'Guessan, Guétawendé Job Wilfried Nassa, Mary Nyantaro, Lucas Otieno Tina, Piyoosh K. Singh, Myriam El Gaaloul, Anne Claire Marrast, Havana Chikoto, Katalin Csermak, Ivan Demin, Dheeraj Mehta, Rashidkhan Pathan, Celine Risterucci, Guoqin Su, Cornelis Winnips, Grace Kaguthi, Bakary Fofana, Martin Peter Grobusch Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial Journal Article In: The Lancet. Infectious diseases, vol. 23, iss. 9, pp. 1051-1061, 2023, ISSN: 1474-4457. Abstract \| BibTeX \| Tags: Adoke Yeka, Adolescent, Adult, Antimalarials, Artemether / pharmacology, Artemether / therapeutic use, Artemisinins, Bernhards Ogutu, Child, Clinical Trial, doi:10.1016/S1473-3099(23)00209-8, Drug Combinations, Ethanolamines / pharmacology, Ethanolamines / therapeutic use, Falciparum* / drug therapy, Falciparum* / parasitology, Fluorenes / pharmacology, Fluorenes / therapeutic use, Humans, Lumefantrine / pharmacology, Lumefantrine / therapeutic use, Malaria, Malaria* / drug therapy, Martin Peter Grobusch, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase II, Plasmodium falciparum, pmid:37327809, PubMed Abstract, Randomized controlled trial, Research Support, Treatment Outcome \| Links: Close Close @article{Ogutu2023, title = {Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial}, author = {Bernhards Ogutu and Adoke Yeka and Sylvia Kusemererwa and Ricardo Thompson and Halidou Tinto and Andre Offianan Toure and Chirapong Uthaisin and Amar Verma and Afizi Kibuuka and Moussa Lingani and Carlos Louren\c{c}o and Ghyslain Mombo-Ngoma and Videlis Nduba and Tiacoh Landry N'Guessan and Gu\'{e}tawend\'{e} Job Wilfried Nassa and Mary Nyantaro and Lucas Otieno Tina and Piyoosh K. Singh and Myriam El Gaaloul and Anne Claire Marrast and Havana Chikoto and Katalin Csermak and Ivan Demin and Dheeraj Mehta and Rashidkhan Pathan and Celine Risterucci and Guoqin Su and Cornelis Winnips and Grace Kaguthi and Bakary Fofana and Martin Peter Grobusch}, url = {https://pubmed.ncbi.nlm.nih.gov/37327809/}, doi = {10.1016/S1473-3099(23)00209-8}, issn = {1474-4457}, year = {2023}, date = {2023-01-01}, journal = {The Lancet. Infectious diseases}, volume = {23}, issue = {9}, pages = {1051-1061}, publisher = {Lancet Infect Dis}, abstract = {Background: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. Methods: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (\>1000 and \<150 000 parasites per μL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and \<12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to \<6 years and 6 to \<12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020\textendash003284\textendash25) and ClinicalTrials.gov (NCT03167242). Findings: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81\textendash98] with 1 day, 47 of 48 [98%, 89\textendash100] with 2 days, and 42 of 43 [98%, 88\textendash100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83\textendash99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93\textendash100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92\textendash100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86\textendash100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83\textendash99] vs 21 of 22 [96%, 77\textendash100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. Interpretation: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). Funding: Novartis and Medicines for Malaria Venture.}, keywords = {Adoke Yeka, Adolescent, Adult, Antimalarials, Artemether / pharmacology, Artemether / therapeutic use, Artemisinins, Bernhards Ogutu, Child, Clinical Trial, doi:10.1016/S1473-3099(23)00209-8, Drug Combinations, Ethanolamines / pharmacology, Ethanolamines / therapeutic use, Falciparum* / drug therapy, Falciparum* / parasitology, Fluorenes / pharmacology, Fluorenes / therapeutic use, Humans, Lumefantrine / pharmacology, Lumefantrine / therapeutic use, Malaria, Malaria* / drug therapy, Martin Peter Grobusch, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase II, Plasmodium falciparum, pmid:37327809, PubMed Abstract, Randomized controlled trial, Research Support, Treatment Outcome}, pubstate = {published}, tppubtype = {article} } Close Background: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. Methods: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per μL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020–003284–25) and ClinicalTrials.gov (NCT03167242). Findings: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81–98] with 1 day, 47 of 48 [98%, 89–100] with 2 days, and 42 of 43 [98%, 88–100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83–99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93–100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92–100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86–100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83–99] vs 21 of 22 [96%, 77–100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. Interpretation: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). Funding: Novartis and Medicines for Malaria Venture. Close
2015
Journal Articles
	S Clinical Trials Partnership RTS Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial Journal Article In: Lancet (London, England), vol. 386, iss. 9988, pp. 31-45, 2015, ISSN: 1474-547X. Abstract \| BibTeX \| Tags: {Africa South of the Sahara / epidemiology, Age Factors, Clinical Trial, Double-Blind Method, Falciparum / epidemiology, Falciparum / prevention & control, Female, Follow-Up Studies, Hospitalization / statistics & numerical data, Humans, Immunization, Immunization Schedule, Incidence, Infant, Malaria, Malaria Vaccines, Male, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase III, PMC5626001, PubMed Abstract, Randomized controlled trial, Research Support, S Clinical Trials Partnership' \| Links: Close Close @article{RTS2015, title = {Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial}, author = {S Clinical Trials Partnership RTS}, url = {https://pubmed.ncbi.nlm.nih.gov/25913272/}, doi = {10.1016/S0140-6736(15)60721-8}, issn = {1474-547X}, year = {2015}, date = {2015-01-01}, journal = {Lancet (London, England)}, volume = {386}, issue = {9988}, pages = {31-45}, publisher = {Lancet}, abstract = {Background The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. Methods From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. Findings 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. Interpretation RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. Funding GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.}, keywords = {{Africa South of the Sahara / epidemiology, Age Factors, Clinical Trial, Double-Blind Method, Falciparum / epidemiology, Falciparum / prevention \& control, Female, Follow-Up Studies, Hospitalization / statistics \& numerical data, Humans, Immunization, Immunization Schedule, Incidence, Infant, Malaria, Malaria Vaccines, Male, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase III, PMC5626001, PubMed Abstract, Randomized controlled trial, Research Support, S Clinical Trials Partnership'}, pubstate = {published}, tppubtype = {article} } Close Background The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. Methods From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. Findings 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. Interpretation RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. Funding GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative. Close