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
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 Sep...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Malaria Journal |
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| Online Access: | https://doi.org/10.1186/s12936-022-04420-2 |
| _version_ | 1797958848331382784 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adama Gansane |
| collection | DOAJ |
| description | 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 ≥ 14–69 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). |
| first_indexed | 2024-04-11T00:24:37Z |
| format | Article |
| id | doaj.art-f65785a4b7b84297a418e877222c7d6a |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-04-11T00:24:37Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-f65785a4b7b84297a418e877222c7d6a2023-01-08T12:05:21ZengBMCMalaria Journal1475-28752023-01-0122111610.1186/s12936-022-04420-2Randomized, 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 malariaAdama Gansane0Moussa Lingani1Adoke Yeka2Alain Nahum3Marielle Bouyou-Akotet4Ghyslain Mombo-Ngoma5Grace Kaguthi6Catalina Barceló7Bart Laurijssens8Cathy Cantalloube9Fiona Macintyre10Elhadj Djeriou11Andreas Jessel12Raphaël Bejuit13Helen Demarest14Anne Claire Marrast15Siaka Debe16Halidou Tinto17Afizi Kibuuka18Diolinda Nahum19Denise Patricia Mawili-Mboumba20Rella Zoleko-Manego21Irene Mugenya22Frederick Olewe23Stephan Duparc24Bernhards Ogutu25Centre National de Recherche et de Formation sur le Paludisme (CNRFP)Institut de Recherche en Science de la Santé - Unité de Recherche Clinique de Nanoro (IRSS-URCN)Infectious Diseases Research Collaboration (IDRC)Centre de Recherches Entomologique de Cotonou (CREC)Département de Parasitologie-Mycologie-Médecine Tropicale, Faculté de Médecine – Université des Sciences de la SantéCentre de Recherches Médicales de Lambaréné (CERMEL)Kenya Medical Research Institute-Centre for Respiratory Diseases Research (KEMRI-CRDR)Medicines for Malaria VentureBEL Pharm ConsultingSanofi Research and DevelopmentMedicines for Malaria VentureSanofi Research and DevelopmentSanofi Research and DevelopmentSanofi Research and DevelopmentMedicines for Malaria VentureMedicines for Malaria VentureCentre National de Recherche et de Formation sur le Paludisme (CNRFP)Institut de Recherche en Science de la Santé - Unité de Recherche Clinique de Nanoro (IRSS-URCN)Infectious Diseases Research Collaboration (IDRC)Centre de Recherches Entomologique de Cotonou (CREC)Département de Parasitologie-Mycologie-Médecine Tropicale, Faculté de Médecine – Université des Sciences de la SantéCentre de Recherches Médicales de Lambaréné (CERMEL)Kenya Medical Research Institute-Centre for Respiratory Diseases Research (KEMRI-CRDR)Centre for Clinical Research, Kenya Medical Research InstituteMedicines for Malaria VentureCentre for Clinical Research, Kenya Medical Research InstituteAbstract 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).https://doi.org/10.1186/s12936-022-04420-2ArtefenomelFerroquineCombination treatmentUncomplicated P. falciparum malariaClinical trialExposure–response |
| spellingShingle | 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 Malaria Journal Artefenomel Ferroquine Combination treatment Uncomplicated P. falciparum malaria Clinical trial Exposure–response |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Artefenomel Ferroquine Combination treatment Uncomplicated P. falciparum malaria Clinical trial Exposure–response |
| url | https://doi.org/10.1186/s12936-022-04420-2 |
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