• View in gallery
    Figure 1.

    Parasite counts for P. vivax asexual forms and gametocytes evaluated using light microscopy and qPCR from pre-dose until parasite clearance. MMV390048 was dosed at time 0.

  • 1.

    World Health Organization , 2021. World malaria report. Available at: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021. Accessed July 11, 2022.

  • 2.

    Duffey M , Blasco B , Burrows JN , Wells TNC , Fidock DA , Leroy D , 2021. Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials. Trends Parasitol 37: 709721.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Mustiere R , Vanelle P , Primas N , 2020. Plasmodial kinase inhibitors targeting malaria: recent developments. Molecules 25: 5949.

  • 4.

    Sternberg AR , Roepe PD , 2020. Heterologous expression, purification, and functional analysis of the Plasmodium falciparum phosphatidylinositol 4-kinase iiibeta. Biochemistry 59: 24942506.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ghidelli-Disse S et al.2014. Identification of Plasmodium PI4 kinase as target of MMV390048 by chemoproteomics. Malar J 13 (Suppl 1 ):38.

  • 6.

    Paquet T et al.2017. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med 9: eaad9735.

  • 7.

    Sinxadi P et al.2020. Safety, tolerability, pharmacokinetics, and antimalarial activity of the novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in healthy volunteers. Antimicrob Agents Chemother 64: e01896-19.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    McCarthy JS et al.2020. A phase 1, placebo-controlled, randomized, single ascending dose study and a volunteer infection study to characterize the safety, pharmacokinetics, and antimalarial activity of the Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048. Clin Infect Dis 71: e657e664.

    • Search Google Scholar
    • Export Citation
  • 9.

    European Medicines Agency , 2017. Guideline on clinical development of fixed combination medicinal products. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development-fixed-combination-medicinal-products-revision-2_en.pdf. Accessed June 2, 2022.

  • 10.

    World Health Organization , 2016. Malaria microscopy quality assurance manual, version 2. Available at: https://apps.who.int/iris/handle/10665/204266. Accessed November 14, 2021.

  • 11.

    Gruenberg M et al.2020. Utility of ultra-sensitive qPCR to detect Plasmodium falciparum and Plasmodium vivax infections under different transmission intensities. Malar J 19: 319.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Mimche SM , Lee CM , Liu KH , Mimche PN , Harvey RD , Murphy TJ , Nyagode BA , Jones DP , Lamb TJ , Morgan ET , 2019. A non-lethal malarial infection results in reduced drug metabolizing enzyme expression and drug clearance in mice. Malar J 18: 234.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    De-Oliveira AC , Carvalho RS , Paixao FH , Tavares HS , Gueiros LS , Siqueira CM , Paumgartten FJ , 2010. Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models. Malar J 9: 81.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    McCarthy JS , Furner RL , Van Dyke K , Stitzel RE , 1970. Effects of malarial infection on host microsomal drug-metabolizing enzymes. Biochem Pharmacol 19: 13411349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Desta Z , Zhao X , Shin JG , Flockhart DA , 2002. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41: 913958.

  • 16.

    Kalow W , 1997. Pharmacogenetics in biological perspective. Pharmacol Rev 49: 369379.

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Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria

Rezika MohammedDepartment of Internal Medicine, University of Gondar Hospital, Gondar, Ethiopia;

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Mezgebu Silamsaw AsresDepartment of Internal Medicine, University of Gondar Hospital, Gondar, Ethiopia;

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Esayas Kebede GudinaJimma University Clinical Trial Unit, Jimma University Institute of Health, Jimma, Ethiopia;
Department of Internal Medicine, Jimma University Institute of Health, Jimma, Ethiopia;

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Wondimagegn AdissuJimma University Clinical Trial Unit, Jimma University Institute of Health, Jimma, Ethiopia;
School of Medical Laboratory Sciences, Jimma University Institute of Health, Jimma, Ethiopia;

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Hilary JohnstoneHJ-Clinical Trial Consultancy, George, South Africa;

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Anne Claire MarrastMedicines for Malaria Venture, Geneva, Switzerland

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Cristina DoniniMedicines for Malaria Venture, Geneva, Switzerland

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Stephan DuparcMedicines for Malaria Venture, Geneva, Switzerland

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Daniel YilmaJimma University Clinical Trial Unit, Jimma University Institute of Health, Jimma, Ethiopia;
Department of Internal Medicine, Jimma University Institute of Health, Jimma, Ethiopia;

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ABSTRACT.

An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Plasmodium vivax malaria. The study was not completed for operational reasons and emerging teratotoxicity data. For the eight adult male patients enrolled, adequate clinical and parasitological response at day 14 (primary endpoint) was 100% (8/8). Asexual parasites and gametocytes were cleared in all patients by 66 and 78 hours postdose, respectively. There were two recurrent P. vivax infections (days 20 and 28) and a new Plasmodium falciparum infection (day 22). MMV390048 exposure in P. vivax patients was lower than previously observed for healthy volunteers. Mild adverse events, mainly headache and gastrointestinal symptoms, were reported by eight patients. Single-dose MMV390048 (120 mg) rapidly cleared asexual parasites and gametocytes in patients with P. vivax malaria and was well tolerated.

Malaria remains major threat to global health.1 The need for new measures to support malaria elimination and the emergence of drug-resistant Plasmodium strains requires the discovery and development of new antimalarial drugs.2

MMV390048 is a phosphatidylinositol 4-kinase inhibitor with in vitro activity against all Plasmodium life cycle stages, excepting late-stage hypnozoites in the liver.35 MMV390048 lacks cross-resistance with current antimalarial drugs,6 and in vivo studies showed both transmission blocking and chemoprotective activity.6 In phase I clinical studies, MMV390048 was well tolerated at doses up to 120 mg.7,8 Pharmacokinetic/pharmacodynamic modeling predicted that an adequate clinical and parasitological response (ACPR) > 80% would be achieved at day 14 posttreatment with a single 120-mg dose of MMV390048 with 92% certainty.8 Thus, MMV390048 has potential as a single-dose therapy for the treatment and control of malaria,68 although this would require combination with a suitable partner drug with antimalarial activity.

This open label, adaptive, phase IIa study was designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of MMV390048 in adult patients with uncomplicated malaria. The study was conducted between October 6, 2017 and January 5, 2018 at two hospitals in Ethiopia (in Gondar and Jimma). Recruitment was suspended on December 4, 2017 to allow assessment of a teratogenicity signal in a concurrent investigation in rodents.9 Although approval to restart the study was obtained in August 2019, the study was terminated on October 21, 2020 for operational reasons related to the coronavirus 2019 pandemic and because of the teratogenic findings. Herein, we briefly describe the study design and report the abbreviated dataset on the eight enrolled patients.

The study protocol was approved by the independent Ethics Committees of the College of Public Health and Medical Sciences, Jimma University (now the Institute of Health Institutional Review Board), the Institutional Review Board of the University of Gondar, Ethiopia, and the Ethiopian National Research Ethics Review Committee and Ethiopian Food and Drug Administration, Addis Ababa, and was registered with ClinicalTrials.gov (NCT02880241). Study conduct conformed to the national regulatory requirements of Ethiopia and the Declaration of Helsinki.

Planned enrollment was for three P. vivax and three P. falciparum cohorts of 17 patients each (102 patients in total). MMV390048 was supplied as 20-mg tablets (Medicines for Malaria Venture, Geneva, Switzerland). The first P. vivax and P. falciparum cohorts were to receive a single 120-mg oral dose of MMV390048 in the fasted state, with de-escalating dosing of subsequent cohorts determined by the results obtained. Four patients were to be enrolled into the P. vivax arm and followed until day 14 before enrolment into the P. falciparum arm was to begin, dependent on an acceptable review by the safety review team.

Eligible patients were adults aged 18–55 years, weighing 40–90 kg with microscopically confirmed P. vivax or P. falciparum monoinfection (1,000–40,000 asexual parasites per microliter of blood), fever or history of fever within the previous 48 hours for P. vivax and 24 hours for P. falciparum, and no signs or symptoms of severe or complicated malaria. Patients were admitted and received a single oral dose of 120-mg MMV390048 on day 0 and remained as inpatients until day 3 and two consecutive negative parasite assessments. Outpatient follow-up visits were made on days 7, 10/11, 14, 17/18, 21, 24/25, and 28. Rescue therapy for P. vivax was chloroquine. At the time of the study start, primaquine was not the standard of care in Ethiopia for patients living in malaria endemic regions. However, primaquine radical cure was administered to six of eight patients at the investigator’s discretion after a negative glucose-6-phosphate dehydrogenase test.

Giemsa-stained thick and thin blood films for parasite identification and enumeration were prepared using standard methods.10 Species-specific Pf_ and Pv_18S rRNA quantitative polymerase chain reaction (qPCR) was consistent with published protocols.11 MMV390048 plasma concentrations were determined using a validated assay and analyzed using non-compartmental methods.7,8 Adverse events were coded according to MedDRA version 23.0.

The primary outcome for P. vivax malaria was unadjusted ACPR at day 14, defined as complete clearance of microscopically detected parasitemia without previous treatment failure. This enabled a rapid readout of clinical efficacy (i.e., early treatment failure) and safety for dose adjustment of subsequent cohorts and progression to enrolment of the P. falciparum arm. Secondary efficacy outcomes for P. vivax were ACPR and recurrence rate at day 28. Safety outcomes included the frequency of adverse events up to day 35, and signs and symptoms of malaria up to day 28. Parasite clearance kinetics and MMV390048 pharmacokinetics were also planned analyses. Summary statistics were prepared for efficacy and safety data; no inferential statistical analysis was performed for this abbreviated dataset.

The eight enrolled patients were males, self-defined as black, mean age 24.5 years (range 20–50 years), with a mean (SD) body mass index of 18.1 (1.2) kg/m2. All were infected with P. vivax malaria with a mean (SD) pre-dose asexual parasite count of 6,406 (6767) parasites/μL.

The primary endpoint of ACPR at day 14 was 100% (8/8). Asexual parasites were cleared by 24 hours postdose in four patients, by 48 hours in two patients, and by 66 hours in the remaining two patients (Figure 1). All patients remained parasite free until day 14. Recurrent P. vivax infection was reported in two patients (days 20 and day 28), both of whom received primaquine. A new P. falciparum infection was detected on day 22 in one patient (no primaquine). Thus, ACPR at day 28 was 62.8% (5/8) in the modified intention-to-treat analysis, and 71.4% (5/7) when the patient with the new P. falciparum infection was excluded.

Figure 1.
Figure 1.

Parasite counts for P. vivax asexual forms and gametocytes evaluated using light microscopy and qPCR from pre-dose until parasite clearance. MMV390048 was dosed at time 0.

Citation: The American Journal of Tropical Medicine and Hygiene 108, 1; 10.4269/ajtmh.22-0567

Gametocytes were detected in all patients at baseline and were cleared by 24 hours postdose in four patients, by 30 hours in two patients, and by 78 hours in two patients (Figure 1). Gametocytes were detectable in the two patients with P. vivax recurrence on days 20 and 28.

Using qPCR, parasite clearance was achieved between 20 and 161 hours (Figure 1), with three recurrences detected (days 17, 20, and 22). Overall, MMV390048 rapidly cleared both asexual parasites and gametocytes, although recurrent infections before day 28 suggest that greater drug exposure is needed to maintain efficacy, particularly in patients with high baseline parasitemia (Figure 1).

MMV390048 pharmacokinetic parameters are shown in Table 1. Although Cmax (peak plasma concentration) was comparable with studies in healthy volunteers, t1/2 (estimated elimination phase half-life) and AUCinf (area under the concentration–time curve from 0 hour to infinity) were lower than previously reported (Table 1).7,8 The reasons for these differences are currently unknown, but drug exposures between patients were highly variable, most likely because of variable bioavailability and the small number of patients available for comparison across the studies. Less likely, but observed for some other antimalarials, are the possible effects on drug metabolism of inflammation caused by P. vivax infection1214 and pharmacogenetic differences.15,16

Table 1

Plasma pharmacokinetic parameters for a single 120-mg dose of MMV390048 in adult patients with P. vivax malaria from Ethiopia compared with previously reported data from healthy volunteers from Australia8 and South Africa7

Pharmacokinetic parameter Ethiopia (N = 8) Australia (N = 6) South Africa (N = 5)
Cmax, μg/mL 0.5 (59.0) 1.1 (36.6) 0.5 (85.5)
Tmax, hours 2.0 (2.0–12.0) 1.0 (1.0–3.0) 1.0 (1.0–3.0)
t1/2, hours 37.4 (57.7) 2135.2 (143.1–271.5)* 206.1 (32.9)
AUClast, μg⋅h/mL 16.7 (57.7) 123.2 (28.5) Not available
AUCinf, μg⋅h/mL 17.3 (57.0) 137.8 (33.6) 82.6 (165.8)

Values are geometric mean (coefficient of variation), except for Tmax, which is median (range). AUCinf = area under the concentration–time curve from 0 hour to infinity; AUClast = area under the concentration–time curve from 0 hour to the last measured time point; Cmax = peak plasma concentration; t1/2 = estimated elimination phase half-life; Tmax = time point at which peak plasma concentration is reached.

The reported t1/2 in this study was median (range).

There were no deaths, serious adverse events, or adverse events leading to study discontinuation. A total of 27 adverse events were reported during the study across all eight patients (Table 2). All adverse events were grade 1 (mild); headache and abdominal discomfort were most commonly reported (Table 2). Seven drug-related adverse events were reported in four patients: abdominal discomfort, abdominal pain, constipation, dyspepsia, headache, neutropenia, and decreased hemoglobin.

Table 2

Adverse events of any cause

Adverse event MMV390048 (N = 8) n (%) patients/n events
At least one adverse event 8 (100.0)/27
Headache 5 (62.5)/6
Abdominal discomfort 2 (25.0)/2
Abdominal pain 1 (12.5)/1
Constipation 1 (12.5)/1
Dyspepsia 1 (12.5)/1
Nausea 1 (12.5)/1
Oral discomfort 1 (12.5)/1
Vomiting 1 (12.5)/1
Ascariasis 1 (12.5)/1
Carbuncle 1 (12.5)/1
Hookworm infection 1 (12.5)/1
Plasmodium falciparum infection 1 (12.5)/1
Upper respiratory tract infection 1 (12.5)/1
Decreased appetite 1 (12.5)/2
Neutropenia* 1 (12.5)/1
Sinus tachycardia* 1 (12.5)/1
Fatigue 1 (12.5)/1
Hemoglobin decreased* 1 (12.5)/1
Arthralgia 1 (12.5)/1
Urinary tract discomfort 1 (12.5)/1

Adverse event of special interest.

There were three adverse events of special interest occurring in two patients. One patient had neutropenia, considered possibly drug related. This event started on day 2 (baseline neutrophil count 3.39 × 109/L; 0.97 × 109/L on day 2) and spontaneously resolved by day 6 and was concurrent with an upper respiratory tract infection that started on day 3. One patient had sinus tachycardia on day 1 that resolved the same day and was considered related to malaria infection. This patient also had decreased hemoglobin on day 2 (baseline 13.9 g/dL; 11.8 g/dL on day 2) that had resolved by day 6 and was considered related to drug treatment and malaria infection.

Clinical laboratory tests showed no drug-related trends. Baseline low platelet and hemoglobin levels, consistent with malaria infection, tended to improve throughout the study. There were no other safety concerns.

In summary, a single oral dose of 120-mg MMV390048 rapidly cleared asexual parasites and gametocytes in eight male patients with P. vivax malaria. ACPR was 100% at day 14, but with recurrent P. vivax infection in two patients (days 20 and 28). MMV390048 drug exposures were lower than expected based on previous findings in healthy volunteers. There were no safety or tolerability concerns with MMV390048 administration.

ACKNOWLEDGMENTS

We thank the patients for their participation. The contributions of the study staff are acknowledged, including Cherinet Abebe, Alemseged Abdissa Lencho, Abebe Genetu Bayih, Gebrehiwot Lemma, Solomon Afework, Zeleke Alemu, Mubarik Taju, Meseret Birhanie Fentahune, Abdulhakim Abamecha Abafogi, Seid Amdala, Kaleab Eskinder, Gelila Meneberu, Rawuda Ebrhaim, Kinde W/Giyorgis, Eshetu Mulisa, Zerihun Befkadu, Bizuworek Sharew, Yeneneh Berhanu, Ligabaw Worku Gebremariam, Melese Abera, Mulugeta Aemro, Begosew Debas, Asnakew Engidaw, and Habtie Tesfa Delelegn. The contributions of Helen Demarest, Susan Podmore, and Charles Stoyanov for additional support in study management are acknowledged. We thank the Swiss Tropical Public Health Institute and Harald Noedl for their contributions to laboratory training during the study and Martina Wibberg of DATAMAP GmbH for statistical support. Naomi Richardson of Magenta Communications, funded by Medicines for Malaria Venture, wrote the first draft of this article and provided editorial and graphic services. The authors confirm that all ongoing and related trials for this drug/intervention are registered (#NCT02880241).This trial is registered at ClinicalTrials.gov (#NCT02880241, https://clinicaltrials.gov/ct2/show/NCT02880241).

REFERENCES

  • 1.

    World Health Organization , 2021. World malaria report. Available at: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021. Accessed July 11, 2022.

  • 2.

    Duffey M , Blasco B , Burrows JN , Wells TNC , Fidock DA , Leroy D , 2021. Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials. Trends Parasitol 37: 709721.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Mustiere R , Vanelle P , Primas N , 2020. Plasmodial kinase inhibitors targeting malaria: recent developments. Molecules 25: 5949.

  • 4.

    Sternberg AR , Roepe PD , 2020. Heterologous expression, purification, and functional analysis of the Plasmodium falciparum phosphatidylinositol 4-kinase iiibeta. Biochemistry 59: 24942506.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ghidelli-Disse S et al.2014. Identification of Plasmodium PI4 kinase as target of MMV390048 by chemoproteomics. Malar J 13 (Suppl 1 ):38.

  • 6.

    Paquet T et al.2017. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med 9: eaad9735.

  • 7.

    Sinxadi P et al.2020. Safety, tolerability, pharmacokinetics, and antimalarial activity of the novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in healthy volunteers. Antimicrob Agents Chemother 64: e01896-19.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    McCarthy JS et al.2020. A phase 1, placebo-controlled, randomized, single ascending dose study and a volunteer infection study to characterize the safety, pharmacokinetics, and antimalarial activity of the Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048. Clin Infect Dis 71: e657e664.

    • Search Google Scholar
    • Export Citation
  • 9.

    European Medicines Agency , 2017. Guideline on clinical development of fixed combination medicinal products. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development-fixed-combination-medicinal-products-revision-2_en.pdf. Accessed June 2, 2022.

  • 10.

    World Health Organization , 2016. Malaria microscopy quality assurance manual, version 2. Available at: https://apps.who.int/iris/handle/10665/204266. Accessed November 14, 2021.

  • 11.

    Gruenberg M et al.2020. Utility of ultra-sensitive qPCR to detect Plasmodium falciparum and Plasmodium vivax infections under different transmission intensities. Malar J 19: 319.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Mimche SM , Lee CM , Liu KH , Mimche PN , Harvey RD , Murphy TJ , Nyagode BA , Jones DP , Lamb TJ , Morgan ET , 2019. A non-lethal malarial infection results in reduced drug metabolizing enzyme expression and drug clearance in mice. Malar J 18: 234.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    De-Oliveira AC , Carvalho RS , Paixao FH , Tavares HS , Gueiros LS , Siqueira CM , Paumgartten FJ , 2010. Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models. Malar J 9: 81.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    McCarthy JS , Furner RL , Van Dyke K , Stitzel RE , 1970. Effects of malarial infection on host microsomal drug-metabolizing enzymes. Biochem Pharmacol 19: 13411349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Desta Z , Zhao X , Shin JG , Flockhart DA , 2002. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41: 913958.

  • 16.

    Kalow W , 1997. Pharmacogenetics in biological perspective. Pharmacol Rev 49: 369379.

Author Notes

Address correspondence to Stephan Duparc, Medicines for Malaria Venture, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland. E-mail: duparcs@mmv.org

Financial support: The study was funded, designed, conducted, and analyzed by Medicines for Malaria Venture. Medicines for Malaria Venture is funded by several donors. Unrestricted funding comes from several donors, including the Foreign Commonwealth and Development Office, German Ministry for Education and Research, Bill & Melinda Gates Foundation, Ireland Department of Foreign Affairs and Trade (IrishAid), Australia Department of Foreign Affairs and Trade, Swiss Agency for Development and Cooperation, and the Principality of Monaco. These funders had no role in the design, conduct, or analysis of the trial.

This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant number INV-007155). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.

Data availability: Anonymised subject data are available on reasonable request from the corresponding author.

Disclosure: A.C.M., C.D., and S.D. are employees of Medicines for Malaria Venture. H.J. is a former independent consultant for Medicines for Malaria Venture.

Authors’ addresses: Rezika Mohammed and Mezgebu Silamsaw Asres, Department of Internal Medicine, University of Gondar Hospital, Gondar, Ethiopia, E-mails: rezikamohammed@yahoo.com and msilamsaw@gmail.com. Esayas Kebede Gudina, Wondimagegn Adissu Jimma, and Daniel Yilma, University Clinical Trial Unit, Jimma University Institute of Health, Jimma, Ethiopia, E-mails: esakgd@gmail.com, wondimagegn.adissu@ju.edu.et, and danielyilmab@gmail.com. Hilary Johnstone, HJ-Clinical Trial Consultancy, George, South Africa, E-mail: hjohnstone@hjclinical.com. Stephan Duparc, Medicines for Malaria Venture, Geneva, Switzerland, E-mail duparcs@mmv.org.

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