Evaluation of the Safety of Primaquine in Combination With Dihydroartemisinin-piperaquine in G6PD Deficient Males in The Gambia (SAFEPRIM-II)

Evaluation of the Safety of Primaquine in Combination With Dihydroartemisinin-piperaquine in G6PD Deficient Males in The Gambia

Evaluation of the Safety of Primaquine in Combination With Dihydroartemisinin-piperaquine in G6PD Deficient Males in The Gambia

Enrollment took longer than anticipated; it was financially and logistically impossible to recruit the final cohort (G6PDd 0.4mg/kg PQ).

The purpose of this study is to evaluate the tolerability and safety of increasing doses of primaquine in combination with dihydroartemisinin-piperaquine in G6PD deficient males.

In the current study the investigators aim to assess safety of PQ, in particular the risk of acute haemolysis, when given together with dihydroartemisinin-piperaquine (DHAP) in G6PD deficient individuals. Forty male participants with haemoglobin levels (≥11g/dL), reduced G6PD enzyme function, and aged ≥10years will be sequentially enrolled into two dosing cohorts consisting of 20 individuals and doses of 0.25 and 0.4 mg/kg PQ in combination with a full three-day course of DHAP. Participants will first be assigned to the lowest open cohort; enrolment in the next cohort is initiated after tolerability and short-term safety is demonstrated at the preceding lower dose. Furthermore, the investigators will include 3 control groups into the first cohort: i) 10 male participants aged ≥10years with normal haemoglobin levels (≥11g/dL) and a reduced G6PD enzyme function will receive DHAP only, ii) 10 male participants with normal haemoglobin levels (≥11g/dL) and normal G6PD enzyme function will receive 0.25 mg/kg PQ in combination with a full three-day course of DHAP, and iii) 10 male participants with normal haemoglobin levels (≥11g/dL) and normal G6PD enzyme function will receive 0.4 mg/kg PQ with DHAP. Enrolment and group assignment Individuals who agree to participate for screening and meet all inclusion criteria, will be invited for enrolment. During this, participants and/or their carers will be informed again about the objectives and practical consequences of participation in the current study and asked to sign an informed consent form. The possibility of withdrawal from the study, at any time and without any declaration of the reason will again be pointed out. After enrolment, participants will be assigned to the lowest-dose open cohort, with enrolment in the second cohort initiated after tolerability and short-term safety is demonstrated at the preceding lower dose (this enrolment to the second cohort accounts for G6PD deficient participants only). Within each cohort, the first 2 participants of the intervention group are treated and monitored for 6 days for immediate side-effects and haematological abnormalities before the rest of the participants of that particular intervention group are enrolled and treated. Once safety of these first 2 participants is confirmed, the next 4 subjects are enrolled and treatment for the next 4 subjects is initiated on day 2 of the last treated participant of the preceding 4 subjects. The last two groups for each intervention group comprise 5 individuals, making a total of 20. After inclusion of the intervention group of the first cohort (n=20) is completed (follow-up day 14 of last participant in that group), a 10-day safety observation period is installed before enrolment of the intervention group of the second cohort is initiated. Interventions and evaluation Clinical follow-up of participants and sampling will be done twice daily for the first 4 days (days 0, 1, 2 and 3) and once daily on days 4, 5, 7, 10, 14 and 28. At each time-point participants will be examined clinically (except for day 28) and a structured questionnaire is used to determine the occurrence of side effects. Furthermore, laboratory safety parameters are measured, including haematology, biochemistry, and urine dipstick for haemoglobinuria/urobilinogen. Five individuals from each intervention group (total of 10) will also be asked to provide seven venous blood samples (of less than 1 mls each) on days 0, 1 and 2 to study pharmacokinetics of PQ in G6PD deficient individuals

G6PD deficient participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days

G6PD deficient participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.25mg/kg of primaquine on the first day of DHAP treatment.

G6PD deficient participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.4mg/kg of primaquine on the first day of DHAP treatment.

G6PD normal participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.25mg/kg of primaquine on the first day of DHAP treatment.

G6PD normal participants will be treated with dihydroartemisinin-piperaquine (Eurartesim®; Sigma Tau) administered as 3 tablets (40mg PPQ, 320mg DHA) in a once daily regimen for three days in combination with a single dose of 0.4mg/kg of primaquine on the first day of DHAP treatment.

Haematology abnormalities during follow-up: haptoglobin concentration measured in venous blood samples by full blood count analysis

Number of participants with treatment-related adverse events graded and evaluated in terms of relatedness

grading and assessing relatedness will be done following according to criteria of the NIH/NIAID division of microbiology and infectious diseases (DMID)https://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Documents/dmidadulttox.pdf

Haematology abnormalities during follow-up: mean corpuscular volume (MCV) measured in venous blood samples by full blood count analysis

Haematology abnormalities during follow-up: red cell distribution width (RDW) measured in venous blood samples by full blood count analysis

Haematology abnormalities during follow-up: leukocyte count measured in venous blood samples by full blood count analysis

Inclusion Criteria: G6PD deficiency by fluorescent Spot test (for intervention groups and control group receiving DHA-PPQ only (N=50) G6PD normal activity by fluorescent Spot test for control groups (N=20) Informed consent by participant or caregiver (an assent is required for those 12-17 years) Exclusion Criteria: Enrolled in another clinical trial Fever: temperature >37.5°C (axillary) or history of fever in the last 24 hours Evidence of severe illness or active infection other than malaria Known allergy to study medications Hb <11 g/dL Antimalarials taken within the last 2 weeks PQ taken within the last 4 weeks and blood transfusion within the last 90 days Current use of tuberculosis or anti-retroviral medication, sulphonamides, dapsone, nitrofurantoin, nalidixic acid, ciprofloxacin, methylene blue, toluidine blue, phenazopyridine and co-trimoxazole. History of severe chronic illness

Eziefula AC, Pett H, Grignard L, Opus S, Kiggundu M, Kamya MR, Yeung S, Staedke SG, Bousema T, Drakeley C. Glucose-6-phosphate dehydrogenase status and risk of hemolysis in Plasmodium falciparum-infected African children receiving single-dose primaquine. Antimicrob Agents Chemother. 2014 Aug;58(8):4971-3. doi: 10.1128/AAC.02889-14. Epub 2014 Jun 9.

Bastiaens GJH, Tiono AB, Okebe J, Pett HE, Coulibaly SA, Goncalves BP, Affara M, Ouedraogo A, Bougouma EC, Sanou GS, Nebie I, Bradley J, Lanke KHW, Niemi M, Sirima SB, d'Alessandro U, Bousema T, Drakeley C. Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials. PLoS One. 2018 Jan 11;13(1):e0190272. doi: 10.1371/journal.pone.0190272. eCollection 2018.