Safety and Efficacy of Different Regimens of Primaquine on Vivax Malaria Treatment in G6PD Deficient Patients

Study Overview
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Brief Summary
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A clinical study to assess the safety and efficacy of alternative regimens of primaquine for radical cure of vivax malaria in glucose 6-phosphate dehydrogenase (G6PD) deficient. G6PD deficient patients with P. vivax monoinfection will be treated with either weekly or delayed one-week course of primaquine, and the currently recommended by national guideline, 12-week chloroquine regimen to compare treatment safety among groups. All groups will be actively monitored for hemolysis during treatment and will have six-month follow-up period to assess treatment efficacy.

Detailed Description
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This is an open-label, randomized, phase II, clinical trial of safety and efficacy. Patients will be screened for eligibility and treated at the Fundação de Medicina Tropical Dr Heitor Vieira Dourado in Manaus and the Centro de Pesquisa em Medicina Tropical (Cepem) in Porto Velho, Brazil. A total of 104 vivax malaria patients will be recruited into the study, 52 G6PD deficient (Arm 1) and 52 G6PD normal (Arm 2). Patients with spectrophotometrically-confirmed G6PD deficiency (10-60% of adjusted mean male activity) will be divided into three subgroups of 10 patient each. All arms will receive standard 3-day chloroquine course. Additionally, Arm 1a will receive a delayed course of primaquine for 7 days, starting only at the fifth-day post-chloroquine initiation [ARM HALTED DUE TO SAFETY CONCERNS]. Arm 1b will receive weekly primaquine, once a week, for 8 weeks. Arm 1c will receive prophylactic 12-week course of chloroquine, as recommended by national guidelines for such patients (control group in terms of safety). Arm 2, the control group of efficacy, will receive standard regimen, comprised of 3-day chloroquine plus concomitant 7-day primaquine. All patients will receive directly observed therapy (DOT) and will be closely monitored for clinical parameters and laboratory markers of hemolysis including hemoglobin, methemoglobin, lactate dehydrogenase, haptoglobin, reticulocytes, indirect bilirubin, aspartate aminotransferase, and urinalysis. All groups will be followed for 6 months after treatment to assess relapse rate. Primary endpoint is the tolerability of the regimens defined by hemoglobin fall. Secondary endpoints include treatment failure (relapse during follow-up), frequency of adverse effects, and rate of hemoglobin fall during treatment.

Official Title
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Safety and Efficacy of Different Regimens of Primaquine on Vivax Malaria Treatment in Glucose 6-phosphate Dehydrogenase Deficient Patients

Conditions
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Vivax Malaria, G6PD Deficiency

Intervention / Treatment
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* Drug: Chloroquine
* Drug: Primaquine
* Drug: Primaquine
* Drug: Chloroquine
* Drug: Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Uncomplicated vivax malaria monoinfection G6PD deficiency ranging from 10%-60% of adjusted mean male activity Baseline hemoglobin >9 g/dL Willing to comply with study requirements Exclusion Criteria: Pregnancy or breastfeeding Comorbidities (hepatopathy and/or nephropathy) Use of antimalarials in the previous two weeks or current use of potentially hemolytic drugs Any condition which would place the subject at undue risk of hemolysis or interfere with the results of the study, as judged by investigator.

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1a: Chloroquine + 5th-day Primaquine<br>[ARM HALTED PREMATURELY DUE TO SAFETY CONCERNS] | Drug: Chloroquine<br>* Standard chloroquine (three days)<br>Drug: Primaquine<br>* Daily Primaquine (0.5 mg of base/kg/day for seven days) starting only at the fifth day post chloroquine initiation.<br>|
| Experimental: 1b: Chloroquine + 8-week Primaquine<br>26 G6PD deficient patients. Directly observed therapy. | Drug: Chloroquine<br>* Standard chloroquine (three days)<br>Drug: Primaquine<br>* Weekly primaquine (0.75 mg of base/kg/week for eight weeks) starting with first dose of chloroquine.<br>|
| Active Comparator: 1c: Chloroquine + 12-week Chloroquine<br>26 G6PD deficient patients. Control group in terms of safety. Directly observed therapy. | Drug: Chloroquine<br>* Standard chloroquine (three days)<br>Drug: Chloroquine<br>* Weekly, once a week chloroquine (5 mg of base/kg/week for twelve weeks)<br>|
| Active Comparator: 2: Standard chloroquine + primaquine<br>52 G6PD normal patients. Control group in terms of efficacy. Directly observed therapy. | Drug: Chloroquine<br>* Standard chloroquine (three days)<br>Drug: Primaquine<br>* Standard primaquine (0.5mg of base/kg/day for seven days) concomitant with chloroquine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute or relative change in hemoglobin < 3g/dL or 30% from baseline | Hemoglobin reduction from baseline after exposure to primaquine for P. vivax treatment | From date of randomization until the date of last dose, assessed up to 12 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regimen efficacy | Relapse rate over follow-up period after treatment | 6 months post treatment | 
| Adverse effects | Presence of adverse reactions as a result of intervention, measured by clinical and laboratory tests | From date of randomization until the date of first documented event, assessed up to 12 weeks. | 
| Change in hemoglobin values over treatment | Absolute variation of hemoglobin levels before and during intervention. | through study completion: before intervention and up to 12 weeks during intervention. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vivax malaria, G6PD deficiency, Acute hemolytic anemia, Primaquine, Weekly primaquine, Chloroquine, Weekly chloroquine, Brazilian Amazon, Oxidative stress