Efficacy of 3 Regimens of Chloroquine and Primaquine for Treatment of P. Vivax Malaria, Cruzeiro do Sul, Acre, Brazil

Study Overview
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Brief Summary
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We plan to assess the efficacy of 3 different regimens of chloroquine and primaquine for the treatment of P. vivax infections in Cruzeiro do Sul, Acre, Brazil. Patients will be divided in 3 different groups: treatment with regular dose of primaquine (0.5 mg/kg per day for 7 days) with directly observed therapy; regular dose of primaquine without directly observed therapy; and increased total dose of primaquine (0.5 mg/kg per day for14 days) with directly observed therapy. All patients will receive chloroquine (CQ) for three days at a daily dose of approximately 25 mg/Kg in accordance with the Brazilian National Malaria Control guidelines. Clinical and parasitologic parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy and for a total period of 168 days (24 weeks) to evaluate chances of recrudescence, relapse, or reinfection. Results from this drug efficacy study will be used to assist the Brazilian Ministry of Health in assessing their national malaria treatment policy for P. vivax malaria.

Detailed Description
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Background: The World Health Organization recommends that antimalarial treatment policies be evaluated every few years to check their efficacy. P. vivax malaria is the most common species in Brazil and cases are concentrated in the Amazon Region in Brazil. Objectives: Assess the efficacy of 3 different regimens of chloroquine and primaquine for the treatment of P. vivax infections in Cruzeiro do Sul, Acre, Brazil. Methods: An in vivo drug efficacy study will be conducted in Cruzeiro do Sul, Acre State, Brazil. A total of 257 study participants ≥5 years of age with parasitologically confirmed P. vivax monoinfections will be included. Patients will be divided in 3 different groups: treatment with regular dose of primaquine (0.5 mg/kg per day for 7 days) with directly observed therapy; regular dose of primaquine without directly observed therapy; and increased total dose of primaquine (0.5 mg/kg per day for14 days) with directly observed therapy. All patients will receive chloroquine (CQ) for three days at a daily dose of approximately 25 mg/Kg in accordance with the Brazilian National Malaria Control guidelines. Primaquine will be given for 7 or 14 days under supervision or not, depending on the study group. Clinical and parasitologic parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy and for a total period of 168 days (24 weeks) to evaluate chances of recrudescence, relapse, or reinfection. Blood samples will be taken to measure the CQ levels in blood on Day 7 and day of failure, if occurring in the initial 28 days of follow up. In addition, a blood sample will be collected on filter paper on first day and on day of suspected failure to help differentiate parasite genotypes using techniques based on polymerase chain reaction. Results from this drug efficacy study will be used to assist the Brazilian Ministry of Health in assessing their national malaria treatment policy for P. vivax malaria.

Official Title
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Efficacy of Three Regimens of Chloroquine and Primaquine for the Treatment of Plasmodium Vivax Malaria in Cruzeiro do Sul, Acre, Brazil

Conditions
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P Vivax, Malaria, Vivax

Intervention / Treatment
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* Drug: Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age ≥5 years 2. Body weight <120 kg 3. Documented fever (axillary temperature ≥37.5o C) or history of fever during the previous 48 hours in the absence of another obvious cause of fever, such as pneumonia, otitis media, etc 4. Monoinfection with P. vivax with parasitemia between 100 and 200,000 asexual parasites/µl as determined by microscopic examination of thick and thin peripheral blood smears 5. Informed consent from the patient or parent/guardian (for those <18 years), assent from child (ages 7 to 17 years inclusive), patients 5 through 6 years old will not need an assent 6. Willingness on the part of the patient to return to the clinic and/or receive home visits for regular check-ups during the 24-week (168 days) follow-up period 7. Place of residence within 30-45 minutes of study site. Exclusion Criteria: 1. Presence of malaria danger signs Unable to drink Vomiting (more than twice in the previous 24 hours) Recent history of convulsions (one or more in the previous 24 hours) Impaired consciousness Unable to sit or stand 2. Presence of signs of severe malaria (WHO criteria) Cerebral malaria (unarousable coma) Severe anemia (hematocrit <15% or clinical signs) hemoglobin <5 mg/ml) (Note: we will use hemoglobin less than 8 mg/ml as exclusion criteria) Renal failure (serum creatinine >3 mg/dL or clinical signs) Pulmonary edema Hypoglycemia (blood glucose <40mg/dL or clinical signs) Shock (systolic blood pressure <70 mm Hg in adults; 50 mm Hg in children) Spontaneous bleeding/disseminate intravascular coagulation Repeated generalized convulsions Acidemia/acidosis (clinical signs) Macroscopic hemoglobinuria Jaundice 3. Self-reported presence of other underlying chronic or severe diseases (e.g., cardiac, renal, hepatic diseases, HIV/AIDS, tuberculosis, malnutrition, psoriasis) 4. History of hypersensitivity reactions to any of the drugs being tested. Mild itching with CQ is not in itself a criterion for exclusion. This occurrence will be evaluated by the study doctor before excluding the patient for this reason alone. 5. Use of drugs with antimalarial activity in the past 30 days. (Annex D) 6. Current pregnancy (either self-reported being pregnant at enrollment or a positive urine or plasma pregnancy test at time of enrollment), previous pregnancy is not an exclusion criteria 7. Hemoglobin <8 mg/mL 8. G6PD deficiency. This will be a late exclusion criteria as soon as the results of G6PD testing becomes available.

Ages Eligible for Study
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Minimum Age: 5 Years

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
Interventional Model Description: We plan to compare 3 different regimens of primaquine for P. vivax treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Primaquine Regular Dose Unsupervised<br>This is the regular primaquine dose Brazil without directly observed therapy. | Drug: Primaquine<br>* Different total dose and supervision.<br>* Other names: Primaquine dose;|
| Active Comparator: Primaquine Regular Dose Supervised<br>This is the regular primaquine dose in Brazil but with directly observed therapy. | Drug: Primaquine<br>* Different total dose and supervision.<br>* Other names: Primaquine dose;|
| Active Comparator: Primaquine Double Dose Unsupervised<br>This is the double total primaquine dose (14 days) in Brazil with directly observed therapy. | Drug: Primaquine<br>* Different total dose and supervision.<br>* Other names: Primaquine dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled | Participants with adequate clinical and parasitologic response among patients enrolled, meaning patients who did not fail treatment by day 28. Those are participants who at day 28 did not present clinical deterioration or presence of parasitemia. | 28 days | 
| Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled | Participants with adequate clinical and parasitologic response among patients enrolled, meaning patients who did not fail treatment by day 168. Those are participants who at day 168 did not present clinical deterioration or presence of parasitemia. | 168 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adequate Clinical and Parasitologic Response Based on Microsatellite-corrected Analysis Per Protocol Day 168 | Participants with microsatellite-corrected adequate clinical and parasitologic response among patients enrolled, meaning patients who did not fail treatment by day 168. Those are participants who at day 168 did not present clinical deterioration or presence of parasitemia with homologous (same genotype) parasites. | 168 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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treatment response, efficacy, primaquine, chloroquine