Clinical trial NCT03610399: Efficacy of 3 Regimens of Chloroquine and Primaquine for Treatment of P. Vivax Malaria, Cruzeiro do Sul, Acre, Brazil
Official title: Efficacy of Three Regimens of Chloroquine and Primaquine for the Treatment of Plasmodium Vivax Malaria in Cruzeiro do Sul, Acre, Brazil
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: P Vivax
Malaria, Vivax
Keywords: treatment response
efficacy
primaquine
chloroquine
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: Ministry of Health, Brazil
name: Evandro Chagas National Institute of Infectious Disease
First posted: 2018-08-01
Enrollment: 257
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: We plan to compare 3 different regimens of primaquine for P. vivax treatment.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

  1. Unable to drink
  2. Vomiting (more than twice in the previous 24 hours)
  3. Recent history of convulsions (one or more in the previous 24 hours)
  4. Impaired consciousness
  5. Unable to sit or stand 2. Presence of signs of severe malaria (WHO criteria)

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  1. Cerebral malaria (unarousable coma)
  2. Severe anemia (hematocrit \<15% or clinical signs) hemoglobin \<5 mg/ml) (Note: we will use hemoglobin less than 8 mg/ml as exclusion criteria)
  3. Renal failure (serum creatinine \>3 mg/dL or clinical signs)
  4. Pulmonary edema
  5. Hypoglycemia (blood glucose \<40mg/dL or clinical signs)
  6. Shock (systolic blood pressure \<70 mm Hg in adults; 50 mm Hg in children)
  7. Spontaneous bleeding/disseminate intravascular coagulation
  8. Repeated generalized convulsions
  9. Acidemia/acidosis (clinical signs)
  10. Macroscopic hemoglobinuria
  11. 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.

Primary outcomes:
measure: Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled
timeFrame: 28 days
measure: Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled
timeFrame: 168 days
Secondary outcomes:
measure: Participants With Adequate Clinical and Parasitologic Response Based on Microsatellite-corrected Analysis Per Protocol Day 168
timeFrame: 168 days
Other outcomes:
Locations:
city: Cruzeiro do Sul
country: Brazil
facility: Hospital do Jurua
Study officials:
affiliation: Centers for Disease Control and Prevention
name: Alexandre Macedo de Oliveira, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chamma-Siqueira NN, Negreiros SC, Ballard SB, Farias S, Silva SP, Chenet SM, Santos EJM, Pereira de Sena LW, Povoa da Costa F, Cardoso-Mello AGN, Marchesini PB, Peterka CRL, Viana GMR, Macedo de Oliveira A. Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2022 Mar 31;386(13):1244-1253. doi: 10.1056/NEJMoa2104226.