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

• Sponsor: Centers for Disease Control and Prevention (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT03610399
• Collaborator: Ministry of Health, Brazil (Other), Evandro Chagas National Institute of Infectious Disease (Other)
• Enrollment: 257
• Location: 1
• Arms: 3
• Actual Duration (Months): 11.1
• Patients Per Site Per Month: 23.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
P Vivax; Malaria, Vivax	Drug: Primaquine	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 257 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: We plan to compare 3 different regimens of primaquine for P. vivax treatment.We plan to compare 3 different regimens of primaquine for P. vivax treatment.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy of Three Regimens of Chloroquine and Primaquine for the Treatment of Plasmodium Vivax Malaria in Cruzeiro do Sul, Acre, Brazil
• Actual Study Start Date: Apr 9, 2018
• Actual Primary Completion Date: Mar 12, 2019
• Actual Study Completion Date: Mar 12, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled [28 days]

   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.

2. Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled [168 days]

   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.

Secondary Outcome Measures

1. Participants With Adequate Clinical and Parasitologic Response Based on Microsatellite-corrected Analysis Per Protocol Day 168 [168 days]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

6. Cerebral malaria (unarousable coma)

7. Severe anemia (hematocrit <15% or clinical signs) hemoglobin <5 mg/ml) (Note: we will use hemoglobin less than 8 mg/ml as exclusion criteria)

8. Renal failure (serum creatinine >3 mg/dL or clinical signs)

9. Pulmonary edema

10. Hypoglycemia (blood glucose <40mg/dL or clinical signs)

11. Shock (systolic blood pressure <70 mm Hg in adults; 50 mm Hg in children)

12. Spontaneous bleeding/disseminate intravascular coagulation

13. Repeated generalized convulsions

14. Acidemia/acidosis (clinical signs)

15. Macroscopic hemoglobinuria

16. 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.

17. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital do Jurua	Cruzeiro do Sul		Brazil

Sponsors and Collaborators

• Centers for Disease Control and Prevention
• Ministry of Health, Brazil
• Evandro Chagas National Institute of Infectious Disease

Investigators

• Principal Investigator: Alexandre Macedo de Oliveira, MD, Centers for Disease Control and Prevention

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Dec 20, 2017

More Information

Publications

None provided.

• Responsible Party: Centers for Disease Control and Prevention
• ClinicalTrials.gov Identifier: NCT03610399
• Other Study ID Numbers: 7061
• First Posted: Aug 1, 2018
• Last Update Posted: Aug 9, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Centers for Disease Control and Prevention: treatment response; efficacy; primaquine; chloroquine
• Additional relevant MeSH terms: Malaria; Malaria, Vivax; Primaquine

Study Results

Participant Flow

Arm/Group Title	Primaquine Regular Dose Unsupervised	Primaquine Regular Dose Supervised	Primaquine Double Dose Unsupervised
Arm/Group Description	This is the regular primaquine dose (3.5 mg/kg) Brazil without directly observed therapy. Primaquine: Different total dose and supervision.	This is the regular primaquine dose (3.5 mg/kg) in Brazil but with directly observed therapy. Primaquine: Different total dose and supervision.	This is the double total primaquine dose (14 days) (7.0 mg/kg) in Brazil with directly observed therapy. Primaquine: Different total dose and supervision.
Period Title: Overall Study
STARTED	63	96	95
COMPLETED	53	78	79
NOT COMPLETED	10	18	16

Baseline Characteristics

Arm/Group Title	Primaquine Regular Dose Unsupervised	Primaquine Regular Dose Supervised	Primaquine Double Dose Unsupervised	Total
Arm/Group Description	This is the regular primaquine dose (3.5 mg/kg) Brazil without directly observed therapy. Primaquine: Different total dose and supervision.	This is the regular primaquine dose (3.5 mg/kg) in Brazil but with directly observed therapy. Primaquine: Different total dose and supervision.	This is the double total primaquine dose (14 days) (7.0 mg/kg) in Brazil with directly observed therapy. Primaquine: Different total dose and supervision.	Total of all reporting groups
Overall Participants	63	96	95	254
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	26.5	20.3	23.5	22.4
Sex: Female, Male (Count of Participants)
Female	28 44.4%	44 45.8%	43 45.3%	115 45.3%
Male	35 55.6%	52 54.2%	52 54.7%	139 54.7%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Brazil	63 100%	96 100%	95 100%	254 100%

Outcome Measures

1. Primary Outcome

Title	Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled
Description	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.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Per-protocol uncorrected analysis.

Arm/Group Title	Primaquine Regular Dose Unsupervised	Primaquine Regular Dose Supervised	Primaquine Double Dose Unsupervised
Arm/Group Description	This is the regular primaquine dose (3.5 mg/kg) Brazil without directly observed therapy. Primaquine: Different total dose and supervision.	This is the regular primaquine dose (3.5 mg/kg) in Brazil but with directly observed therapy. Primaquine: Different total dose and supervision.	This is the double total primaquine dose (14 days) (7.0 mg/kg) in Brazil with directly observed therapy. Primaquine: Different total dose and supervision.
Measure Participants	63	89	90
Number [participants]	61 96.8%	88 91.7%	90 94.7%

2. Primary Outcome

Title	Participants With Adequate Clinical and Parasitologic Response Among Patients Enrolled
Description	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.
Time Frame	168 days

Outcome Measure Data

Analysis Population Description

Per-protocol uncorrected analysis.

Arm/Group Title	Primaquine Regular Dose Unsupervised	Primaquine Regular Dose Supervised	Primaquine Double Dose Unsupervised
Arm/Group Description	This is the regular primaquine dose (3.5 mg/kg) Brazil without directly observed therapy. Primaquine: Different total dose and supervision.	This is the regular primaquine dose (3.5 mg/kg) in Brazil but with directly observed therapy. Primaquine: Different total dose and supervision.	This is the double total primaquine dose (14 days) (7.0 mg/kg) in Brazil with directly observed therapy. Primaquine: Different total dose and supervision.
Measure Participants	53	78	79
Number [participants]	29 46%	44 45.8%	67 70.5%

3. Secondary Outcome

Title	Participants With Adequate Clinical and Parasitologic Response Based on Microsatellite-corrected Analysis Per Protocol Day 168
Description	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.
Time Frame	168 days

Outcome Measure Data

Analysis Population Description

Microsatellite-corrected analysis excludes participants who, during follow-up, presented with heterologous infections (genotype different) or whose genotype could not be determined. This reduced the number of overall participants by 12 for the 'Primaquine Regular Dose Unsupervised' arm; 17 participants in the 'Primaquine Regular Dose Supervised' arm; and 8 participants in the 'Primaquine Double Dose Unsupervised' arm, in comparison to the totals in the Participant Flow section.

Arm/Group Title	Primaquine Regular Dose Unsupervised	Primaquine Regular Dose Supervised	Primaquine Double Dose Unsupervised
Arm/Group Description	This is the regular primaquine dose (3.5 mg/kg) Brazil without directly observed therapy. Primaquine: Different total dose and supervision.	This is the regular primaquine dose (3.5 mg/kg) in Brazil but with directly observed therapy. Primaquine: Different total dose and supervision.	This is the double total primaquine dose (14 days) (7.0 mg/kg) in Brazil with directly observed therapy. Primaquine: Different total dose and supervision.
Measure Participants	41	61	71
Number [Participants]	29 46%	44 45.8%	67 70.5%

Adverse Events

Time Frame	During patient follow-up, 6 months.
Arm/Group Title	Primaquine Regular Dose Unsupervised		Primaquine Regular Dose Supervised		Primaquine Double Dose Unsupervised
Arm/Group Description	This is the regular primaquine dose (3.5 mg/kg) Brazil without directly observed therapy. Primaquine: Different total dose and supervision.		This is the regular primaquine dose (3.5 mg/kg) in Brazil but with directly observed therapy. Primaquine: Different total dose and supervision.		This is the double total primaquine dose (14 days) (7.0 mg/kg) in Brazil with directly observed therapy. Primaquine: Different total dose and supervision.
All Cause Mortality
	Primaquine Regular Dose Unsupervised		Primaquine Regular Dose Supervised		Primaquine Double Dose Unsupervised
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/63 (0%)		0/96 (0%)		0/95 (0%)
Serious Adverse Events
	Primaquine Regular Dose Unsupervised		Primaquine Regular Dose Supervised		Primaquine Double Dose Unsupervised
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/63 (0%)		0/96 (0%)		0/95 (0%)
Other (Not Including Serious) Adverse Events
	Primaquine Regular Dose Unsupervised		Primaquine Regular Dose Supervised		Primaquine Double Dose Unsupervised
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/63 (0%)		0/96 (0%)		0/95 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.