Malaria, VivaxPhase 2/3NCT02691910

Efficacy of Chloroquine (CQ) Alone Compared to Concomitant CQ and Primaquine for Plasmodium Vivax Infection

A Phase 2/3 study testing Chloroquine and Primaquine in people with Malaria, Vivax, run by Oswaldo Cruz Foundation at 2 sites in Brazil.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 5 years and older
Conditions the study is for: Malaria, Vivax
What is being tested?: Chloroquine and Primaquine
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 204 participants
Where: 2 sitesBrazil
Study dates: Aug 2014to Sep 2015
Phase: Phase 2/3
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 5 years and older
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

Slide-confirmed mono-infection with P. vivax
Age > 5 years
Ability to swallow oral medication
Axillary temperature ≥ 37.5º C or history of fever during the previous 48 hours
Patient or caregiver agrees to comply with the study protocol (including blood collections and return visits) and provides written informed consent.

Who cannot join

General danger signs or symptoms of severe malaria requiring hospitalization
Signs or symptoms of severe malnutrition, defined as weight-for-age ≤ 3 standard deviations below the mean (NCHS/WHO normalized reference values)
Slide-confirmed co-infection with any other Plasmodium species
Severe anemia, defined as Hg<8g/100 ml
Known hypersensitivity to any of the drugs being evaluated
Presence of febrile conditions caused by diseases other than malaria

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Serious or chronic medical condition by history (cardiac, renal, hepatic diseases, sickle cell disease, HIV/AIDS)
Pregnant or breastfeeding women
Prior history of hemolysis or severe anemia
Regular medication which may interfere with antimalarial pharmacokinetics

Trial locations and contacts

2 sites in 1 country.

Brazil2 sites

Oswaldo Cruz Foundation
Rio de Janeiro, Rio de Janeiro, 21040-360
Institute of Biomedical Sciences, University of Sao Paulo
São Paulo, São Paulo, 05508-900

Other trials in Brazil

About this study

Official title: Efficacy of Chloroquine (CQ) Alone Compared to Concomitant CQ and Primaquine (PQ) for the Treatment of Uncomplicated Plasmodium Vivax Infection

This is a randomized open-label trial to evaluate the efficacy of chloroquine (CQ) alone compared to chloroquine+primaquine (CQ+PQ) in the treatment of uncomplicated malaria caused by Plasmodium vivax infection in a endemic area in the westernmost part of the Amazon Basin of Brazil. The duration of follow up for evaluating CQ efficacy as a schizonticidal drug was 28 days. The duration of complete follow up to detect recurrent P. vivax infections by passive surveillance was six months. All patients in the CQ alone arm received 7 days of PQ treatment (3.5mg/kg total dose) starting on day 28 of the study follow-up.

Read the detailed description

OBJECTIVE- To assess the efficacy of co-administered chloroquine+primaquine (CQ+PQ) vs.CQ alone (PQ being postponed up to day 28 of CQ therapy) as a schizontocidal therapy (28-day follow-up) and as radical cure among uncomplicated P. vivax malaria (6-month follow-up). Specifically:

To measure the clinical and parasitological efficacy of CQ+PQ vs. CQ alone, over 28 days of follow-up.
To measure the time to the first recurrent vivax malaria episode, between days 29 and 180 of follow-up.

METHODS - This is a randomized, open-label. The duration of follow up for evaluating CQ efficacy as a schizonticidal drug was 28 days. The duration of complete follow up to detect recurrent P. vivax infections by passive surveillance was six months. All patients in the CQ alone arm received 7 days of PQ (3.5mg/kg total dose) starting on day 28 of the follow-up. 2.1 STUDY SITE AND POPULATION - The study was carried out in the city of Cruzeiro do Sul , Acre State, in the westernmost part of the Amazon Basin of Brazil. The study population was patients aged above 5 years diagnosed with uncomplicated P. vivax malaria, who gave permission for study inclusion. 2.2 INCLUSION CRITERIA - mono-infection with P. vivax, age >5 years, ability to swallow oral medication, axillary temperature ≥37.5ºC (or history of fever in the last 48 hours) or to agree to comply with the study and provides written informed consent. 2.3 EXCLUSION CRITERIA FOR ENROLLMENT - severe malaria requiring hospitalization, severe malnutrition (weight-for-age ≤ 3 standard deviations below the mean), co-infection with any other Plasmodium species, severe anemia (Hg<8g/100 ml), hypersensitivity to CQ or PQ, febrile conditions caused by diseases other than malaria, serious or chronic medical condition, pregnant or breastfeeding women, prior history of hemolysis or severe anemia or regular medication which may interfere with antimalarial pharmacokinetics. 2.4 ENROLLMENT PROCEDURES 2.4.1. CLINICAL EVALUATION - All patients were evaluated for signs of febrile illness other than malaria, and signs of severe disease/danger in order to exclude the patient from participating in the study. Female of childbearing age was asked about pregnant and lactating. On screening and each subsequent visit, the patient was asked about fever in the last 48 hours and his/her current temperature was measured. Any disease/surgical conditions, drug allergies, use of medication or herbal supplements was recorded. The patient's pulse rate, respiratory rate, height, weight and the results of a baseline physical examination was recorded. This was done on screening and each subsequent visit. 2.5. LABORATORY EVALUATIONS ON-SITE a - Urine β-HCG pregnancy test was conducted on women aged 13-49 b - Two thick blood smears were prepared on day 0 and at each follow-up visit (days 1, 2, 3, 7, 14, 21, 28, 180). One thick smears was examined on site to verify parasite species and a formal parasite count. The second slide was archived for later examination. Two qualified microscopists read all the slides independently. Discordant results were re-examined by a third microscopist, and parasite density was calculated by averaging the two closest counts. Microscopic diagnosis of malaria (parasite-specific DNA and gametocyte-specific RNA transcripts) was further confirmed by real-time quantitative PCR on days 0, 1, 2, 3, 28 and on the day of any parasite recurrence. c - Venous blood samples was collected on days 0, 1, 2, 3, 7, 28 and on the day of any parasite recurrence. It was used for on-site G6PD testing and a full blood count and hemoglobin measurement in addition to preparing thick smears. Plasma samples were stored at -80°C (or liquid nitrogen) and shipped to the central laboratory in São Paulo for immunological measurements (antibodies, cytokines). The remaining whole-blood aliquots were cryopreserved for DNA and RNA extraction and CQ measurements (the later on days 0 and 28 and on the day of any parasite recurrence). The whole-blood samples collected on day 0 and on the day of any parasite recurrence were cryopreserved for ex-vivo drug resistance assays. d - Finger-prick blood samples collected on days 14, 21, and 180 were used for hemoglobin measurements and to prepare thick smears. Remaining finger-prick blood samples were spotted onto FTA membranes for long-term DNA storage at 4°C. e - G6PD testing was conducted on-site on day 0. If the patient was G6PD deficient, she/he was excluded. 2.6 SUBSEQUENT FOLLOW UP Each patient was clinically reassessed on days 1, 2, 3, 7, 14, 21, 28 and 180. Venous blood (days 1, 2, 3, 7, 28) or capillary (finger prick) blood samples (days 14, 21, 180) was examined for malaria parasites at each visit and on any other day if the patient spontaneously returns with fever or worsening symptoms. Hemoglobin status - measured on days 0, 1, 2, 3, 7, 14, 21, 28, 180, and on the day of any parasite recurrence. Drug level testing- venous blood should be collected on days 0, 7, 28 and on the day of recurrent parasitemia to measure concentrations of CQ. Molecular testing - P. vivax isolates from recurrent infections up to day 28 would be genotypically compared with those from day 0 using a panel of 14 highly polymorphic microsatellite markers in order to determine whether the recurrence is due to the only or major parasite population present in the original infection, to a minor parasite subpopulation that could be detected on day 0 or to a completely different parasite population. 2.7 TREATMENT All participants received CQ (total dose, 25 mg base/kg) and PQ (total dose, 3.5mg/kg) supervised by a study nurse. CQ: on days 0 (10mg/kg), 1 and 2 (7.5mg/kg). PQ: once a day (0.5 mg/kg) for seven days, starting either on day 0 of CQ treatment (concurrent CQ-PQ treatment arm) or on day 28 (CQ alone arm). 2.8 FOLLOW-UP PROCEDURES 2.8.1. Active Surveillance - Study participants were visited on days 0, 1, 2, 3, 7, 14, 21, 28, and 180. At each visit, a questionnaire was completed asking about history or fever currently or in the preceding month and a venous or capillary sample was collected for blood slide examination and to check for parasitemia. 2.8.2. Passive Surveillance - Patients were advised to return to the health center on any day if symptoms, sign of danger (unable to drink or breastfeed, vomiting everything, presenting with convulsions, lethargic or unconscious, unable to sit or stand, presenting with difficult breathing), if they are still sick or if there is any cause for worry. During the period of PQ administration, anyone reporting dark urine or abdominal cramps (signs of toxicity) should seek medical attention. 2.8.3. Rescue treatment - A recurrent vivax parasitaemia within 28 days is potentially a recrudescent infection. These patients would be re-treated with the standard CQ-PQ co-administration regimen and remain in the study. After 28 days, a recurrent vivax parasitaemia is more likely a relapse or a new infection. These patients would be treated with the standard CQ-PQ co-administration regimen. Patients who develop severe malaria would be admitted to hospital and treated according to the guidelines of the Ministry of Health of Brazil. 2.8.4. Discontinuation/Withdrawal of Participants from Study Treatment Each participant had the right to withdraw from the study at any time. The investigator would withdraw a participant if the participant had blood transfusion or a fall in Hb to less than 7g/dL or a macroscopic haemoglobinuria or a fall in Hb by >25% (within the first 14 days or 8 weeks, as above) or significant protocol deviation, disease progression, lost of follow up, use of drugs with antimalarial activity, an important adverse event or an emergency event.
END-POINTS 3.1 Schizontocidal Efficacy of Chloroquine It was derived by the risk of recurrence until day 28 in the CQ only arm.

Schizontocidal Therapeutic Failure (TF): clinical deterioration which requires hospitalization in the presence of asexual parasitemia OR asexual parasitemia with temperature > 37.5°C between days 3 and 28 OR parasitemia between days 7 and 28, irrespective of the clinical condition.
Adequate Schizontocidal Response (ACR): absence of parasitemia on days 7, 14, 21 and 28 without previously meeting the criteria of TF. 3.2 Safety end points The main concern with PQ lies in the risk of severe hemolytic reactions, and a fall in haemoglobin. However, decreasing hemoglobin can also occur following P. vivax malaria. It is therefore vital to monitor for evidence of hemolysis and clinical significant fall in Hb. Hemoglobin concentration was assessed on days 0, 1, 2, 3, 7, 14, 21, 28, and 180, with the lowest levels expected from day 3 to 14. 3.2.1.Adverse Event (AE): Any unfavourable and unintended sign, symptom or disease temporally associated with the use of the study medication, without necessarily a causal relationship. 3.2.2.Adverse Reaction (AR). An untoward and unintended sign, symptom or disease judged as having a suspected causal relationship to the study medication. 3.2.3.Serious Adverse Event (SAE). Any untoward medical occurrence that at any dose results in death or risk of death, requires hospitalization, results in persistent or significant disability/incapacity.

STATISTICAL ANALYSIS The primary outcome and the safety data were analyzed on a modified intention-to-treat population. A conservative analysis will be repeated on the per protocol population excluding patients with subsequent major protocol violations. The primary outcome will be the proportion of therapeutic failure observed up to day 28 of follow-up in each study arm. The investigators will compare the cumulative incidence of P. vivax recurrence between study arms. SPSS version 17.0 will be used for data management and analysis. Data will be analyzed by Kaplan-Meier (KM) method and per-protocol analysis. The time to the first parasite recurrence within 28 days of follow-up (primary outcome) and between days 29 and 180 (secondary outcome) will be calculated using KM estimates (survival analysis). Statistical comparisons will be made between the arms using the log rank test. The proportions of clinical and parasitological failure, and adequate clinical and parasitological response at day 28 will be calculated, with their respective 95% confidence intervals.
ETHICAL ISSUES - The study were fully explained to the participants and ask for their consent/assent to participate. Consenting participants might terminate their participation at any time. All case record forms were accessed only by authorized staff members. Participants were informed of the results of the exams and clinical assessments at each follow-up visit.
DEFINITION OF TREATMENT OUTCOMES

Early treatment failure (ETF)
danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia
parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature
parasitaemia on day 3 with axillary temperature ≥ 37.5 ºC
parasitaemia on day 3 ≥25% of count on day 0
Late treatment failure
Late clinical failure (LCF)
danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 in patients who did not previously meet any of the criteria of early treatment failure
parasitaemia on any day between day 4 and day 28 with axillary temperature ≥37.5ºC (or history of fever) in patients who did not previously meet any of the criteria of early treatment failure
Late parasitological failure (LPF) - Parasitaemia on any day between day 7 and day 28 with axillary temperature <37.5ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure.
Adequate clinical and parasitological response - Absence of parasitaemia on day 28, irrespective of temperature, in patients who did not previously meet any of the criteria of ETF, LCF or LPF.

Conditions: Malaria, Vivax
Being tested: Chloroquine, Primaquine
Keywords: malaria, Plasmodium vivax, treatment, Chloroquine, Primaquine
Medical subject headings: Malaria, Vivax, Malaria

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ChloroquineDrug
Also called Chloroquine diphosphate
10mg/kg on day 0 and 7.5mg/kg on days 1 and 2. Total dose, 25 mg base/kg. Tablet containing 150mg of base.
PrimaquineDrug
0.5 mg/kg once a day, for seven days. Total dose, 3.5mg/kg.

Study groups in NCT02691910
Study group	Role	What they receive
CONCURRENT CHLOROQUINE+PRIMAQUINE	Active comparator	The infected individuals were treated with the standard chloroquine (CQ)+primaquine(PQ) regimen to malaria caused by Plasmodium vivax. * Chloroquine (tablet containing 150mg of base) - it was given on days 0 (10mg/kg), 1 (7.5mg/kg) and 2 (7.5mg/kg). Total dose, 25 mg base/kg. * Primaquine - it was given once a day (0.5 mg/kg) for seven days, starting on day 0 of CQ treatment. Total dose, 3.5mg/kg The medications were administered under direct observation and the patient was monitored for vomiting for 60 minutes. Receives: Drug: Chloroquine; Drug: Primaquine
CHLOROQUINE	Experimental	The infected individuals were initially treated with chloroquine (CQ) alone and the primaquine(PQ) was introduced on day 28. * Chloroquine (tablet containing 150mg of base) - it was given on days 0 (10mg/kg), 1 (7.5mg/kg) and 2 (7.5mg/kg). Total dose, 25 mg base/kg. * Primaquine - it was given once a day (0.5 mg/kg) for seven days, starting on day 28 of CQ treatment. Total dose, 3.5mg/kg. The medications were administered under direct observation and the patient was monitored for vomiting for 60 minutes. Receives: Drug: Chloroquine

What is being measured

The primary outcome is the main question the study is designed to answer.

Early treatment failure
danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia OR parasitaemia on day 2 higher than on day 0 OR parasitaemia on day 3 with axillary temperature ≥ 37.5 ºC OR parasitaemia on day 3 ≥ 25% of count on day 0
Measured: within the first 3 days

Secondary outcomes (2)

Late clinical failure
danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 OR parasitaemia on any day between day 4 and day 28 with axillary temperature ≥ 37.5 ºC (or history of fever) in patients who did not previously meet any of the criteria of early treatment failure
Measured: 28 days
Late parasitological failure
presence of parasitaemia on any day between day 7 and day 28 with axillary temperature < 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure
Measured: 28 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Aug 2014Sep 2015

First posted25 Feb 2016 (estimated)
Study startAug 2014
Primary completionAug 2015
Study completionSep 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (24)Papers the sponsor has linked to this study.
Other trials for Malaria, VivaxStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2/3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 204 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02691910
Sponsor's protocol ID: 404067/2012-3
Other IDs: 550.565
Status last verified: Feb 2016
First submitted: 22 Feb 2016
Last updated: 25 Feb 2016
Results posted: No
Data monitoring committee: No
Individual data sharing: No

Publications

Alvarez G, Pineros JG, Tobon A, Rios A, Maestre A, Blair S, Carmona-Fonseca J. Efficacy of three chloroquine-primaquine regimens for treatment of Plasmodium vivax malaria in Colombia. Am J Trop Med Hyg. 2006 Oct;75(4):605-9.
PubMed 17038680
Anez A, Navarro-Costa D, Yucra O, Garnica C, Melgar V, Moscoso M, Arteaga R, Nakao G. [Therapeutic response of Plasmodium vivax to chloroquine in Bolivia]. Biomedica. 2012 Oct-Dec;32(4):527-35. doi: 10.1590/S0120-41572012000400008. Spanish.
PubMed 23715228
Arias AE, Corredor A. Low response of Colombian strains of Plasmodium vivax to classical antimalarial therapy. Trop Med Parasitol. 1989 Mar;40(1):21-3.
PubMed 2662351
Baird JK. Resistance to therapies for infection by Plasmodium vivax. Clin Microbiol Rev. 2009 Jul;22(3):508-34. doi: 10.1128/CMR.00008-09.
PubMed 19597012
Baird JK, Leksana B, Masbar S, Fryauff DJ, Sutanihardja MA, Suradi, Wignall FS, Hoffman SL. Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels. Am J Trop Med Hyg. 1997 Jun;56(6):621-6. doi: 10.4269/ajtmh.1997.56.621.
PubMed 9230792
Baird KJ, Maguire JD, Price RN. Diagnosis and treatment of Plasmodium vivax malaria. Adv Parasitol. 2012;80:203-70. doi: 10.1016/B978-0-12-397900-1.00004-9.
PubMed 23199489
Baird JK, Tiwari T, Martin GJ, Tamminga CL, Prout TM, Tjaden J, Bravet PP, Rawlins S, Ferrel M, Carucci D, Hoffman SL. Chloroquine for the treatment of uncomplicated malaria in Guyana. Ann Trop Med Parasitol. 2002 Jun;96(4):339-48. doi: 10.1179/000349802125001023.
PubMed 12171615
Bray PG, Deed S, Fox E, Kalkanidis M, Mungthin M, Deady LW, Tilley L. Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum. Biochem Pharmacol. 2005 Oct 15;70(8):1158-66. doi: 10.1016/j.bcp.2005.07.021.
PubMed 16139253
Carmona-Fonseca J, Maestre A. Prevention of Plasmodium vivax malaria recurrence: efficacy of the standard total dose of primaquine administered over 3 days. Acta Trop. 2009 Nov;112(2):188-92. doi: 10.1016/j.actatropica.2009.07.024. Epub 2009 Aug 3.
PubMed 19653988
Castillo CM, Osorio LE, Palma GI. Assessment of therapeutic response of Plasmodium vivax and Plasmodium falciparum to chloroquine in a Malaria transmission free area in Colombia. Mem Inst Oswaldo Cruz. 2002 Jun;97(4):559-62. doi: 10.1590/s0074-02762002000400020.
PubMed 12118291
de Santana Filho FS, Arcanjo AR, Chehuan YM, Costa MR, Martinez-Espinosa FE, Vieira JL, Barbosa Md, Alecrim WD, Alecrim Md. Chloroquine-resistant Plasmodium vivax, Brazilian Amazon. Emerg Infect Dis. 2007 Jul;13(7):1125-6. doi: 10.3201/eid1307.061386. No abstract available.
PubMed 18214203
Egan TJ. Chloroquine and primaquine: combining old drugs as a new weapon against falciparum malaria? Trends Parasitol. 2006 Jun;22(6):235-7. doi: 10.1016/j.pt.2006.03.006. Epub 2006 Apr 3.
PubMed 16580880
Garavelli PL, Corti E. Chloroquine resistance in Plasmodium vivax: the first case in Brazil. Trans R Soc Trop Med Hyg. 1992 Mar-Apr;86(2):128. doi: 10.1016/0035-9203(92)90535-k. No abstract available.
PubMed 1440766
Marques MM, Costa MR, Santana Filho FS, Vieira JL, Nascimento MT, Brasil LW, Nogueira F, Silveira H, Reyes-Lecca RC, Monteiro WM, Lacerda MV, Alecrim MG. Plasmodium vivax chloroquine resistance and anemia in the western Brazilian Amazon. Antimicrob Agents Chemother. 2014;58(1):342-7. doi: 10.1128/AAC.02279-12. Epub 2013 Oct 28.
PubMed 24165179
Naing C, Aung K, Win DK, Wah MJ. Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries. Trans R Soc Trop Med Hyg. 2010 Nov;104(11):695-705. doi: 10.1016/j.trstmh.2010.08.009. Epub 2010 Sep 20.
PubMed 20850161

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
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Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 25 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Efficacy of Chloroquine (CQ) Alone Compared to Concomitant CQ and Primaquine (PQ) for the Treatment of Uncomplicated Plasmodium Vivax Infection
ClinicalTrials.gov ID: NCT02691910
Acronym / sponsor ID: 404067/2012-3
Conditions: Malaria, Vivax
Keywords: malaria, Plasmodium vivax, treatment, Chloroquine, Primaquine
Phase: Phase 2/3
Study type: Interventional
Recruitment status: Completed
Enrolment: 204 participants (actual)
Lead sponsor: Oswaldo Cruz FoundationUniversity, hospital or other
Collaborators: University of Sao Paulo
Study start: Aug 2014
Primary completion: Aug 2015 (actual)
Study completion: Sep 2015 (actual)
First posted: 25 Feb 2016 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

OBJECTIVE- To assess the efficacy of co-administered chloroquine+primaquine (CQ+PQ) vs.CQ alone (PQ being postponed up to day 28 of CQ therapy) as a schizontocidal therapy (28-day follow-up) and as radical cure among uncomplicated P. vivax malaria (6-month follow-up). Specifically:

To measure the clinical and parasitological efficacy of CQ+PQ vs. CQ alone, over 28 days of follow-up.
To measure the time to the first recurrent vivax malaria episode, between days 29 and 180 of follow-up.

METHODS - This is a randomized, open-label. The duration of follow up for evaluating CQ efficacy as a schizonticidal drug was 28 days. The duration of complete follow up to detect recurrent P. vivax infections by passive surveillance was six months. All patients in the CQ alone arm received 7 days of PQ (3.5mg/kg total dose) starting on day 28 of the follow-up. 2.1 STUDY SITE AND POPULATION - The study was carried out in the city of Cruzeiro do Sul , Acre State, in the westernmost part of the Amazon Basin of Brazil. The study population was patients aged above 5 years diagnosed with uncomplicated P. vivax malaria, who gave permission for study inclusion. 2.2 INCLUSION CRITERIA - mono-infection with P. vivax, age >5 years, ability to swallow oral medication, axillary temperature ≥37.5ºC (or history of fever in the last 48 hours) or to agree to comply with the study and provides written informed consent. 2.3 EXCLUSION CRITERIA FOR ENROLLMENT - severe malaria requiring hospitalization, severe malnutrition (weight-for-age ≤ 3 standard deviations below the mean), co-infection with any other Plasmodium species, severe anemia (Hg<8g/100 ml), hypersensitivity to CQ or PQ, febrile conditions caused by diseases other than malaria, serious or chronic medical condition, pregnant or breastfeeding women, prior history of hemolysis or severe anemia or regular medication which may interfere with antimalarial pharmacokinetics. 2.4 ENROLLMENT PROCEDURES 2.4.1. CLINICAL EVALUATION - All patients were evaluated for signs of febrile illness other than malaria, and signs of severe disease/danger in order to exclude the patient from participating in the study. Female of childbearing age was asked about pregnant and lactating. On screening and each subsequent visit, the patient was asked about fever in the last 48 hours and his/her current temperature was measured. Any disease/surgical conditions, drug allergies, use of medication or herbal supplements was recorded. The patient's pulse rate, respiratory rate, height, weight and the results of a baseline physical examination was recorded. This was done on screening and each subsequent visit. 2.5. LABORATORY EVALUATIONS ON-SITE a - Urine β-HCG pregnancy test was conducted on women aged 13-49 b - Two thick blood smears were prepared on day 0 and at each follow-up visit (days 1, 2, 3, 7, 14, 21, 28, 180). One thick smears was examined on site to verify parasite species and a formal parasite count. The second slide was archived for later examination. Two qualified microscopists read all the slides independently. Discordant results were re-examined by a third microscopist, and parasite density was calculated by averaging the two closest counts. Microscopic diagnosis of malaria (parasite-specific DNA and gametocyte-specific RNA transcripts) was further confirmed by real-time quantitative PCR on days 0, 1, 2, 3, 28 and on the day of any parasite recurrence. c - Venous blood samples was collected on days 0, 1, 2, 3, 7, 28 and on the day of any parasite recurrence. It was used for on-site G6PD testing and a full blood count and hemoglobin measurement in addition to preparing thick smears. Plasma samples were stored at -80°C (or liquid nitrogen) and shipped to the central laboratory in São Paulo for immunological measurements (antibodies, cytokines). The remaining whole-blood aliquots were cryopreserved for DNA and RNA extraction and CQ measurements (the later on days 0 and 28 and on the day of any parasite recurrence). The whole-blood samples collected on day 0 and on the day of any parasite recurrence were cryopreserved for ex-vivo drug resistance assays. d - Finger-prick blood samples collected on days 14, 21, and 180 were used for hemoglobin measurements and to prepare thick smears. Remaining finger-prick blood samples were spotted onto FTA membranes for long-term DNA storage at 4°C. e - G6PD testing was conducted on-site on day 0. If the patient was G6PD deficient, she/he was excluded. 2.6 SUBSEQUENT FOLLOW UP Each patient was clinically reassessed on days 1, 2, 3, 7, 14, 21, 28 and 180. Venous blood (days 1, 2, 3, 7, 28) or capillary (finger prick) blood samples (days 14, 21, 180) was examined for malaria parasites at each visit and on any other day if the patient spontaneously returns with fever or worsening symptoms. Hemoglobin status - measured on days 0, 1, 2, 3, 7, 14, 21, 28, 180, and on the day of any parasite recurrence. Drug level testing- venous blood should be collected on days 0, 7, 28 and on the day of recurrent parasitemia to measure concentrations of CQ. Molecular testing - P. vivax isolates from recurrent infections up to day 28 would be genotypically compared with those from day 0 using a panel of 14 highly polymorphic microsatellite markers in order to determine whether the recurrence is due to the only or major parasite population present in the original infection, to a minor parasite subpopulation that could be detected on day 0 or to a completely different parasite population. 2.7 TREATMENT All participants received CQ (total dose, 25 mg base/kg) and PQ (total dose, 3.5mg/kg) supervised by a study nurse. CQ: on days 0 (10mg/kg), 1 and 2 (7.5mg/kg). PQ: once a day (0.5 mg/kg) for seven days, starting either on day 0 of CQ treatment (concurrent CQ-PQ treatment arm) or on day 28 (CQ alone arm). 2.8 FOLLOW-UP PROCEDURES 2.8.1. Active Surveillance - Study participants were visited on days 0, 1, 2, 3, 7, 14, 21, 28, and 180. At each visit, a questionnaire was completed asking about history or fever currently or in the preceding month and a venous or capillary sample was collected for blood slide examination and to check for parasitemia. 2.8.2. Passive Surveillance - Patients were advised to return to the health center on any day if symptoms, sign of danger (unable to drink or breastfeed, vomiting everything, presenting with convulsions, lethargic or unconscious, unable to sit or stand, presenting with difficult breathing), if they are still sick or if there is any cause for worry. During the period of PQ administration, anyone reporting dark urine or abdominal cramps (signs of toxicity) should seek medical attention. 2.8.3. Rescue treatment - A recurrent vivax parasitaemia within 28 days is potentially a recrudescent infection. These patients would be re-treated with the standard CQ-PQ co-administration regimen and remain in the study. After 28 days, a recurrent vivax parasitaemia is more likely a relapse or a new infection. These patients would be treated with the standard CQ-PQ co-administration regimen. Patients who develop severe malaria would be admitted to hospital and treated according to the guidelines of the Ministry of Health of Brazil. 2.8.4. Discontinuation/Withdrawal of Participants from Study Treatment Each participant had the right to withdraw from the study at any time. The investigator would withdraw a participant if the participant had blood transfusion or a fall in Hb to less than 7g/dL or a macroscopic haemoglobinuria or a fall in Hb by >25% (within the first 14 days or 8 weeks, as above) or significant protocol deviation, disease progression, lost of follow up, use of drugs with antimalarial activity, an important adverse event or an emergency event.
END-POINTS 3.1 Schizontocidal Efficacy of Chloroquine It was derived by the risk of recurrence until day 28 in the CQ only arm.

Schizontocidal Therapeutic Failure (TF): clinical deterioration which requires hospitalization in the presence of asexual parasitemia OR asexual parasitemia with temperature > 37.5°C between days 3 and 28 OR parasitemia between days 7 and 28, irrespective of the clinical condition.
Adequate Schizontocidal Response (ACR): absence of parasitemia on days 7, 14, 21 and 28 without previously meeting the criteria of TF. 3.2 Safety end points The main concern with PQ lies in the risk of severe hemolytic reactions, and a fall in haemoglobin. However, decreasing hemoglobin can also occur following P. vivax malaria. It is therefore vital to monitor for evidence of hemolysis and clinical significant fall in Hb. Hemoglobin concentration was assessed on days 0, 1, 2, 3, 7, 14, 21, 28, and 180, with the lowest levels expected from day 3 to 14. 3.2.1.Adverse Event (AE): Any unfavourable and unintended sign, symptom or disease temporally associated with the use of the study medication, without necessarily a causal relationship. 3.2.2.Adverse Reaction (AR). An untoward and unintended sign, symptom or disease judged as having a suspected causal relationship to the study medication. 3.2.3.Serious Adverse Event (SAE). Any untoward medical occurrence that at any dose results in death or risk of death, requires hospitalization, results in persistent or significant disability/incapacity.

STATISTICAL ANALYSIS The primary outcome and the safety data were analyzed on a modified intention-to-treat population. A conservative analysis will be repeated on the per protocol population excluding patients with subsequent major protocol violations. The primary outcome will be the proportion of therapeutic failure observed up to day 28 of follow-up in each study arm. The investigators will compare the cumulative incidence of P. vivax recurrence between study arms. SPSS version 17.0 will be used for data management and analysis. Data will be analyzed by Kaplan-Meier (KM) method and per-protocol analysis. The time to the first parasite recurrence within 28 days of follow-up (primary outcome) and between days 29 and 180 (secondary outcome) will be calculated using KM estimates (survival analysis). Statistical comparisons will be made between the arms using the log rank test. The proportions of clinical and parasitological failure, and adequate clinical and parasitological response at day 28 will be calculated, with their respective 95% confidence intervals.
ETHICAL ISSUES - The study were fully explained to the participants and ask for their consent/assent to participate. Consenting participants might terminate their participation at any time. All case record forms were accessed only by authorized staff members. Participants were informed of the results of the exams and clinical assessments at each follow-up visit.
DEFINITION OF TREATMENT OUTCOMES

Early treatment failure (ETF)
danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia
parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature
parasitaemia on day 3 with axillary temperature ≥ 37.5 ºC
parasitaemia on day 3 ≥25% of count on day 0
Late treatment failure
Late clinical failure (LCF)
danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 in patients who did not previously meet any of the criteria of early treatment failure
parasitaemia on any day between day 4 and day 28 with axillary temperature ≥37.5ºC (or history of fever) in patients who did not previously meet any of the criteria of early treatment failure
Late parasitological failure (LPF) - Parasitaemia on any day between day 7 and day 28 with axillary temperature <37.5ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure.
Adequate clinical and parasitological response - Absence of parasitaemia on day 28, irrespective of temperature, in patients who did not previously meet any of the criteria of ETF, LCF or LPF.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
CONCURRENT CHLOROQUINE+PRIMAQUINE	Active comparator	Drug: Chloroquine, Drug: PrimaquineThe infected individuals were treated with the standard chloroquine (CQ)+primaquine(PQ) regimen to malaria caused by Plasmodium vivax. * Chloroquine (tablet containing 150mg of base) - it was given on days 0 (10mg/kg), 1 (7.5mg/kg) and 2 (7.5mg/kg). Total dose, 25 mg base/kg. * Primaquine - it was given once a day (0.5 mg/kg) for seven days, starting on day 0 of CQ treatment. Total dose, 3.5mg/kg The medications were administered under direct observation and the patient was monitored for vomiting for 60 minutes.
CHLOROQUINE	Experimental	Drug: ChloroquineThe infected individuals were initially treated with chloroquine (CQ) alone and the primaquine(PQ) was introduced on day 28. * Chloroquine (tablet containing 150mg of base) - it was given on days 0 (10mg/kg), 1 (7.5mg/kg) and 2 (7.5mg/kg). Total dose, 25 mg base/kg. * Primaquine - it was given once a day (0.5 mg/kg) for seven days, starting on day 28 of CQ treatment. Total dose, 3.5mg/kg. The medications were administered under direct observation and the patient was monitored for vomiting for 60 minutes.

Who may qualify

Ages: 5 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (5 listed)

Slide-confirmed mono-infection with P. vivax
Age > 5 years
Ability to swallow oral medication
Axillary temperature ≥ 37.5º C or history of fever during the previous 48 hours
Patient or caregiver agrees to comply with the study protocol (including blood collections and return visits) and provides written informed consent.

Key exclusion criteria (10 listed)

General danger signs or symptoms of severe malaria requiring hospitalization
Signs or symptoms of severe malnutrition, defined as weight-for-age ≤ 3 standard deviations below the mean (NCHS/WHO normalized reference values)
Slide-confirmed co-infection with any other Plasmodium species
Severe anemia, defined as Hg<8g/100 ml
Known hypersensitivity to any of the drugs being evaluated

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ChloroquineAlso: Chloroquine diphosphate10mg/kg on day 0 and 7.5mg/kg on days 1 and 2. Total dose, 25 mg base/kg. Tablet containing 150mg of base.	Drug	CHLOROQUINE, CONCURRENT CHLOROQUINE+PRIMAQUINE
Primaquine0.5 mg/kg once a day, for seven days. Total dose, 3.5mg/kg.	Drug	CONCURRENT CHLOROQUINE+PRIMAQUINE

Primary outcome

Early treatment failure
Time frame: within the first 3 days
danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia OR parasitaemia on day 2 higher than on day 0 OR parasitaemia on day 3 with axillary temperature ≥ 37.5 ºC OR parasitaemia on day 3 ≥ 25% of count on day 0

2 secondary outcomes

Late clinical failure
Time frame: 28 days
Late parasitological failure
Time frame: 28 days

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2016.
Background: PubMed 17038680Alvarez G, Pineros JG, Tobon A, Rios A, Maestre A, Blair S, Carmona-Fonseca J. Efficacy of three chloroquine-primaquine regimens for treatment of Plasmodium vivax malaria in Colombia. Am J Trop Med Hyg. 2006 Oct;75(4):605-9.
Background: PubMed 23715228Anez A, Navarro-Costa D, Yucra O, Garnica C, Melgar V, Moscoso M, Arteaga R, Nakao G. [Therapeutic response of Plasmodium vivax to chloroquine in Bolivia]. Biomedica. 2012 Oct-Dec;32(4):527-35. doi: 10.1590/S0120-41572012000400008. Spanish.
Background: PubMed 2662351Arias AE, Corredor A. Low response of Colombian strains of Plasmodium vivax to classical antimalarial therapy. Trop Med Parasitol. 1989 Mar;40(1):21-3.
Background: PubMed 19597012Baird JK. Resistance to therapies for infection by Plasmodium vivax. Clin Microbiol Rev. 2009 Jul;22(3):508-34. doi: 10.1128/CMR.00008-09.
Background: PubMed 9230792Baird JK, Leksana B, Masbar S, Fryauff DJ, Sutanihardja MA, Suradi, Wignall FS, Hoffman SL. Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels. Am J Trop Med Hyg. 1997 Jun;56(6):621-6. doi: 10.4269/ajtmh.1997.56.621.
Background: PubMed 23199489Baird KJ, Maguire JD, Price RN. Diagnosis and treatment of Plasmodium vivax malaria. Adv Parasitol. 2012;80:203-70. doi: 10.1016/B978-0-12-397900-1.00004-9.
Background: PubMed 12171615Baird JK, Tiwari T, Martin GJ, Tamminga CL, Prout TM, Tjaden J, Bravet PP, Rawlins S, Ferrel M, Carucci D, Hoffman SL. Chloroquine for the treatment of uncomplicated malaria in Guyana. Ann Trop Med Parasitol. 2002 Jun;96(4):339-48. doi: 10.1179/000349802125001023.
Background: PubMed 16139253Bray PG, Deed S, Fox E, Kalkanidis M, Mungthin M, Deady LW, Tilley L. Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum. Biochem Pharmacol. 2005 Oct 15;70(8):1158-66. doi: 10.1016/j.bcp.2005.07.021.
Background: PubMed 19653988Carmona-Fonseca J, Maestre A. Prevention of Plasmodium vivax malaria recurrence: efficacy of the standard total dose of primaquine administered over 3 days. Acta Trop. 2009 Nov;112(2):188-92. doi: 10.1016/j.actatropica.2009.07.024. Epub 2009 Aug 3.
Background: PubMed 12118291Castillo CM, Osorio LE, Palma GI. Assessment of therapeutic response of Plasmodium vivax and Plasmodium falciparum to chloroquine in a Malaria transmission free area in Colombia. Mem Inst Oswaldo Cruz. 2002 Jun;97(4):559-62. doi: 10.1590/s0074-02762002000400020.
Background: PubMed 18214203de Santana Filho FS, Arcanjo AR, Chehuan YM, Costa MR, Martinez-Espinosa FE, Vieira JL, Barbosa Md, Alecrim WD, Alecrim Md. Chloroquine-resistant Plasmodium vivax, Brazilian Amazon. Emerg Infect Dis. 2007 Jul;13(7):1125-6. doi: 10.3201/eid1307.061386. No abstract available.
Background: PubMed 16580880Egan TJ. Chloroquine and primaquine: combining old drugs as a new weapon against falciparum malaria? Trends Parasitol. 2006 Jun;22(6):235-7. doi: 10.1016/j.pt.2006.03.006. Epub 2006 Apr 3.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

MARCELO U FERREIRA, MD-PHD study director

Biomedical Sciences Institute of São Paulo University

SIMONE L ANDRADE, MD-PHD principal investigator

Oswaldo Cruz Foundation

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Chloroquine and Primaquine in people with Malaria, Vivax, run by Oswaldo Cruz Foundation at 2 sites in Brazil.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Early treatment failure (time frame: within the first 3 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02691910, which also lists 24 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2016.