Effectiveness of Malaria Treatment in Mexico

NCT02394197 | Completed Phase 4 DMC

• 3 other identifiers: INSP CI-624PAHO-MEX/07/005015PAHOERC-162-MEX
• Study Type: interventional
• Target: 153
• Locations: 0 countries
• Sites: N/A

Brief Summary

In the context of malaria elimination in the Americas, solid evidence is necessary of the effectiveness of anti-malarial control measures delivered to the affected individuals. In the Americas, most P. vivax infections are sensitive to Chloroquine (CQ) and Primaquine (PQ), and the most effective treatment worldwide comprises administration of a total dose of 25 milligrams (mg)/Kilogram (kg) weight of CQ distributed in three days and 3.5 mg/kg body weight of PQ administered during 14 days (T14). In Mexico, CQ and PQ have been administered since the late 50´s to treat malarious patients. In 1999 the National Malaria Control Program implemented an intermittent single doses treatment (ISD) as part of the overall strategy. After the blood sample was obtained for diagnosis of symptomatic patients, a single combined dose of CQ and PQ was administered, and after malaria infection confirmation, additional doses were administered monthly alternating each three months, during 3 years. Although, the number of malaria cases were reduced in most affected regions, in Southern México, many patients under ISD present recurrent blood infections, presumably relapse episodes were observed. Working hypothesis: the administration of ISD is low effective to eliminate relapse episodes and its effectiveness depends on the coincidence of the relapse episodes and the administration of the medication), while the T14 is highly effective to eliminate P. vivax primary and relapse infections. Objective: To determine the antimalarial drug effectiveness of the ISD and T14, based on CQ and PQ for the treatment of uncomplicated P. vivax infection (primary and recurrent blood infections) in Southern Mexico. Methods: The study was carried out in malaria affected communities of Southern Mexico, following the WHO recommendations for clinical studies. Symptomatic patients diagnosed with P. vivax infection that meet the inclusion criteria, were invited to participate. After they accepted by informed consent, patients were semi-randomized and treated with either T14 (14-day treatment) or ISD (18 intermittent single doses of CQ-PQ). Clinical, parasitological, molecular and serological parameters were monitor over a 12-month follow up period to evaluate the treatment outcomes to cure blood infection and relapsing episodes. The study was conducted from February-2007 to October-2010. The results of this study will be used to assist the Ministry of Health of México in assessing the current national treatment guidelines for uncomplicated P. vivax malaria

Conditions

Malaria

Keywords

Plasmodium vivax; Mexico; treatment; chloroquine; primaquine; 14-day treatment (T14); intermittent single doses (ISD)

Outcome Measures

Primary Outcomes (3)

• Changes in the presence and density of asexual parasites in thick blood smears by microscopy

  Proportion of patients at each time-point by intervention, presenting parasitemia and mean density by examining thick blood films stained with 10% Giemsa. The two thick smears were independently examined under a light microscope using oil immersion 100 × by two trained laboratory technicians. Asexual and sexual parasite densities were determined by counting the number of parasites against 200 white blood cells (WBC) (or 500 WBC, if less than 10 parasites were encountered in 200 WBC fields), assuming 7,000 WBC/μl of blood. At least 500 fields or the whole blood smear were examined before a sample was recorded as negative.

  at days 2, 3, 7, 14, 21, 28 and monthly from month 2 to month 12, post-treatment administration

• Changes in the presence and severity of clinical symptoms

  The proportion of patients at each time-point by intervension, that present any of the following symptoms; fever, headache, myalgias, arthralgias or paroxysm were indicated by patient reference or detected by field team search; by a clinical revision of the patient, using a calibrated thermometer. Othe signs were search by the clinician as jaundice (yellowish pigmentation of the skin, the conjunctival membranes over the sclerae (whites of the eyes), erythema, herpes-like small blisters on the lips and /or outer edges of the mouth and pruritus or any itching.

  at days 2, 3, 7, 14, 21, 28 and anytime or monitor monthly during 12months, post-treatment administration

• Changes in the presence of recurrent infections

  Comparing the proportion of patients presenting recurrent infections at any time schedule or unschedule (symptomatic or asymptomatic) detected by any diagnosed method

  any time from month 1 to month 12, post T14 or during ISD treatment

Secondary Outcomes (2)

• Changes in the detection of parasite DNA in blood samples

  at days 2, 3, 7, 14, 21, 28 and when antibody response were increased up to 12 months

• Changes in the antibodies against blood stages of P. vivax

  Monthly; from Day 28 to month 12 post-treatment administration

Study Arms (2)

14-day treatment (T14)

ACTIVE COMPARATOR

The operational treatment-dose was administered by mouth. The number of tablets of Chloroquine phosphate of 150 mg for three days (x-x-x/ number of tablets of Primaquine (15mg or 5 mg)), daily during 14 days. For 1 year old subjects only chloroquine (1-½-½/ ½ of 5 mg); for 2-5 years old (1-¾-1/ 1 of 5 mg); 6-12 years old (2-1-2/ 2 of 5 mg); 13 years old and over with about 60 kg of body weight (3-2-2/ 1 of 15 mg) and above 60 kg of body weight (4-3-3 / 1 of 15 mg). According to the age group as indicated by the Mexican guidelines for vector borne diseases control (http://www.salud.gob.mx/unidades/cdi/nom/032ssa202.html) (Table 10)

Drug: Chloroquine phosphate; Drug: primaquine

Intermittent single doses (ISD)

EXPERIMENTAL

The single dose medication was administered orally according to age group as the operational table: (number of tablets of chloroquine phosphate of 150 mg / number of tablets of primaquine (15mg or 5 mg)): for 1 year old (½ / 1 of 5 mg); for 2¬-5 years old (1 / 2 of 5 mg); 6-12 years old (2 / 4 of 5 mg); 13 years old and over of about 60 kg of body weight (3 / 2 of 15 mg), and above 60 kg of body weight (4 / 3 of 15 mg). It is administered on Days 0 (after the detection of infection by microscopy), and Days 30, 60, 180, 210, 240 and 360 as indicated in the National guidelines for vector borne diseases control (http://www.salud.gob.mx/unidades/cdi/nom/032ssa202.html).

Drug: Chloroquine phosphate; Drug: primaquine

Interventions

Chloroquine phosphate DRUG

use at operational doses by age group according to the Mexican guidelines for vector borne diseases

Also known as: aralen

14-day treatment (T14); Intermittent single doses (ISD)

primaquine DRUG

use at operational doses by age group according to the Mexican guidelines for vector borne diseases

14-day treatment (T14); Intermittent single doses (ISD)

Eligibility Criteria

• Age: 1 Year - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Confirmed P. vivax mono- infection by microscopy
• \- Parasitemia, minimum of 500 asexual parasites per µl of blood.
• \- Presence of axillary temperature ≥ 37.5 or history of fever during the past 48 hours
• \- Ability to swallow oral medication
• \- Informed consent from the patient, or from the parent or guardian in the case of children under 7 years old, or both consents by participant and parent for individual´s age ranging within 7 and 18 years old.
• \- Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule.
• Patients living in accessible villages, desirable less than 1 hour far from our facility by car.

You may not qualify if:

• \- Mixed species infection with another plasmodium species
• \- Presence of signs of danger, or severe malaria, according to the definitions of WHO http://whqlibdoc.who.int/publications/2010/9789241547925\_eng.pdf?ua=1
• \- if they presented signs of severe malnutrition or anemia
• \- had taken an anti-malaria treatment or had a malaria infection within the previous two months.
• \- Pregnant woman or positive pregnant test or breast feeding
• \- History of hypersensitivity to CQ or PQ
• \- Previous malaria attack within one year, identified at the malaria nominal record, sanitary jurisdiction VII of Chiapas, Mexico.
• \- had another cause for their fever or other chronic diseases as hypertension, diabetes, liver or kidney disease, etc.
• \- if they lived in communities at distances farther than one hour by motor vehicle from the facility.

Sponsors & Collaborators

• LILIA GONZALEZ CERON: lead
• Instituto de Diagnóstico y Referencia Epidemiológicos (InDRE), Mexico: collaborator
• Centro Nacional de Vigilancia Epidemiológica y control de enfermedades (CENAVECE), Mexico: collaborator
• Jurisdicción Sanitaria VII, Chiapas, México: collaborator
• Pan American Health Organization: collaborator

Related Publications (13)

• Rodriguez MH, Betanzos-Reyes AF; Grupo de Trabajo de Malaria del Sistema Mesoamericano de Salud Publica. [Plan to improve malaria control towards its elimination in Mesoamerica]. Salud Publica Mex. 2011;53 Suppl 3:S333-48. Spanish.

  PMID: 22344378 BACKGROUND

• White NJ. Preventing antimalarial drug resistance through combinations. Drug Resist Updat. 1998 Mar;1(1):3-9. doi: 10.1016/s1368-7646(98)80208-2.

  PMID: 17092790 BACKGROUND

• COATNEY GR. Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg. 1963 Mar;12:121-8. doi: 10.4269/ajtmh.1963.12.121. No abstract available.

  PMID: 14021822 BACKGROUND

• Baird JK, Basri H, Subianto B, Fryauff DJ, McElroy PD, Leksana B, Richie TL, Masbar S, Wignall FS, Hoffman SL. Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine. J Infect Dis. 1995 Jun;171(6):1678-82. doi: 10.1093/infdis/171.6.1678.

  PMID: 7769318 BACKGROUND

• Galappaththy GN, Omari AA, Tharyan P. Primaquine for preventing relapses in people with Plasmodium vivax malaria. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004389. doi: 10.1002/14651858.CD004389.pub2.

  PMID: 17253504 BACKGROUND

• Murphy GS, Basri H, Purnomo, Andersen EM, Bangs MJ, Mount DL, Gorden J, Lal AA, Purwokusumo AR, Harjosuwarno S, et al. Vivax malaria resistant to treatment and prophylaxis with chloroquine. Lancet. 1993 Jan 9;341(8837):96-100. doi: 10.1016/0140-6736(93)92568-e.

  PMID: 8093414 BACKGROUND

• malERA Consultative Group on Drugs. A research agenda for malaria eradication: drugs. PLoS Med. 2011 Jan 25;8(1):e1000402. doi: 10.1371/journal.pmed.1000402.

  PMID: 21311580 BACKGROUND

• Ruebush TK 2nd, Marquino W, Zegarra J, Neyra D, Villaroel R, Avila JC, Diaz C, Beltran E. Practical aspects of in vivo antimalarial drug efficacy testing in the Americas. Am J Trop Med Hyg. 2003 Apr;68(4):391-7.

  PMID: 12875285 BACKGROUND

• Rubio JM, Benito A, Roche J, Berzosa PJ, Garcia ML, Mico M, Edu M, Alvar J. Semi-nested, multiplex polymerase chain reaction for detection of human malaria parasites and evidence of Plasmodium vivax infection in Equatorial Guinea. Am J Trop Med Hyg. 1999 Feb;60(2):183-7. doi: 10.4269/ajtmh.1999.60.183.

  PMID: 10072133 BACKGROUND

• Gonzalez-Ceron L, Rodriguez MH. An enzyme-linked immunosorbent assay using detergent-soluble Plasmodium vivax antigen for seroepidemiological surveys. Trans R Soc Trop Med Hyg. 1991 May-Jun;85(3):358-61. doi: 10.1016/0035-9203(91)90289-b.

  PMID: 1949138 BACKGROUND

• Gonzalez-Ceron L, Rodriguez MH, Betanzos AF, Abadia A. [Efficacy of a rapid test to diagnose Plasmodium vivax in symptomatic patients of Chiapas, Mexico]. Salud Publica Mex. 2005 Jul-Aug;47(4):282-7. doi: 10.1590/s0036-36342005000400005. Spanish.

  PMID: 16259289 BACKGROUND

• Gonzalez-Ceron L, Mu J, Santillan F, Joy D, Sandoval MA, Camas G, Su X, Choy EV, Torreblanca R. Molecular and epidemiological characterization of Plasmodium vivax recurrent infections in southern Mexico. Parasit Vectors. 2013 Apr 18;6:109. doi: 10.1186/1756-3305-6-109.

  PMID: 23597046 BACKGROUND

• Gonzalez-Ceron L, Rodriguez MH, Sandoval MA, Santillan F, Galindo-Virgen S, Betanzos AF, Rosales AF, Palomeque OL. Effectiveness of combined chloroquine and primaquine treatment in 14 days versus intermittent single dose regimen, in an open, non-randomized, clinical trial, to eliminate Plasmodium vivax in southern Mexico. Malar J. 2015 Oct 30;14:426. doi: 10.1186/s12936-015-0938-2.

  PMID: 26518132 DERIVED

Related Links

• MEXICAN GUIDELINES THAT INCLUDE MALARIA TREATMENT NOM-032-SSA2-2002
• WHO, 2009 (METHODS FOR SURVEILLANCE OF ANTIMALARIAL DRUG EFFICACY)

MeSH Terms

Conditions

Malaria; Malaria, Vivax

Interventions

chloroquine diphosphate; Chloroquine; Primaquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• LILIA GONZALEZ-CERON, PHD

  NATIONAL INSTITUTE FOR PUBLIC HEALTH-MEXICO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Researcher in medical Sciences

Study Record Dates

• First Submitted: March 16, 2015
• First Posted: March 20, 2015
• Study Start: February 1, 2008
• Primary Completion: September 1, 2010
• Study Completion: September 1, 2010
• Last Updated: March 20, 2015

Record last verified: 2015-03