Clinical trial NCT04222088: TES of Artemether-lumefantrine for Pf and Chloroquine for Pv in the Philippines From 2013-2014
Official title: Efficacy and Safety of Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria and Chloroquine for Plasmodium Vivax in the Philippines From 2013-2014
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Malaria
Falciparum Malaria
Vivax Malaria
Malaria Recrudescence
Keywords: malaria
TES
Plasmodium falciparum
Artemether-lumefantrine
Plasmodium vivax
Chloroquine
Lead sponsor: Research Institute for Tropical Medicine, Philippines
Sponsor class: OTHER_GOV
Collaborators: name: World Health Organization
First posted: 2020-01-09
Enrollment: 159
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The population of interest consists of patients aged between \> 6 months to 59 years old diagnosed with uncomplicated falciparum and vivax malaria attending the study health clinic, and having given, or whose parents or legal guardians have given an informed consent for study inclusion and assent in children as appropriate.

Brief summary: An antimalarial drug efficacy trial was conducted for artemether-lumefantrine (AL) and chloroquine (CQ) in the three (3) municipalities (Bataraza, Brookes and Rizal) of Palawan. Study subjects are febrile individuals between \> 6 months old and 59 years old with confirmed uncomplicated P. falciparum or P. vivax infections. Patients with P. falciparum was treated with Artemether-lumefantrine administered 3 days (Days 0, 1 and 2) according to body weight. Primaquine at 0.75 mg base/kg body weight single dose was given on Day 3. For Plasmodium vivax patients chloroquine were administered according to body weight at a total dose of 25 mg/kg over 3 days (10 mg/kg on Day 0; 10 mg/kg on Day 1 and 5 mg/kg on Day 2), and primaquine following the National Treatment Guidelines.

During the period that this report covers, 84 and 75 patients met the inclusion criteria for Pf and Pv respectively. Clinical and parasitological parameters were monitored over a 28-day follow-up period for both drugs.

The presence of only 1 Late Clinical Failure (LCF) of P. falciparum parasitemia out of 84 enrolled patients and 2 Late Parasitological Failure (LPF) of P. vivax patients out of 75 enrolled patients within the 28 days follow up suggest that both drugs are still efficacious.

Detailed description: In 2002, the Philippines changed its antimalarial drug policy to the combination treatment, CQ+SP as 1st-line treatment and artemether-lumefantrine as 2nd-line treatment. The DOH prescribed the use of artemether-lumefantrine (AL) combination as the second-line drug, limiting its use only in the treatment of confirmed Plasmodium falciparum until a further study on its efficacy was done before making it as the first-line treatment. Consequently, AL became the first-line drug for falciparum malaria in the 2009 revised drug policy. The DOH in the past 6 years (2002-2007) adopted the use of AL in the highly endemic areas of the country and conducted therapeutic efficacy studies (TES) in 3 sentinel sites: Kalinga-Isabela, Palawan, and several Mindanao provinces showing 97-100% efficacy. Whereas CQ+SP showed variability and declining efficacy, results ranged from 70%-95% (CARAGA region). In Sultan Kudarat province, results in 2006-2007 showed 90% efficacy of CQ+SP and 96% for AL for falciparum malaria.

In the 2009 drug policy, chloroquine (CQ) remains the primary treatment for P. vivax malaria, with primaquine as an anti-relapse drug. Previous studies (1999-2005) elsewhere in the country have shown 100% efficacy of CQ or the CQ+PQ combination. However, in 2011, recurrence of parasitemia was observed in one of 117 enrolled patients in Palawan. The last TES of AL as a first-line drug of choice for falciparum malaria was made in 2007. This study will update this drug's efficacy for this parasite and that of P. vivax.

STUDY OBJECTIVES The general objective of this study is to assess the therapeutic efficacy and safety artemether-lumefantrine for the treatment of uncomplicated P. falciparum infections and of chloroquine for the treatment of P. vivax infections in Palawan province, the Philippines from 2013-2014.

The specific objectives are:

* To measure the clinical and parasitological efficacy of artemether-lumefantrine (AL) among patients aged between \> 6 months and 59 years old suffering from uncomplicated falciparum malaria, by determining the proportion of patients with Early Treatment Failure (ETF), Late Clinical Failure (LTF), Late Parasitological Failure (LPF), or with an Adequate Clinical and Parasitological Response (ACPR) as indicators of efficacy;
* To measure the clinical and parasitological efficacy of Chloroquine among patients aged between \> 6 months and 59 years old suffering from vivax malaria, by determining the proportion of patients with clinical and parasitological failure, or with an Adequate Clinical and Parasitological Response (ACPR) as indicators of efficacy;
* To evaluate the incidence of adverse events;
* To formulate recommendations to enable the Department of Health to make informed decisions about the possible need for updating of the current national antimalarial treatment guidelines.

STUDY DESIGN The design of this surveillance study is a one-arm, prospective evaluation of the clinical and parasitological response to directly observed treatment for uncomplicated falciparum and vivax malaria. Individuals with uncomplicated malaria who meet the study inclusion criteria will be enrolled, treated on-site with AL, and monitored for a period of 28 days if they have falciparum malaria, and with chloroquine if with vivax malaria, and monitored for a period of 28 days. The follow-up consists of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations. Study patients have been classified as therapeutic failures (early or late) or adequate responders based on the results of these assessments. The proportion of patients experiencing a therapeutic failure during the follow-up period has been used to estimate the efficacy of the study drug(s). Polymerase Chain Reaction (PCR) analysis will also help distinguish between a true recrudescence due to treatment failure and episodes of re-infection.

STUDY AREA The study was conducted in the Rural Health Units (RHU) of Bataraza, Brookes Point, and Rio Tuba Nickel Foundation Inc. Hospital (RTNFI). However, due to the difficulty of recruiting patients in RTNFI, recruitment was stopped in October 2013 and was replaced by the RHU of Rizal. Several factors influenced the selection of sites: adequate numbers of patients with symptomatic, uncomplicated P. falciparum or P. vivax malaria; willingness and availability of the selected health care facility staff to participate in the trial and to support the work with laboratory space; access of patients to the health facility for weekly follow-ups; availability of the Municipality Health Officer (MHO), the nurse and a trained Medical Technologist to take responsibility for conducting the trail, and security.

SAMPLE SIZE Treatment failure to AL in the area being 0-5 %, 5% has been chosen as the estimated therapeutic failure rate of the drug. At a confidence level of 95% and with precision around the estimate of 10%, 18 patients will be needed. With a 20% increase to allow losses to follow-up and withdrawals during the 28-day follow-up period, 22 patients need to be included. But in order for the sample to be representative, a minimum of 50 P. falciparum and 50 P. vivax patients need to be included and a maximum of 75 patients for Plasmodium falciparum and 75 Plasmodium vivax will be enrolled.

SAMPLING TECHNIQUE All individuals who consulted at the selected rural health units met the inclusion criteria and had none of the exclusion criteria were included in the study.

DATA MANAGEMENT The principal investigator has ensured that the study protocol is strictly adhered to throughout and that all data are collected and recorded correctly on the CRF. Laboratory and clinical data have been recorded on a daily basis in the CRF designed for the study. Data that are derived from source documents are consistent with the source documents or the discrepancies were explained. Any changes or corrections to a CRF were dated and explained and did not obscure the original entry. All CRF was checked for completeness. After the study was completed, data were entered onto a database using double independent data entry. The data were stored in a computer database maintaining confidentiality in accordance with the national data legislation.

ETHICAL CONSIDERATIONS Participants were recruited after the study received favorable approval of the protocol, participant information sheet, and written informed consent form from RITM Institutional Review Board (IRB). The study document versions given written approval by the IRB were used. The study was carried out according to the ethical guidelines in the Declaration of Helsinki (version 2008), applicable guidelines of ICH-GCP (E6); and applicable regulations of the Department of Health, Manila. The participant's written informed consent was secured before enrolment and prior to initiating procedures specific to this study. For potential participants below 18 years old, this consent was obtained from either parent or a legally accepted guardian. An independent witness was present during the process of obtaining informed consent from a participant or parents/legal guardian who was illiterate.

Eligibility criteria: Inclusion Criteria:

* Above 6 months old to 59 years old;
* Mono-infection with P. falciparum (1000-100 000 asexual forms per µl) and P. vivax (≥250/ul)
* Axillary temperature ≥37.5 °C or oral/rectal temperature of ≥38 °C;
* Glucose-6-dehydrogenase (G6PD) test normal for vivax patients if available
* Ability to swallow medication;
* Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule;
* Informed consent from the patient or from a parent or legal guardian in the case of children less than 18 years old;
* Informed assent from any minor participant aged 12 - 17 years; and
* Consent for pregnancy testing from female of child-bearing potential and from their parent or guardian if under 18 years old.

Exclusion Criteria:

* Presence of general danger signs among children \<5 years old or other signs of severe and complicated falciparum malaria according to current WHO definitions
* Mixed Plasmodium species;
* Presence of severe malnutrition
* Presence of febrile conditions due to diseases other than malaria (measles, acute lower tract respiratory infection, severe diarrhea with dehydration, etc.), or other known underlying chronic or severe diseases (e.g. cardiac, renal, hepatic diseases, HIV/AIDS)
* History of hypersensitivity reactions to any of the drug(s) being tested or used as alternative treatment.

Primary outcomes:
measure: Early Treatment Failure (ETF)
timeFrame: Day 1-3
measure: Late Clinical Failure (LCF)
timeFrame: Day 4-28
measure: Late Parasitological Failure (LPF)
timeFrame: day 7 to day 28
measure: Adequate Clinical and Parasitological Response (ACPR)
timeFrame: Day 0-28
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Research Institute for Tropical Medicine, Philippines
name: Fe Esperanza Caridad J Espino, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Council for International Organizations of Medical Sciences. International ethical guidelines for biomedical research involving human subjects. Bull Med Ethics. 2002 Oct;(182):17-23.
citation: World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. No abstract available.