P. Falciparum Resistance to Artemisinin in Vietnam

NCT02604966 | Unknown Phase 4

• 1 other identifier: NIMPE - ITM- P.f
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

At the end of 2012, the Institute of Tropical Medicine in collaboration with National Institute of Malariology Parasitology and Entomology (NIMPE) conducted a study in Quang Nam province, central Vietnam, to assess the efficacy of the national DHA-PPQ regimen for the treatment of uncomplicated P. falciparum malaria infections, both in adults and in children. Results showed that about 30% of the study participants were parasitaemic at day 3. Parasite clearance rate was estimated at 6.2h, which was comparable to figures from Pailin, Cambodia, where artemisinin resistance were previously reported . However, results from this study have to be interpreted bearing in mind that: (i) the age-based drug dosing scheme used has been criticized as insufficient to clear parasites and (ii) DHA-PPQ drugs used (Artecan™), Vietnam, are not produced under Good Manufacturing Practices (GMPs). However, those results prompted the NMCP and WHO to declare Quang Nam, Binh Phuoc, Dak Nong, and Gia Lai provinces as a "Tier I area" (credible evidence of artemisinin resistance) in May 2013. By end of 2014 a fifth province, Khanh Hoa, was declared Tier I (Dr Hong, Personal Communication). Except for the south-eastern province of Binh Phuoc, artemisinin resistance has never been confirmed with an artemisinin based monotherapy in Central Vietnam. Therefore, in order to confirm artemisinin resistance in Central Vietnam , a study with oral artemisinin-based monotherapy, using WHO prequalified AS and DHA-PPQ and recommended dosing scheme of 4mg/kg/day for AS and DHA, is needed. In the arm where study participants are treated with 3 days of AS monotherapy, treatment will be followed by an additional 3-day course of DHA-PPQ to effectively clear all parasites. The aim of the present study is to confirm artemisinin resistance in Central Vietnam by assessing P. falciparum clearance time and rate after AS monotherapy (WHO recommended dosage). The investigators will conduct a two-arm open label, randomized study, with one arm receiving AS monotherapy for 3 days + 3-day of DHA-PPQ, and a second arm receiving 3 days of DHA-PPQ.

Conditions

Drug Resistant Malaria Due to Plasmodium Falciparum

Keywords

P. falciparum; resistance to artemisinin; Central Vietnam

Outcome Measures

Primary Outcomes (1)

• Median parasite clearance time after treatment with Artesunate or with DHA - PIP

  Median parasite clearance time (total hours) in both arms (by light microscopy (LM) and quantitative real time PCR (qPCR)) will be computed using the 12-hourly parasite density measurements from day0 till parasite clearance. Parasite clearance time (in hours) will be computed using the Parasite Clearance Estimator tool available online (http://www.wwarn.org/toolkit/data-management/parasite-clearance-estimator).

  From time of first treatment dose (day0 hh-mm) until day and time of parasite clearance (=two consecutive blood samples are found negative for parasites) assessed up day 42

Secondary Outcomes (1)

• Number of patients with Adequate Clinical and Parasitological Response (ACPR) to DHA-PPQ for the treatment for uncomplicated P falciparum malaria infections in central Vietnam.

  From day0 to day 42

Other Outcomes (3)

• Ex vivo susceptibility of P. falciparum isolates to AS, DHA , PPQ and CQ (Mean IC50 and IC90)

  At day0 and day of recurrence of P.falciparum parasitemia after initial clearance assessed up to day 42

• Number of patients carrying asexual and sexual parasites during 42 days follow up

  From day0 to day 42

• Number of patients with parasites carrying molecular markers of Plasmodium falciparum resistance to artemisinins.

  From day 0 to day42

Study Arms (2)

Artesunate (AS) group

EXPERIMENTAL

P. falciparum infected patients randomly allocated to this arm will be treated with AS (50mg/tablet) 4 mg/kg body weight once daily for three days followed by DHA-PPQ (40mg of DHA +320mg of PPQ/tablet) once daily for three days.

Drug: Artesunate (AS) group

DHA - PPQ group

ACTIVE COMPARATOR

P. falciparum infected patients randomly allocated to this arm will be treated with the combination DHA-PPQ (40mg of DHA +320mg of PPQ/tablet) once daily for three days.

Drug: DHA - PPQ group

Interventions

Artesunate (AS) group DRUG

Oral treatment with AS at 4mg/kg/day for 3 days followed by three days of DHA - PPQ in order to insure total parasite clearance. Randomization is done by blocks of ten.

Also known as: AS group

Artesunate (AS) group

DHA - PPQ group DRUG

Oral treatment with 3-day course of DHA - PPQ. Randomization is done by blocks of ten.

DHA - PPQ group

Eligibility Criteria

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

You may qualify if:

• Mono-infection with P. falciparum;
• Parasite density (trophozoites) between 500-100,000/µl;
• Fever (axillary temperature 37.5C) or history of fever in the previous 24h.;
• Ability to swallow oral medication;
• Ability and willingness to comply with the study protocol and with the study visit schedule;
• Written informed consent/assent to participate to the trial.

You may not qualify if:

• Mixed or mono-infection with another Plasmodium species confirmed by microscopy;
• General danger signs or symptoms of severe malaria according to WHO definitions;
• Signs or symptoms of severe malnutrition (weight-for-age ≤ 3 standard deviations below the mean (NCHS/WHO normalized reference values));
• Anaemia (Hb \<7g/dl in adults (\<5g/dl in children));
• Pregnancy or lactation (urine test for β HCG);
• Concomitant acute illness necessitating specific treatment (antibiotics);
• Underlying chronic severe illness (e.g. cardiac, renal, hepatic diseases, HIV/AIDS);
• Known hypersensitivity to any of the drugs being evaluated;
• Regular use of medication that may interfere with antimalaria pharmacokinetics

Sponsors & Collaborators

• National Institute of Malariology, Parasitology and Entomology, Vietnam: lead
• Institute of Tropical Medicine, Belgium: collaborator

Study Sites (1)

Chu R Cam commune

Pleiku, Gialai, Vietnam

RECRUITING

Related Publications (7)

• Thriemer K, Hong NV, Rosanas-Urgell A, Phuc BQ, Ha do M, Pockele E, Guetens P, Van NV, Duong TT, Amambua-Ngwa A, D'Alessandro U, Erhart A. Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam. Antimicrob Agents Chemother. 2014 Dec;58(12):7049-55. doi: 10.1128/AAC.02746-14. Epub 2014 Sep 15.

  PMID: 25224002 BACKGROUND

• Hien TT, Thuy-Nhien NT, Phu NH, Boni MF, Thanh NV, Nha-Ca NT, Thai le H, Thai CQ, Toi PV, Thuan PD, Long le T, Dong le T, Merson L, Dolecek C, Stepniewska K, Ringwald P, White NJ, Farrar J, Wolbers M. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J. 2012 Oct 26;11:355. doi: 10.1186/1475-2875-11-355.

  PMID: 23101492 BACKGROUND

• Rosanas-Urgell A, Mueller D, Betuela I, Barnadas C, Iga J, Zimmerman PA, del Portillo HA, Siba P, Mueller I, Felger I. Comparison of diagnostic methods for the detection and quantification of the four sympatric Plasmodium species in field samples from Papua New Guinea. Malar J. 2010 Dec 14;9:361. doi: 10.1186/1475-2875-9-361.

  PMID: 21156052 BACKGROUND

• Four Artemisinin-Based Combinations (4ABC) Study Group. A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial. PLoS Med. 2011 Nov;8(11):e1001119. doi: 10.1371/journal.pmed.1001119. Epub 2011 Nov 8.

  PMID: 22087077 BACKGROUND

• Wampfler R, Mwingira F, Javati S, Robinson L, Betuela I, Siba P, Beck HP, Mueller I, Felger I. Strategies for detection of Plasmodium species gametocytes. PLoS One. 2013 Sep 27;8(9):e76316. doi: 10.1371/journal.pone.0076316. eCollection 2013.

  PMID: 24312682 BACKGROUND

• Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, Lim P, Mao S, Sopha C, Sam B, Anderson JM, Duong S, Chuor CM, Taylor WR, Suon S, Mercereau-Puijalon O, Fairhurst RM, Menard D. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis. 2013 Dec;13(12):1043-9. doi: 10.1016/S1473-3099(13)70252-4. Epub 2013 Sep 11.

  PMID: 24035558 BACKGROUND

• Rovira-Vallbona E, Van Hong N, Kattenberg JH, Huan RM, Hien NTT, Ngoc NTH, Guetens P, Hieu NL, Mai TT, Duong NTT, Duong TT, Phuc BQ, Xa NX, Erhart A, Rosanas-Urgell A. Efficacy of dihydroartemisinin/piperaquine and artesunate monotherapy for the treatment of uncomplicated Plasmodium falciparum malaria in Central Vietnam. J Antimicrob Chemother. 2020 Aug 1;75(8):2272-2281. doi: 10.1093/jac/dkaa172.

  PMID: 32437557 DERIVED

MeSH Terms

Interventions

Artesunate; Population Groups

Intervention Hierarchy (Ancestors)

Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Sesquiterpenes; Terpenes; Hydrocarbons; Demography; Population Characteristics

Study Officials

• Duong Tran, MD, PhD

  National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam

  PRINCIPAL INVESTIGATOR

• Anna Rosanas-Urgell, MD, PhD

  Institute of Tropical Medicine, Antwerp, Belgium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Phuc Bui, MD, PhD

CONTACT

+84 913522 874; phucnimpe@yahoo.com

Duong Tran, MD, PhD

CONTACT

+84916895919; tranthanhduong@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2015
• First Posted: November 16, 2015
• Study Start: April 1, 2015
• Primary Completion: September 1, 2016
• Study Completion: December 1, 2016
• Last Updated: December 21, 2015

Record last verified: 2015-10

Locations

VN (1)