Arterolane-PQP Versus DHA-PQP in Uncomplicated Falciparum Malaria in Eastern Myanmar

An Open-label Randomized Trial to Assess the Therapeutic Efficacy of Arterolane-piperaquine Versus Dihydroartemisinin-piperaquine for the Treatment of Uncomplicated Falciparum Malaria in Eastern Myanmar, an Area of Emerging Artemisinin-resistant Falciparum Malaria

Emerging resistance to artemisinins and their partner drugs severely threatens the treatment of falciparum malaria in Myanmar with artemisinin combination therapies. To inform drug policy, it is crucial to evaluate alternative antimalarial treatments.

The investigators here propose a randomized clinical trial comparing parasite clearance parameters and efficacy of 3 days arterolane-piperaquine with standard treatment with 3 days dihydroartemisinin (DHA)-piperaquine in adult patients with uncomplicated falciparum malaria in Myanmar stratified for the presence of "K13" mutation in the infecting parasite strains.

Study Overview

• Status: Withdrawn
• Conditions: Uncomplicated Falciparum Malaria; Artemisinin-resistant
• Intervention / Treatment: Drug: Arterolane maleate-piperaquine phosphate (Synriam); Drug: Dihydroartemisinin-piperaquine phosphate (Duocotexin)

Detailed Description

Primary Objective:

- To assess the parasite clearance half-life of arterolane-piperaquine compared to DHA-piperaquine in patients with artemisinin resistant uncomplicated falciparum malaria, defined by presence of the "K13" mutations in the infecting parasite strain.

Secondary Objectives :

• To assess the therapeutic efficacy of arterolane-piperaquine and DHA-piperaquine for the treatment of uncomplicated falciparum malaria or mixed infection (P.falciparum (PF) + a non-falciparum species) at Day 42, stratified by presence of artemisinin resistance in the infecting parasite strain.
• To assess the frequency of adverse events and serious adverse events of arterolane-piperaquine compared to DHA-piperaquine.
• To assess other efficacy parameters related to parasite clearance and parasite cure rate as well as the gametocyte carriage.
• To obtain pharmacokinetic (PK) and pharmacokinetic/pharmacodynamics (PK/PD) data on arterolane-piperaquine and DHA-piperaquine.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged ≥ 18 year old
• Symptomatic malaria infection, i.e. history of fever or presence of fever >37.5°c (tympanic) within the last 24 hours.
• Microscopic confirmation of asexual stages of P.falciparum (may be mixed with non-falciparum species) with a parasitaemia >10,000 parasites/µL
• Able to take oral medication
• Willingness and ability of patients to comply with the study protocol for the duration of the study
• Written informed consent given to participate in the trial

Exclusion Criteria:

• Pregnancy or lactation (urine test for β HCG to be performed on any woman of child bearing age 18 to 45 year old)
• P.falciparum asexual stage parasitaemia greater than or equal to 4% red blood cells (175,000/µL).

• Signs or symptoms indicative of severe malaria:

  • Impaired consciousness
  • Severe anaemia (Hct<15%)
  • Bleeding disorder -evidenced by epistaxis, bleeding gums, frank haematuria, bleeding from venipuncture sites
  • Respiratory distress
  • Severe jaundice
• Have taken a full course DHA-piperaquine, artemether-lumefantrin or other antimalarial treatment in the previous 42 days
• Known hypersensitivity to artemisinins or to piperaquine - defined as history of erythroderma/other severe cutaneous reaction or angioedema
• History of splenectomy

• History of taking medicinal products that are known to prolong the QTc interval, including:

  • Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol).
  • Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive agents.

  • Certain antimicrobial agents, including agents of the following classes:

    • macrolides (e.g. erythromycin, clarithromycin),
    • fluoroquinolones (e.g. moxifloxacin, sparfloxacin),
    • imidazole and triazole antifungal agent,
    • pentamidine and saquinavir.
  • The non-sedating antihistamines terfenadine, astemizole, mizolastine.
  • Other drugs: cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.
• History of taking any drug which is known to be metabolised by the cytochrome enzyme CYP2D6 including flecainide, metoprol, imipramine, amitriptyline, clomipramine.
• Family history of sudden unexplained death, or personal or family history of predisposing cardiac conditions for arrhythmia/QT prolongation (including congenital long QT syndrome, arrhythmia, QTc interval greater than 450 milliseconds with either Bazett or Fridericia correction).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arterolane maleate-piperaquine phosphate (Synriam)	Drug: Arterolane maleate-piperaquine phosphate (Synriam)
Experimental: Dihydroartemisinin-piperaquine phosphate (Duocotexin)	Drug: Dihydroartemisinin-piperaquine phosphate (Duocotexin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral blood parasite half-life	Peripheral blood parasite half-life of the linear portion of the natural logarithm parasite clearance curve in patients with parasitaemia at inclusion >10,000 parasites/µL	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
42 day PCR corrected adequate clinical and parasitological response (ACPR)	42 days

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Mahidol Oxford Tropical Medicine Research Unit; Department of Medical Research, Lower Myanmar
• Investigators: Principal Investigator: Arjen M Dondorp, MD, Mahidol Oxfrod Tropical Medicine Research Unit

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Anticipated): June 1, 2017
• Study Completion (Anticipated): June 1, 2017

Study Registration Dates

• First Submitted: May 26, 2015
• First Submitted That Met QC Criteria: May 29, 2015
• First Posted (Estimate): June 3, 2015

Study Record Updates

• Last Update Posted (Estimate): November 3, 2015
• Last Update Submitted That Met QC Criteria: November 2, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Arterolane-piperaquine; Dehydroartemisinin-piperaquine; therapeutic efficacy; Uncomplicated falciparum malaria; Artemisinin-resistant
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Piperaquine; Artenimol
• Other Study ID Numbers: BAKMAL1501