Methylene Blue Against Falciparum Malaria in Burkina Faso (BlueACTn)

Safety of Artesunate-amodiaquine Combined With Methylene Blue or Primaquine for Falciparum Malaria Treatment in African Children: A Randomised Controlled Trial

Safety of artesunate-amodiaquine combined with methylene blue or primaquine for falciparum malaria treatment in African children: A randomised controlled trial

Elimination has become the goal of malaria programmes in an increasing number of endemic countries and regions. As resistance against artemisinin compounds has recently started to emerge in South-East Asia, there is a clear need to develop alternative malaria drug combinations. Adding another anti-malarial with a short half-life such as methylene blue to standard ACT (artemisinin-based combination therapy) could be a strategy to prevent artemisinin resistance development. Moreover, adding a gametocytocidal drug to ACT reduces the probability of transmission of P. falciparum parasites including drug-resistant parasites.

Objectives: The primary objective of this trial is to investigate the safety of artesunate (AS) - amodiaquine (AQ) - methylene blue (MB) compared to AS - AQ - primaquine (PQ) in young children with uncomplicated falciparum malaria in Burkina Faso.

Study Overview

• Status: Completed
• Conditions: Malaria, Falciparum
• Intervention / Treatment: Drug: Methylene Blue; Drug: Primaquine

Detailed Description

The overall goal of the underlying research project is to develop a MB-based first-line drug combination regimen against uncomplicated falciparum malaria in SSA.

The primary objective of this study is: To study the safety of the triple combination AS-AQ-MB compared to AS-AQ-PQ in the treatment of uncomplicated falciparum malaria in young African children. The secondary objective of this study is: To study the efficacy of this MB-based triple combination in comparison with standard ACT-PQ in the treatment of uncomplicated falciparum malaria in young African children.

It is a mono-center, open randomised controlled non-inferiority study in children with uncomplicated falciparum malaria in Burkina Faso. Patients will be randomised to two treatment groups (arms):

1. AS-AQ-MB
2. AS-AQ-PQ

Study population: Children aged 6-59 months with uncomplicated falciparum malaria from Nouna Hospital in north-western Burkina Faso.

Sample size: 100 patients (50 per study arm).

Treatment: The group AS-AQ-MB will receive once daily a fixed dose AS-AQ formulation combined with once daily MB (15 mg/kg) over a three days period. The control group will receive once daily a fixed dose AS-AQ over three days combined with a single dose of PQ on day 2 (0.25 mg/kg).

Endpoints: Primary endpoint is the haemoglobin value on day 7 compared to baseline. Secondary endpoints are adverse events (AE), adequate clinical and parasitological response (ACPR) rate (PCR-corrected for recrudescences), as well as gametocyte prevalence and density.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Burkina Faso
  • Nouna, Burkina Faso
    • CRSN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Weight ≥ 6 kg
• Uncomplicated malaria caused by P. falciparum
• Asexual parasites ≥ 2 000/µl and ≤ 100 000/µl
• Axillary temperature ≥ 37.5°C or a history of fever during the last 24 hours
• Burkinabe nationality
• Permanent residence in the study area with no intention of leaving during the surveillance period
• Written informed consent of parents or care takers

Exclusion Criteria:

• Severe malaria
• Mixed malaria infection
• Vomiting (>2 times within 24 hours before the visit)
• Any apparent significant disease, including severe malnutrition
• A history of a previous, significant adverse reaction or known allergy to one or more of the study drugs
• Anaemia (haemoglobin < 7 g/dl)
• Treated in the same trial before
• All modern antimalarial treatment prior to inclusion (last seven days)
• Therapy with serotonin reuptake inhibitors (e.g. citalopram, escitalopram, fluoxetine, Paroxetine, Sertraline)
• Simultaneous participation in another investigational study
• Patients with known HIV/AIDS disease
• Therapy with drugs known to inhibit the liver enzymes cytochrome 2A6 (e.g. methoxsalen, pilocarpine, tranylcypromine) and/or cytochrome 2C8 (e.g. trimethoprim, ketoconazole, ritonavir, saquinavir, lopinavir, gemfibrozil, montelukast)

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: AS-AQ-MB; Once daily a fixed dose artesunate-amodiaquine formulation combined with once daily methylene blue (15 mg/kg) over a three days period.	Drug: Methylene Blue; 50 patients will receive methylene blue; Other Names: 3,7-bis(Dimethylamino)-phenothiazine-5-ium chloride
Active Comparator: AS-AQ-PQ; Once daily a fixed dose artesunate-amodiaquine over three days combined with a single dose of primaquine on day 2 (0.25 mg/kg).	Drug: Primaquine; 50 patients will receive primaquine; Other Names: (±)-N4-(6-Methoxychinolin-8-yl)pentan-1,4-diamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Haemoglobin Compared to the Baseline	Haemoglobin concentrations will be measured in the field using a HemoCue® (HemoCue® AB, Angelholm, Sweden)	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gametocyte Prevalence	measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up	28 days
Adverse Events (AE)	Reports of observed or self-reported adverse event	28 days
Mothers/Caretakers Questionnaire on Acceptance	Acceptance of the different treatment regimens by mothers/caretakers	14 days
Gametocyte Density	measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up	28 days

Collaborators and Investigators

• Sponsor: Heidelberg University
• Collaborators: Centre de Recherche en Sante de Nouna, Burkina Faso
• Investigators: Principal Investigator: Olaf Müller, Prof. Dr., Heidelberg University

Publications and helpful links

General Publications

• Mendes Jorge M, Ouermi L, Meissner P, Compaore G, Coulibaly B, Nebie E, Krisam J, Klose C, Kieser M, Jahn A, Lu G, D Alessandro U, Sie A, Mockenhaupt FP, Muller O. Safety and efficacy of artesunate-amodiaquine combined with either methylene blue or primaquine in children with falciparum malaria in Burkina Faso: A randomized controlled trial. PLoS One. 2019 Oct 10;14(10):e0222993. doi: 10.1371/journal.pone.0222993. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: June 28, 2016
• First Submitted That Met QC Criteria: July 29, 2016
• First Posted (Estimate): August 1, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2020
• Last Update Submitted That Met QC Criteria: March 11, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: falciparum malaria; sub saharan; africa; elimination disorder
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Primaquine; Methylene Blue; Phenothiazine
• Other Study ID Numbers: UniHD008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided