BlueACTn: Methylene Blue Against Falciparum Malaria in Burkina Faso

• Sponsor: Heidelberg University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02851108
• Collaborator: Centre de Recherche en Sante de Nouna, Burkina Faso (Other)
• Enrollment: 100
• Location: 1
• Arms: 2
• Actual Duration (Months): 4
• Patients Per Site Per Month: 24.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria, Falciparum	Drug: Methylene Blue; Drug: Primaquine	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety of Artesunate-amodiaquine Combined With Methylene Blue or Primaquine for Falciparum Malaria Treatment in African Children: A Randomised Controlled Trial
• Actual Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in Haemoglobin Compared to the Baseline [7 days]

   Haemoglobin concentrations will be measured in the field using a HemoCue® (HemoCue® AB, Angelholm, Sweden)

Secondary Outcome Measures

1. Gametocyte Prevalence [28 days]

   measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up

2. Adverse Events (AE) [28 days]

   Reports of observed or self-reported adverse event

3. Mothers/Caretakers Questionnaire on Acceptance [14 days]

   Acceptance of the different treatment regimens by mothers/caretakers

4. Gametocyte Density [28 days]

   measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 59 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CRSN	Nouna		Burkina Faso

Sponsors and Collaborators

• Heidelberg University
• Centre de Recherche en Sante de Nouna, Burkina Faso

Investigators

• Principal Investigator: Olaf Müller, Prof. Dr., Heidelberg University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Olaf Mueller, Prof. Dr., Heidelberg University
• ClinicalTrials.gov Identifier: NCT02851108
• Other Study ID Numbers: UniHD008
• First Posted: Aug 1, 2016
• Last Update Posted: Mar 25, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Olaf Mueller, Prof. Dr., Heidelberg University: falciparum malaria; sub saharan; africa; elimination disorder
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum; Primaquine; Phenothiazine; Methylene Blue

Study Results

Participant Flow

Arm/Group Title	AS-AQ-MB	AS-AQ-PQ
Arm/Group Description	Once daily a fixed dose artesunate-amodiaquine formulation combined with once daily methylene blue (15 mg/kg) over a three days period. Methylene Blue: 50 patients will receive methylene blue	Once daily a fixed dose artesunate-amodiaquine over three days combined with a single dose of primaquine on day 2 (0.25 mg/kg). Primaquine: 50 patients will receive primaquine
Period Title: Overall Study
STARTED	50	50
COMPLETED	42	49
NOT COMPLETED	8	1

Baseline Characteristics

Arm/Group Title	AS-AQ-MB	AS-AQ-PQ	Total
Arm/Group Description	Once daily a fixed dose artesunate-amodiaquine formulation combined with once daily methylene blue (15 mg/kg) over a three days period. Methylene Blue: 50 patients will receive methylene blue	Once daily a fixed dose artesunate-amodiaquine over three days combined with a single dose of primaquine on day 2 (0.25 mg/kg). Primaquine: 50 patients will receive primaquine	Total of all reporting groups
Overall Participants	50	50	100
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	42.34 (12.34)	38.2 (13.93)	40.27 (13.26)
Sex: Female, Male (Count of Participants)
Female	24 48%	25 50%	49 49%
Male	26 52%	25 50%	51 51%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	12.91 (3.16)	12.18 (2.98)	12.55 (3.08)
Length of current disease episode (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	1.94 (1.32)	1.96 (1.28)	1.95 (1.29)
Prior treatment of current disease episode (Count of Participants)
Count of Participants [Participants]	16 32%	13 26%	29 29%
Any other prior illnesses within last 7 days (Count of Participants)
Yes	4 8%	2 4%	6 6%
No	46 92%	48 96%	94 94%
Temperature ([°C]) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [[°C]]	37.80 (0.81)	37.79 (0.79)	37.80 (0.79)
Hemoglobin ([g/dl]) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [[g/dl]]	10.16 (1.62)	9.68 (1.42)	9.92 (1.53)
P.falciparum merozoites paras. density (parasites/µl blood) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [parasites/µl blood]	30373.60 (32808.10)	23318.80 (25199.72)	26846.20 (29319.34)
P.falciparum gamotocytes parasite density (for those patients with gametocytes) (parasites/µl blood) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [parasites/µl blood]	200.0 (123.29)	170.0 (110.58)	181.54 (111.49)
G6PD phenotype (Count of Participants)
Deficient	7 14%	7 14%	14 14%
Heterozygous	11 22%	5 10%	16 16%
Normal	32 64%	38 76%	70 70%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AS-AQ-MB	AS-AQ-PQ
Arm/Group Description	Once daily a fixed dose artesunate-amodiaquine formulation combined with once daily methylene blue (15 mg/kg) over a three days period. Methylene Blue: 50 patients will receive methylene blue	Once daily a fixed dose artesunate-amodiaquine over three days combined with a single dose of primaquine on day 2 (0.25 mg/kg). Primaquine: 50 patients will receive primaquine
Measure Participants	50	49
Mean (Standard Deviation) [g/dl]	0.18 (1.42)	0.54 (0.94)

2. Secondary Outcome

Title	Gametocyte Prevalence
Description	measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Adverse Events (AE)
Description	Reports of observed or self-reported adverse event
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Mothers/Caretakers Questionnaire on Acceptance
Description	Acceptance of the different treatment regimens by mothers/caretakers
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Gametocyte Density
Description	measured microscopically at baseline and on day 1, 2, 3, 7, 14, and 28 of follow-up
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	AS-AQ-MB		AS-AQ-PQ
Arm/Group Description	Once daily a fixed dose artesunate-amodiaquine formulation combined with once daily methylene blue (15 mg/kg) over a three days period. Methylene Blue: 50 patients will receive methylene blue		Once daily a fixed dose artesunate-amodiaquine over three days combined with a single dose of primaquine on day 2 (0.25 mg/kg). Primaquine: 50 patients will receive primaquine
All Cause Mortality
	AS-AQ-MB		AS-AQ-PQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AS-AQ-MB		AS-AQ-PQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/50 (4%)		0/50 (0%)
Blood and lymphatic system disorders
Severe anemia	1/50 (2%)	1	0/50 (0%)	0
Infections and infestations
Severe malaria	1/50 (2%)	1	0/50 (0%)	0
Other (Not Including Serious) Adverse Events
	AS-AQ-MB		AS-AQ-PQ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/50 (66%)		28/50 (56%)
Gastrointestinal disorders
Gastro-intestinal symptoms	14/50 (28%)	19	13/50 (26%)	16
Respiratory, thoracic and mediastinal disorders
Respiratory symptoms	20/50 (40%)	25	20/50 (40%)	35

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.