Back to resultsSuperiority of ArTiMist Versus Quinine in Children With Severe Malaria
Primary Purpose
Plasmodium Falciparum Malaria
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Artemether Sublingual Spray
Quinine
Sponsored by
About this trial
This is an interventional treatment trial for Plasmodium Falciparum Malaria focused on measuring Plasmodium infections, Remittent fever, Artemether, Artemesinins, Quinine, Malaria, Protozoan infections, sublingual drug delivery, Parasitic disease, Antiprotozoan agents
Eligibility Criteria
Inclusion Criteria:
- The patient's legally acceptable representative has provided informed consent and the patient has assented (where relevant) to participation in the trial
- The patient is a child that weighs between 5.00 kg and 15.00 kg inclusive
- The patient has falciparum malaria as evidenced by thick or thin blood smears of ≥ 500 P Falciparum per mcl (patients with mixed infections may be included provided ≥ 500 P Falciparum per mcl)
The patient has either:
- severe or complicated falciparum malaria as determined by the investigator based on the WHO criteria for severity, and/or
- uncomplicated falciparum malaria but is unable to tolerate oral medication as a result of gastrointestinal complications such as vomiting or diarrhoea.
Exclusion Criteria:
- The patient's legally acceptable representative does not provide informed consent for participation, or the child if capable, does not assent to participation in the trial.
- Ability to tolerate oral therapy
- Patient has received any antimalarial therapy within the 7 days prior to first study drug administration.
- Patient has evidence of significant co-infections (this does not include mixed Plasmodium infections).
- Patient has a contraindication, allergy or is otherwise intolerant to either artemether or quinine .
Sites / Locations
- Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
- Navrongo Health Research Centre
- Rwinkwavu District Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
ArTiMist
Quinine
Arm Description
Outcomes
Primary Outcome Measures
Parasitological Success (MITT)
Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose
Parasitological Success (PP)
Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose
Secondary Outcome Measures
Parasite Clearance Time (PCT) [MITT Population]
Parasite clearance time (PCT). Time in hours from the initiation of therapy until the first of two successive parasite negative smears (zero parasite counts) are obtained
PCT 90 [MITT Population]
Time for parasite counts to fall by 90%
PCT 50 [MITT Population]
Time for parasite counts to fall by 50%
PRR 24 [MITT Population]
The percentage reduction in parasite counts 24 hours after first dose
PRR 12 [MITT Population]
The percentage reduction in parasite counts 12 hours after first dose
Fever Clearance Time (FCT)
Time in hours from the initiation of therapy until the disappearance of fever (tympanic temperature < 38.0) that lasted at least 24 hours.
Complete Cure Rate
The complete resolution of clinical signs and symptoms, malaria-related laboratory abnormalities, and elimination of asexual parasites by Day 7, with no recurrence up to Day 28 (+/- 2 days), and the 48h parasite count to be < 25% of baseline with no clinical deterioration
Early Treatment Failure
Early treatment failure is indicated by one or more of the following:
Parasite count on Day 2 > Day 0, irrespective of temperature
Parasite count on Day 3 > 0 with tympanic temperature ≥ 38.0°C
Parasite count on Day 3 ≥ 25% of baseline
Administration of rescue antimalarial treatment
Late Clinical Failure
Signs of severe malaria on any day between Day 4 and Day 28 in the presence of parasitaemia, without previously meeting any of the criteria of early treatment failure
Presence of parasitaemia and tympanic temperature ≥ 38.0°C (or history of fever), on any day between Day 4 and Day 28, without previously meeting any of the criteria of early treatment failure
Late Parasitological Failure
o Parasitaemia on any day from Day 7 to Day 28 and tympanic temperature ≤ 38.0°C
Time to Return to Full Consciousness
Time in hours to return to full consciousness (Blantyre Coma Scale = 5), if level of consciousness is reduced (Blantyre Coma Scale <5) prior to dosing or within 24hours of first dosing.
For the Blantyre Coma Scale
Total - maximum 5, eye movement - maximum 1, best motor response - maximum 2, best verbal response - maximum 2
Time to Return to Normal Per os Status
Time in hours to return to normal per os status. Normal per os was when the investigator considered the patient to be able to eat and drink normally.
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events, of Possible, Probably and Definite Causalities
Number of Deaths or Neurological Sequelae at Day 28
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01258049
Brief Title
Superiority of ArTiMist Versus Quinine in Children With Severe Malaria
Official Title
A Phase III, Randomised, Open Labelled, Active Controlled, Multi Centre, Superiority Trial of ArTiMist™ Versus Intravenous Quinine in Children With Severe or Complicated Falciparum Malaria, or Uncomplicated Falciparum Malaria With Gastrointestinal Complications.
Study Type
Interventional
2. Study Status
Record Verification Date
January 2014
Overall Recruitment Status
Completed
Study Start Date
December 2010 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
September 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Proto Pharma Ltd
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to demonstrate that ArTiMist (sublingual artemether spray) is better than intravenous quinine in reducing parasite counts by >= 90% within 24 hours after the start of treatment in children with severe malaria, or uncomplicated malaria with gastrointestinal complications
Detailed Description
Malaria causes significant morbidity and mortality in children in developing countries, despite the availability of highly effective antimalarial therapy. One of the key contributing factors is the delay in the initiation of treatment.
ArTiMist is a sublingual formulation of the established antimalarial treatment, artemether. In previous studies good bioavailability has been demonstrated. In an exploratory study (ART003) ArTiMist demonstrated a non statistically significant improvement of 26% (when compared to intravenous quinine) in the numbers of patients experiencing a parasite reduction of >= 90% within 24 hours of the initiation of treatment.
This Phase 3 study is being conducted to establish whether treatment with ArTiMist in children with severe falciparum malaria or uncomplicated falciparum malaria with gastrointestinal complications is at least 20% superior in providing parasitological success (defined as >= 90% reduction in parasite count at 24 hours after start of treatment) when compared to intravenous quinine.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Plasmodium Falciparum Malaria
Keywords
Plasmodium infections, Remittent fever, Artemether, Artemesinins, Quinine, Malaria, Protozoan infections, sublingual drug delivery, Parasitic disease, Antiprotozoan agents
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
151 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ArTiMist
Arm Type
Experimental
Arm Title
Quinine
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Artemether Sublingual Spray
Other Intervention Name(s)
ArTiMist
Intervention Description
Artemether sublingual spray administered at 3 mg/kg (milligrams per kilogram) at specified timepoints
Intervention Type
Drug
Intervention Name(s)
Quinine
Intervention Description
Quinine administered intravenously, 20 mg/kg loading dose followed by 10 mg/kg every eight hours
Primary Outcome Measure Information:
Title
Parasitological Success (MITT)
Description
Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose
Time Frame
24 hours after start of treatment
Title
Parasitological Success (PP)
Description
Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose
Time Frame
24 hours after start of treatment
Secondary Outcome Measure Information:
Title
Parasite Clearance Time (PCT) [MITT Population]
Description
Parasite clearance time (PCT). Time in hours from the initiation of therapy until the first of two successive parasite negative smears (zero parasite counts) are obtained
Time Frame
28 days after start of treatment
Title
PCT 90 [MITT Population]
Description
Time for parasite counts to fall by 90%
Time Frame
28 days after start of treatment
Title
PCT 50 [MITT Population]
Description
Time for parasite counts to fall by 50%
Time Frame
28 days after start of treatment
Title
PRR 24 [MITT Population]
Description
The percentage reduction in parasite counts 24 hours after first dose
Time Frame
28 days after start of treatment
Title
PRR 12 [MITT Population]
Description
The percentage reduction in parasite counts 12 hours after first dose
Time Frame
28 days after start of treatment
Title
Fever Clearance Time (FCT)
Description
Time in hours from the initiation of therapy until the disappearance of fever (tympanic temperature < 38.0) that lasted at least 24 hours.
Time Frame
28 days after start of treatment
Title
Complete Cure Rate
Description
The complete resolution of clinical signs and symptoms, malaria-related laboratory abnormalities, and elimination of asexual parasites by Day 7, with no recurrence up to Day 28 (+/- 2 days), and the 48h parasite count to be < 25% of baseline with no clinical deterioration
Time Frame
28 days after the start of treatment
Title
Early Treatment Failure
Description
Early treatment failure is indicated by one or more of the following:
Parasite count on Day 2 > Day 0, irrespective of temperature
Parasite count on Day 3 > 0 with tympanic temperature ≥ 38.0°C
Parasite count on Day 3 ≥ 25% of baseline
Administration of rescue antimalarial treatment
Time Frame
Three days after the start of treatment
Title
Late Clinical Failure
Description
Signs of severe malaria on any day between Day 4 and Day 28 in the presence of parasitaemia, without previously meeting any of the criteria of early treatment failure
Presence of parasitaemia and tympanic temperature ≥ 38.0°C (or history of fever), on any day between Day 4 and Day 28, without previously meeting any of the criteria of early treatment failure
Time Frame
28 days after the start of treatment
Title
Late Parasitological Failure
Description
o Parasitaemia on any day from Day 7 to Day 28 and tympanic temperature ≤ 38.0°C
Time Frame
28 days after the start of treatment
Title
Time to Return to Full Consciousness
Description
Time in hours to return to full consciousness (Blantyre Coma Scale = 5), if level of consciousness is reduced (Blantyre Coma Scale <5) prior to dosing or within 24hours of first dosing.
For the Blantyre Coma Scale
Total - maximum 5, eye movement - maximum 1, best motor response - maximum 2, best verbal response - maximum 2
Time Frame
28 days after start of treatment
Title
Time to Return to Normal Per os Status
Description
Time in hours to return to normal per os status. Normal per os was when the investigator considered the patient to be able to eat and drink normally.
Time Frame
28 days after start of treatment
Title
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events, of Possible, Probably and Definite Causalities
Time Frame
28 days after start of treatment
Title
Number of Deaths or Neurological Sequelae at Day 28
Time Frame
28 days after start of treatment
10. Eligibility
Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
The patient's legally acceptable representative has provided informed consent and the patient has assented (where relevant) to participation in the trial
The patient is a child that weighs between 5.00 kg and 15.00 kg inclusive
The patient has falciparum malaria as evidenced by thick or thin blood smears of ≥ 500 P Falciparum per mcl (patients with mixed infections may be included provided ≥ 500 P Falciparum per mcl)
The patient has either:
severe or complicated falciparum malaria as determined by the investigator based on the WHO criteria for severity, and/or
uncomplicated falciparum malaria but is unable to tolerate oral medication as a result of gastrointestinal complications such as vomiting or diarrhoea.
Exclusion Criteria:
The patient's legally acceptable representative does not provide informed consent for participation, or the child if capable, does not assent to participation in the trial.
Ability to tolerate oral therapy
Patient has received any antimalarial therapy within the 7 days prior to first study drug administration.
Patient has evidence of significant co-infections (this does not include mixed Plasmodium infections).
Patient has a contraindication, allergy or is otherwise intolerant to either artemether or quinine .
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daryl Bendel, MBChB MFPM
Organizational Affiliation
Xidea Solutions Limited
Official's Role
Study Chair
Facility Information:
Facility Name
Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
City
Ouagadougou
ZIP/Postal Code
01 BP 2208
Country
Burkina Faso
Facility Name
Navrongo Health Research Centre
City
Navrongo
ZIP/Postal Code
P.O. Box 114
Country
Ghana
Facility Name
Rwinkwavu District Hospital
City
Rwinkwavu
State/Province
Eastern Province
Country
Rwanda
12. IPD Sharing Statement
Citations:
PubMed Identifier
26303805
Citation
Bendel D, Rulisa S, Ansah P, Sirima S. Efficacy of a novel sublingual spray formulation of artemether in African children with Plasmodium falciparum malaria. Antimicrob Agents Chemother. 2015 Nov;59(11):6930-8. doi: 10.1128/AAC.00243-15. Epub 2015 Aug 24.
Results Reference
derived
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Superiority of ArTiMist Versus Quinine in Children With Severe Malaria
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