Superiority of ArTiMist Versus Quinine in Children With Severe Malaria

Phase 3

Completed

Conditions: Plasmodium Falciparum Malaria

Interventions: Drug: Quinine
Drug: Artemether Sublingual Spray

Registration Number: NCT01258049

Lead Sponsor: Proto Pharma Ltd

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 151

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 .

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Quinine	Quinine	-
ArTiMist	Artemether Sublingual Spray	-

Primary Outcome Measures

Name	Time	Method
Parasitological Success (MITT)	24 hours after start of treatment	Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose
Parasitological Success (PP)	24 hours after start of treatment	Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose

Secondary Outcome Measures

Name	Time	Method
Parasite Clearance Time (PCT) [MITT Population]	28 days after start of treatment	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]	28 days after start of treatment	Time for parasite counts to fall by 90%
PCT 50 [MITT Population]	28 days after start of treatment	Time for parasite counts to fall by 50%
PRR 24 [MITT Population]	28 days after start of treatment	The percentage reduction in parasite counts 24 hours after first dose
PRR 12 [MITT Population]	28 days after start of treatment	The percentage reduction in parasite counts 12 hours after first dose
Fever Clearance Time (FCT)	28 days after start of treatment	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	28 days after the start of treatment	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	Three days after the start of treatment	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	28 days after the start of treatment	* 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	28 days after the start of treatment	o Parasitaemia on any day from Day 7 to Day 28 and tympanic temperature ≤ 38.0°C
Time to Return to Full Consciousness	28 days after start of treatment	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	28 days after start of treatment	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	28 days after start of treatment
Number of Deaths or Neurological Sequelae at Day 28	28 days after start of treatment

Trial Locations

Locations (3): Rwinkwavu District Hospital
🇷🇼
Rwinkwavu, Eastern Province, Rwanda
Navrongo Health Research Centre
🇬🇭
Navrongo, Ghana
Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
🇧🇫
Ouagadougou, Burkina Faso