Superiority of ArTiMist Versus Quinine in Children With Severe Malaria

Study Overview
=================
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.

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.

Conditions
-----------------
Plasmodium Falciparum Malaria

Intervention / Treatment
-----------------
* Drug: Artemether Sublingual Spray
* Drug: Quinine


Participation Criteria
=================
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 .
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ArTiMist<br> | Drug: Artemether Sublingual Spray<br>* Artemether sublingual spray administered at 3 mg/kg (milligrams per kilogram) at specified timepoints<br>* Other names: ArTiMist;|
| Active Comparator: Quinine<br> | Drug: Quinine<br>* Quinine administered intravenously, 20 mg/kg loading dose followed by 10 mg/kg every eight hours<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasitological Success (MITT) | Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose | 24 hours after start of treatment | 
| Parasitological Success (PP) | Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose | 24 hours after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 28 days after start of treatment | 
| PCT 90 [MITT Population] | Time for parasite counts to fall by 90% | 28 days after start of treatment | 
| PCT 50 [MITT Population] | Time for parasite counts to fall by 50% | 28 days after start of treatment | 
| PRR 24 [MITT Population] | The percentage reduction in parasite counts 24 hours after first dose | 28 days after start of treatment | 
| PRR 12 [MITT Population] | The percentage reduction in parasite counts 12 hours after first dose | 28 days after start of treatment | 
| 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. | 28 days after start of treatment | 
| 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 | 28 days after the start of treatment | 
| 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 | Three days after the start of 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 | 28 days after the start of treatment | 
| Late Parasitological Failure | o Parasitaemia on any day from Day 7 to Day 28 and tympanic temperature ≤ 38.0°C | 28 days after the start of treatment | 
| 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 | 28 days after start of treatment | 
| 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. | 28 days after start of treatment | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parasitic disease, Plasmodium infections, Remittent fever, Artemether, Artemesinins, Quinine, Malaria, Protozoan infections, sublingual drug delivery, Antiprotozoan agents