Superiority of ArTiMist Versus Quinine in Children With Severe Malaria

• Parasitological success [ Time Frame: 24 hours after start of treatment ] [ Designated as safety issue: No ]
  Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose
  
  

• Complete cure (crude and PCR (polymerase chain reaction) adjusted) [ Time Frame: 28 days after the start of treatment ] [ Designated as safety issue: No ]
  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
  
  
• Parasite clearance [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
  • 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
  • Parasite reduction ratio at 12 hours (PRR12) and 24 hours (PRR24) after first dose
  • Time for parasite count to fall by 50% (PCT50) and 90% (PCT90)
  
  
• Fever clearance time (FCT) [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
  Time in hours from the initiation of therapy until the disappearance of fever (tympanic temperature < 38.0) for at least 24 hours.
  
  
• Early treatment failure [ Time Frame: Three days after the start of treatment ] [ Designated as safety issue: No ]

  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 [ Time Frame: 28 days after the start of treatment ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: 28 days after the start of treatment ] [ Designated as safety issue: No ]
  o Parasitaemia on any day from Day 7 to Day 28 and tympanic temperature ≤ 38.0°C
  
  
• Time to return to normal clinical status [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
  • Time in hours to return to normal per os status
  • 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
  
  
• Number and incidence of treatment emergent adverse events and serious adverse events, of possible, probably and definite causalities [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: Yes ]
  
• Number of deaths or neurological sequelae at Day 28 [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: Yes ]
  

Malaria casues 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.