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Superiority of ArTiMist Versus Quinine in Children With Severe Malaria

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Proto Pharma Ltd
ClinicalTrials.gov Identifier:
NCT01258049
First received: December 9, 2010
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

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


Condition Intervention Phase
Plasmodium Falciparum Malaria
Drug: Artemether Sublingual Spray
Drug: Quinine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Proto Pharma Ltd:

Primary Outcome Measures:
  • Parasitological Success (MITT) [ 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

  • Parasitological Success (PP) [ 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


Secondary Outcome Measures:
  • Parasite Clearance Time (PCT) [MITT Population] [ 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

  • PCT 90 [MITT Population] [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
    Time for parasite counts to fall by 90%

  • PCT 50 [MITT Population] [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
    Time for parasite counts to fall by 50%

  • PRR 24 [MITT Population] [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
    The percentage reduction in parasite counts 24 hours after first dose

  • PRR 12 [MITT Population] [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
    The percentage reduction in parasite counts 12 hours after first dose

  • 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) that lasted at least 24 hours.

  • Complete Cure Rate [ 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

  • 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 Full Consciousness [ Time Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]

    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 Frame: 28 days after start of treatment ] [ Designated as safety issue: No ]
    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 [ 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 ]

Enrollment: 151
Study Start Date: December 2010
Study Completion Date: September 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ArTiMist Drug: Artemether Sublingual Spray
Artemether sublingual spray administered at 3 mg/kg (milligrams per kilogram) at specified timepoints
Other Name: ArTiMist
Active Comparator: Quinine Drug: Quinine
Quinine administered intravenously, 20 mg/kg loading dose followed by 10 mg/kg every eight hours

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The patient's legally acceptable representative has provided informed consent and the patient has assented (where relevant) to participation in the trial
  2. The patient is a child that weighs between 5.00 kg and 15.00 kg inclusive
  3. 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)
  4. 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:

  1. 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.
  2. Ability to tolerate oral therapy
  3. Patient has received any antimalarial therapy within the 7 days prior to first study drug administration.
  4. Patient has evidence of significant co-infections (this does not include mixed Plasmodium infections).
  5. Patient has a contraindication, allergy or is otherwise intolerant to either artemether or quinine .
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01258049

Locations
Burkina Faso
Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
Ouagadougou, Burkina Faso, 01 BP 2208
Ghana
Navrongo Health Research Centre
Navrongo, Ghana, P.O. Box 114
Rwanda
Rwinkwavu District Hospital
Rwinkwavu, Eastern Province, Rwanda
Sponsors and Collaborators
Proto Pharma Ltd
Investigators
Study Chair: Daryl Bendel, MBChB MFPM Xidea Solutions Limited
  More Information

No publications provided

Responsible Party: Proto Pharma Ltd
ClinicalTrials.gov Identifier: NCT01258049     History of Changes
Other Study ID Numbers: ART004
Study First Received: December 9, 2010
Results First Received: September 13, 2013
Last Updated: January 27, 2014
Health Authority: Rwanda: Ethics Committee
Ghana : Food and Drugs Board
Burkina Fasu: Ministry of Health

Keywords provided by Proto Pharma Ltd:
Plasmodium infections
Remittent fever
Artemether
Artemesinins
Quinine
Malaria
Protozoan infections
sublingual drug delivery
Parasitic disease
Antiprotozoan agents

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Parasitic Diseases
Protozoan Infections
Artemether
Quinine
Analgesics
Analgesics, Non-Narcotic
Anthelmintics
Anti-Infective Agents
Antifungal Agents
Antimalarials
Antiparasitic Agents
Antiplatyhelmintic Agents
Antiprotozoal Agents
Central Nervous System Agents
Coccidiostats
Muscle Relaxants, Central
Neuromuscular Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Schistosomicides
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014