CClinicalTrials.gg
Sign In
CompletedNCT01258049Updated Feb 28, 2014Results posted

Superiority of ArTiMist Versus Quinine in Children With Severe Malaria

A Phase 3 interventional study of Artemether Sublingual Spray and Quinine in Plasmodium Falciparum Malaria, sponsored by Proto Pharma Ltd. Completed at 3 sites in 3 countries. Per ClinicalTrials.gov, last updated 2014-02-28.

Sponsored by Proto Pharma Ltd · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
151
Allocation
Randomized
Sex
All
01

Study 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

Read the 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.

02

Conditions studied

  • Plasmodium Falciparum Malaria

Keywords

  • Plasmodium infections
  • Remittent fever
  • Artemether
  • Artemesinins
  • Quinine
  • Malaria
  • Protozoan infections
  • sublingual drug delivery
  • Parasitic disease
  • Antiprotozoan agents
03

In context

Malaria

1,299 studies on the registry are indexed under Malaria; 86 are open to participants now.

This study's enrollment of 151 is below the median of 220 across 1,027 interventional studies indexed under Malaria.

Browse Malaria studies →

Lead sponsor

Proto Pharma Ltd is the lead sponsor of 2 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
Child (0–17), Adult (18–64), Older adult (65+)
Sexes eligible
All
Accepts healthy volunteers
No

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

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 .
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
151 participants (actual)

Study arms

  • Experimental
    ArTiMist

    Drug: Artemether Sublingual Spray

  • Active comparator
    Quinine

    Drug: Quinine

Interventions

  • DrugArtemether Sublingual Spray

    Artemether sublingual spray administered at 3 mg/kg (milligrams per kilogram) at specified timepoints

    Also known as: ArTiMist

  • DrugQuinine

    Quinine administered intravenously, 20 mg/kg loading dose followed by 10 mg/kg every eight hours

06

What researchers measure

Primary outcomes

  1. Parasitological Success (MITT)

    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

  2. Parasitological Success (PP)

    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 outcomes

  1. 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

    Time frame: 28 days after start of treatment

  2. PCT 90 [MITT Population]

    Time for parasite counts to fall by 90%

    Time frame: 28 days after start of treatment

  3. PCT 50 [MITT Population]

    Time for parasite counts to fall by 50%

    Time frame: 28 days after start of treatment

  4. PRR 24 [MITT Population]

    The percentage reduction in parasite counts 24 hours after first dose

    Time frame: 28 days after start of treatment

  5. PRR 12 [MITT Population]

    The percentage reduction in parasite counts 12 hours after first dose

    Time frame: 28 days after start of treatment

  6. 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.

    Time frame: 28 days after start of treatment

  7. 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

    Time frame: 28 days after the start of treatment

  8. 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

    Time frame: Three days after the start of treatment

  9. 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

    Time frame: 28 days after the start of treatment

  10. Late Parasitological Failure

    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

  11. 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 frame: 28 days after start of treatment

  12. 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.

    Time frame: 28 days after start of treatment

  13. 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

  14. Number of Deaths or Neurological Sequelae at Day 28

    Time frame: 28 days after start of treatment

07

Results

Posted Feb 28, 2014

Participant flow

Participant flow — Overall Study
MilestoneArTiMistQuinine
Started7774
Completed7572
Not completed22

Outcome measures

PrimaryParasitological Success (MITT)

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
Reported as:
Number · participants
Parasitological Success (MITT)
participantsArTiMistQuinine
Success6628
Not Success443
Statistical analysis
  • ArTiMist vs Quinine · Regression, Logistic · p = <0.005 · Percentage difference: 54.85 · 95% CI 42.25 to 67.45
SecondaryParasite 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

Time frame:
28 days after start of treatment
Reported as:
Mean · hours
Parasite Clearance Time (PCT) [MITT Population]
hoursArTiMistQuinine
Parasite Clearance Time (PCT) [MITT Population]30.29 ± 13.2168.30 ± 98.04
Statistical analysis
  • ArTiMist · ANCOVA · p = <0.05 · Mean difference (final values): -38.97 · 95% CI -62.22 to -15.72
SecondaryPCT 90 [MITT Population]

Time for parasite counts to fall by 90%

Time frame:
28 days after start of treatment
Reported as:
Mean · hours
PCT 90 [MITT Population]
hoursArTiMistQuinine
PCT 90 [MITT Population]15.02 ± 5.8227.93 ± 18.03
Statistical analysis
  • ArTiMist vs Quinine · ANCOVA · p = <0.005 · Mean difference (final values): -12.91 · 95% CI -17.38 to -8.44
SecondaryPCT 50 [MITT Population]

Time for parasite counts to fall by 50%

Time frame:
28 days after start of treatment
Reported as:
Mean · hours
PCT 50 [MITT Population]
hoursArTiMistQuinine
PCT 50 [MITT Population]9.42 ± 5.7218.58 ± 9.19
Statistical analysis
  • ArTiMist vs Quinine · Regression, Cox · p = <0.005 · Mean difference (final values): -9.16 · 95% CI -11.71 to - 6.61
SecondaryPRR 24 [MITT Population]

The percentage reduction in parasite counts 24 hours after first dose

Time frame:
28 days after start of treatment
Reported as:
Mean · percentage of baseline
PRR 24 [MITT Population]
percentage of baselineArTiMistQuinine
PRR 24 [MITT Population]98.2 ± 6.1244.5 ± 114.27
Statistical analysis
  • ArTiMist vs Quinine · ANCOVA · p = <0.005 · Mean difference (final values): 54.02 · 95% CI 27.05 to 80.98
SecondaryPRR 12 [MITT Population]

The percentage reduction in parasite counts 12 hours after first dose

Time frame:
28 days after start of treatment
Reported as:
Mean · percentage of baseline
PRR 12 [MITT Population]
percentage of baselineArTiMistQuinine
PRR 12 [MITT Population]47.6 ± 70.28-132.2 ± 765.92
Statistical analysis
  • ArTiMist vs Quinine · ANCOVA · p = 0.06 · Mean difference (final values): 174.09 · 95% CI -10.44 to 358.61mean parasite counts increased in the first 12 hours for patients on quinine treatment
SecondaryFever 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.

Time frame:
28 days after start of treatment
Reported as:
Mean · hours
Fever Clearance Time (FCT)
hoursArTiMistQuinine
Fever Clearance Time (FCT)42.6 ± 34.4741.6 ± 22.73
Statistical analysis
  • ArTiMist vs Quinine · Regression, Cox · p = 0.86 · Mean difference (final values): 0.96 · 95% CI -10.16 to 12.08
SecondaryComplete 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

Time frame:
28 days after the start of treatment
Reported as:
Number · participants
Complete Cure Rate
participantsArTiMistQuinine
Cure4146
No Cure1417
Statistical analysis
  • ArTiMist vs Quinine · Regression, Logistic · p = 0.99 · Percentage difference: 0.99 · 95% CI 0.42 to 2.36
SecondaryEarly 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

Time frame:
Three days after the start of treatment
Reported as:
Number · participants
Early Treatment Failure
participantsArTiMistQuinine
Early Treatment Failure014
SecondaryLate 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

Time frame:
28 days after the start of treatment
Reported as:
Number · participants
Late Clinical Failure
participantsArTiMistQuinine
Late Clinical Failure31
PrimaryParasitological Success (PP)

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
Reported as:
Number · participants
Parasitological Success (PP)
participantsArTiMistQuinine
Success6528
Not Success341
Statistical analysis
  • ArTiMist vs Quinine · Regression, Linear · p = <0.005 · Percentage difference: 55.01 · 95% CI 42.44 to 67.58
SecondaryLate Parasitological Failure

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
Reported as:
Number · participants
Late Parasitological Failure
participantsArTiMistQuinine
Late Parasitological Failure1214
SecondaryTime 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 frame:
28 days after start of treatment
Reported as:
Mean · hours
Time to Return to Full Consciousness
hoursArTiMistQuinine
Time to Return to Full Consciousness20.8 ± 9.5823.0 ± 16.52
SecondaryTime 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.

Time frame:
28 days after start of treatment
Reported as:
Mean · hours
Time to Return to Normal Per os Status
hoursArTiMistQuinine
Time to Return to Normal Per os Status22.1 ± 12.8925.3 ± 16.28
SecondaryNumber 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
Reported as:
Number · participants
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events, of Possible, Probably and Definite Causalities
participantsArTiMistQuinine
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events, of Possible, Probably and Definite Causalities56
SecondaryNumber of Deaths or Neurological Sequelae at Day 28
Time frame:
28 days after start of treatment
Reported as:
Number · participants
Number of Deaths or Neurological Sequelae at Day 28
participantsArTiMistQuinine
Number of Deaths or Neurological Sequelae at Day 2800

Adverse events

Collected over Adverse events were reported from the time of signing informed consent until the final study visit. Adverse events that started or worsened after start of treatment were considered Treatment Emergent.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
ArTiMist—4/77 (5.2%)43/77 (55.8%)
Quinine—10/74 (13.5%)44/74 (59.5%)
Most frequent serious events
Most frequent serious events
EventArTiMistQuinine
AnaemiaBlood and lymphatic system disorders2/777/74
Cerebral MalariaInfections and infestations0/771/74
GastroenteritisInfections and infestations0/771/74
MalariaInfections and infestations0/771/74
BronchopneumoniaInfections and infestations1/770/74
SepsisInfections and infestations1/770/74
Most frequent other events
Most frequent other events
EventArTiMistQuinine
MalariaInfections and infestations17/7714/74
AnaemiaBlood and lymphatic system disorders6/7712/74
PyrexiaGeneral disorders7/776/74
Respiratory Tract InfectionInfections and infestations7/773/74
CoughRespiratory, thoracic and mediastinal disorders6/772/74
VomitingGastrointestinal disorders5/772/74
Abdominal painGastrointestinal disorders0/774/74
ProteinuriaRenal and urinary disorders1/774/74
BronchitisRespiratory, thoracic and mediastinal disorders4/772/74

Baseline characteristics

Age, Continuous
Age, Continuous(years)ArTiMistQuinineTotal
Mean2.8 ± 1.342.5 ± 1.232.6 ± 1.29
Sex: Female, Male
Sex: Female, Male(Participants)ArTiMistQuinineTotal
Female403979
Male373572
Region of Enrollment
Region of Enrollment(participants)ArTiMistQuinineTotal
Ghana252550
Burkina Faso252550
Rwanda272451
Disease Definition - Severe or complicated malaria
Disease Definition - Severe or complicated malaria(participants)ArTiMistQuinineTotal
Severe or complicated malaria4951100
Uncomplicated malaria with GI complications282351
Weight
Weight(kg)ArTiMistQuinineTotal
Mean11.7 ± 2.411.2 ± 2.511.4 ± 2.5
Pulse rate
Pulse rate(bpm)ArTiMistQuinineTotal
Mean146 ± 20.2147 ± 26.3146 ± 23.3
Tympanic Temperature
Tympanic Temperature(Degrees Centigrade)ArTiMistQuinineTotal
Mean38.6 ± 1.138.6 ± 1.038.6 ± 1.1
Respiratory Rate
Respiratory Rate(breaths/min)ArTiMistQuinineTotal
Mean36.7 ± 11.035.9 ± 11.336.3 ± 11.2

3 further baseline measures are reported on the registry.

08

Study locations

3 sites
  • Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
    Ouagadougou, 01 BP 2208, Burkina Faso
  • Navrongo Health Research Centre
    Navrongo, P.O. Box 114, Ghana
  • Rwinkwavu District Hospital
    Rwinkwavu, Eastern Province, Rwanda
09

References and documents

Publications

  • 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. PubMed 26303805 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 28, 2014, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01258049
Lead sponsor
Proto Pharma Ltd
Responsible party
Sponsor
First posted
Dec 10, 2010
Start date
Dec 2010
Primary completion
Aug 2012
Completion
Sep 2012
Results posted
Feb 28, 2014
Last update
Feb 28, 2014

Study contacts

Daryl Bendel, MBChB MFPM
study chair · Xidea Solutions Limited

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jan 2014. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Malaria→

Other studies from this sponsor

Proto Pharma Ltd

Start the discussion