Falciparum Malaria
Conditions
Keywords
Plasmodium infections, Remittent fever, Artemether, Artemisinins, quinine, Malaria, Protozoan Infections, Anti-Infective Agents, Antiprotozoal Agents, Schistosomicides, Pharmacologic Actions, Malaria, Falciparum, Antimalarials, Antiparasitic Agents, Parasitic Diseases, sublingual
Brief summary
The purpose of this study is to compare the efficacy of Artemether Sublingual Spray (ArTiMist™) with intravenous quinine in children with severe or complicated falciparum malaria, or children with uncomplicated malaria with gastrointestinal complications.
Interventions
DRUGQuinine
20 mg/kg intravenous quinine loading dose, followed by 10 mg/kg intravenously every 8 hours until resumption of normal oral therapy
DRUGArtemether
Artemether sublingual spray 3 mg/kg at protocol specified timepoints until resumption of normal oral therapy
Sponsors
Xidea Solutions Limited
Proto Pharma Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. The patient's parent or attendant relative 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 and 15 kg (kilogram) 3. The patient has falciparum malaria as evidenced by 1. Thick or thin blood smears of \> 500 P falciparum per mcl (microlitre)(patients with mixed infections may be included provided \>500 P Falciparum /mcl) and /or 2. Positive RDT (rapid diagnostic test)for malaria 4. The patient has either 1. severe or complicated malaria as determined by the Investigator based on the WHO criteria for severity, or 2. the patient has uncomplicated malaria but is unable to tolerate oral medication as a result of gastrointestinal complications such as vomiting or diarrhoea.
Exclusion criteria
1. Attending relative or parent 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 treatment with an artemisinin or quinine in the last 24 hours 4. Patient has evidence of significant co-infections (this does not include mixed Plasmodium infections). 5. Patient is allergic or intolerant to artemisinins.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parasitological Success Defined as a Reduction in Parasite Count of ≥ 90% of Baseline at 24 Hours After the First Dose | 24 hours after first dose | — |
| Time for Parasite Count to Fall by 90% PCT(90) | 3h (hours), 6h, 12h, 18h, 24h, 30h, 36h, 48h, 54h, 60h | The time taken for the parasite count to fall 90% from baseline |
| Time for Parasite Count to Fall by 50% PCT(50) | 3 h (hours) , 6h, 12h, 18h, 24h, 30h, 36h, 48h, 54h, 60h | The time taken for the parasite count to fall 50% from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite Clearance Time | 3h (hours), 6h, 12h, 18h, 24h, 30h, 36h, 48h, 54h, 60h | Time in hours from the initiation of therapy until the first of two successive parasite-negative smears were obtained |
| Parasite Reduction Ratio (PRR) at 24 h (Hours) After the First Dose | 24 hours after first dose | Reduction in parasitaemia from baseline at 24 h after the first dose of study medication |
| Parasite Reduction Ratio (PRR) at 12 Hours After the First Dose | 12 h (hours) after first dose | Reduction in parasitaemia from baseline at 12 hours after the first dose of study medication |
Participant flow
Recruitment details
Patients were recruited at a single study centre in Rwanda during December 2009.
Participants by arm
| Arm | Count |
|---|---|
| ArTiMist Artemether Sublingual Spray 3 mg/kg administered at 0, 8, 24, 36, 48, and 60 hours | 16 |
| Intravenous Quinine Intravenous Quinine. Loading dose of 20 mg/kg and subsequent doses of 10 mg/kg 8 hourly | 15 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Intravenous Quinine | ArTiMist | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 16 Participants | 31 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 3.64 years STANDARD_DEVIATION 2.46 | 3.03 years STANDARD_DEVIATION 1.5 | 3.32 years STANDARD_DEVIATION 2 |
| Region of Enrollment Rwanda | 15 participants | 16 participants | 31 participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 16 | 11 / 15 |
| serious Total, serious adverse events | 0 / 16 | 1 / 15 |
Outcome results
Primary
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 first dose
Population: For the efficacy endpoints, the analysis was based on the Full Analysis Set (FAS) which was defined as all patients that received at least 1 dose of trial medication and had at least 1 post dose parasite count at 12 h (hours) or 24 h after start of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ArTiMist | Parasitological Success Defined as a Reduction in Parasite Count of ≥ 90% of Baseline at 24 Hours After the First Dose | 14 participants |
| Intravenous Quinine | Parasitological Success Defined as a Reduction in Parasite Count of ≥ 90% of Baseline at 24 Hours After the First Dose | 10 participants |
Comparison: The sample size was not statistically determined in this initial trial with ArTimist. For the primary outcome analysis, the percentage of patients defined as having success were determined. The difference between ArTiMist and quinine, along with its 95% confidence interval (CI) were determined. The difference between treatments were compared using Fisher's Exact testp-value: 0.1795% CI: [-0.3, 53.7]Fisher Exact
Primary
Time for Parasite Count to Fall by 50% PCT(50)
The time taken for the parasite count to fall 50% from baseline
Time frame: 3 h (hours) , 6h, 12h, 18h, 24h, 30h, 36h, 48h, 54h, 60h
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Time for Parasite Count to Fall by 50% PCT(50) | 12.0 hours | Standard Deviation 6.48 |
| Intravenous Quinine | Time for Parasite Count to Fall by 50% PCT(50) | 10.8 hours | Standard Deviation 7.42 |
Comparison: The PCT50 was determined for each patient as the time in minutes/seconds, when the parasite count fell by 50% The PCT50 was appropriately summarised for each treatment for the FAS . The times were presented graphically for each endpoint using a life-table curve (Kaplan-Meier method). For each endpoint the survival curves were compared by the log-rank test. The hazard ratio was calculated along with its 95% CI.p-value: 0.7695% CI: [0.34, 2.18]Log Rank
Primary
Time for Parasite Count to Fall by 90% PCT(90)
The time taken for the parasite count to fall 90% from baseline
Time frame: 3h (hours), 6h, 12h, 18h, 24h, 30h, 36h, 48h, 54h, 60h
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Time for Parasite Count to Fall by 90% PCT(90) | 17.6 hours | Standard Deviation 7.34 |
| Intravenous Quinine | Time for Parasite Count to Fall by 90% PCT(90) | 19.8 hours | Standard Deviation 13.59 |
Comparison: The time for the parasite count to fall by 90% (PCT90) was determined for each patient as the time in minutes/seconds, when the parasite count fell by 90% The PCT90 was appropriately summarised for each treatment for the FAS . The times were presented graphically for each endpoint using a life-table curve (Kaplan-Meier method). For each endpoint the survival curves were compared by the log-rank test. The hazard ratio was calculated along with its 95% CI.p-value: 0.795% CI: [0.48, 3.01]Log Rank
Secondary
Parasite Clearance Time
Time in hours from the initiation of therapy until the first of two successive parasite-negative smears were obtained
Time frame: 3h (hours), 6h, 12h, 18h, 24h, 30h, 36h, 48h, 54h, 60h
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Parasite Clearance Time | 35.7 Hours | Standard Deviation 41.97 |
| Intravenous Quinine | Parasite Clearance Time | 51.2 Hours | Standard Deviation 79.04 |
Secondary
Parasite Reduction Ratio (PRR) at 12 Hours After the First Dose
Reduction in parasitaemia from baseline at 12 hours after the first dose of study medication
Time frame: 12 h (hours) after first dose
Population: For the efficacy endpoints, the analysis was based on the Full Analysis Set (FAS) which was defined as all patients that received at least 1 dose of trial medication and had at least 1 post dose parasite count at 12 h or 24 h
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ArTiMist | Parasite Reduction Ratio (PRR) at 12 Hours After the First Dose | 79.6 Percent reduction |
| Intravenous Quinine | Parasite Reduction Ratio (PRR) at 12 Hours After the First Dose | 75.9 Percent reduction |
Secondary
Parasite Reduction Ratio (PRR) at 24 h (Hours) After the First Dose
Reduction in parasitaemia from baseline at 24 h after the first dose of study medication
Time frame: 24 hours after first dose
Population: For the efficacy endpoints, the analysis was based on the Full Analysis Set (FAS) which was defined as all patients that received at least 1 dose of trial medication and had at least 1 post dose parasite count at 12 h or 24 h
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ArTiMist | Parasite Reduction Ratio (PRR) at 24 h (Hours) After the First Dose | 100.0 Percent reduction |
| Intravenous Quinine | Parasite Reduction Ratio (PRR) at 24 h (Hours) After the First Dose | 96.9 Percent reduction |