Plasmodium Falciparum Malaria
Conditions
Keywords
Plasmodium infections, Remittent fever, Artemether, Artemesinins, Quinine, Malaria, Protozoan infections, sublingual drug delivery, Parasitic disease, Antiprotozoan agents
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.
Interventions
DRUGArtemether Sublingual Spray
Artemether sublingual spray administered at 3 mg/kg (milligrams per kilogram) at specified timepoints
DRUGQuinine
Quinine administered intravenously, 20 mg/kg loading dose followed by 10 mg/kg every eight hours
Sponsors
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 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 .
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parasitological Success (MITT) | 24 hours after start of treatment | Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose |
| Parasitological Success (PP) | 24 hours after start of treatment | Parasitological success defined as a reduction in parasite count of ≥ 90% of baseline at 24 hours after the first dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PCT 90 [MITT Population] | 28 days after start of treatment | Time for parasite counts to fall by 90% |
| PCT 50 [MITT Population] | 28 days after start of treatment | Time for parasite counts to fall by 50% |
| PRR 24 [MITT Population] | 28 days after start of treatment | The percentage reduction in parasite counts 24 hours after first dose |
| PRR 12 [MITT Population] | 28 days after start of treatment | The percentage reduction in parasite counts 12 hours after first dose |
| Fever Clearance Time (FCT) | 28 days after start of treatment | Time in hours from the initiation of therapy until the disappearance of fever (tympanic temperature \< 38.0) that lasted at least 24 hours. |
| Early Treatment Failure | Three days after the start of treatment | 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 |
| Complete Cure Rate | 28 days after the start of treatment | 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 |
| Late Parasitological Failure | 28 days after the start of treatment | o Parasitaemia on any day from Day 7 to Day 28 and tympanic temperature ≤ 38.0°C |
| Time to Return to Full Consciousness | 28 days after start of treatment | 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 | 28 days after start of treatment | 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 | 28 days after start of treatment | — |
| Number of Deaths or Neurological Sequelae at Day 28 | 28 days after start of treatment | — |
| Late Clinical Failure | 28 days after the start of treatment | * 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 |
| Parasite Clearance Time (PCT) [MITT Population] | 28 days after start of treatment | 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 |
Countries
Burkina Faso, Ghana, Rwanda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ArTiMist Doses of 3 mg/kg were administered sublingually at: 0 h, 8 h, 24 h, 36 h, 48 h, and 60 h.
Following the initial six doses, subjects could, at the discretion of the Investigator receive a further four daily doses of 3 mg/kg ArTiMist™ to complete a seven day treatment course, or be converted to another suitable treatment or a suitable course of combination therapy in accordance with national drugs policy where applicable. | 77 |
| Quinine A loading dose of 20 mg/kg was given over four hours and thereafter 10 mg/kg was given every eight hours until the subject was able to swallow. Thereafter, patients were given quinine syrup or crushed tablets (10 mg/kg every eight hours) or another suitable treatment to ensure they received at least seven days of therapy, or be converted to another suitable treatment or a suitable course of combination therapy, in accordance with national drugs policy where applicable | 74 |
| Total | 151 |
Baseline characteristics
| Characteristic | ArTiMist | Quinine | Total |
|---|---|---|---|
| Age, Continuous | 2.8 years STANDARD_DEVIATION 1.34 | 2.5 years STANDARD_DEVIATION 1.23 | 2.6 years STANDARD_DEVIATION 1.29 |
| Blantyre Coma Scale 5 | 60 participants | 53 participants | 113 participants |
| Blantyre Coma Scale < 5 | 17 participants | 21 participants | 38 participants |
| Disease Definition - Severe or complicated malaria Severe or complicated malaria | 49 participants | 51 participants | 100 participants |
| Disease Definition - Severe or complicated malaria Uncomplicated malaria with GI complications | 28 participants | 23 participants | 51 participants |
| Parasite Count (median) | 86572 p falciparum /mcl | 66077 p falciparum /mcl | 76325 p falciparum /mcl |
| Parasite Counts | 133884 p falciparum /mcl STANDARD_DEVIATION 129715 | 155321 p falciparum /mcl STANDARD_DEVIATION 202213 | 144602 p falciparum /mcl STANDARD_DEVIATION 165964 |
| Pulse rate | 146 bpm STANDARD_DEVIATION 20.2 | 147 bpm STANDARD_DEVIATION 26.3 | 146 bpm STANDARD_DEVIATION 23.3 |
| Region of Enrollment Burkina Faso | 25 participants | 25 participants | 50 participants |
| Region of Enrollment Ghana | 25 participants | 25 participants | 50 participants |
| Region of Enrollment Rwanda | 27 participants | 24 participants | 51 participants |
| Respiratory Rate | 36.7 breaths/min STANDARD_DEVIATION 11 | 35.9 breaths/min STANDARD_DEVIATION 11.3 | 36.3 breaths/min STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 40 Participants | 39 Participants | 79 Participants |
| Sex: Female, Male Male | 37 Participants | 35 Participants | 72 Participants |
| Tympanic Temperature | 38.6 Degrees Centigrade STANDARD_DEVIATION 1.1 | 38.6 Degrees Centigrade STANDARD_DEVIATION 1 | 38.6 Degrees Centigrade STANDARD_DEVIATION 1.1 |
| Weight | 11.7 kg STANDARD_DEVIATION 2.4 | 11.2 kg STANDARD_DEVIATION 2.5 | 11.4 kg STANDARD_DEVIATION 2.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 77 | 44 / 74 |
| serious Total, serious adverse events | 4 / 77 | 10 / 74 |
Outcome results
Primary
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
Population: The Modified Intention to Treat (MITT) population included all randomised subjects who received at least one dose of study medication and had evaluable parasite counts at 24 hours after first dosing.~7 subjects for ArTiMist and 3 subjects for quinine were excluded due to no baseline or 24 h parasite count
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ArTiMist | Parasitological Success (MITT) | Success | 66 participants |
| ArTiMist | Parasitological Success (MITT) | Not Success | 4 participants |
| Quinine | Parasitological Success (MITT) | Success | 28 participants |
| Quinine | Parasitological Success (MITT) | Not Success | 43 participants |
Comparison: In ART003, the parasite success rate for quinine was 67.7%. On the assumption that the parasite success rate was 70% for quinine in this study and in order to demonstrate that ArTiMist™ is superior to quinine by at least 20% the success rate for ArTiMist™ should be at least 90%. Using these figures, and assuming a power of 80%, an alpha of 0.05 (two sided) and based on an equal allocation to the ArTiMist™ and quinine treatment arms, the number of subjects (n) required on each treatment was 59.p-value: <0.00595% CI: [42.25, 67.45]Regression, Logistic
Primary
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
Population: The Per Protocol (PP) population included the subjects in the MITT population who had received at least 80% of doses up to the time of discharge from the hospital, had evaluable data up to and including Day 28 and had no major protocol violations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ArTiMist | Parasitological Success (PP) | Success | 65 participants |
| ArTiMist | Parasitological Success (PP) | Not Success | 3 participants |
| Quinine | Parasitological Success (PP) | Not Success | 41 participants |
| Quinine | Parasitological Success (PP) | Success | 28 participants |
p-value: <0.00595% CI: [42.44, 67.58]Regression, Linear
Secondary
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
Population: For some subjects, this endpoint was not evaluable and/or not all data was received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ArTiMist | Complete Cure Rate | Cure | 41 participants |
| ArTiMist | Complete Cure Rate | No Cure | 14 participants |
| Quinine | Complete Cure Rate | Cure | 46 participants |
| Quinine | Complete Cure Rate | No Cure | 17 participants |
p-value: 0.9995% CI: [0.42, 2.36]Regression, Logistic
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ArTiMist | Early Treatment Failure | 0 participants |
| Quinine | Early Treatment Failure | 14 participants |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Fever Clearance Time (FCT) | 42.6 hours | Standard Deviation 34.47 |
| Quinine | Fever Clearance Time (FCT) | 41.6 hours | Standard Deviation 22.73 |
p-value: 0.8695% CI: [-10.16, 12.08]Regression, Cox
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ArTiMist | Late Clinical Failure | 3 participants |
| Quinine | Late Clinical Failure | 1 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ArTiMist | Late Parasitological Failure | 12 participants |
| Quinine | Late Parasitological Failure | 14 participants |
Secondary
Number of Deaths or Neurological Sequelae at Day 28
Time frame: 28 days after start of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ArTiMist | Number of Deaths or Neurological Sequelae at Day 28 | 0 participants |
| Quinine | Number of Deaths or Neurological Sequelae at Day 28 | 0 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ArTiMist | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events, of Possible, Probably and Definite Causalities | 5 participants |
| Quinine | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events, of Possible, Probably and Definite Causalities | 6 participants |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Parasite Clearance Time (PCT) [MITT Population] | 30.29 hours | Standard Deviation 13.21 |
| Quinine | Parasite Clearance Time (PCT) [MITT Population] | 68.30 hours | Standard Deviation 98.04 |
p-value: <0.0595% CI: [-62.22, -15.72]ANCOVA
Secondary
PCT 50 [MITT Population]
Time for parasite counts to fall by 50%
Time frame: 28 days after start of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | PCT 50 [MITT Population] | 9.42 hours | Standard Deviation 5.72 |
| Quinine | PCT 50 [MITT Population] | 18.58 hours | Standard Deviation 9.19 |
p-value: <0.005Regression, Cox
Secondary
PCT 90 [MITT Population]
Time for parasite counts to fall by 90%
Time frame: 28 days after start of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | PCT 90 [MITT Population] | 15.02 hours | Standard Deviation 5.82 |
| Quinine | PCT 90 [MITT Population] | 27.93 hours | Standard Deviation 18.03 |
p-value: <0.00595% CI: [-17.38, -8.44]ANCOVA
Secondary
PRR 12 [MITT Population]
The percentage reduction in parasite counts 12 hours after first dose
Time frame: 28 days after start of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | PRR 12 [MITT Population] | 47.6 percentage of baseline | Standard Deviation 70.28 |
| Quinine | PRR 12 [MITT Population] | -132.2 percentage of baseline | Standard Deviation 765.92 |
p-value: 0.0695% CI: [-10.44, 358.61]ANCOVA
Secondary
PRR 24 [MITT Population]
The percentage reduction in parasite counts 24 hours after first dose
Time frame: 28 days after start of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | PRR 24 [MITT Population] | 98.2 percentage of baseline | Standard Deviation 6.12 |
| Quinine | PRR 24 [MITT Population] | 44.5 percentage of baseline | Standard Deviation 114.27 |
p-value: <0.00595% CI: [27.05, 80.98]ANCOVA
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Time to Return to Full Consciousness | 20.8 hours | Standard Deviation 9.58 |
| Quinine | Time to Return to Full Consciousness | 23.0 hours | Standard Deviation 16.52 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ArTiMist | Time to Return to Normal Per os Status | 22.1 hours | Standard Deviation 12.89 |
| Quinine | Time to Return to Normal Per os Status | 25.3 hours | Standard Deviation 16.28 |