Malaria, Falciparum
Conditions
Keywords
Malaria, hearing, co-artemether, auditory, Plasmodium falciparum, marsh fever, Plasmodium infections, remittent fever, paludism, artemether, artemisinins, benflumetol, lumefantrine
Brief summary
To evaluate the potential effects of artemether- lumefantrine on the auditory function
Interventions
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Inclusion criteria
* 12 years of age or older * Accepts Healthy Volunteers * P. falciparum parasitemia between 1,000 and 100,000 parasites/μl * History of fever or presence of fever (temperature ≥ 37.5°C)
Exclusion criteria
* Signs/symptoms of severe/complicated malaria * Ingestion of various antimalarial drugs, or antibiotics in the previous 2 weeks to 2 months * History of any drug-related hearing impairment * Abnormal hearing function at study entry * Exposure to sustained loud noises, by self-report, within the past 24 hours * Present ear problems * Pregnant or lactating (urine test for β-HCG) to be performed on any woman of child bearing age) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Auditory Abnormalities at Day 7 Assessed by Auditory Brainstem Response (ABR) Wave III Latency Changes on Day 7(a Type of Hearing Test) | 7 days | To demonstrate the safety of artemether-lumefantrine after 3 days of treatment in patients with acute, uncomplicated falciparum malaria by testing the null hypothesis that the rate of auditory abnormalities is ≥ 15% in the population treated with artemether-lumefantrine as assessed by ABR at Day 7 following initiation of treatment compared with their baseline values. An auditory nerve abnormality is here defined as a greater than 0.30 ms change in Wave III latency from baseline to Day 7. Exact Pearson-Clopper two-sided 95% confidence limits were constructed for all three treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline (Day 1), 3, 7, 28 and Day 42 | Audiometric measurements such as pure-tone threshold (air conduction tested at 250 to 8000 HZ) day 3, 7, 28 and 42 following initiation of treatment, including changes from baseline. Pure-tone average (PTA) calculated for each ear by averaging the pure-tone threshold values at 500, 1000, 2000 and 3000 HZ. |
| Relationship Between Changes in Auditory Function and Treatment Groups | From Baseline to Day 7 | ABR Wave III latency (ms) changes from baseline to Day 7 in the three drug exposure groups. |
| Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Days 14, 28 and 42 | Percentage of patients with clearance of asexual parasitemia (observed by optical microscopy) within 7 days of initiation of trial treatment without recrudescence within 14, 28 and 42 days respectively after initiation of treatment. Patients with recurrent parasitemia and paired PCR results were classified as either a new infection (different paired genotypes) or a recrudescence (matching paired genotypes). Patients without paired PCR results or ambiguous results were classified as treatment failures. |
Countries
Colombia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Artemether-lumefantrine (Coartem) Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight. | 159 |
| Atovaquone-proguanil (Malarone) Atovaquone-proguanil (Malarone) tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for 3 days dosage dependent on body weight. | 53 |
| Artesunate-mefloquine Artesunate (Plasmotrim) 50 mg tablet; based on body weight for a dosage of 4 mg/kg/day for 3 days- mefloquine (Mephaquin) 250 mg tablets; based on body weight for a total dosage of 25 mg/kg once daily on days 2 and 3. | 53 |
| Total | 265 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal Test Procedure Results | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Atovaquone-proguanil (Malarone) | Artesunate-mefloquine | Artemether-lumefantrine (Coartem) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 21 Participants | 18 Participants | 51 Participants | 90 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 35 Participants | 108 Participants | 175 Participants |
| Age Continuous | 25.1 years STANDARD_DEVIATION 11.16 | 25.2 years STANDARD_DEVIATION 11.26 | 25.6 years STANDARD_DEVIATION 11.6 | 25.4 years STANDARD_DEVIATION 11.4 |
| Body Weight | 60.3 kg STANDARD_DEVIATION 14.54 | 65.2 kg STANDARD_DEVIATION 15.37 | 62.8 kg STANDARD_DEVIATION 14.39 | 62.8 kg STANDARD_DEVIATION 14.64 |
| Sex: Female, Male Female | 19 Participants | 22 Participants | 63 Participants | 104 Participants |
| Sex: Female, Male Male | 34 Participants | 31 Participants | 96 Participants | 161 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 159 | 17 / 53 | 30 / 53 |
| serious Total, serious adverse events | 0 / 159 | 0 / 53 | 1 / 53 |
Outcome results
Primary
Percentage of Participants With Auditory Abnormalities at Day 7 Assessed by Auditory Brainstem Response (ABR) Wave III Latency Changes on Day 7(a Type of Hearing Test)
To demonstrate the safety of artemether-lumefantrine after 3 days of treatment in patients with acute, uncomplicated falciparum malaria by testing the null hypothesis that the rate of auditory abnormalities is ≥ 15% in the population treated with artemether-lumefantrine as assessed by ABR at Day 7 following initiation of treatment compared with their baseline values. An auditory nerve abnormality is here defined as a greater than 0.30 ms change in Wave III latency from baseline to Day 7. Exact Pearson-Clopper two-sided 95% confidence limits were constructed for all three treatment groups.
Time frame: 7 days
Population: Safety per protocol set defined as all the randomized patients who took at least 80% of the entire recommended dose and had a valid baseline and Day 7 ABR Wave III latency evaluation and did not use any meds having an ototoxic effect.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Artemether-lumefantrine (Coartem) | Percentage of Participants With Auditory Abnormalities at Day 7 Assessed by Auditory Brainstem Response (ABR) Wave III Latency Changes on Day 7(a Type of Hearing Test) | 2.6 Percentage of Participants |
Comparison: One-sided null hypothesis that the incidence rate of ABR Wave III latency changes is greater than or equal to 15%.~Increase in ABR Wave III latency between baseline and Day 7 of greater than 0.3 ms.p-value: <0.0001One-sided exact test for a single propn.
Secondary
Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test)
Audiometric measurements such as pure-tone threshold (air conduction tested at 250 to 8000 HZ) day 3, 7, 28 and 42 following initiation of treatment, including changes from baseline. Pure-tone average (PTA) calculated for each ear by averaging the pure-tone threshold values at 500, 1000, 2000 and 3000 HZ.
Time frame: Baseline (Day 1), 3, 7, 28 and Day 42
Population: Safety per protocol patients who had a valid ABR at baseline and on the specified day were included.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline Right Ear | 12.2 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 3 Right Ear | -2.5 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 7 Right Ear | -2.2 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 28 Right Ear | -2.7 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 42 Right Ear | -3.0 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline Left Ear | 11.4 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 3 Left Ear | -1.2 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 7 Left Ear | -1.7 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 28 Left Ear | -2.0 dB |
| Artemether-lumefantrine (Coartem) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 42 Left Ear | -1.5 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 28 Left Ear | -1.8 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline Right Ear | 12.0 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline Left Ear | 11.3 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 42 Right Ear | -3.3 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 3 Right Ear | -2.4 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 42 Left Ear | -2.1 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 7 Left Ear | -1.3 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 7 Right Ear | -2.6 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 3 Left Ear | -1.5 dB |
| Atovaquone-proguanil (Malarone) | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 28 Right Ear | -2.6 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 7 Left Ear | -1.4 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 28 Right Ear | -3.6 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 42 Right Ear | -3.1 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline Left Ear | 12.5 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 28 Left Ear | -2.5 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 3 Left Ear | -1.2 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Baseline Right Ear | 12.7 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 42 Left Ear | -3.0 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 3 Right Ear | -1.9 dB |
| Artesunate-mefloquine | Auditory Changes Following 3 Days of Treatment at Days 3, 7, 28, and 42 Days as Assessed by Pure Tone Thresholds Assessments (a Type of Hearing Test) | Change from baseline to Day 7 Right Ear | -2.6 dB |
Secondary
Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42
Percentage of patients with clearance of asexual parasitemia (observed by optical microscopy) within 7 days of initiation of trial treatment without recrudescence within 14, 28 and 42 days respectively after initiation of treatment. Patients with recurrent parasitemia and paired PCR results were classified as either a new infection (different paired genotypes) or a recrudescence (matching paired genotypes). Patients without paired PCR results or ambiguous results were classified as treatment failures.
Time frame: Days 14, 28 and 42
Population: Full Analysis Set defined as all randomized patients with confirmed malaria at baseline, who had at least one dose of study drug and had at least one relevant post-baseline efficacy assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Artemether-lumefantrine (Coartem) | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 28 | 98.7 Percentage of Participants |
| Artemether-lumefantrine (Coartem) | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 14 | 99.4 Percentage of Participants |
| Artemether-lumefantrine (Coartem) | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 42 | 97.5 Percentage of Participants |
| Atovaquone-proguanil (Malarone) | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 28 | 98.1 Percentage of Participants |
| Atovaquone-proguanil (Malarone) | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 14 | 100.0 Percentage of Participants |
| Atovaquone-proguanil (Malarone) | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 42 | 98.1 Percentage of Participants |
| Artesunate-mefloquine | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 14 | 98.1 Percentage of Participants |
| Artesunate-mefloquine | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 42 | 98.1 Percentage of Participants |
| Artesunate-mefloquine | Efficacy of Polymerase Chain Reaction (PCR) Adjusted Malaria Cure Rates of the Three Treatment Regimens at Days 14, 28 and 42 | Day 28 | 98.1 Percentage of Participants |
Secondary
Relationship Between Changes in Auditory Function and Treatment Groups
ABR Wave III latency (ms) changes from baseline to Day 7 in the three drug exposure groups.
Time frame: From Baseline to Day 7
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Artemether-lumefantrine (Coartem) | Relationship Between Changes in Auditory Function and Treatment Groups | Baseline Right Ear | 3.86 ms |
| Artemether-lumefantrine (Coartem) | Relationship Between Changes in Auditory Function and Treatment Groups | Change from baseline to Day 7 Right Ear | 0.01 ms |
| Artemether-lumefantrine (Coartem) | Relationship Between Changes in Auditory Function and Treatment Groups | Baseline Left Ear | 3.85 ms |
| Artemether-lumefantrine (Coartem) | Relationship Between Changes in Auditory Function and Treatment Groups | Change from baseline to Day 7 Left Ear | 0.01 ms |
| Atovaquone-proguanil (Malarone) | Relationship Between Changes in Auditory Function and Treatment Groups | Change from baseline to Day 7 Left Ear | -0.01 ms |
| Atovaquone-proguanil (Malarone) | Relationship Between Changes in Auditory Function and Treatment Groups | Baseline Right Ear | 3.89 ms |
| Atovaquone-proguanil (Malarone) | Relationship Between Changes in Auditory Function and Treatment Groups | Baseline Left Ear | 3.88 ms |
| Atovaquone-proguanil (Malarone) | Relationship Between Changes in Auditory Function and Treatment Groups | Change from baseline to Day 7 Right Ear | -0.01 ms |
| Artesunate-mefloquine | Relationship Between Changes in Auditory Function and Treatment Groups | Change from baseline to Day 7 Left Ear | -0.03 ms |
| Artesunate-mefloquine | Relationship Between Changes in Auditory Function and Treatment Groups | Change from baseline to Day 7 Right Ear | -0.04 ms |
| Artesunate-mefloquine | Relationship Between Changes in Auditory Function and Treatment Groups | Baseline Left Ear | 3.82 ms |
| Artesunate-mefloquine | Relationship Between Changes in Auditory Function and Treatment Groups | Baseline Right Ear | 3.86 ms |