Trial Outcomes & Findings for Evaluation of Potential Effect of Artemether - Lumefantrine and Malaria Drugs on Auditory Function (NCT NCT00444106)

Last Updated: 2011-04-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

265 participants

Primary outcome timeframe

7 days

Results posted on

2011-04-05

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	159	53	53
Overall Study Completed Treatment Period	159	53	53
Overall Study COMPLETED	157	52	52
Overall Study NOT COMPLETED	2	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.
Overall Study Lost to Follow-up	2	1	0
Overall Study Abnormal Test Procedure Results	0	0	1

Baseline Characteristics

Evaluation of Potential Effect of Artemether - Lumefantrine and Malaria Drugs on Auditory Function

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Artemether-lumefantrine (Coartem) n=159 Participants Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.	Atovaquone-proguanil (Malarone) n=53 Participants Atovaquone-proguanil (Malarone) tablets containing 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for 3 days dosage dependent on body weight.	Artesunate-mefloquine n=53 Participants 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.	Total n=265 Participants Total of all reporting groups
Age, Categorical <=18 years	51 Participants n=5 Participants	21 Participants n=7 Participants	18 Participants n=5 Participants	90 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	108 Participants n=5 Participants	32 Participants n=7 Participants	35 Participants n=5 Participants	175 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age Continuous	25.6 years STANDARD_DEVIATION 11.6 • n=5 Participants	25.1 years STANDARD_DEVIATION 11.16 • n=7 Participants	25.2 years STANDARD_DEVIATION 11.26 • n=5 Participants	25.4 years STANDARD_DEVIATION 11.4 • n=4 Participants
Sex: Female, Male Female	63 Participants n=5 Participants	19 Participants n=7 Participants	22 Participants n=5 Participants	104 Participants n=4 Participants
Sex: Female, Male Male	96 Participants n=5 Participants	34 Participants n=7 Participants	31 Participants n=5 Participants	161 Participants n=4 Participants
Body Weight	62.8 kg STANDARD_DEVIATION 14.39 • n=5 Participants	60.3 kg STANDARD_DEVIATION 14.54 • n=7 Participants	65.2 kg STANDARD_DEVIATION 15.37 • n=5 Participants	62.8 kg STANDARD_DEVIATION 14.64 • n=4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Artemether-lumefantrine (Coartem) n=151 Participants Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.	Atovaquone-proguanil (Malarone) Atovaquone-proguanil (Malarone) 250mg tablets once daily for 3 days dosage dependent on body weight.	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.
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 Interval 0.7 to 6.6	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Artemether-lumefantrine (Coartem) n=148 Participants Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.	Atovaquone-proguanil (Malarone) n=51 Participants Atovaquone-proguanil (Malarone) 250mg tablets once daily for 3 days dosage dependent on body weight.	Artesunate-mefloquine n=47 Participants 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.
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 Interval -1.8 to -0.5	-1.5 dB Interval -2.6 to -0.3	-1.2 dB Interval -2.2 to -0.1
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 Interval 11.4 to 13.0	12.0 dB Interval 10.5 to 13.6	12.7 dB Interval 11.2 to 14.2
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 Interval -3.1 to -1.9	-2.4 dB Interval -3.6 to -1.2	-1.9 dB Interval -3.0 to -0.7
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 Interval -2.9 to -1.5	-2.6 dB Interval -4.0 to -1.1	-2.6 dB Interval -3.9 to -1.3
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 Interval -3.5 to -1.9	-2.6 dB Interval -4.2 to -1.0	-3.6 dB Interval -4.8 to -2.3
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 Interval -3.8 to -2.2	-3.3 dB Interval -4.9 to -1.7	-3.1 dB Interval -4.2 to -1.9
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 Interval 10.5 to 12.3	11.3 dB Interval 9.9 to 12.7	12.5 dB Interval 10.8 to 14.3
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 Interval -2.4 to -0.9	-1.3 dB Interval -2.8 to 0.2	-1.4 dB Interval -2.8 to -0.1
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 Interval -2.8 to -1.1	-1.8 dB Interval -3.0 to -0.5	-2.5 dB Interval -4.3 to -0.7
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 Interval -2.7 to -0.4	-2.1 dB Interval -3.5 to -0.6	-3.0 dB Interval -4.7 to -1.3

SECONDARY outcome

Timeframe: From Baseline to Day 7

ABR Wave III latency (ms) changes from baseline to Day 7 in the three drug exposure groups.

Outcome measures

Outcome measures
Measure	Artemether-lumefantrine (Coartem) n=151 Participants Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.	Atovaquone-proguanil (Malarone) n=50 Participants Atovaquone-proguanil (Malarone) 250mg tablets once daily for 3 days dosage dependent on body weight.	Artesunate-mefloquine n=45 Participants 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.
Relationship Between Changes in Auditory Function and Treatment Groups Change from baseline to Day 7 Left Ear	0.01 ms Interval -0.01 to 0.03	-0.01 ms Interval -0.04 to 0.02	-0.03 ms Interval -0.07 to 0.0
Relationship Between Changes in Auditory Function and Treatment Groups Baseline Right Ear	3.86 ms Interval 3.83 to 3.9	3.89 ms Interval 3.84 to 3.94	3.86 ms Interval 3.8 to 3.93
Relationship Between Changes in Auditory Function and Treatment Groups Change from baseline to Day 7 Right Ear	0.01 ms Interval -0.01 to 0.03	-0.01 ms Interval -0.04 to 0.02	-0.04 ms Interval -0.08 to 0.01
Relationship Between Changes in Auditory Function and Treatment Groups Baseline Left Ear	3.85 ms Interval 3.82 to 3.88	3.88 ms Interval 3.84 to 3.93	3.82 ms Interval 3.77 to 3.88

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Artemether-lumefantrine (Coartem) n=151 Participants Artemether-lumefantrine (Coartem) tablets containing 20 mg artemether and 120 mg lumefantrine twice a day for 3 days dosage dependent on body weight.	Atovaquone-proguanil (Malarone) n=53 Participants Atovaquone-proguanil (Malarone) 250mg tablets once daily for 3 days dosage dependent on body weight.	Artesunate-mefloquine n=53 Participants 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.
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 Interval 96.5 to 100.0	100.0 Percentage of Participants Interval 93.3 to 100.0	98.1 Percentage of Participants Interval 89.9 to 100.0
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 Interval 95.5 to 99.8	98.1 Percentage of Participants Interval 89.9 to 100.0	98.1 Percentage of Participants Interval 89.9 to 100.0
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 Interval 93.7 to 99.3	98.1 Percentage of Participants Interval 89.7 to 100.0	98.1 Percentage of Participants Interval 89.9 to 100.0

Adverse Events

Artemether-lumefantrine

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Atovaquone-proguanil

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Artesunate-Mefloquine

Serious events: 1 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Artemether-lumefantrine n=159 participants at risk Artemether-lumefantrine	Atovaquone-proguanil n=53 participants at risk Atovaquone-proguanil	Artesunate-Mefloquine n=53 participants at risk Artesunate-Mefloquine
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	0.00% 0/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	1.9% 1/53 • Number of events 1 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.

Other adverse events

Other adverse events
Measure	Artemether-lumefantrine n=159 participants at risk Artemether-lumefantrine	Atovaquone-proguanil n=53 participants at risk Atovaquone-proguanil	Artesunate-Mefloquine n=53 participants at risk Artesunate-Mefloquine
Gastrointestinal disorders Abdominal pain	1.9% 3/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	3.8% 2/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	7.5% 4/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.
Gastrointestinal disorders Diarrhoea	1.9% 3/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	3.8% 2/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	13.2% 7/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.
Gastrointestinal disorders Vomiting	1.3% 2/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	17.0% 9/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	28.3% 15/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.
General disorders Pyrexia	3.8% 6/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	7.5% 4/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	3.8% 2/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.
Nervous system disorders Dizziness	5.7% 9/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	9.4% 5/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	26.4% 14/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.
Nervous system disorders Headache	3.1% 5/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	13.2% 7/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	13.2% 7/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.
Psychiatric disorders Insomnia	0.00% 0/159 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	0.00% 0/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.	7.5% 4/53 Safety Set- All patients who received at least one dose of study drug and had at least one post baseline safety assessment.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER