Trial Outcomes & Findings for Aggressive Antipyretics for Fever Reduction in CNS Malaria (NCT NCT03399318)
NCT ID: NCT03399318
Last Updated: 2024-03-05
Results Overview
Mean maximum temperature (Tmax). Tmax will be defined as the highest temperature during the study duration (72 hours) in degrees Celsius recorded by a continuous temperature monitor. The continuous temperature monitors are not magnetic resonance imaging (MRI) compatible. If TMAX is a clinical temperature obtained when continuous monitoring data is not available, the clinical TMAX will be used as the primary outcome.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
256 participants
Primary outcome timeframe
72 hours
Results posted on
2024-03-05
Participant Flow
The trial was conducted in Malawi and Zambia from 2019 to 2022. In Malawi, enrolment occurred at Queen Elizabeth Central Hospital in Blantyre. In Zambia, the trial was conducted at the University Teaching Hospital in Lusaka and Chipata Central Hospital in the Eastern Province. This work was approved by the appropriate ethics review boards in Zambia and Malawi and at the University of Rochester in the United States.
Participant milestones
| Measure |
Aggressive Antipyretics (AA)
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
Overall Study
STARTED
|
128
|
128
|
|
Overall Study
COMPLETED
|
128
|
128
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
One research file was lost and these data were not otherwise recoverable.
Baseline characteristics by cohort
| Measure |
Aggressive Antipyretics (AA)
n=128 Participants
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=128 Participants
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
Total
n=256 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
4.4 years
n=128 Participants
|
3.8 years
n=128 Participants
|
4.1 years
n=256 Participants
|
|
Sex: Female, Male
Female
|
59 Participants
n=128 Participants
|
56 Participants
n=128 Participants
|
115 Participants
n=256 Participants
|
|
Sex: Female, Male
Male
|
69 Participants
n=128 Participants
|
72 Participants
n=128 Participants
|
141 Participants
n=256 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=128 Participants
|
0 Participants
n=128 Participants
|
0 Participants
n=256 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=128 Participants
|
0 Participants
n=128 Participants
|
0 Participants
n=256 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=128 Participants
|
0 Participants
n=128 Participants
|
0 Participants
n=256 Participants
|
|
Race (NIH/OMB)
Black or African American
|
128 Participants
n=128 Participants
|
128 Participants
n=128 Participants
|
256 Participants
n=256 Participants
|
|
Race (NIH/OMB)
White
|
0 Participants
n=128 Participants
|
0 Participants
n=128 Participants
|
0 Participants
n=256 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=128 Participants
|
0 Participants
n=128 Participants
|
0 Participants
n=256 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=128 Participants
|
0 Participants
n=128 Participants
|
0 Participants
n=256 Participants
|
|
Region of Enrollment
Malawi
|
74 Participants
n=128 Participants
|
72 Participants
n=128 Participants
|
146 Participants
n=256 Participants
|
|
Region of Enrollment
Zambia
|
54 Participants
n=128 Participants
|
56 Participants
n=128 Participants
|
110 Participants
n=256 Participants
|
|
Weight
|
15.1 units on a scale - kg
STANDARD_DEVIATION 4.4 • n=128 Participants
|
14.0 units on a scale - kg
STANDARD_DEVIATION 3.2 • n=128 Participants
|
14.6 units on a scale - kg
STANDARD_DEVIATION 3.8 • n=256 Participants
|
|
Admission temperature
|
38.1 degrees of Celsius (°C)
STANDARD_DEVIATION 1.3 • n=128 Participants
|
38.1 degrees of Celsius (°C)
STANDARD_DEVIATION 1.3 • n=128 Participants
|
38.1 degrees of Celsius (°C)
STANDARD_DEVIATION 1.3 • n=256 Participants
|
|
Cerebral malaria
|
83 Participants
n=128 Participants
|
72 Participants
n=128 Participants
|
155 Participants
n=256 Participants
|
|
Blantyre Coma Score
0
|
2 Participants
n=128 Participants
|
6 Participants
n=128 Participants
|
8 Participants
n=256 Participants
|
|
Blantyre Coma Score
1
|
22 Participants
n=128 Participants
|
27 Participants
n=128 Participants
|
49 Participants
n=256 Participants
|
|
Blantyre Coma Score
2
|
48 Participants
n=128 Participants
|
50 Participants
n=128 Participants
|
98 Participants
n=256 Participants
|
|
Blantyre Coma Score
3
|
21 Participants
n=128 Participants
|
16 Participants
n=128 Participants
|
37 Participants
n=256 Participants
|
|
Blantyre Coma Score
4
|
12 Participants
n=128 Participants
|
11 Participants
n=128 Participants
|
23 Participants
n=256 Participants
|
|
Blantyre Coma Score
5
|
23 Participants
n=128 Participants
|
18 Participants
n=128 Participants
|
41 Participants
n=256 Participants
|
|
Seizures
None
|
23 participants
n=127 Participants • One research file was lost and these data were not otherwise recoverable.
|
20 participants
n=128 Participants • One research file was lost and these data were not otherwise recoverable.
|
43 participants
n=255 Participants • One research file was lost and these data were not otherwise recoverable.
|
|
Seizures
Single and brief
|
16 participants
n=127 Participants • One research file was lost and these data were not otherwise recoverable.
|
10 participants
n=128 Participants • One research file was lost and these data were not otherwise recoverable.
|
26 participants
n=255 Participants • One research file was lost and these data were not otherwise recoverable.
|
|
Seizures
Multiple or prolonged
|
88 participants
n=127 Participants • One research file was lost and these data were not otherwise recoverable.
|
98 participants
n=128 Participants • One research file was lost and these data were not otherwise recoverable.
|
186 participants
n=255 Participants • One research file was lost and these data were not otherwise recoverable.
|
|
Had received antipyretics
|
115 participants
n=128 Participants
|
110 participants
n=128 Participants
|
225 participants
n=256 Participants
|
|
Had received anticonvulsant
|
64 Participants
n=128 Participants
|
69 Participants
n=128 Participants
|
133 Participants
n=256 Participants
|
|
Quantative parasite count
|
3281 parasite per microliter
n=92 Participants • Quantitative counts are only applicable to participants who had parasite in their blood. Those who were smear negative on enrolment due to rapid antimalairal administration were not included in the analysis. These individuals had their diagnosis confirmed by a rapid diagnostic test
|
1890 parasite per microliter
n=89 Participants • Quantitative counts are only applicable to participants who had parasite in their blood. Those who were smear negative on enrolment due to rapid antimalairal administration were not included in the analysis. These individuals had their diagnosis confirmed by a rapid diagnostic test
|
2100 parasite per microliter
n=181 Participants • Quantitative counts are only applicable to participants who had parasite in their blood. Those who were smear negative on enrolment due to rapid antimalairal administration were not included in the analysis. These individuals had their diagnosis confirmed by a rapid diagnostic test
|
|
HRP2-(ng/ml)
|
123 ng/ml
n=128 Participants
|
86 ng/ml
n=128 Participants
|
108 ng/ml
n=256 Participants
|
|
Packed Cell Volume
|
28 percent - %
STANDARD_DEVIATION 7 • n=128 Participants
|
29 percent - %
STANDARD_DEVIATION 7 • n=128 Participants
|
29 percent - %
STANDARD_DEVIATION 7 • n=256 Participants
|
|
Creatinine
|
0.64 units on a scale - mg/dL
STANDARD_DEVIATION 0.23 • n=128 Participants
|
0.63 units on a scale - mg/dL
STANDARD_DEVIATION 0.20 • n=128 Participants
|
0.64 units on a scale - mg/dL
STANDARD_DEVIATION 0.22 • n=256 Participants
|
|
HIV Positive
|
3 Participants
n=128 Participants
|
4 Participants
n=128 Participants
|
7 Participants
n=256 Participants
|
PRIMARY outcome
Timeframe: 72 hoursMean maximum temperature (Tmax). Tmax will be defined as the highest temperature during the study duration (72 hours) in degrees Celsius recorded by a continuous temperature monitor. The continuous temperature monitors are not magnetic resonance imaging (MRI) compatible. If TMAX is a clinical temperature obtained when continuous monitoring data is not available, the clinical TMAX will be used as the primary outcome.
Outcome measures
| Measure |
Aggressive Antipyretics (AA)
n=128 Participants
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=128 Participants
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
Mean Maximum Temperature
|
38.6 degrees of Celsius
Interval 38.4 to 38.7
|
39.2 degrees of Celsius
Interval 39.1 to 39.3
|
PRIMARY outcome
Timeframe: 72 hoursPopulation: One research file was lost and these data were not otherwise recoverable
Seizures were categorized as none, single and brief, or multiple or prolonged, yielding a three-category outcome.
Outcome measures
| Measure |
Aggressive Antipyretics (AA)
n=127 Participants
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=128 Participants
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
Seizure Severity
None
|
107 Participants
|
88 Participants
|
|
Seizure Severity
Single and brief
|
10 Participants
|
6 Participants
|
|
Seizure Severity
Multiple or Prolonged
|
10 Participants
|
34 Participants
|
SECONDARY outcome
Timeframe: 72 hoursPopulation: Exclusion of 38 children with missing data
Parasite clearance was based upon AUC for plasma HRP2 concentration every six hours
Outcome measures
| Measure |
Aggressive Antipyretics (AA)
n=108 Participants
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=110 Participants
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
Parasite Clearance
|
86.3 ng*hr/mL
Interval 78.2 to 94.4
|
80 ng*hr/mL
Interval 71.5 to 88.4
|
SECONDARY outcome
Timeframe: 72 hoursAUC fever for temperatures above 37.5 degrees Celsius based upon continuous temperature monitoring A secondary efficacy measure included fever exposure as measured by the area under the temperature × time curve for T≥38.5°C during the 72-hour follow-up period, categorized as 0, \> 0 and \< 2, and ≥ 2 degree-hours. An ordinal logistic regression model assuming proportional odds with terms for treatment group, country, and disease severity as covariates was used to derive the estimated adjusted treatment group odds ratio and associated 95% confidence interval. Sensitivity analyses with best-case and worst-case imputation were performed to accommodate missing data for the 12 participants with insufficient temperature data to determine the proper outcome category
Outcome measures
| Measure |
Aggressive Antipyretics (AA)
n=128 Participants
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=128 Participants
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best)
0
|
67 Participants
|
37 Participants
|
|
Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best)
> 0 and < 2
|
47 Participants
|
54 Participants
|
|
Area-under-the-curve (AUC) of Fever ≥ 38.5°C (Best)
≥ 2
|
14 Participants
|
37 Participants
|
Adverse Events
Aggressive Antipyretics (AA)
Serious events: 15 serious events
Other events: 102 other events
Deaths: 3 deaths
Usual Care (UC).
Serious events: 25 serious events
Other events: 87 other events
Deaths: 10 deaths
Serious adverse events
| Measure |
Aggressive Antipyretics (AA)
n=128 participants at risk
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=128 participants at risk
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
General disorders
Death
|
2.3%
3/128 • Number of events 3 • 72 hours
|
7.8%
10/128 • Number of events 10 • 72 hours
|
|
Vascular disorders
Any bleeding
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
Vascular disorders
Clinical signs of bleeding
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
Renal and urinary disorders
Creatinine increase
|
2.3%
3/128 • Number of events 5 • 72 hours
|
0.00%
0/128 • 72 hours
|
|
Nervous system disorders
Neurologic deficits at discharge
|
7.0%
9/128 • Number of events 9 • 72 hours
|
7.8%
10/128 • Number of events 10 • 72 hours
|
|
General disorders
Shock
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
Vascular disorders
Shock with necrotic digits
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
Nervous system disorders
Status epilepticus and prolonged apnea
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
Other adverse events
| Measure |
Aggressive Antipyretics (AA)
n=128 participants at risk
AA children received a loading dose of acetaminophen (30 mg/kg) followed by 15 mg/kg every 6 hours regardless of clinical temperature for 72 hours. No loading dose was given if an antipyretic had been administered in the past 24 hours. In addition, AA children received ibuprofen 10mg/kg Q6 hours for 72 hours. A cooling fan was added for anyone with persistent fevers. When T≥38.5°C was detected, 15 mg/kg of placebo was added in the AA group.
|
Usual Care (UC).
n=128 participants at risk
UC children received 15 mg/kg of acetaminophen as needed every 6 hours for T≥38.5°C based upon clinical axillary temperatures obtained every 2 hours in Malawi and every 6 hours in Zambia. No loading dose was given if an antipyretic had been administered in the past 24 hours. To maintain double-blinding, an initial loading dose of placebo and placebos for acetaminophen and ibuprofen were used in the UC group.
|
|---|---|---|
|
Vascular disorders
Any bleeding
|
13.3%
17/128 • Number of events 18 • 72 hours
|
7.0%
9/128 • Number of events 10 • 72 hours
|
|
Vascular disorders
Clinical signs of bleeding
|
3.9%
5/128 • Number of events 5 • 72 hours
|
1.6%
2/128 • Number of events 2 • 72 hours
|
|
Renal and urinary disorders
Creatinine increase
|
47.7%
61/128 • Number of events 100 • 72 hours
|
37.5%
48/128 • Number of events 81 • 72 hours
|
|
Gastrointestinal disorders
Diarrhea
|
0.78%
1/128 • Number of events 1 • 72 hours
|
1.6%
2/128 • Number of events 2 • 72 hours
|
|
Metabolism and nutrition disorders
Elevated lactate
|
9.4%
12/128 • Number of events 18 • 72 hours
|
14.8%
19/128 • Number of events 24 • 72 hours
|
|
General disorders
Fell from bed
|
1.6%
2/128 • Number of events 2 • 72 hours
|
1.6%
2/128 • Number of events 2 • 72 hours
|
|
Hepatobiliary disorders
Hyperbilirubinemia
|
50.0%
64/128 • Number of events 144 • 72 hours
|
51.6%
66/128 • Number of events 150 • 72 hours
|
|
Metabolism and nutrition disorders
Hypoglycemia
|
0.00%
0/128 • 72 hours
|
2.3%
3/128 • Number of events 3 • 72 hours
|
|
General disorders
Misc. lab change
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
Injury, poisoning and procedural complications
Nasogastric tube injury
|
0.78%
1/128 • Number of events 1 • 72 hours
|
0.00%
0/128 • 72 hours
|
|
Blood and lymphatic system disorders
Bleeding occult
|
9.4%
12/128 • Number of events 13 • 72 hours
|
5.5%
7/128 • Number of events 8 • 72 hours
|
|
General disorders
Drop in level of consciousness
|
0.78%
1/128 • Number of events 1 • 72 hours
|
0.00%
0/128 • 72 hours
|
|
Nervous system disorders
Prolonged hospitalization.
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
General disorders
Systemic allergic reaction
|
0.78%
1/128 • Number of events 1 • 72 hours
|
0.00%
0/128 • 72 hours
|
|
Skin and subcutaneous tissue disorders
Urticaria
|
0.00%
0/128 • 72 hours
|
0.78%
1/128 • Number of events 1 • 72 hours
|
|
General disorders
Vomiting
|
7.8%
10/128 • Number of events 12 • 72 hours
|
7.0%
9/128 • Number of events 13 • 72 hours
|
Additional Information
Professor Gretchen L. Birbeck
University of Rochester
Phone: + 1(517) 505-0283
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place