Fever
Conditions
Brief summary
To assess the rapidity of onset of antipyretic effect and the efficacy and safety of a single dose of IV acetaminophen (IV APAP) versus oral (PO) acetaminophen in the treatment of fever induced by a standard dose of endotoxin
Detailed description
A Phase III, Randomized, Double-Blind, Double-Dummy, Single-Dose Study of the Efficacy and Safety of Intravenous Acetaminophen Versus Oral Acetaminophen for the Treatment of Endotoxin-Induced Fever in Healthy Adult Males
Interventions
DRUGIntravenous acetaminophen plus oral placebo
Single dose of 1 gm IV acetaminophen
DRUGOral acetaminophen plus IV placebo
Single dose of 1 g PO APAP
BIOLOGICALReference standard endotoxin (RSE)
To subjects in both study arms: Administration of a 1 ng/kg body weight test dose of RSE to induce fever and test for fever response. Observation period of at least 60 minutes to ensure no exaggerated systemic responses, followed by administration of a 4 ng/kg of RSE to induce fever.
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
(Screening) To be eligible for entry into the Study, Subjects must meet all of the following criteria at Screening: * Provide written Informed Consent prior to participation in the Study * Be a healthy male between the ages of 18 and 75 years of age, inclusive, at Randomization * Have a Body Mass Index (BMI) ≥ 19 and ≤ 45 lbs/in2 * Have the ability to read and understand the Study procedures and have the ability to communicate meaningfully with the Study Investigator and staff * Be free of physical, mental, or medical conditions which, in the opinion of the Investigator, may confound quantifying assessments for the Study * Be willing to abstain from smoking cigarettes or using nicotine products from the time of admission to Clinic until Study Completion Inclusion Criteria (Pre-Randomization) To be eligible for Randomization, Subjects must meet each of the following criteria: * Be free of evidence of infection based upon clinical assessment and blood (Complete Blood Count- CBC) and urine testing * Have an average baseline oral temperature that is equal to or below 37 ºC (98.6 ºF) and does not vary more than 0.4 ºC (0.7 ºF) from lowest to highest on three assessments performed during a 30-minute period * Not develop a medically significant allergic or exaggerated systemic response to administration of a test dose of reference standard endotoxin * Develop a core temperature of at least 38.6 ºC (101.5 ºF) after IV reference standard endotoxin dosed per Study guidelines and have a fever response to endotoxin that is at or near the peak temperature by virtue of two consecutive temperature assessments 5 minutes apart that are within 0.2 ºC (0.4 ºF) of each other
Exclusion criteria
* Has been treated with any medication having antipyretic effects (e.g., corticosteroid,non-steroidal anti-inflammatory drug \[NSAID\], aspirin, or acetaminophen) within 2 days of clinic admission (aspirin at low dose for cardiac prophylaxis is allowed, but should not be taken on the day of the Study) * Has significant medical disease(s), laboratory abnormalities, or condition(s) that in the Investigator's judgment could compromise the Subject's welfare, ability to communicate with the Study staff, complete Study activities, or would otherwise contraindicate Study participation * Has known hypersensitivity or contraindication to receiving endotoxin that in the Investigator's clinical judgment merits discontinuation from further Study participation * Has known hypersensitivity to acetaminophen, the inactive ingredients (excipients) of the intravenous (IV) or oral (PO) acetaminophen formulation or the Rescue Medications (ibuprofen, aspirin, and ketorolac) * Has known or suspected recent history of alcohol or drug abuse or dependence as defined by Diagnostic Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria * Has a history of nasal polyps, angioedema, significant or actively treated bronchospastic disease, or any other significant medical condition that contraindicates participation in the Study or receiving endotoxin, Study Medication, or Rescue Medication * Has an active infection or other disease or condition that may cause abnormal alterations in body temperature * Has impaired liver function, e.g.Alanine aminotransferase (ALT) greater than or equal to 3 times the upper limit of normal, bilirubin greater than 3.0, active hepatic disease, or evidence of clinically significant liver disease (e.g., cirrhosis or hepatitis) * Has participated in another clinical Study (investigational or marketed product) within 30 days of Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Rapidity of Onset of Antipyretic Effect at 2 Hours (Measured as Weighted Sum of Temperature Differences Over 2 Hours, WSTD2) | 0-2 hours | This outcome measures when the antipyretic effect begins by statistical analysis of WSTD2, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 2 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to a Reduction in Temperature From T0 to T360 Minutes. | 6 hours | This outcome measures how much time it took to observe a decrease in subjects' core body temperature by 0.8 ºC, 1.0 ºC, and 1.5 ºC from the temperature at T0 and from the temperature at the peak after T0 through T360 (6 hours). The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
| Maximum Temperature Reduction Observed From T0 to T360 Minutes | T0-T360 minutes | This outcome measures the maximum core temperature reduction observed from T0 to T360 minutes. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
| Subject's Global Evaluation of Study Medication at T360 Minutes | T360 minutes | This outcome measures how satisfied the subject was with the study treatment. The subject was asked to answer Overall, how would you rate study treatments? at T360 minutes using a 4-point categorical scale (0=poor, 1=fair, 2=good, 3=excellent). |
| WSTD4 | 0-4 hours | This outcome measure is a statistical analysis of WSTD4, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 4 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
| WSTD3 | 0-3 hours | This outcome measure is a statistical analysis of WSTD3, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 3 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
| WSTD5 | 0-5 hours | This outcome measure is a statistical analysis of WSTD5, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 5 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
| WSTD6 | 0-6 hours | This outcome measure is a statistical analysis of WSTD6, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 6 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder. |
| The Percentage of Subjects With Temperature < 38 ºC and < 38.5 ºC at Any Timepoint During the Time From T0 to T360 Minutes | T0 to T360 minutes | This outcome measures what percentage of total subjects had a temperature \< 38 ºC and \< 38.5 ºC at any timepoint during the time from T0 to T360 minutes. |
Countries
United States
Participant flow
Recruitment details
Healthy Adult males at one site in the United States
Pre-assignment details
Eligible subjects were given intravenous (IV) endotoxin 1 ng/kg as a test dose and observed for 1 hour. Next, subjects were administered a 4 ng/kg pyrogenic IV endotoxin dose and monitored until a core temperature of at least 38.6 ºC was reached. Subjects achieving a sufficient fever response were then randomly assigned to study treatments.
Participants by arm
| Arm | Count |
|---|---|
| PO APAP 1 g group of subjects randomly selected to receive 1 g of oral acetaminophen and 100 ml of intravenous placebo solution as the study treatment | 51 |
| IV APAP 1 g / 100 ml Solution group of subjects randomly selected to receive 1 g of acetaminophen in 100 ml of intravenous solution and oral placebo as the study treatment | 54 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Vomited within 2 hours of receiving drug | 15 | 9 |
Baseline characteristics
| Characteristic | IV APAP 1 g / 100 ml Solution | PO APAP 1 g | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 54 Participants | 51 Participants | 105 Participants |
| Age, Continuous | 33.8 years STANDARD_DEVIATION 11.6 | 32.1 years STANDARD_DEVIATION 9.07 | 33 years STANDARD_DEVIATION 10.52 |
| Region of Enrollment United States | 54 participants | 51 participants | 105 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 54 Participants | 51 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 51 | 13 / 54 |
| serious Total, serious adverse events | 0 / 51 | 0 / 54 |
Outcome results
Primary
The Rapidity of Onset of Antipyretic Effect at 2 Hours (Measured as Weighted Sum of Temperature Differences Over 2 Hours, WSTD2)
This outcome measures when the antipyretic effect begins by statistical analysis of WSTD2, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 2 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: 0-2 hours
Population: mITT population defined as all randomized subjects who received at least 1 full dose of oral study medication (subject not vomiting within 2 hours after oral study drug) or 1 full dose of IV study medication(subject having received all 100 mls solution). This analysis was performed with imputation for non-physiological temperature swing zone effect
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | The Rapidity of Onset of Antipyretic Effect at 2 Hours (Measured as Weighted Sum of Temperature Differences Over 2 Hours, WSTD2) | 0.3 Degrees Celsius | Standard Deviation 0.41 |
| PO APAP 1 g | The Rapidity of Onset of Antipyretic Effect at 2 Hours (Measured as Weighted Sum of Temperature Differences Over 2 Hours, WSTD2) | 0.6 Degrees Celsius | Standard Deviation 0.55 |
Secondary
Maximum Temperature Reduction Observed From T0 to T360 Minutes
This outcome measures the maximum core temperature reduction observed from T0 to T360 minutes. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: T0-T360 minutes
Population: Analysis performed on the mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | Maximum Temperature Reduction Observed From T0 to T360 Minutes | -0.8 Degrees Celsius | Standard Deviation 0.46 |
| PO APAP 1 g | Maximum Temperature Reduction Observed From T0 to T360 Minutes | -1.1 Degrees Celsius | Standard Deviation 0.42 |
Secondary
Subject's Global Evaluation of Study Medication at T360 Minutes
This outcome measures how satisfied the subject was with the study treatment. The subject was asked to answer Overall, how would you rate study treatments? at T360 minutes using a 4-point categorical scale (0=poor, 1=fair, 2=good, 3=excellent).
Time frame: T360 minutes
Population: Analysis performed on the mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | Subject's Global Evaluation of Study Medication at T360 Minutes | Poor (0) | 0 participants |
| IV APAP 1 g / 100 ml Solution | Subject's Global Evaluation of Study Medication at T360 Minutes | Fair (1) | 7 participants |
| IV APAP 1 g / 100 ml Solution | Subject's Global Evaluation of Study Medication at T360 Minutes | Good (2) | 18 participants |
| IV APAP 1 g / 100 ml Solution | Subject's Global Evaluation of Study Medication at T360 Minutes | Excellent (3) | 20 participants |
| PO APAP 1 g | Subject's Global Evaluation of Study Medication at T360 Minutes | Excellent (3) | 21 participants |
| PO APAP 1 g | Subject's Global Evaluation of Study Medication at T360 Minutes | Poor (0) | 2 participants |
| PO APAP 1 g | Subject's Global Evaluation of Study Medication at T360 Minutes | Good (2) | 11 participants |
| PO APAP 1 g | Subject's Global Evaluation of Study Medication at T360 Minutes | Fair (1) | 2 participants |
Secondary
The Percentage of Subjects With Temperature < 38 ºC and < 38.5 ºC at Any Timepoint During the Time From T0 to T360 Minutes
This outcome measures what percentage of total subjects had a temperature \< 38 ºC and \< 38.5 ºC at any timepoint during the time from T0 to T360 minutes.
Time frame: T0 to T360 minutes
Population: Analysis performed on mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | The Percentage of Subjects With Temperature < 38 ºC and < 38.5 ºC at Any Timepoint During the Time From T0 to T360 Minutes | temperature < 38 ºC | 40 percentage of participants |
| IV APAP 1 g / 100 ml Solution | The Percentage of Subjects With Temperature < 38 ºC and < 38.5 ºC at Any Timepoint During the Time From T0 to T360 Minutes | temperature < 38.5 ºC | 84 percentage of participants |
| PO APAP 1 g | The Percentage of Subjects With Temperature < 38 ºC and < 38.5 ºC at Any Timepoint During the Time From T0 to T360 Minutes | temperature < 38 ºC | 67 percentage of participants |
| PO APAP 1 g | The Percentage of Subjects With Temperature < 38 ºC and < 38.5 ºC at Any Timepoint During the Time From T0 to T360 Minutes | temperature < 38.5 ºC | 92 percentage of participants |
Secondary
Time to a Reduction in Temperature From T0 to T360 Minutes.
This outcome measures how much time it took to observe a decrease in subjects' core body temperature by 0.8 ºC, 1.0 ºC, and 1.5 ºC from the temperature at T0 and from the temperature at the peak after T0 through T360 (6 hours). The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: 6 hours
Population: Analysis was performed on the mITT population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temperature of 0.8 ºC from T0 temp | 4.8 Hours | Standard Deviation 0.96 |
| IV APAP 1 g / 100 ml Solution | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temp of 0.8 ºC from the peak T0-T360 | 3.5 Hours | Standard Deviation 1.23 |
| IV APAP 1 g / 100 ml Solution | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temperature of 1.0 ºC from T0 temp | 5.1 Hours | Standard Deviation 0.85 |
| IV APAP 1 g / 100 ml Solution | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temp of 1.0 ºC from the peak T0-T360 | 3.8 Hours | Standard Deviation 0.87 |
| IV APAP 1 g / 100 ml Solution | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temperature of 1.5 ºC from T0 temp | 5.7 Hours | Standard Deviation 0.45 |
| IV APAP 1 g / 100 ml Solution | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temp of 1.5 ºC from the peak T0-T360 | 5.1 Hours | Standard Deviation 0.17 |
| PO APAP 1 g | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temperature of 1.5 ºC from T0 temp | 5.6 Hours | Standard Deviation 0.64 |
| PO APAP 1 g | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temperature of 0.8 ºC from T0 temp | 4.7 Hours | Standard Deviation 1.41 |
| PO APAP 1 g | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temp of 1.0 ºC from the peak T0-T360 | 2.9 Hours | Standard Deviation 1.16 |
| PO APAP 1 g | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temp of 0.8 ºC from the peak T0-T360 | 2.4 Hours | Standard Deviation 1.16 |
| PO APAP 1 g | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temp of 1.5 ºC from the peak T0-T360 | 4.2 Hours | Standard Deviation 1.19 |
| PO APAP 1 g | Time to a Reduction in Temperature From T0 to T360 Minutes. | reduction in temperature of 1.0 ºC from T0 temp | 5.0 Hours | Standard Deviation 1.24 |
Secondary
WSTD3
This outcome measure is a statistical analysis of WSTD3, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 3 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: 0-3 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | WSTD3 | 0.2 degrees Celsius | Standard Deviation 0.73 |
| PO APAP 1 g | WSTD3 | 0.5 degrees Celsius | Standard Deviation 0.85 |
Secondary
WSTD4
This outcome measure is a statistical analysis of WSTD4, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 4 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: 0-4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | WSTD4 | -0.20 degrees Celsius | Standard Deviation 1.06 |
| PO APAP 1 g | WSTD4 | -0.02 degrees Celsius | Standard Deviation 1.12 |
Secondary
WSTD5
This outcome measure is a statistical analysis of WSTD5, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 5 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: 0-5 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | WSTD5 | -0.7 degrees Celsius | Standard Deviation 1.43 |
| PO APAP 1 g | WSTD5 | -0.7 degrees Celsius | Standard Deviation 1.41 |
Secondary
WSTD6
This outcome measure is a statistical analysis of WSTD6, which is the weighted sum of temperature differences from the subject's core temperature at each assessment time point through the first 6 hours compared with the subject's core temperature at T0, weighted by the time elapsed between each 2 consecutive time points. The subject's core temperature was measured using an ingestible temperature monitoring capsule and associated data recorder.
Time frame: 0-6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV APAP 1 g / 100 ml Solution | WSTD6 | -1.4 degrees Celsius | Standard Deviation 1.88 |
| PO APAP 1 g | WSTD6 | -1.7 degrees Celsius | Standard Deviation 1.7 |