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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
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IV acetaminophen plus oral placebo. | Experimental | Administration of a 1 ng/kg body weight test dose of RSE to 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. Randomization to receive 1 g of acetaminophen in 100 ml of intravenous solution and oral placebo. |
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| Oral acetaminophen plus IV placebo. | Active Comparator | Administration of a 1 ng/kg body weight test dose of RSE to 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. Randomization to receive oral acetaminophen 1 g plus 100 ml of intravenous placebo solution. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intravenous acetaminophen plus oral placebo | Drug | Single dose of 1 gm IV acetaminophen |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | 0-2 hours |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria (Screening) To be eligible for entry into the Study, Subjects must meet all of the following criteria at Screening:
Inclusion Criteria (Pre-Randomization) To be eligible for Randomization, Subjects must meet each of the following criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| New Orleans Center for Clinical Research-Knoxville | Knoxville | Tennessee | 37920 | United States |
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.
Healthy Adult males at one site in the United States
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| ID | Title | Description |
|---|---|---|
| FG000 | Oral Acetaminophen (PO APAP) 1 g | group of subjects randomly selected to receive 1 g of oral acetaminophen as the study treatment |
| FG001 | Intravenous Acetaminophen (IV APAP) 1 g / 100 ml Solution |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Oral acetaminophen plus IV placebo | Drug | Single dose of 1 g PO APAP |
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| Reference standard endotoxin (RSE) | Biological | 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. |
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| 6 hours |
| 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. | T0-T360 minutes |
| 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). | T360 minutes |
| 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. | T0 to T360 minutes |
| 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. | 0-3 hours |
| 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. | 0-4 hours |
| 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. | 0-5 hours |
| 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. | 0-6 hours |
group of subjects randomly selected to receive 1 g /100 ml of intravenous acetaminophen solution as the study treatment
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | mITT(modified intent to treat) population was used for age continuous baseline measure. mITT is defined as the all randomized subjects who received at least one full dose of oral or intravenous study medication without vomiting less than 2 hours after the oral study medication dose. 81 subjects were included in the mITT group with 36 subjects in the oral acetaminophen arm and 45 subjects in the IV acetaminophen arm. | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
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| 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. | 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 | Posted | Sep 2009 | Mean | Standard Deviation | Degrees Celsius | 0-2 hours |
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| 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. | Analysis was performed on the mITT population. | Posted | Sep 2009 | Mean | Standard Deviation | Hours | 6 hours |
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| 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. | Analysis performed on the mITT population. | Posted | Sep 2009 | Mean | Standard Deviation | Degrees Celsius | T0-T360 minutes |
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| 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). | Analysis performed on the mITT population. | Posted | Sep 2009 | Number | participants | T360 minutes |
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| 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. | Analysis performed on mITT population. | Posted | Sep 2009 | Number | percentage of participants | T0 to T360 minutes |
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| 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. | Posted | Mean | Standard Deviation | degrees Celsius | 0-3 hours |
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| 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. | Posted | Mean | Standard Deviation | degrees Celsius | 0-4 hours |
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| 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. | Posted | Mean | Standard Deviation | degrees Celsius | 0-5 hours |
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| 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. | Posted | Mean | Standard Deviation | degrees Celsius | 0-6 hours |
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Treatment Emergent Adverse Events(TEAEs)were reported from T0 (on or after the start of study medication) to 6 hours after study medication was administered to the subject.
TEAEs are adverse events that start on or after the start of study medication.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
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| EG000 | Oral Acetaminophen (PO APAP) 1 g | group of subjects randomly selected to receive 1 g of oral acetaminophen as the study treatment | 0 | 51 | 17 | 51 | ||
| EG001 | Intravenous Acetaminophen (IV APAP) 1 g / 100 ml Solution | group of subjects randomly selected to receive 1 g /100 ml of intravenous acetaminophen solution as the study treatment | 0 | 54 | 13 | 54 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (10.0) | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (10.0) | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (10.0) | Non-systematic Assessment |
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Protocol and statistical analysis plan were amended to clarify endpoints prior to database lock and analysis.
Neither the Institution nor the Investigator shall have the right to publish the Institution findings without prior written consent of Cadence.
| Title | Organization | Phone | Extension | |
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| Lawrence Hill | Mallinckrodt Pharmaceuticals | (908) 238-6370 | lawrence.hill@mallinckrodt.com |
| ID | Term |
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| D005334 | Fever |
| ID | Term |
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| D001832 | Body Temperature Changes |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
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| D000082 | Acetaminophen |
| ID | Term |
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| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
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| >=65 years |
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| Male |
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