Efficacy and Safety of Intravenous Acetaminophen Over 48 Hrs for the Treatment of Post-op Pain After Gynecologic Surgery

• Sponsor: Mallinckrodt (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00399568
• Collaborator: (none)
• Enrollment: 331
• Locations: 27
• Arms: 2
• Duration (Months): 10
• Patients Per Site: 12.3
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This study will be investigating the efficacy and safety administration of multiple doses of intravenous (IV) acetaminophen (IVAPAP) in the 48 hour period following Gynecologic Surgery.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain; Hysterectomy	Drug: IV Acetaminophen; Drug: IV Placebo 100 mL solution	Phase 3

Detailed Description

The research hypothesis is that IV Acetaminophen will provide greater reduction in pain intensity and greater pain relief for moderate and severe pain as compared to placebo in the 48 hours following surgery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 331 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Parallel, Multiple-Dose Study of the Analgesic Efficacy and Safety of IV Acetaminophen (APAP) Versus Placebo Over 48 Hours(Hrs) for the Treatment of Postoperative Pain After Gynecologic Surgery
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Sep 1, 2007
• Actual Study Completion Date: Sep 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IV acetaminophen 1 g/100 mL solution	Drug: IV Acetaminophen; Intravenous acetaminophen 1 g/100 mL; Other Names: IV Acetaminophen (IV APAP)
Placebo Comparator: IV Placebo 100 mL solution	Drug: IV Placebo 100 mL solution; IV Placebo 100 mL solution dosed at same frequency as IV Acetaminophen every 6 hours (q6h); Other Names: IV Placebo (non-active product)

Outcome Measures

Primary Outcome Measures

1. Sum of Pain Intensity at Rest-Baseline to 24 Hours (SPI24rest), 1 Gram IV Acetaminophen vs. Placebo. [Baseline (just prior to the first dose) through 24 hours]

   The Sum of Pain Intensity (SPI) score incorporates the analgesic effects on pain intensity (PI) from Baseline to 24 hours. SPI was measured by the 100 millimeter (mm) long Visual Analog Scale (VAS) over 24 hours after treatment. Subjects were asked to mark the level of pain they were experiencing at a certain timepoint on the scale The 100mm VAS scale was used with the left terminus (0 mm) of the scale "No Pain" and the right terminus (100 mm) with "Worst Pain Imaginable". The range of measurement is 0-2400 mm for 24 hours.

2. Sum Pain Intensity at Rest-Baseline to 48 Hours (SPI48rest), 1 Gram IV Acetaminophen vs. Placebo [Baseline (just prior to the first dose) through 48 hours]

   The Sum of Pain Intensity (SPI) score incorporates the analgesic effects on pain intensity (PI) from Baseline to 48 hours. SPI was measured by the 100 millimeter (mm) long Visual Analog Scale (VAS) over 48 hours after treatment. Subjects were asked to mark the level of pain they were experiencing at a certain timepoint on the scale The 100 mm VAS scale was used with the left terminus (0 mm) of the scale "No Pain" and the right terminus (100 mm) with "Worst Pain Imaginable". The range of measurement is 0-4800 mm for 48 hours.

Secondary Outcome Measures

1. Subjects Who Experienced at Least One Treatment-emergent Adverse Event (TEAE) [First dose through 7 day follow up]

   Number of subjects who experienced at least one treatment emergent adverse event (TEAE) A TEAE is an adverse event that occurs on or after administration of the first dose of study medication (T0)

2. Subjects Who Experienced at Least One Treatment-emergent Serious Adverse Event. [32 days following first dose of study medication.]

   Number of subjects who reported SAEs during the study. A serious Adverse event (SAE) is defined as any untoward medical occurence at any dose of study medication that: Results in Death, Is Life Threatening, Requires inpatient hospitalization or causes prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, or Is an important medical event

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Undergo gynecologic surgery using standard abdominal approach such as midline or Pfannenstiel incision

• 18-75 years of age

• Body Mass Index (BMI) between 19-45

• American Society of Anesthesiologists (ASA) risk class of I, II, III

• Not have received neuraxial (spinal or epidural) opioid analgesics prior to or during surgery

• Moderate to Severe pain at rest

Exclusion Criteria:

• Requires any additional surgical procedures either related or unrelated to gynecologic surgery during same hospitalization

• Procedures involving only minimal incisions such as laparotomy, laparoscopy, supraumbilical or Maylard incisions

• Has know hypersensitivity to opioids, acetaminophen, or the excipients of IV acetaminophen

• Known history of alcohol or drug abuse or misuse

• Has impaired liver function Aspartate transaminase(AST), Alanine aminotransferase(ALT), bilirubin greater than or equal to 2 times upper limit of normal

• Has significant medical disease(s), or conditions that may contraindicate participation in the study

• Has participated in another clinical trial within 30 days of surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama (Anesthesiology)	Birmingham	Alabama	United States	35249
2	Helen Keller Hospital	Sheffield	Alabama	United States	35660
3	Arizona Research Center, Inc (JC Lincoln)	Phoenix	Arizona	United States	85023
4	Arizona Research Center, Inc. (Arrowhead)	Phoenix	Arizona	United States	85023
5	Precision Trials	Phoenix	Arizona	United States	85032
6	Arcadia Methodist Hospital	Arcadia	California	United States	91007
7	Glendale Adventist Medical Center	Glendale	California	United States	91206
8	Huntington Memorial Hospital	Pasadena	California	United States	91105
9	Accurate Clinical Trials, Inc.	San Clemente	California	United States	92672
10	Visions Clinical Research	Boynton Beach	Florida	United States	33414
11	G and G Research, Inc.	Fort Pierce	Florida	United States	34950
12	Century Clinical Research, INC	Holly Hill	Florida	United States	32117
13	Nature Coast Clinical Research	Inverness	Florida	United States	34452
14	University of Miami School of Medicine Dept. of Anesthesiology	Miami	Florida	United States	33136
15	Treasure Coast Obstetrics and Gynecology	Vero Beach	Florida	United States	32960
16	William Beaumont Hospital	Royal Oak	Michigan	United States	48073
17	Cooper Anesthesia	Camden	New Jersey	United States	08103
18	St. Peters University Hospital, Anesthesiology	New Brunswick	New Jersey	United States	08901
19	Albany Medical College Dept. of Anesthesiology	Albany	New York	United States	11208
20	Jacobi Medical Center (Albert Einstein College of Medicine)	Bronx	New York	United States	10461
21	Weill Medical College	New York	New York	United States	10021
22	Stony Brook Anesthesiology Health Sciences Cente	Stony Brook	New York	United States	11794
23	The Ohio State University Medical Center	Columbus	Ohio	United States	43210
24	Allegheny Pain Managment	Altoona	Pennsylvania	United States	16602
25	Thomas Jefferson University Dept. of Anesthesiology	Philadelphia	Pennsylvania	United States	19107
26	Memorial Herman/Memorial City Hospital	Houston	Texas	United States	77024
27	Texas Woman's Hospital	Houston	Texas	United States	77024

Sponsors and Collaborators

• Mallinckrodt

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT00399568
• Other Study ID Numbers: CPI-APA-301
• First Posted: Nov 15, 2006
• Last Update Posted: Oct 21, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Mallinckrodt: Pain; Gynecologic; IV Acetaminophen; Postoperative; Analgesic
• Additional relevant MeSH terms: Pain, Postoperative; Acetaminophen

Study Results

Participant Flow

Recruitment Details	Gynecologists and/or anesthesiologists were selected to participate as Principal Investigators.
Pre-assignment Detail	Subjects were required to meet eligibility criteria prior to surgery and then again had to meet post surgical inclusion criteria.Subjects had to achieve a sufficient pain intensity score prior to entering the study.

Arm/Group Title	IV Acetaminophen 1 g/100 mL Solution	IV Placebo 100 mL Solution
Arm/Group Description	All subjects randomized to receive Intravenous (IV) Acetaminophen 1 g/100 mL solution every 6 hours for 48 hours for a total of 8 doses.	All subjects randomized to receive Intravenous (IV) placebo 100 mL solution every 6 hours for 48 hours for a total of 8 doses.
Period Title: Overall Study
STARTED	166	165
COMPLETED	154	156
NOT COMPLETED	12	9

Baseline Characteristics

Arm/Group Title	IV Acetaminophen 1 g/100 mL Solution	IV Placebo 100 mL Solution	Total
Arm/Group Description	All subjects randomized to receive Intravenous (IV) Acetaminophen 1 g/100 mL solution every 6 hours for 48 hours for a total of 8 doses.	All subjects randomized to receive Intravenous (IV) placebo 100 mL solution every 6 hours for 48 hours for a total of 8 doses.	Total of all reporting groups
Overall Participants	166	165	331
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	163 98.2%	161 97.6%	324 97.9%
>=65 years	3 1.8%	4 2.4%	7 2.1%
Sex: Female, Male (Count of Participants)
Female	166 100%	165 100%	331 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	166 100%	165 100%	331 100%

Outcome Measures

1. Primary Outcome

Title	Sum of Pain Intensity at Rest-Baseline to 24 Hours (SPI24rest), 1 Gram IV Acetaminophen vs. Placebo.
Description	The Sum of Pain Intensity (SPI) score incorporates the analgesic effects on pain intensity (PI) from Baseline to 24 hours. SPI was measured by the 100 millimeter (mm) long Visual Analog Scale (VAS) over 24 hours after treatment. Subjects were asked to mark the level of pain they were experiencing at a certain timepoint on the scale The 100mm VAS scale was used with the left terminus (0 mm) of the scale "No Pain" and the right terminus (100 mm) with "Worst Pain Imaginable". The range of measurement is 0-2400 mm for 24 hours.
Time Frame	Baseline (just prior to the first dose) through 24 hours

Outcome Measure Data

Analysis Population Description

All efficacy analyses were conducted using the mITT population, defined as those subjects who received a complete dose of study medication prior to a request for rescue medication.

Arm/Group Title	IV Acetaminophen 1 g/100 ml Solution	IV Placebo 100 ml Solution
Arm/Group Description	mITT Population IV acetaminophen 1 g/100 ml Solution	mITT Population IV Placebo 100 ml solution
Measure Participants	162	159
Mean (Standard Deviation) [units on a scale (in millimeters)]	1793.3 (481.49)	1845.3 (420.21)

2. Secondary Outcome

Title	Subjects Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)
Description	Number of subjects who experienced at least one treatment emergent adverse event (TEAE) A TEAE is an adverse event that occurs on or after administration of the first dose of study medication (T0)
Time Frame	First dose through 7 day follow up

Outcome Measure Data

Analysis Population Description

All analyses of safety were conducted on the Safety population, which included those subjects who received any portion of a dose of study medication.

Arm/Group Title	IV Acetaminophen 1g/100 ml Solution	IV Placebo 100 ml Solution
Arm/Group Description	Safety Population (defined as those subjects who received any portion of a dose of IV acetaminophen 1g/100 ml solution)	Safety Population(defined as those subjects who received any portion of a dose of IV Placebo 100 ml solution)
Measure Participants	166	165
Number [Subjects]	141	149

3. Primary Outcome

Title	Sum Pain Intensity at Rest-Baseline to 48 Hours (SPI48rest), 1 Gram IV Acetaminophen vs. Placebo
Description	The Sum of Pain Intensity (SPI) score incorporates the analgesic effects on pain intensity (PI) from Baseline to 48 hours. SPI was measured by the 100 millimeter (mm) long Visual Analog Scale (VAS) over 48 hours after treatment. Subjects were asked to mark the level of pain they were experiencing at a certain timepoint on the scale The 100 mm VAS scale was used with the left terminus (0 mm) of the scale "No Pain" and the right terminus (100 mm) with "Worst Pain Imaginable". The range of measurement is 0-4800 mm for 48 hours.
Time Frame	Baseline (just prior to the first dose) through 48 hours

Outcome Measure Data

Analysis Population Description

All efficacy analyses were conducted using the mITT population, defined as those subjects who received a complete dose of study medication prior to a request for rescue medication.

Arm/Group Title	IV Acetaminophen 1 g/100 ml Solution	IV Placebo 100 ml Solution
Arm/Group Description	mITT Population IV acetaminophen 1 g/100 ml Solution	mITT Population IV Placebo 100 ml solution
Measure Participants	162	159
Mean (Standard Deviation) [units on a scale (in millimeters)]	3612.4 (966.66)	3718.2 (829.21)

4. Secondary Outcome

Title	Subjects Who Experienced at Least One Treatment-emergent Serious Adverse Event.
Description	Number of subjects who reported SAEs during the study. A serious Adverse event (SAE) is defined as any untoward medical occurence at any dose of study medication that: Results in Death, Is Life Threatening, Requires inpatient hospitalization or causes prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, or Is an important medical event
Time Frame	32 days following first dose of study medication.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IV Acetaminophen 1 g/100 ml Solution	IV Placebo 100 ml Solution
Arm/Group Description	mITT Population IV acetaminophen 1 g/100 ml Solution	mITT Population IV Placebo 100 ml solution
Measure Participants	162	159
Number [Subjects]	11	14

Adverse Events

Time Frame	Adverse Events were reported from the start of study medication until the follow up visit on Day 7 (+/- 2 days). Serious Adverse Events were collected for 32 days following start of study medication
Arm/Group Title	IV Acetaminophen 1g/100 mL Solution		IV Placebo 100 mL Solution
Arm/Group Description	Safety Population (defined as those subjects who received any portion of a dose of IV acetaminophen 1g/100 mL solution)		Safety Population (defined as those subjects who received any portion of a dose of IV Placebo 100 mL solution)
All Cause Mortality
	IV Acetaminophen 1g/100 mL Solution		IV Placebo 100 mL Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IV Acetaminophen 1g/100 mL Solution		IV Placebo 100 mL Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/166 (6.6%)		14/165 (8.5%)
Blood and lymphatic system disorders
Neutropenia	1/166 (0.6%)		0/165 (0%)
Gastrointestinal disorders
Abdominal pain lower	1/166 (0.6%)		0/165 (0%)
Ileus	1/166 (0.6%)		2/165 (1.2%)
Small intestinal obstruction	1/166 (0.6%)		0/165 (0%)
General disorders
Pyrexia	1/166 (0.6%)		1/165 (0.6%)
Infections and infestations
Abdominal abscess	0/166 (0%)		1/165 (0.6%)
Pelvic abscess	0/166 (0%)		2/165 (1.2%)
Vaginal infection	0/166 (0%)		1/165 (0.6%)
Injury, poisoning and procedural complications
Accidental overdose	1/166 (0.6%)		5/165 (3%)
Postoperative ileus	0/166 (0%)		1/165 (0.6%)
Seroma	2/166 (1.2%)		0/165 (0%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/166 (0.6%)		0/165 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/166 (0%)		1/165 (0.6%)
Pulmonary embolism	1/166 (0.6%)		1/165 (0.6%)
Vascular disorders
Aneurysm	1/166 (0.6%)		0/165 (0%)
Deep vein thrombosis	0/166 (0%)		1/165 (0.6%)
Haemorrhage	0/166 (0%)		1/165 (0.6%)
Other (Not Including Serious) Adverse Events
	IV Acetaminophen 1g/100 mL Solution		IV Placebo 100 mL Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	135/166 (81.3%)		145/165 (87.9%)
Blood and lymphatic system disorders
Anaemia	13/166 (7.8%)		11/165 (6.7%)
Cardiac disorders
Tachycardia	8/166 (4.8%)		13/165 (7.9%)
Gastrointestinal disorders
Abdominal distension	9/166 (5.4%)		8/165 (4.8%)
Constipation	48/166 (28.9%)		49/165 (29.7%)
Flatulence	21/166 (12.7%)		28/165 (17%)
Nausea	96/166 (57.8%)		88/165 (53.3%)
Vomiting	37/166 (22.3%)		28/165 (17%)
General disorders
Pyrexia	19/166 (11.4%)		37/165 (22.4%)
Musculoskeletal and connective tissue disorders
Back Pain	3/166 (1.8%)		9/165 (5.5%)
Nervous system disorders
Dizziness	10/166 (6%)		16/165 (9.7%)
Headache	22/166 (13.3%)		17/165 (10.3%)
Psychiatric disorders
Insomnia	18/166 (10.8%)		10/165 (6.1%)
Skin and subcutaneous tissue disorders
Pruritis	24/166 (14.5%)		21/165 (12.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigator may publish only after cooperative publication or 18 months after sponsor's final evaluation of study data, whichever occurs first. At least 60 days prior to submission for publication, investigator must submit manuscript to sponsor for review and comment. Sponsor has 60 day period thereafter to respond with comment. Investigator will remove confidential information at the request of sponsor.