A Study Comparing the Effectiveness and Safety of Extended Release (ER) Tramadol Hydrochloride (HCl)/Acetaminophen With Immediate Release (IR) Tramadol HCl/Acetaminophen in Participants With Moderate to Severe Postoperative Pain

A Randomized, Active-Controlled, Parallel Group, Double-Blind Study to Compare the Efficacy and Safety of Tramadol HCl/Acetaminophen ER and IR in Subjects Who Complain of Moderate to Severe Postoperative Pain

The purpose of this study is to compare the efficacy and safety of extended release (ER) tramadol hydrochloride (HCl)/acetaminophen with immediate release (IR) tramadol HCl/acetaminophen in participants with moderate to severe (very serious, life threatening) postoperative pain.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: Tramadol HCl/Acetaminophen ER; Drug: Tramadol HCl/Acetaminophen IR

Detailed Description

This study is a randomized (study drug assigned by chance), multicenter (when more than 1 hospital or medical school team work on a medical research study), active-controlled, parallel group (each group of participants will be treated at the same time), double-blind (neither physician nor participant knows the treatment that the participant receives) study. The duration of the treatment will be 2 days and will be conducted in 4 periods: screening period (from 33 to 2 days before study drug administration to the first surgical incision), surgical period (to 1 day before study drug administration), qualification period (1 day) and double-blind treatment period (1 to 2 days). Participants will be randomly assigned to 2 groups: study drug treatment group (ER) and comparator treatment group (IR). Participants will be administered 2 tablets of ER tramadol HCl (75 milligram [mg])/acetaminophen (650 mg) along with 2 tablets of placebo matching to IR tramadol HCl/acetaminophen in study drug treatment group; and 2 tablets of IR tramadol HCl (37.5 mg)/acetaminophen (325 mg) along with 2 tablets of placebo matching to ER tramadol HCl/acetaminophen in comparator treatment group respectively at 0, 12, 24 and 36 hours. Participants will also be administered 2 tablets of placebo matching to IR tramadol HCl/acetaminophen in study drug treatment group; and 2 tablets of IR tramadol HCl/acetaminophen in comparator treatment group respectively at 6, 18, 30 and 42 hours. Participants will be administered investigational product at 6-hour interval from the time of the first investigational product administration over 48 hours. Efficacy will be assessed using 11-point numeric rating scale (NRS). Participants' safety will be monitored throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants who are scheduled to have standard primary (non-revision) unilateral (having to do with only 1 side of a structure) total knee replacement arthroplasty (TKRA-surgery to fix a joint) for non-inflammatory (no swelling, redness, and pain in tissues caused by injury or damage) degenerative joint disease (NIDJD)
• Participants who are capable of oral (having to do with the mouth) intake
• Women must be: postmenopausal (for at least 1 year), surgically sterile, abstinent (not having sexual intercourse), or practicing a highly effective method of birth control before participation in the study and who agree to continue to use the same method of birth control throughout the study in cases of women of childbearing potential
• Male participants must practice contraception, and must agree not to donate his sperms for 1 month after the last dose of study drug
• Participants who will complain of baseline pain of intensity of greater than or equal to 4 on 11-point numeric rating scale (NRS) measured within 1 hour prior to randomization (study drug assigned by chance) and a maximum of 6 hours after discontinuation of participant controlled analgesia (PCA) after at least 12 hours of application following TKRA

Exclusion Criteria:

• Participants with Illness history (severe [very serious, life threatening] hepatic [having to do with the liver] failure, severe renal [having to do with the kidney] failure; severe respiratory depression; risk for mental fog with head injury or brain lesions [abnormal area of tissue, such as a wound, sore, rash, or boil]; digestive ulcer [sore], severe blood abnormalities; severe cardiac insufficiency; aspirin asthma [asthmatic attack-breathing disorder in which there is a wheezing and difficulty in breathing; caused by non-steroidal anti-inflammatory drugs] or history of aspirin asthma; history of epilepsy [seizure disorder]; rheumatism, significant psychiatric disorder or taking antipsychotic drugs for psychiatric treatment)
• Administration of disallowed therapy such as: administration of oral, patch, injection or local analgesics (drug used to control pain) acting centrally (the brain and the spinal cord) or peripherally (not central) before study drug administration after completion of PCA application, surgery is conducted simultaneously in addition to TKRA, administration of monoamine oxidase (MAO) inhibitors or discontinuation of the administration within 2 weeks, tricyclic antidepressants that may increase the seizure (sudden, uncontrolled muscle spasms and loss of consciousness resulting from abnormal brain function) risk when concomitantly (given at the same time) administered, neuroleptics, or drugs that may lower the seizure threshold, use of sedatives (a medication to calm or make less anxious) other than that used for general anesthesia (loss of sensation or feeling) during surgery
• Participants who used any study drug or investigational medical device within 30 days before the start of the treatment
• Participants requiring postoperative intensive care unit (ICU) care
• Participants having hypersensitivity to tramadol or acetaminophen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tramadol Hydrochloride/Acetaminophen ER; Participants will be administered 2 oral tablets of extended release (ER) tramadol HCl (75 milligram [mg])/acetaminophen (650 mg) and 2 tablets of placebo matching to immediate release (IR) tramadol HCl/acetaminophen orally every 12 hours up to 36 hours, and 2 tablets of placebo matching to IR tramadol HCl/acetaminophen every 6 hours up to 42 hours.	Drug: Tramadol HCl/Acetaminophen ER; 2 tablets of ER (tramadol HCl [75 mg]/acetaminophen [650 mg]) will be administered at 0, 12, 24 and 36 hours; Other Names: Ultracet
Active Comparator: Tramadol HCl/Acetaminophen IR; Participants will be administered 2 oral tablets of IR tramadol HCl (37.5 mg)/acetaminophen (325 mg) and 2 tablets of placebo matching to ER tramadol HCl/acetaminophen at 0, 12, 24 and 36 hours, and 2 tablets of IR tramadol HCl/acetaminophen at 6, 18, 30 and 42 hours.	Drug: Tramadol HCl/Acetaminophen IR; 2 tablets of IR (tramadol HCl [37.5 mg]/acetaminophen [325 mg]) at 0, 6, 12, 18, 24, 30, 36 and 42 hours; Other Names: Ultracet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sum of Pain Intensity Difference (SPID) at Hour 48	The SPID is time-weighted sum of all observations of pain intensity difference (PID) collected at each measurement time point from Baseline to 48 hours. PID: Baseline pain intensity (PI) minus current PI; PI was assessed using 11-point numeric rating scale (NRS, 0=no pain to 10=worst pain imaginable). PI score ranges from 0-3 where 0=no pain and 3=severe pain. PI score of 0=NRS score of 0, PI score of 1=NRS score >=1 and <=3, PI score of 2=NRS score of >=4 and <=6 and PI score of 3=NRS score of >=7 and <=10. Total score for SPID at 48 hours (SPID48) ranges from -144 (worst) to 144 (best).	Hour 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sum of Pain Intensity Difference (SPID) at Hour 6, 12 and 24	The SPID is time-weighted sum of all observations of PID collected at each measurement time point from Baseline to 24 hours. PID: Baseline PI minus current PI; PI was assessed using 11-point NRS, 0=no pain to 10=worst pain imaginable. PI score ranges from 0-3 where 0=no pain and 3=severe pain. PI score of 0=NRS score of 0, PI score of 1=NRS score >=1 and <=3, PI score of 2=NRS score of >=4 and <=6 and PI score of 3=NRS score of >=7 and <=10. Total score ranges from -18 (worst) to 18 (best) for SPID6, -36 (worst) to 36 (best) for SPID12 and -72 (worst) to 72 (best) for SPID24.	Hour 6, 12, 24
Total Pain Relief (TOTPAR) Score	Pain relief was measured on a 5-point categorical scale of 0-4 (0=no change, 1=slight relief, 2=moderate relief, 3=fair relief, 4=pain resolved completely). TOTPAR was calculated as the time-weighted sum over all pain relief up to 48 hours. Total score ranges from 0 (worst) to 24 (best) for TOTPAR6, 0 (worst) to 48 (best) for TOTPAR12, 0 (worst) to 96 (best) for TOTPAR24 and 0 (worst) to 192 (best) for TOTPAR48.	Hour 6, 12, 24, 48
Sum of Total Pain Relief and Sum of Pain Intensity Difference (SPRID)	The SPRID is sum of SPID and TOTPAR. In SPID, PI score ranges from 0-3 where 0=no pain and 3=severe pain. PI score of 0=NRS score of 0, PI score of 1=NRS score >=1 and <= 3, PI score of 2=NRS score of >=4 and <=6 and PI score of 3=NRS score of >=7 and <=10. In TOTPAR, pain relief score ranges from 0-4 (0=no change, 1=slight relief, 2=moderate relief, 3=fair relief, 4=pain resolved completely). Total score ranges from -18 (worst) to 42 (best) for SPRID6, -36 (worst) to 84 (best) for SPRID12, -72 (worst) to 168 (best) for SPRID24 and -144 (worst) to 336 (best) for SPRID48.	Hour 6, 12, 24, 48
Time to the First Rescue Medication Administered Because of Insufficient Pain Relief	The time until administration of the first rescue medication (rescue medications are medicines that are administered to the participants when the efficacy of the study drug is not satisfactory, or the effect of the study drug is too great and is likely to cause a hazard to the participant, or to manage an emergency situation) because of insufficient pain relief after administration of the study drug was recorded. Rescue medications allowed were oral or injection of tramadol HCl (intramuscular [directly into muscle] or intravenous injection [directly into vein]).	Baseline up to Day 3
Number of Doses of Rescue Medication Administered Because of Insufficient Pain Relief	The frequency of the rescue medication (rescue medications are medicines that are administered to the participants when the efficacy of the study drug is not satisfactory, or the effect of the study drug is too great and is likely to cause a hazard to the participant, or to manage an emergency situation) because of insufficient pain relief was measured after administration of the study drug. Rescue medications allowed were oral or injection of tramadol HCl (intramuscular or intravenous injection).	Baseline up to Day 3
Dosage of Rescue Medication Administered Because of Insufficient Pain Relief	The dosage of the rescue medication (rescue medications are medicines that are administered to the participants when the efficacy of the study drug is not satisfactory, or the effect of the study drug is too great and is likely to cause a hazard to the participant, or to manage an emergency situation) because of insufficient pain relief was measured after administration of the study drug. Rescue medications allowed were oral or injection of tramadol HCl (intramuscular or intravenous injection).	Baseline up to Day 3
Patient Global Impression of Change (PGIC) Score	The PGIC was used to assess the degree of participant's overall improvement with treatment, and participants were instructed to assess how much the overall status had been improved after investigational product administration compared to baseline in 7 grades (1=Very much improved and B=Very much worsened).	Day 3

Collaborators and Investigators

• Sponsor: Janssen Korea, Ltd., Korea
• Investigators: Study Director: Janssen Korea Ltd. Clinical Trial, Janssen Korea Ltd.

Publications and helpful links

General Publications

• Park YB, Ha CW, Cho SD, Lee MC, Lee JH, Seo SS, Kang SB, Kyung HS, Choi CH, Chang N, Rhim HY, Bin SI. A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement. Curr Med Res Opin. 2015 Jan;31(1):75-84. doi: 10.1185/03007995.2014.975338. Epub 2014 Oct 31.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: March 18, 2013
• First Submitted That Met QC Criteria: March 18, 2013
• First Posted (Estimate): March 20, 2013

Study Record Updates

• Last Update Posted (Estimate): June 20, 2013
• Last Update Submitted That Met QC Criteria: June 18, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Acetaminophen; Pain, Postoperative; Ultracet; Tramadol Hydrochloride
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Tramadol
• Other Study ID Numbers: CR016636; TRAMAPPAI3005