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Efficacy and Safety of Ibuprofen and Caffeine in Dental Pain

Primary Purpose

Pain, Postoperative, Tooth Diseases

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
ibuprofen + caffeine
ibuprofen
ibuprofen
caffeine
ibuprofen + caffeine
placebo
placebo
caffeine
ibuprofen
ibuprofen + caffeine
Sponsored by
Boehringer Ingelheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pain, Postoperative

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Males and females 18 to 55 years of age;
  • Outpatients scheduled to undergo surgical extraction of 3-4 impacted third molar(s), with a minimum of two mandibular extractions. The two mandibular third molars may be partial bony impactions or full bony impactions (as long as the trauma rating is not severe and the surgeons do not feel the subject will have extreme post-surgical pain) OR there may be a combination of one full bony impaction with the second mandibular being a soft tissue impaction or partial bony impaction. Maxillary third molars (or supernumerary teeth) of any type can be extracted;
  • Use of only the following preoperative medication(s)/ anesthetic(s): topical benzocaine, short-acting local anesthetic (mepivacaine or lidocaine) with or without vasoconstrictor and/or nitrous oxide;
  • Reliable, cooperative, and of adequate intelligence to record the requested information on the analgesic questionnaire form;
  • Examined by the attending oral surgeon or physician and medically cleared to participate in the study;
  • Scheduled to undergo a qualifying surgical procedure;
  • In good general health, with a BMI of 30 or less, and have no contraindications to any of the study medications or anesthetic drugs;
  • Subjects have at least a categorical pain score of moderate and a numerical rating scale (NRS) score of 5 or greater within 4.5 hours from the time of the last suture.

Exclusion criteria:

  • Presence of a serious medical condition (e.g., poorly controlled hypertension, poorly controlled diabetes, significantly impaired cardiac, renal or hepatic function, hyper- or hypothyroidism);
  • Use of a prescription or non-prescription drug with which the administration of ibuprofen or any other non steroidal anti inflammatory or caffeine is contraindicated;
  • Acute local infection at the time of surgery that could confound the post-surgical evaluation;
  • Females who are pregnant, lactating, of child-bearing potential, or post-menopausal for less than 2 years and not using a medically approved method of contraception (i.e., oral, transdermal, intravaginal or implanted contraceptives, intrauterine device, diaphragm, condom, abstinence, or surgical sterility), or females who test positive on a urine-based pregnancy test;
  • Presence or history (within 2 years of enrollment) of bleeding disorder(s) or peptic ulcer disease;
  • History of alcoholism or substance abuse within the last year, or is currently abusing alcohol or other mood-altering drugs (e.g., cannabis). Subjects who are taking central nervous system or other psychotropic drugs (including St. Johns Wort, or any other nutritional supplement known to have psychotropic effects) may be enrolled if they have been on stable doses of medication for at least 2 months, will maintain this dose throughout the study, and their condition is judged by the Principal Investigator to be well-controlled;
  • Habituation to analgesic drugs or caffeine (i.e., routine use of oral analgesics 5 or more times per week or ingestion of 4 or more caffeine-containing drinks daily); use of "high energy" drinks more than once per week;
  • Use of any type of systemic corticosteroid within the past 30 days or a history of current or previous use of anabolic steroids;
  • History of allergic reaction (e.g., asthma, rhinitis, swelling, shock, or hives) to acetaminophen, ibuprofen, naproxen, aspirin, celecoxib, or any other non steroidal anti inflammatory or caffeine;
  • Prior use of any type of analgesic or non steroidal anti inflammatory within 5 half-lives of that drug before surgery, except for pre-anesthetic medication and anesthesia for the procedure;
  • Ingestion of any caffeine-containing beverages, chocolate, or alcohol 6 hours or less before surgery;
  • Has impaired liver function, e.g., serum Alanine transaminase, aspartate aminotransferase, alkaline phosphatase, or Gamma-glutamyltransferase greater than 2.5 times the upper limit of normal, or blood urea nitrogen, creatinine, or bilirubin greater than 1.5 times the upper limit of normal without a known benign explanation;
  • Has known history of a positive HIV antibody test or known HIV infection;
  • Has a known history of Hepatitis B or C;
  • Has a clinically significant abnormal electrocardiogram (ECG) at screening as determined by the Investigator:
  • Has taken an investigational product within the past 30 days;
  • Has previously been entered into this study;
  • The subject is a member of the study site staff either directly involved with the study, an employee of the Sponsor, or a relative of study site personnel directly involved with the study or Sponsor.

Sites / Locations

  • 1335.1.202 Boehringer Ingelheim Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Other

Other

Other

Other

Other

Other

Arm Label

Caffeine-Ibuprofen

Placebo-Ibuprofen/Caffeine

Ibuprofen/Caffeine-Ibuprofen/Caffeine

Ibuprofen-Ibuprofen

Caffeine-Ibuprofen/Caffeine

Placebo-Ibuprofen

Arm Description

Study Stage 1: One Caffeine 100 mg tablet after dental surgery; Arm Type: Active Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one ibuprofen 400 mg tablet, while awake, over 5 days; Arm Type: Active Comparator

Study Stage 1: One Placebo tablet after dental surgery Arm Type: Placebo Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg/Caffeine tablet, while awake, over 5 days; Arm Type: Experimental

Study Stage 1: One Ibuprofen 400 mg/Caffeine 100 mg tablet after dental surgery: Arm Type Experimental - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg/Caffeine 100 mg tablet, while awake, over 5 days; Arm Type Experimental

Study Stage 1: One Ibuprofen 400 mg tablet after dental surgery; Arm Type Active Comparator - Study Stage 2: Subsequent to stage 1, every 6-8 hours one Ibuprofen 400 mg tablet, while awake, over 5 days; Arm type; Active Comparator

Study Stage 1: One Caffeine 100 mg tablet after dental surgery. Arm Type; Active Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400mg/Caffeine 100 mg tablet, while awake, over 5 days; Arm Type: Experimental

Study Stage 1: One Placebo tablet after dental surgery Arm Type: Placebo Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg tablet, while awake over 5 days; Arm Type: Active Comparator

Outcomes

Primary Outcome Measures

Time-weighted Sum of Pain Relief (PAR) and Pain Intensity Difference (PID) From 0 to 8 Hours (SPRID0-8h)
SPRID0-8h: Time-weighted sum of PAR and PID from 0 to 8 hours, score range: -40 (worst) to 112 (best). PI was assessed on a 0-10 numerical pain rating scale (NPRS), where 0=no pain and 10=worst possible pain, pre-dose and at 0.25,0.5,0.75,1,1.5,2,3,4,5, 6,7 and 8 hours; PAR was assessed on a 5-point verbal rating scale (VRS) (0=none to 4=complete) at the same post-dose time points. Time-weights were equal to the elapsed time (hour) between the time point of interest and the preceding time point. All PAR and pain intensity (PI) assessments completed after the patient had taken rescue medication or the second dose of study medication, whichever was first, until hour 8 were considered missing. Last observation carried forward (LOCF) was used with the last completed PI/PAR assessments prior to first rescue/second study medication, whichever was first, to impute missing values up to 8 hours.

Secondary Outcome Measures

Time-weighted Sum of Pain Relief (PAR) and Pain Intensity Difference (PID) From 0 to 2 Hours (SPRID0-2h)
SPRID0-2h: Time-weighted sum of PAR and PID from 0 to 2 hours, score range: -10 (worst) to 28 (best). PI was assessed on a 0-10 numerical pain rating scale (NPRS), where 0=no pain and 10=worst possible pain, pre-dose and at 0.25,0.5,0.75,1,1.5 and 2 hours; PAR was assessed on a 5-point verbal rating scale (VRS) (0=none to 4=complete) at the same post-dose time points. Time-weights were equal to the elapsed time (hour) between the time point of interest and the preceding time point. All PAR and pain intensity (PI) assessments completed after the patient had taken rescue medication or the second dose of study medication, whichever was first, until hour 2 was considered missing. Last observation carried forward (LOCF) was used with the last completed PI/PAR assessments prior to first rescue/second study medication, whichever was first, to impute missing values up to 2 hours.
Duration of Pain Relief
Duration of pain relief was defined as the time between the administration of first dose of trial medication and first dose of rescue medication or second dose of trial medication, whichever was first. Duration of pain relief was censored at 8 hours.
Time to Meaningful Pain Relief
Time to meaningful pain relief was captured by a stopwatch, which was started by the study staff immediately after the administration of the first dose of trial medication and which was to be stopped by the patient as soon as he/she felt meaningful pain relief. Time to meaningful pain relief was censored at 8 hours.

Full Information

First Posted
August 22, 2013
Last Updated
September 27, 2016
Sponsor
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT01929031
Brief Title
Efficacy and Safety of Ibuprofen and Caffeine in Dental Pain
Official Title
A Single-centre, Double-blind, Randomised, Two-stage, Parallel-group Study to Assess the Efficacy and Safety of the Fixed Dose Combination of Ibuprofen 400 mg and Caffeine 100 mg Versus Ibuprofen 400 mg, Caffeine 100 mg and Placebo in Patients With Postoperative Dental Pain
Study Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Completed
Study Start Date
August 2013 (undefined)
Primary Completion Date
March 2014 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary objective of this study is to compare the efficacy of a combination product containing ibuprofen 400 mg and caffeine 100 mg versus either ingredient alone as well as placebo for the treatment of post-surgical dental pain over an eight-hour period followed by a single dose of study medication (study stage 1). A secondary objective is to evaluate efficacy of multiple doses of the combination in comparison to ibuprofen alone over a 5-day post-surgical period (study stage 2).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pain, Postoperative, Tooth Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
562 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Caffeine-Ibuprofen
Arm Type
Other
Arm Description
Study Stage 1: One Caffeine 100 mg tablet after dental surgery; Arm Type: Active Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one ibuprofen 400 mg tablet, while awake, over 5 days; Arm Type: Active Comparator
Arm Title
Placebo-Ibuprofen/Caffeine
Arm Type
Other
Arm Description
Study Stage 1: One Placebo tablet after dental surgery Arm Type: Placebo Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg/Caffeine tablet, while awake, over 5 days; Arm Type: Experimental
Arm Title
Ibuprofen/Caffeine-Ibuprofen/Caffeine
Arm Type
Other
Arm Description
Study Stage 1: One Ibuprofen 400 mg/Caffeine 100 mg tablet after dental surgery: Arm Type Experimental - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg/Caffeine 100 mg tablet, while awake, over 5 days; Arm Type Experimental
Arm Title
Ibuprofen-Ibuprofen
Arm Type
Other
Arm Description
Study Stage 1: One Ibuprofen 400 mg tablet after dental surgery; Arm Type Active Comparator - Study Stage 2: Subsequent to stage 1, every 6-8 hours one Ibuprofen 400 mg tablet, while awake, over 5 days; Arm type; Active Comparator
Arm Title
Caffeine-Ibuprofen/Caffeine
Arm Type
Other
Arm Description
Study Stage 1: One Caffeine 100 mg tablet after dental surgery. Arm Type; Active Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400mg/Caffeine 100 mg tablet, while awake, over 5 days; Arm Type: Experimental
Arm Title
Placebo-Ibuprofen
Arm Type
Other
Arm Description
Study Stage 1: One Placebo tablet after dental surgery Arm Type: Placebo Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg tablet, while awake over 5 days; Arm Type: Active Comparator
Intervention Type
Drug
Intervention Name(s)
ibuprofen + caffeine
Intervention Description
FDC tablet
Intervention Type
Drug
Intervention Name(s)
ibuprofen
Intervention Description
tablet.
Intervention Type
Drug
Intervention Name(s)
ibuprofen
Intervention Description
tablet
Intervention Type
Drug
Intervention Name(s)
caffeine
Intervention Description
tablet
Intervention Type
Drug
Intervention Name(s)
ibuprofen + caffeine
Intervention Description
Fixed Dose Combination (FDC) tablet
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
tablet
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
tablet
Intervention Type
Drug
Intervention Name(s)
caffeine
Intervention Description
tablet
Intervention Type
Drug
Intervention Name(s)
ibuprofen
Intervention Description
tablet
Intervention Type
Drug
Intervention Name(s)
ibuprofen + caffeine
Intervention Description
FDC tablet
Primary Outcome Measure Information:
Title
Time-weighted Sum of Pain Relief (PAR) and Pain Intensity Difference (PID) From 0 to 8 Hours (SPRID0-8h)
Description
SPRID0-8h: Time-weighted sum of PAR and PID from 0 to 8 hours, score range: -40 (worst) to 112 (best). PI was assessed on a 0-10 numerical pain rating scale (NPRS), where 0=no pain and 10=worst possible pain, pre-dose and at 0.25,0.5,0.75,1,1.5,2,3,4,5, 6,7 and 8 hours; PAR was assessed on a 5-point verbal rating scale (VRS) (0=none to 4=complete) at the same post-dose time points. Time-weights were equal to the elapsed time (hour) between the time point of interest and the preceding time point. All PAR and pain intensity (PI) assessments completed after the patient had taken rescue medication or the second dose of study medication, whichever was first, until hour 8 were considered missing. Last observation carried forward (LOCF) was used with the last completed PI/PAR assessments prior to first rescue/second study medication, whichever was first, to impute missing values up to 8 hours.
Time Frame
0 to 8 hours
Secondary Outcome Measure Information:
Title
Time-weighted Sum of Pain Relief (PAR) and Pain Intensity Difference (PID) From 0 to 2 Hours (SPRID0-2h)
Description
SPRID0-2h: Time-weighted sum of PAR and PID from 0 to 2 hours, score range: -10 (worst) to 28 (best). PI was assessed on a 0-10 numerical pain rating scale (NPRS), where 0=no pain and 10=worst possible pain, pre-dose and at 0.25,0.5,0.75,1,1.5 and 2 hours; PAR was assessed on a 5-point verbal rating scale (VRS) (0=none to 4=complete) at the same post-dose time points. Time-weights were equal to the elapsed time (hour) between the time point of interest and the preceding time point. All PAR and pain intensity (PI) assessments completed after the patient had taken rescue medication or the second dose of study medication, whichever was first, until hour 2 was considered missing. Last observation carried forward (LOCF) was used with the last completed PI/PAR assessments prior to first rescue/second study medication, whichever was first, to impute missing values up to 2 hours.
Time Frame
0 to 2 hours
Title
Duration of Pain Relief
Description
Duration of pain relief was defined as the time between the administration of first dose of trial medication and first dose of rescue medication or second dose of trial medication, whichever was first. Duration of pain relief was censored at 8 hours.
Time Frame
8 hours
Title
Time to Meaningful Pain Relief
Description
Time to meaningful pain relief was captured by a stopwatch, which was started by the study staff immediately after the administration of the first dose of trial medication and which was to be stopped by the patient as soon as he/she felt meaningful pain relief. Time to meaningful pain relief was censored at 8 hours.
Time Frame
8 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Males and females 18 to 55 years of age; Outpatients scheduled to undergo surgical extraction of 3-4 impacted third molar(s), with a minimum of two mandibular extractions. The two mandibular third molars may be partial bony impactions or full bony impactions (as long as the trauma rating is not severe and the surgeons do not feel the subject will have extreme post-surgical pain) OR there may be a combination of one full bony impaction with the second mandibular being a soft tissue impaction or partial bony impaction. Maxillary third molars (or supernumerary teeth) of any type can be extracted; Use of only the following preoperative medication(s)/ anesthetic(s): topical benzocaine, short-acting local anesthetic (mepivacaine or lidocaine) with or without vasoconstrictor and/or nitrous oxide; Reliable, cooperative, and of adequate intelligence to record the requested information on the analgesic questionnaire form; Examined by the attending oral surgeon or physician and medically cleared to participate in the study; Scheduled to undergo a qualifying surgical procedure; In good general health, with a BMI of 30 or less, and have no contraindications to any of the study medications or anesthetic drugs; Subjects have at least a categorical pain score of moderate and a numerical rating scale (NRS) score of 5 or greater within 4.5 hours from the time of the last suture. Exclusion criteria: Presence of a serious medical condition (e.g., poorly controlled hypertension, poorly controlled diabetes, significantly impaired cardiac, renal or hepatic function, hyper- or hypothyroidism); Use of a prescription or non-prescription drug with which the administration of ibuprofen or any other non steroidal anti inflammatory or caffeine is contraindicated; Acute local infection at the time of surgery that could confound the post-surgical evaluation; Females who are pregnant, lactating, of child-bearing potential, or post-menopausal for less than 2 years and not using a medically approved method of contraception (i.e., oral, transdermal, intravaginal or implanted contraceptives, intrauterine device, diaphragm, condom, abstinence, or surgical sterility), or females who test positive on a urine-based pregnancy test; Presence or history (within 2 years of enrollment) of bleeding disorder(s) or peptic ulcer disease; History of alcoholism or substance abuse within the last year, or is currently abusing alcohol or other mood-altering drugs (e.g., cannabis). Subjects who are taking central nervous system or other psychotropic drugs (including St. Johns Wort, or any other nutritional supplement known to have psychotropic effects) may be enrolled if they have been on stable doses of medication for at least 2 months, will maintain this dose throughout the study, and their condition is judged by the Principal Investigator to be well-controlled; Habituation to analgesic drugs or caffeine (i.e., routine use of oral analgesics 5 or more times per week or ingestion of 4 or more caffeine-containing drinks daily); use of "high energy" drinks more than once per week; Use of any type of systemic corticosteroid within the past 30 days or a history of current or previous use of anabolic steroids; History of allergic reaction (e.g., asthma, rhinitis, swelling, shock, or hives) to acetaminophen, ibuprofen, naproxen, aspirin, celecoxib, or any other non steroidal anti inflammatory or caffeine; Prior use of any type of analgesic or non steroidal anti inflammatory within 5 half-lives of that drug before surgery, except for pre-anesthetic medication and anesthesia for the procedure; Ingestion of any caffeine-containing beverages, chocolate, or alcohol 6 hours or less before surgery; Has impaired liver function, e.g., serum Alanine transaminase, aspartate aminotransferase, alkaline phosphatase, or Gamma-glutamyltransferase greater than 2.5 times the upper limit of normal, or blood urea nitrogen, creatinine, or bilirubin greater than 1.5 times the upper limit of normal without a known benign explanation; Has known history of a positive HIV antibody test or known HIV infection; Has a known history of Hepatitis B or C; Has a clinically significant abnormal electrocardiogram (ECG) at screening as determined by the Investigator: Has taken an investigational product within the past 30 days; Has previously been entered into this study; The subject is a member of the study site staff either directly involved with the study, an employee of the Sponsor, or a relative of study site personnel directly involved with the study or Sponsor.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
1335.1.202 Boehringer Ingelheim Investigational Site
City
Salt Lake City
State/Province
Utah
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32333328
Citation
Forderreuther S, Lampert A, Hitier S, Lange R, Weiser T. The Impact of Baseline Pain Intensity on the Analgesic Efficacy of Ibuprofen/Caffeine in Patients with Acute Postoperative Dental Pain: Post Hoc Subgroup Analysis of a Randomised Controlled Trial. Adv Ther. 2020 Jun;37(6):2976-2987. doi: 10.1007/s12325-020-01297-y. Epub 2020 Apr 24.
Results Reference
derived
PubMed Identifier
28805281
Citation
Weiser T, Richter E, Hegewisch A, Muse DD, Lange R. Efficacy and safety of a fixed-dose combination of ibuprofen and caffeine in the management of moderate to severe dental pain after third molar extraction. Eur J Pain. 2018 Jan;22(1):28-38. doi: 10.1002/ejp.1068. Epub 2017 Aug 14.
Results Reference
derived

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Efficacy and Safety of Ibuprofen and Caffeine in Dental Pain

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