A Study of Flurbiprofen 8.75 mg Lozenge in Patient With Pharyngitis

A Randomized, Double-Blind, Placebo-Controlled Multiple-Dose Study to Determine the Efficacy, Onset, and Duration of Action of Flurbiprofen 8.75 mg Lozenge Compared to Its Vehicle Control Lozenge in Patients With Painful Pharyngitis

The purposes of this study is to demonstrate the analgesic efficacy of flurbiprofen 8.75 mg lozenge compared to its vehicle lozenge and to demonstrate the safety of the flurbiprofen lozenge throughout the course of treating sore throat due to acute pharyngitis.

Study Overview

• Status: Completed
• Conditions: Pharyngitis
• Intervention / Treatment: Drug: Flurbiprofen; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 204
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Storrs, Connecticut, United States, 06268
      • University of Connecticut, Student Health Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The patient has a complaint of sore throat.
2. If the patient is a female of childbearing potential, she has been using effective contraception since the last date of menses and is not breast-feeding or lactating.
3. If the patient is a female of childbearing potential, the patient must have a negative urine pregnancy.
4. The patient has provided written informed consent prior to any study-related procedures.

Exclusion Criteria:

1. The patient has a history of an upper gastrointestinal ulcer within the past 60 days, is currently experiencing clinically significant upper gastrointestinal complaints, or is currently taking medication regularly (≥ three times in the previous week).
2. The patient has a history of any hepatic disease or renal dysfunction.
3. The patient has a history of chronic analgesic use (≥ three times per week over the prior four weeks). (Patients on low-dose aspirin therapy may be allowed in the study per investigator's clinical decision.)

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: flurbiprofen 8.75 mg lozenge; Participants sucked flurbiprofen 8.75mg lozenge every 3-6 hours up to 5 lozenges a day as needed for pain for 7 days.	Drug: Flurbiprofen; Participants were instructed to suck one flurbiprofen 8.75 mg lozenge during the initial two-hour clinic visit. Upon discharge, participants were instructed to use study medication lozenge every 3-6 hours as needed for pain, up to a total of 5 study lozenges in 24 hours.
Placebo Comparator: Placebo lozenge; Participants sucked vehicle placebo lozenge every 3-6 hours up to 5 lozenges a day as needed for pain for 7 days.	Drug: Placebo; Participants were instructed to suck one placebo lozenge during the initial two-hour clinic visit. Upon discharge, participants were instructed to use study medication lozenge every 3-6 hours as needed for pain, up to a total of 5 study lozenges in 24 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time Weighted Sum of Pain Intensity Differences (SPID) in Sore Throat Pain Intensity Scale (STPIS) Over the 24 Hours Post-baseline (STPIS SPID24)	STPIS measures sore throat pain intensity on a 100-mm visual analog scale completed by participants. A mark at 0-mm indicates no pain upon swallowing and 100-mm indicates severe pain. SPID24 was calculated as the sum of the time-weighted pain intensity differences from baseline until 24 hours. The full range was -114609 (complete pain relief within 2 minutes of dosing that lasts 24 hours) to 29191 (maximum pain within 2 minutes lasting 24 hours) using the mean baseline STPIS. Participants with a last recorded time point <21 hours were considered Not Evaluable. If a participant used rescue medication, all post-rescue STPIS values in the 24-hour interval were assigned the baseline value for STPIS. Missing scores of STPIS with non-missing STPIS scores at earlier and later assessments were imputed using linear interpolation assuming the time of the missing assessment to be the nominal time since initial dose.	baseline (pre-dose), 24 hours post-dose (every 2 minutes for one hour; every 10 minutes until hour 2; every 30 minutes until hour 6; and every hour the participant was awake between hours 7-24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigators' Clinical Assessment (CLIN) Of Study Medication as a Treatment for Sore Throat at 24 Hours After Initial Dose	Investigators assessed the effectiveness of study medication on the patient's sore throat at 24 hours following initial dose by answering the following question: "Considering the patient's response to the study medicine over the past 24 hours, how do you rate the study medicine as a treatment for sore throat?" Responses were poor, fair, good, very good or excellent.	24 hours
Time Weighted Sum of Pain Intensity Differences (SPID) in Sore Throat Pain Intensity Scale (STPIS) Over the 2 Hours Post-baseline (STPIS SPID2)	STPIS measures sore throat pain intensity on a 100-mm visual analog scale completed by participants. A mark at 0-mm indicates no pain upon swallowing and 100-mm indicates severe pain. SPID2 was calculated as the sum of the time-weighted pain intensity differences from baseline until 2 hours post dosing. The full range was -9405 (complete pain relief within 2 minutes of dosing that lasts 2 hours) to 2395 (maximum pain within 2 minutes lasting 2 hours) using the mean baseline STPIS. If a participant used rescue medication (acetaminophen 650mg was allowed as needed post dose), all post-rescue STPIS values in the 24-hour interval were assigned the baseline value for STPIS. Missing scores of STPIS with non-missing STPIS scores at earlier and later assessments (recorded or derived due to rescue) were imputed using linear interpolation assuming the time of the missing assessment to be the nominal time since initial dose.	baseline (pre-dose), 2 hours post-dose (every 2 minutes for one hour; every 10 minutes until hour 2)
Time Weighted Summed Differences in Difficulty Swallowing Scale (DSS) During the Initial 2 Hours From Baseline	Participants were asked to evaluate his/her difficulty swallowing (dysphagia) using a 100-mm visual analog scale at Baseline and 2 hours post dose. Participants were instructed to swallow and "Place a line on the scale that best characterizes how difficult it is to swallow now." A mark at 0-mm indicated no difficulty and 100-mm indicated very difficult. Data is reported as the sum of the time-weighted pain intensity differences from baseline until 2 hours post dose. The full range was -9192 (no difficulty swallowing within 10 minutes of dosing that lasts 2 hours) to 2808 (maximum difficulty swallowing within 10 minutes lasting 2 hours) using the baseline DSS value. Missing values of DSS with non-missing values at assessments before and after were calculated using linear interpolation.	baseline (pre-dose), 2 hours post-dose (every 10 minutes until hour 2)
Time Weighted Summed Differences in Difficulty Swallowing Scale (DSS) During the Initial 24 Hours From Baseline	Participants were asked to evaluate his/her difficulty swallowing (dysphagia) using a 100-mm visual analog scale at Baseline and until 24 hours post dose. Participants were instructed to swallow and "Place a line on the scale that best characterizes how difficult it is to swallow now." A mark at 0-mm indicated no difficulty and 100-mm indicated very difficult. Data is reported as the sum of the time-weighted pain intensity differences from baseline until 24 hours post dose. The full range was -110304 (no difficulty swallowing within 10 minutes of dosing that lasts 24 hours) to 33696 (maximum difficulty swallowing within 10 minutes lasting 24 hours) using the baseline DSS value. Missing values of DSS with non-missing values at assessments before and after were calculated using linear interpolation.	baseline (pre-dose), 24 hours post-dose (every 10 minutes until hour 2, every 30 minutes until hour 6, hourly from 7-24 hours)
Time Weighted Summed Differences in Swollen Throat Scale (SwoTS) During the Initial 2 Hours From Baseline	The participant was asked to evaluate how swollen his/her throat felt using a 100-mm visual analog scale at Baseline and at 1 hour, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, and 2 hours. The patient was instructed to swallow and "Place a line on the scale that best characterizes how swollen your throat feels now." A mark at 0-mm indicated not swollen and 100-mm indicated very swollen. The full range of the sum of the time-weighted swollen throat differences from baseline until 2 hours was -9336 (throat did not feel swollen at all within 1 hour of dosing and lasted 2 hours) to 2664 (maximum swollen throat reported within 1 hour and lasting 2 hours) using the mean baseline SwoTS.	baseline (pre-dose), 2 hours post-dose (at 1 hour, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, and 2 hours)
Time Weighted Summed Differences in Swollen Throat Scale (SwoTS) During the Initial 24 Hours From Baseline	The participant was asked to evaluate how swollen his/her throat felt using a 100-mm visual analog scale at Baseline and specified timeframes until 24 hours. The patient was instructed to swallow and "Place a line on the scale that best characterizes how swollen your throat feels now." A mark at 0-mm indicated not swollen and 100-mm indicated very swollen. The full range of the sum of the time-weighted swollen throat differences from baseline until 24 hours was -112032 (throat did not feel swollen at all within 1 hour of dosing and lasted 24 hours) to 31968 (maximum swollen throat reported within 1 hour and lasting 24 hours) using the mean baseline SwoTS.	baseline (pre-dose), 24 hours post-dose (1 hour, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 2 hours, 2½ hours, 3 hours, 3½ hours, 4 hours, 4½ hours, 5 hours, 5½ hours, and 6 hours after the first dose, hourly from 7-24 hours)
Change From Baseline at 24 Hours in the Tonsillo-Pharyngitis Assessment (TPA) Scores in Participants With Baseline TPA Scores >=8	Tonsillo-Pharyngitis Assessment, or TPA, is an index of seven clinical features of the pain-producing condition itself, pharyngeal inflammation. The clinical features concern temperature, oropharyngeal color, size of tonsils, number of enanthems, largest size of cervical lymph node, number of lymph nodes, and maximum tenderness of lymph nodes. Each variable was rated on a scale of 0-3, with 0 representing the normal value, and 3 representing severe inflammation. The seven values are added together to create the TPA, ranging from 0-21. Negative change values represent improvement of symptoms.	Baseline (pre-dose), 24 hours post-dose
Practitioner's Assessment of Pharyngeal Inflammation (P.A.I.N.) Scores at 24 Hours After Initial Dose	P.A.I.N is a four step scale in which physicians rate the severity of pharyngeal inflammation: No inflammation, mild, moderate and severe inflammation.	24 hours post-dose
Participant Satisfaction Scores 24 Hours After Initial Dose	After 24 hours of treatment, participants rated their satisfaction with the treatment on a 7-step scale from extremely dissatisfied to extremely satisfied.	24 hours
Investigators' Clinical Assessment (CLIN) Of Study Medication as a Treatment for Sore Throat at the End of the Study (Day 7)	Investigators assessed the effectiveness of study medication on the patient's sore throat at the end of the study by answering the following question: "Considering the patient's response to the study medicine over the past 7 days, how do you rate the study medicine as a treatment for sore throat?" Responses were poor, fair, good, very good or excellent.	Day 7
Time Weighted Sum of Pain Intensity Differences (SPID) in Sore Throat Pain Intensity Scale Over 24 Hours Post-baseline (STPIS SPID24) For Participants With Baseline Practitioner's Assessment of Pharyngeal Inflammation (PAIN) of Moderate or Severe	STPIS measures sore throat pain intensity on a 100-mm visual analog scale completed by participants. A mark at 0-mm indicates no pain upon swallowing and 100-mm indicates severe pain. For the subgroup of patients with moderate/severe pharyngeal inflammation at baseline, SPID24 was calculated as the sum of the time weighted pain intensity differences from baseline until 24 hours. Taking inclusion criteria into account, the full range was -116196 (no pain at any post-dose time (0) - average baseline) to 27804 (maximum possible pain (100) - average baseline). Participants with their last recorded time point <21 hours were considered Not Evaluable. If a participant used rescue medication (acetaminophen 650mg was allowed as needed), all post-rescue STPIS values in the 24-hour interval were assigned the baseline value for STPIS. Missing scores of STPIS with non-missing STPIS scores at earlier and later assessments were imputed using linear interpolation.	baseline (pre-dose), 24 hours post-dose (every 2 minutes for one hour; every 10 minutes until hour 2; every 30 minutes until hour 6; and every hour the participant was awake between hours 7-24)
Sore Throat Relief Rating Scale (STRRS) At 2 Hours After Initial Dose	Participants used a 6-category relief scale (no relief to complete relief) to grade the relief of his/her throat pain. The patient was instructed to swallow and: "Considering how your throat felt before you took the study medicine, circle the phrase that best describes the relief of your sore throat now."	2 hours
Time Weighted Sum of Pain Intensity Differences (SPID) in Sore Throat Pain Intensity Scale (STPIS) at Each Post-Dose Time Point Until the Time Point at Which Comparison of the Arms Yielded a P-value <=0.05	Data reported in summary form in Primary Outcome #1 are reported here at each post-dose timepoint until the comparison resulted in a P-value <=0.05 between the two treatment arms. STPIS was used to measure sore throat pain intensity using a 100-mm visual analog scale completed by participants that measures "pain on swallowing" (odynophagia). A mark at 0-mm indicates no pain and 100-mm indicates severe pain. The full range of the scale varies by timepoint due to the time weighting sum of SPID. The full scale at 40 minutes post dose was -3188 (complete pain relief within 2 minutes of dosing that lasts 40 minutes) to 812 (maximum pain within 2 minutes lasting 40 minutes) using the mean baseline STPIS. If a participant used rescue medication (acetaminophen 650mg was allowed as needed), all post-rescue STPIS values in the 24-hour interval were assigned the baseline value for STPIS. Missing scores of STPIS with non-missing STPIS scores at earlier and later assessments (rec	baseline (pre-dose), up to 23 hours post-dose (every 2 minutes for one hour; every 10 minutes until hour 2; every 30 minutes until hour 6; and every hour the participant was awake between hours 7-23)
Kaplan-Meier Estimates for Sore Throat Pain Intensity Scale (STPIS) Time to Definite Improvement	As part of a protocol amendment, some participants defined a definite improvement level (DIL) relative to their actual pretreatment STPIS on the 100-mm visual analog scale. This was done after completing the 7 day trial. An alternative definition of STPIS time to onset of relief was the time from initial dose to the time the participant reaching DIL for at least 30 minutes. Data were censored if DIL was not achieved by 120 minutes following initial dose. Definite improvement must also occur prior to re-dosing or using rescue medication.	2 hours
Kaplan-Meier Estimates for Sore Throat Pain Intensity Scale (STPIS) Time to Definite Improvement Duration of Relief Using Participant-Defined Definite Improvement Levels (DIL)	As part of a protocol amendment, some participants defined a definite improvement level (DIL) relative to their actual pretreatment STPIS on the 100-mm visual analog scale. This was done after completing the 7 day trial. The time of first achieving DIL for 30 minutes within 6 hours (or until rescue or re-dosing) post-dosing will be determined. And the time falling below DIL within 6 hours will be determined. Duration is then defined as the time from first DIL until falling below DIL. Duration was set to zero if the STPIS score does not reach the DIL for at least 30 minutes for STPIS during the 6 hours.	6 hours

Collaborators and Investigators

• Sponsor: Reckitt Benckiser LLC
• Investigators: Study Director: Timothy J Shea, BS, Reckitt Benckiser Inc.

Publications and helpful links

General Publications

• Shephard A, Smith G, Aspley S, Schachtel B. Efficacy of flurbiprofen 8.75 mg lozenges for streptococcal and non-streptococcal sore throat: pooled analysis of two randomised, placebo-controlled studies. Abstract presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 27 - 30 April 2013, Berlin.
• Shephard A, Smith G, Aspley S, Schachtel B. Symptomatic relief in streptococcal and non-streptococcal sore throat patients: pooled analysis of two randomised, placebo-controlled studies. Abstract presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 27-30 April 2013, Berlin.
• Schachtel B, Aspley S, Berry P, Shephard A, Sanner K, Shea T, Smith G, Schachtel E. Chief Complaint: the therapeutogenic stimulus as the primary, individualized endpoint in clinical trials. Journal of Pain 2012;13(4)Supplement:S6.
• Shephard A, Smith G, Aspley S, Schachtel BP. Randomised, double-blind, placebo-controlled studies on flurbiprofen 8.75 mg lozenges in patients with/without group A or C streptococcal throat infection, with an assessment of clinicians' prediction of 'strep throat'. Int J Clin Pract. 2015 Jan;69(1):59-71. doi: 10.1111/ijcp.12536. Epub 2014 Oct 9.
• Schachtel BP, McCormick CG and Giefer EE. Patient-reported outcomes (PRO's) in the pharyngitis pain model. Abstract presented at the International Association for the Study of Pain (IASP) Scientific Conference, Montreal, Canada. 2009
• Schachtel BP, Aspley S, Sternberg M, Berry P, Muir N, Sanner K, Rezuke J, Savino L, Shephard A, Shea T, Schachtel E. Onset of demulcent and analgesic activity of flurbiprofen lozenge. Int J Clin Pharm 2012;34:143-258.
• Aspley S, Schachtel B, Berry P, Shephard A, Sanner K, Shea T, Smith G. The Chief Complaint: evidence of its use as an endpoint in a clinical trial. Journal of Pain 2012;13(4)Supplement:S4.
• Aspley S, Schachtel B, Berry P, Shephard A, Sanner K, Savino L, Rezuke J, Shea T, Smith G. Treatment of odynophagia and dysphagia by flurbiprofen 8.75 mg lozenges. Pain Research & Management 2012;17(3):203.
• Schachtel B, Aspley S, Berry P, Shephard A, Shea T,Sanner K, Smith G,Schachtel E. Efficacy of flurbiprofen 8.75mg lozenges in patients with swollen/inflamed sore throat. Abstract presented at the 14th World Congress on Pain, 27 - 31 August 2012, Milan.
• Schachtel B, Aspley S, Berry P, Smith G, Shephard A, Shea T, Schachtel E. A patient-centered method for determining onset of action. Clinical Pharmacology in Drug Development 2012;1(4):194-195.
• Schachtel B, Aspley S, Berry P, Shephard A, Shea T, Smith G, Sanner K, Savino L, Rezuke J, Schachtel E. Efficacy and duration of flurbiprofen 8.75 mg lozenge. Clinical Pharmacology in Drug Development 2012;1(4):194.
• Schachtel B, Aspley S, Berry P, Shephard A, Shea T, Smith G, Schachtel E. A new cough model: de-hawthornizing a clinical trial. Clinical Pharmacology in Drug Development 2012;1(4):195.
• Aspley S, Schachtel B, Berry P, Shephard A, Shea T, Smith G, Schachtel E. Flurbiprofen lozenges in patients with a "bad sore throat". Journal of Pain 2013;14(4):S59.
• Schachtel B, Aspley S, Berry P, Shephard A, Shea T, Smith G, Schachtel E. The "Definite Improvement Level" (DIL) as a determinant of drug efficacy. Journal of Pain 2013;14(4):S5.
• Aspley S, Shephard A, Schachtel E, Sanner K, Savino L, Schachtel B. Efficacy of flurbiprofen 8.75 mg lozenge in patients with a swollen and inflamed sore throat. Curr Med Res Opin. 2016 Sep;32(9):1529-38. doi: 10.1080/03007995.2016.1187119. Epub 2016 May 18.

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: January 13, 2010
• First Submitted That Met QC Criteria: January 13, 2010
• First Posted (Estimate): January 14, 2010

Study Record Updates

• Last Update Posted (Actual): September 21, 2017
• Last Update Submitted That Met QC Criteria: August 23, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Pharyngitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Flurbiprofen
• Other Study ID Numbers: TH 0901