An Alternative to Antibiotics for the Symptomatic Relief of Sore Throat – Evidence from a Randomised Controlled Study of Flurbiprofen Lozenge

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EV0007 An alternative to antibiotics for the symptomatic relief of sore throat – evidence from a randomised controlled study of flurbiprofen lozenge

Adrian Shephard,1 Tim Shea,2 Gary Smith,1 Emily Schachtel,3 Bernard Schachtel3,4 1Reckitt Benckiser, Slough, Berkshire, UK; 2Reckitt Benckiser, Parsippany, NJ, USA; 3Schachtel Research Company, Jupiter, FL, USA; 4Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA.

INTRODUCTION Onset of analgesia was assessed using the double stopwatch method: Figure 1. Proportion of Strep A/C patients achieving first perceived relief Figure 4. Proportion of non-Strep A/C patients achieving meaningful relief Antibiotics continue to be overprescribed for sore throat1–3 Two stopwatches were started when the patient placed the study medication in their mouth 100 100 In a recent study in six countries, 50% of all patients with sore throat (46% in Denmark) The patient was asked to depress the first stopwatch when they first perceived any pain relief 100% were prescribed antibiotics for their sore throat3 and to depress the second stopwatch when they experienced meaningful relief 90 90 87.5% Most sore throats (85–95% in adults) are caused by a viral infection, for which antibiotics All adverse events (AEs) were recorded 80 80 are ineffective4 76.1% 70 70 Bacteria such as group A streptococcus (Strep A) and group C streptococcus (Strep C) can cause Statistical analysis Flurbiprofen (N=34) 5 Onset of analgesia was determined by calculating the Kaplan–Meier median time to first 60 60 sore throat but these infections are generally self-limiting and complications are rare; therefore, Placebo (N=8) antibiotics are usually unnecessary6 perceived relief, time to first perceived relief confirmed by meaningful relief, and time to 50 50 Regardless of the cause, most patients with sore throat want pain relief rather than an antibiotic meaningful relief for both treatment groups 40 40 38.5% so they should be offered treatments with effective analgesic action7 Patients who had no meaningful relief within 3 hours were censored to 3 hours 30 30 A lozenge containing a low dose (8.75 mg) of the anti-inflammatory drug, flurbiprofen, has been meaningful relief (%) Flurbiprofen (N=67)

developed for the effective treatment of sore throat symptoms irrespective of whether the cause rst perceived relief (%) 20 20 is streptococcal or non-streptococcal8,9 Placebo (N=13)

10 Proportion of patients achieving 10 RESULTS Proportion of patients achieving This study aimed to establish the time to onset of analgesia of flurbiprofen 8.75 mg lozenge in Patient population 0 0 patients with and without streptococcal infection A total of 122 patients were randomised to flurbiprofen (n=101) or placebo (n=21); all patients 0 30 60 90 120 150 180 0 30 60 90 120 150 180 completed the 3-hour study Minutes from dosing Minutes from dosing METHODS Mean age was 19.5 years and 58.2% of the patients were female (Table 2) Study design Strep A or Strep C infection was detected by throat culture in 34.4% of the patients A randomised, double-blind, placebo-controlled, single-dose, single centre, parallel group clinical trial Baseline characteristics were similar for both treatment groups Safety ClinicalTrials.gov identifier: NCT01986361 Figure 2. Proportion of non-Strep A/C patients achieving first perceived relief Ten patients (9.9%) in the flurbiprofen group and one patient (4.8%) in the placebo group Table 2. Baseline demographics and characteristics Study population reported an AE during the 3-hour observation period (p=0.69 for flurbiprofen vs. placebo) Characteristic Flurbiprofen Placebo Overall There were two AEs in the flurbiprofen group, which were considered to be possibly or probably Study inclusion criteria were: 100 8.75 mg (n=101) (n=21) (N=122) related to study treatment (abdominal discomfort and throat irritation) (p=1.00 vs. placebo) Aged ≥18 years with recent onset (≤4 days) sore throat 95.5% 90 There were no serious AEs and no patient discontinued from the study because of an AE Moderate or severe pain on the Throat Pain Scale (TPS; a 4-point categorical scale: no, mild, Age, mean (SD), years 19.5 (2.02) 19.6 (1.36) 19.5 (1.92) 80 moderate or severe pain) Female, n (%) 58 (57.4) 13 (61.9) 71 (58.2) ≥6 on the Sore Throat Scale (STS; a 0–10 Likert scale) 70 69.2% DISCUSSION TPA total score, mean (SD) 9.8 (2.57) 10.3 (2.82) 9.9 (2.61) 60 At least one symptom of URTI on the URTI Questionnaire (a questionnaire on the presence/ Onset of analgesia with flurbiprofen 8.75 mg lozenge was perceived quickly by both patients absence of 39 different symptoms of URTI) PAIN, n (%) 50 with or without Strep A/C (median times of 9.2 and 11.2 minutes, respectively) ≥5 on the Tonsillo-Pharyngitis Assessment (TPA; an index of seven objective features of No inflammation 0 0 0 40 Flurbiprofen (N=67) In comparison, onset of analgesia with oral (systemic) analgesics is approximately 10 pharyngeal inflammation, with a maximum possible score of 21 ) (Table 1) Mild inflammation 37 (36.6) 7 (33.3) 44 (36.1) 20–30 minutes11,12 30 Placebo (N=13) Moderate inflammation 58 (57.4) 14 (66.7) 72 (59.0) Pain reduction was sustained and later confirmed to be meaningful to patients with or without

Table 1. Tonsillo-Pharyngitis Assessment Severe inflammation 6 (5.9) 0 6 (4.9) rst perceived relief (%) 20 Strep A/C (median times of 41.1 and 43.0 minutes, respectively) 10 These findings suggest that flurbiprofen 8.75 mg lozenge provides fast and meaningful relief to Item 0 Point 1 Point 2 Points 3 Points Proportion of patients achieving TPS, n (%) adults with acute sore throat, regardless of the cause Oral temperature ≤98.6ºF 98.7–98.9ºF 99.0–99.9ºF ≥100.0ºF 0 Moderate 68 (67.3) 8 (38.1) 76 (62.3) Flurbiprofen 8.75 mg lozenge can be recommended as an effective first-line treatment for Oropharyngeal colour Normal/pink Slightly red Red Beefy red Severe 33 (32.7) 13 (61.9) 46 (37.7) 0 30 60 90 120 150 180 sore throat, while antibiotics should be reserved for patients with a serious infection or those Minutes from dosing at increased risk of complications6 Size of tonsils Normal/ Slightly Moderately Much STS score, mean (SD) 7.4 (0.97) 7.3 (1.02) 7.4 (0.98) absent enlarged enlarged enlarged STPIS, mean (SD), mm 73.8 (9.78) 73.8 (9.64) 73.8 (9.71) Number of oropharyngeal None Few Several Many enanthems (vesicles, petechiae Strep A-positive, n (%) 15 (14.9) 3 (14.3) 18 (14.8) or exudates) CONCLUSIONS Strep C-positive, n (%) 19 (18.8) 5 (23.8) 24 (19.7) Figure 3. Proportion of Strep A/C patients achieving meaningful relief Largest size of anterior cervical Normal Slightly Moderately Much Flurbiprofen 8.75 mg lozenge starts working quickly to relieve lymph nodes enlarged enlarged enlarged PAIN, Practitioner’s Assessment of Pharyngeal Inflammation; SD, standard deviation; STPIS, Sore Throat Pain Intensity patients’ sore throat symptoms, providing meaningful relief 100 Number of anterior cervical Normal Slightly Moderately Greatly Scale; Strep A, group A streptococcus; Strep C, group C streptococcus; STS, Sore Throat Scale; TPA, Tonsillo-Pharyngitis to those with or without Strep A/C infection lymph nodes increased increased increased Assessment; TPS, Throat Pain Scale 90 80 82.4% Flurbiprofen 8.75 mg lozenge can be recommended as a Maximum tenderness of some Not tender Slightly Moderately Very Onset of analgesia anterior cervical lymph nodes tender tender tender first-line treatment for sore throat and an alternative to Median time to first perceived relief for patients receiving flurbiprofen was 9.2 minutes 70 (95% CI: 3.5, 22.4) for patients with Strep A/C (Figure 1) and 11.2 minutes (95% CI: 7.6, 14.4) 60 62.5% immediate antibiotic prescribing Study medication for patients without Strep A/C (Figure 2) 50 Patients were randomised to receive one sugar-based flurbiprofen 8.75 mg lozenge or one Median time to first perceived relief confirmed by meaningful relief for patients receiving sugar-based matching placebo lozenge 40 Flurbiprofen (N=34) flurbiprofen was 10.6 minutes (95% CI: 3.9, 24.3) for patients with Strep A/C and 13.4 minutes Placebo (N=8) Study assessments (95% CI: 8.6, 19.5) for patients without Strep A/C 30

meaningful relief (%) REFERENCES The practitioner completed several assessments at baseline including the TPA and the Median time to meaningful relief for patients receiving flurbiprofen was 41.1 minutes 20 Practitioner’s Assessment of Pharyngeal Inflammation (PAIN; a four-category scale to rate (95% CI: 29.7, 47.2) for patients with Strep A/C (Figure 3) and 43.0 minutes (95% CI: 35.5, 57.2) 1. Gulliford MC, et al. BMJ Open 2014;4:e006245; 2. Barnett ML, Linder JA. JAMA Intern Med 2014;174:138–40;

Proportion of patients achieving 10 the extent of pharyngeal inflammation: none, mild, moderate, severe) for patients without Strep A/C (Figure 4) 3. Cordoba G, et al. BMC Fam Pract 2015;16:7; 4. Worrall GJ. Can Fam Physician 2007;53:1961–2; 5. ESCMID Sore 0 Throat Guideline Group, et al. Clin Microbiol Infect 2012;18(Suppl 1):1–28; 6. Essack S, Pignatari AC. Int J Clin Pract Rapid strep tests and throat cultures were conducted at baseline to detect streptococcal throat For the placebo group, median time to first perceived relief was 19.3 minutes (95% CI: 4.8, 30.3) 2013;67(Suppl 180):4–9; 7. van Driel ML, et al. Ann Fam Med 2006;4:494–9; 8. Schachtel B, et al. Pain 2014;155:422–8; 0 30 60 90 120 150 180 infections; antibiotics were provided to patients with microbiological evidence of Strep A (or but median time to meaningful relief could not be calculated due to the high percentage of 9. Shephard A, et al. Int J Clin Pract 2015;69:59–71; 10. Schachtel BP, et al. Clin Pharmacol Ther 2002;71:375–80; Strep C, if clinically indicated) patients (52.4%) who did not achieve meaningful relief within 3 hours Minutes from dosing 11. Mehlisch DR, Sykes J. Int J Clin Pract 2013;67(Suppl 178):3–8; 12. Sedinkin AA, et al. Vestn Otorhinolaryngol 2004;5:52–3.

Poster presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 25–28 April 2015, Copenhagen, Denmark. Funding and acknowledgements: This study was funded by Reckitt Benckiser. Editorial assistance was provided by Elements Communications Ltd (Westerham, UK) and funded by Reckitt Benckiser.