EV0489

Diagnosis of streptococcal throat infection in a randomised controlled study of flurbiprofen lozenge

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

Table 2. Clinical Assessment of Strep A Throat When assessing the individual features on the CAST, only ‘beefy red throat’ and ‘large tonsils’ Figure 3. Percentage pain intensity difference in Strep A-negative patients INTRODUCTION were significantly more common among Strep A-positive patients than Strep A-negative Most sore throats are due to a viral upper respiratory tract infection (URTI) but a small proportion Historical findings Physical findings Symptoms patients (p<0.01) Time since dosing (minutes) are caused by a bacterial infection1,2 or environmental factor3,4 History of Any fever Swollen anterior Headache Beefy red throat had a sensitivity of 44.4% and a specificity of 84.6% 0 60 120 180 Group A streptococcus (Strep A) is the main bacterial cause of sore throat for which History of recurrent Fever >102°F cervical lymph nodes Nausea 0 1,2 2 Large tonsils had a sensitivity of 88.9% and a specificity of 44.2% may be indicated but only 5–15% of sore throats in adults are caused by Strep A Strep A Palatal petechiae Tender anterior Muscle aches -5 cervical lymph nodes Strep A infection should either be confirmed or risk factors identified before antibiotics are History of sore -10 5 Pharyngeal swelling No complaint Table 4. Throat culture results versus the Clinical Assessment of Strep A Throat prescribed as unnecessary use is a major cause of antibiotic resistance throat >2 weeks Absence of -15.6% Red tonsils of coughing -15 However, identification of Strep A infection remains a challenge because of the broad overlap swollen nodes CAST, n Throat culture, n -19.9% -18.6% Sudden onset of No complaint between the signs and symptoms of bacterial and viral sore throats coupled with the costs and Beefy red throat -20 sore throat Halitosis of other cold Strep A- Strep C- Strep A/C- Other Overall time associated with diagnostic tests2 Large tonsils positive positive negative Close contact with Distinct symptoms -25 Initially, it may be preferable to advise patients about non-antibiotic treatments that provide Tonsils of Unlikely 3 4 23 0 30 another patient with “strep breath” Systemic malaise -30 symptomatic relief with antibiotics reserved if the condition does not improve or worsens unequal size Strep A pharyngitis Absence of Uncertain 10 14 41 4 69 -35 * *

Fatigue Mean PID on the STPIS (%) We studied the efficacy of a lozenge containing the non-steroidal anti-inflammatory drug, Prevalence of Tonsillar exudates Likely 5 6 11 0 22 -35.9% ** -35.5% Absence of other Severe sore -40 flurbiprofen, for the symptomatic relief of sore throat Strep A pharyngitis -39.6% URTI findings throat pain Very likely 0 0 1 0 1 Placebo (n=18) In the same study, we also determined the accuracy of Strep A diagnosis based on clinical features alone in the community -45 Overall 18 24 76 4 122 Flurbiprofen 8.75 mg (n=86)

Strep A, group A streptococcus; URTI, upper respiratory tract infection CAST, Clinical Assessment of Strep A Throat METHODS PID, pain intensity difference; STPIS, Sore Throat Pain Intensity Scale *p<0.05 vs. placebo; **p<0.01 vs. placebo Study design Statistical analysis Efficacy A randomised, double-blind, placebo-controlled, single-dose, single centre, parallel group clinical trial Mean %PID at 3 hours (based on the STPIS) was -32.8% in the flurbiprofen group and -13.0% in the The accuracy of the CAST (and each feature on the CAST) for the diagnosis of Strep A was Safety ClinicalTrials.gov identifier: NCT01986361 assessed by calculating the sensitivity and specificity placebo group (least square [LS] mean difference = 20.0%, 95% CI: -0.8%, 40.9%, p=0.06) (Figure 1) Ten patients (9.9%) in the flurbiprofen group and one patient (4.8%) in the placebo group For Strep A-positive patients, mean %PID at 3 hours (based on the STPIS) was -16.8% in the Sensitivity: the percentage of Strep A-positive patients (confirmed by culture) who had a likely reported an AE during the 3-hour observation period (p=0.69 for flurbiprofen vs. placebo) Study population or very likely diagnosis on the CAST (or had the CAST feature) flurbiprofen group and 2.7% in the placebo group (LS mean difference = 20.3%, 95% CI: -18.3%, Study inclusion criteria were: 58.9%, p=0.30) (Figure 2) There were two AEs in the flurbiprofen group, which were considered to be possibly Specificity: the percentage of Strep A-negative patients who had an uncertain or unlikely Aged ≥18 years with recent onset (≤4 days) sore throat For Strep A-negative patients, mean %PID at 3 hours (based on the STPIS) was -35.5% in the or probably related to study treatment (abdominal discomfort and throat irritation) diagnosis on the CAST (or did not have the CAST feature) (p=1.00 vs. placebo) Moderate or severe pain on the Throat Pain Scale (TPS; a 4-point categorical scale: no, mild, flurbiprofen group and -15.6% in the placebo group (LS mean difference = 19.8%, 95% CI: 4.0%, Efficacy of flurbiprofen 8.75 mg and placebo lozenges was determined based on percentage 35.6%, p<0.05) (Figure 3) There were no serious AEs and no patient discontinued from the study because of an AE moderate or severe pain) pain intensity difference (%PID) at 1, 2 and 3 hours on the STPIS ≥6 on the Sore Throat Scale (STS; a 0–10 Likert scale) Figure 1. Percentage pain intensity difference in the overall population At least one symptom of URTI on the URTI Questionnaire (a questionnaire on the presence/ DISCUSSION absence of 39 different symptoms of URTI) RESULTS Time since dosing (minutes) This study highlights the difficulty in diagnosing Strep A using clinical features alone and, ≥5 on the Tonsillo-Pharyngitis Assessment (TPA; an index of seven objective features of Patient population 0 60 120 180 therefore, the risks of antibiotic mis-prescribing pharyngeal inflammation, with a maximum possible score of 216) (Table 1) 0 A total of 122 patients were randomised to flurbiprofen (n=101) or placebo (n=21); all patients If diagnosis of Strep A in this study was based on clinical features alone, 18 patients completed the 3-hour study -5 Table 1. Tonsillo-Pharyngitis Assessment without Strep A (14.8% of the study population) would have been given antibiotics Mean age was 19.5 years and 58.2% of the patients were female (Table 3) -10 unnecessarily and 13 patients with Strep A (10.6% of the study population) would Item 0 Point 1 Point 2 Points 3 Points Baseline characteristics were similar for both treatment groups -15 -13.0% have not received antibiotics -15.4% Oral temperature ≤98.6ºF 98.7–98.9ºF 99.0–99.9ºF ≥100.0ºF -20 In the absence of an accurate diagnosis or risk factors, patients can be recommended -20.9% Oropharyngeal colour Normal/pink Slightly red Red Beefy red Table 3. Baseline demographics and characteristics -25 symptomatic treatments instead of antibiotics and be re-assessed if the condition does Size of tonsils Normal/ Slightly Moderately Much not improve or worsens Characteristic Flurbiprofen Placebo Overall -30 absent enlarged enlarged enlarged In this study, a single dose of flurbiprofen 8.75 mg lozenge reduced pain by approximately

8.75 mg (n=101) (n=21) (N=122) Mean PID on the STPIS (%) Number of oropharyngeal None Few Several Many -35 -32.8% 17–31% in patients with Strep A and 36–40% in patients without Strep A, consistent with Age, mean (SD), years 19.5 (2.02) 19.6 (1.36) 19.5 (1.92) ** -35.2% 8 enanthems (vesicles, petechiae -40 -37.7% a clinically important change in acute pain or exudates) Female, n (%) 58 (57.4) 13 (61.9) 71 (58.2) Placebo (n=21) Practitioners should consider recommending flurbiprofen 8.75 mg lozenge to adults with TPA total score, mean (SD) 9.8 (2.57) 10.3 (2.82) 9.9 (2.61) Largest size of anterior cervical Normal Slightly Moderately Much Flurbiprofen 8.75 mg (n=101) sore throat, while antibiotics can be reserved for patients with a serious infection or those lymph nodes enlarged enlarged enlarged PAIN, n (%) at increased risk of complications5 Number of anterior cervical Normal Slightly Moderately Greatly No inflammation 0 0 0 lymph nodes increased increased increased PID, pain intensity difference; STPIS, Sore Throat Pain Intensity Scale Mild inflammation 37 (36.6) 7 (33.3) 44 (36.1) **p<0.01 vs. placebo Maximum tenderness of some Not tender Slightly Moderately Very anterior cervical lymph nodes tender tender tender Moderate inflammation 58 (57.4) 14 (66.7) 72 (59.0) Severe inflammation 6 (5.9) 0 6 (4.9) Figure 2. Percentage pain intensity difference in Strep A-positive patients CONCLUSION Study medication TPS, % In the absence of a microbiologically confirmed diagnosis, Patients were randomised to receive one sugar-based flurbiprofen 8.75 mg lozenge or one Moderate 68 (67.3) 8 (38.1) 76 (62.3) Time since dosing (minutes) practitioners should consider recommending non-antibiotic sugar-based matching placebo lozenge Severe 33 (32.7) 13 (61.9) 46 (37.7) 10 3.9% treatments such as flurbiprofen 8.75 mg lozenge for acute STS score, mean (SD) 7.4 (0.97) 7.3 (1.02) 7.4 (0.98) 5 2.7% Study assessments sore throat The practitioner made several assessments at baseline, including: STPIS, mean (SD), mm 73.8 (9.78) 73.8 (9.64) 73.8 (9.71) 0 60 120 180 Clinical Assessment of Strep A Throat (CAST), a categorical scale indicating the likelihood PAIN, Practitioner’s Assessment of Pharyngeal Inflammation; SD, standard deviation; STPIS, Sore Throat Pain Intensity Scale; -5 STS, Sore Throat Scale; TPA, Tonsillo-Pharyngitis Assessment; TPS, Throat Pain Scale of Strep A infection (unlikely, uncertain, likely or very likely) based on six historical -10 features, 16 physical findings and eight symptoms (Table 2) -15 REFERENCES Practitioner’s Assessment of Pharyngeal Inflammation (PAIN), a categorical scale indicating Diagnosis of Strep A -16.8% the extent of pharyngeal inflammation (none, mild, moderate or severe) Using the clinical features on the CAST, the practitioner was uncertain of the diagnosis in -20 1. ESCMID Sore Throat Guideline Group, et al. Clin Microbiol Infect 2012;18(Suppl 1):1–28. 2. Shulman ST, et al. Clin Infect Dis 2012;55:1279–82. Rapid strep tests and throat cultures were conducted at baseline to detect streptococcal throat 69 (56.6%) patients and thought that 30 (24.6%) were unlikely to have Strep A and 23 (18.9%) -25 Mean PID on the STPIS (%) -27.2% 3. Renner B, et al. Inflamm Res 2012;61:1041–52. infections; antibiotics were provided to patients with microbiological evidence of Strep A were likely or very likely to have Strep A (Table 4) -26.9% Placebo (n=3) -30 4. Renner B, et al. Inflamm Res 2013;62:1045–51. (or group C streptococcus [Strep C], if clinically indicated) Strep A was confirmed by throat culture in 18 patients (14.8%) -31.3% Flurbiprofen 8.75 mg (n=15) -35 5. Essack S, Pignatari AC. Int J Clin Pract 2013;67(Suppl 180):4–9. The patients rated throat pain on the Sore Throat Pain Intensity Scale (STPIS; a 100-mm visual Of the 23 considered likely or very likely to have Strep A on the CAST, only 5 (21.7%) had Strep A 6. Schachtel BP, et al. Clin Pharmacol Ther 2002;71:375–80. 7 analogue scale ) at baseline and at 1, 2 and 3 hours post-dose confirmed by throat culture 7. Schachtel BP, et al. Clin Pharmacol Ther 1984;36:151–6. All adverse events (AEs) were recorded Overall, the sensitivity of the CAST was 27.8% and the specificity was 82.7% PID, pain intensity difference; STPIS, Sore Throat Pain Intensity Scale 8. Farrar JT. J Pain Symptom Manage 2003;25:406–11.

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.