1. PRELIMINARY FINDINGS FROM THE FEASIBILITY STUDY FOR A RANDOMISED CONTROLLED TRIAL OF CLARITHROMYCIN IN CHRONIC RHINOSINUSITIS
J Bewick, L Masterson, S Carrie, V S Sunkaraneni, S K Ahmed, A Sama, C Hopkins & C Philpott
Presenter: J Bewick, James Paget University Hospital,
INTRODUCTION
METHODS
RESULTS
DISCUSSION
There is currently conflicting level 1 evidence in the use of long-term antibiotics for chronic rhinosinusitis without nasal polyps (CRSsNPs). Macrolide use in chronic panbronchiolitis significantly improved survival but also improved the CRS symptoms thought in part to be due to its immunomodulatory effect.
Large RCTs in respiratory medicine showing benefit are available and EPOS 2012 recommended similar sized studies in CRS patients to evaluate effect. Many non-controlled trials have shown a reduction in symptoms on low-dose therapy1. 2 RCTs are available to date and show conflicting evidence. Wallwork3 showed statistically significantly symptom improvement in the CRS group (with Roxithromycin) particularly when IgE levels were not elevated (correlates with work by Suzuki2). Later work by Videler4 using Azithromycin did not show a significant effect. In the latter group a mixed with/without nasal polyps cohort was used leading to speculation that there was higher levels of IgE and hence less benefit seen.
Further RCT research is required to clarify which patient groups benefit to avoid drug side affects and potential bacterial resistance. The primary aim of this study was to assess recruitment and retention of patients for a formal RCT as well as provide preliminary data on symptomatic improvement. This study was funded by the Royal College of Surgeons through a pump priming grant and was included on the NIHR portfolio
Participants were recruited in 6 UK centres:
James Paget University Hospital, Great Yarmouth
Guys & St Thomas Hospital, London
Royal Surrey County Hospital, Guildford
Queens Medical Centre, Nottingham
Freeman Hospital, Newcastle
Queen Elizabeth Hospital, Birmingham
The study aimed to recruit 50 patients during Following recruitment from clinic patients meeting the inclusion criteria participated in the study protocol outlined in figure 1.
Inclusion criteria
Chronic rhinosinusitis without Nasal Polyps
Age over 16 and less than 70
Maximal medical therapy not previously tried
Exclusion criteria
Nasal polyps/Allergic fungal rhinosinusitis/other inflammatory conditions affecting the sinonasal tract/Immunodeficiency/Contraindication to clarithromycin
The study primarily sought to assess the feasibility of conducting a larger RCT according to the protocol although some preliminary data is also presented.
Primary outcomes measures
Number of patient recruited over time
Compliance with assessments and treatment
Time taken to perform assessments
Loss to follow-up
Over 13 months, 52 adults participated from 4 centres
Patients declining entry
Four patients declined participation due to travelling time
Four at a 6th centre due to estimated visit duration.
Dropouts
Two unable to take medication, 1 did not attending 3-month appointment and 1 patient withdrew (reason unknown).
Compliance
Clarithromycin contraindicated in 1 patient; adverse reaction in 1 patient after 5 weeks; 1 patient unable to tolerate
Incorrect Recruitment
Six patients were over the age of 70 when recruited
Assessment tools.
Visits took between minutes, patient feedback in Table 1
Questionnaire return rates were good (44 to date at 12 weeks). Initial clinical investigation (e.g. Saccharin test, rhinomanometry, Sniffin’ Sticks) at visit 1 was also good but less good at subsequent visits (see Table 2). Adherence to the study protocol varied between centres.
Preliminary results
Paired t-tests on preliminary data showed mean SNOT-22 scores improved at 3 months sustained at 6 months (Table 3). A clinically significant (≥9) point reduction in SNOT-22 scores at 3 months was seen in 50% and was higher in the IgE positive patients (Table 3, although low numbers of patients overall). Nine patients listed for surgery to date.
The results show that patients are willing to participate, comply with medication and adhere to study protocol and hence a full RCT is feasible. Retention rates of 96 % were achieved. Compliance rates with medication was good and on the whole many patients viewed participations in the study as a positive action.
As would be expected there are issues which need to be taken into account when conducting a larger study. These focus on:
Technical issues with the tools used
Disparity between study centres
An abundance of older patient over 70 years (should the inclusion criteria be revised?)
Need for training and a central research nurse lead
Resources to ensure CT scans are performed at appropriate intervals
With some revision of the protocol and implementation of training recruitment to a larger RCT will become more realistic.
Table 2
Clinical test
Completion rate Visit 1
Completion rate Visit 2
Saccharin 50 42
Sniffin’ Sticks 46
16 (at least 5 due to technical problems)
IgE
n/a
Table 1 Patient feedback (15 interviewed to date after 6 months in trial)
11 – ‘no negative aspects’
1 – discomfort with saccharin tablet
1 - said the ‘sniffin sticks’ made her feel light-headed
1 patient said ‘a positive aspect was feeling as though they have helped other people by participating in research’
1- incorrect prescription given
1- not informed to continue Nasonex/douching when completed antibiotics
1- ‘CT before and after would be better’
1- felt longer follow-up incorporating each season would be better
REFERENCES
1.Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps A summary for otorhinolaryngologists. Rhinology. 2012;50(1):1-12.
2.Suzuki H, Ikeda K, Honma R, Gotoh S, Oshima T, Furukawa M, et al. Prognostic factors of chronic rhinosinusitis under long-term low-dose macrolide therapy. ORL J Otorhinolaryngol Relat Spec. 2000;62(3):121-7.
3.Videler WJ, Badia L, Harvey RJ, Gane S, Georgalas C, van der Meulen FW, et al. Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial. Allergy. 2011;66(11):
4.Wallwork B, Coman W, Mackay-Sim A, Greiff L, Cervin A. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope. 2006;116(2):
5. Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009;34(5):
Figure 1 Visit: 1 Prior to starting medication
CT sinuses, Nasal Endoscopy, Saccharin test, Sniffin’ Sticks, IgE level, RAST
Questionnaires SNOT-22, SF-12, EQ-5D
Intervention – 12 weeks course
Clarithromycin 250mg bd orally
Nasonex (mometasone) nasal spray 2 squirts bd both nostrils; Neil Med rinse bottle and sachets bd
Visit 2: At 12-weeks after starting medication
Nasal Endoscopy/Saccharin/Sniffin’ Sticks test
SNOT-22, SF12/ EQ-SD
Return to normal clinical pathway
Visit 3: At 12-weeks after stopping medication
(Postal and phone correspondence)
SNOT-22, SF12, EQ-SD and invite personal feedback comments
Table 3
a) SNOT 22 outcomes
Number of patients
Pre –treatment SNOT 22 score
Post-treatment SNOT 22 score
P-value
SNOT 22 (12 week) 44
39.75
32.32
0.007
SNOT 22 (6 months) 28
39.29
32.54
0.055
b) IgE levels
Reduction in SNOT 22 score of >9 at 3 months
IgE positive 10
7 (70%)
IgE negative 31
13 (42%)