GSK Medicine: Study Number: Title: Rationale: Phase: Study Period Study Design: Group 1 (Test Group) Group 2 (Reference group):

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in the country. GSK Medicine: Mouthwash containing0.2 % weight by volume (w/v) of Chlorhexidine digluconate Study Number: Title: A clinical study to evaluate the efficacy of pre-procedural and pre-surgical rinsing with an antimicrobial agent in reducing bacteria in dental aerosols and in the oral cavity. Rationale: The microbiological sampling was being investigated in this study to show the effect of a Chlorhexidine digluconate mouthrinse on the organisms contained within dental aerosols and on the total number of plaque bacteria in the mouth 1, 3 and 7 days post implant surgery. The aim of this study was to investigate the effect of a Chlorhexidine digluconate mouthrinse on the organisms contained within dental aerosols and on the total number of plaque bacteria in the mouth 1, 3 and 7 days post implant surgery. Phase: Phase 4 Study Period: 26-Feb -15 to 29-Feb-16 Study Design: This was a single centre, examiner blind, randomised, controlled, two treatment, parallel group study which consisted of 6 Visits: Visit 1 (Screening), Visit 2 (Baseline), Visit 3 (Surgery) Visit 4 (Day 1 Post-surgery), Visit 5 (Day 3 Post -surgery) and Visit 6 ( Day 7 Post-surgery). At the Screening (Visit 1), subjects were evaluated for suitability to participate in the study based on stated inclusion and exclusion criteria. Subjects also underwent a gross Oral Soft Tissue (OST) examination followed by an Oral Hard Tissue (OHT) examination. For eligible subjects, the microbiological sample sites and surgical site (the planned sampling site if two implants were being placed) were identified, and subjects were then invited to attend a Baseline visit (within 12 weeks of the Screening visit). Eligible subjects abstained from brushing over a 12 hour period (-2 hours, + 5 hours) prior to the Baseline visit (Visit 2). At the Baseline visit (Visit 2), OST and OHT examinations were carried out and then the initial plaque sample collection was undertaken at the previously identified microbiological sample sites. Microbial plaque sampling was done and subjects also provided an unstimulated 1 millilitre (ml) sample of saliva. The microbiological sampling site consisted of the surgical site, a site contralateral to the surgical site (or an adjacent tooth if the contralateral site also required an implant), and the tongue. These sites were used for microbiological sampling throughout the entirety of the study. For the microbial plaque sampling an individual cotton swab was used at each identified site for up to 20 seconds in order to harvest a plaque sample and was immediately placed into 1 ml phosphate buffered saline in a sterile Eppendorf tube. Plaque and saliva samples were stored at -70 degrees centigrade ( C) prior to processing. Deoxyribonucleic acid (DNA) extraction was carried out and then the samples were analysed using two different methods at the end of the study: qpcr technique was used to determine the total number of bacteria in the plaque samples. Next generation sequencing was performed on an Illumina (MiSeq) platform using the 16S rrna gene as target to determine the richness of bacteria present in the saliva samples. After microbial sampling, subjects were randomised to their allocated treatment group: Group 1 (Test Group): 0.2% w/v Chlorhexidine digluconate mouthrinse pre-procedurally(dental prophylaxis) and two weeks brushing and rinsing (mouthwash containing 0.2% w/v Chlorhexidine digluconate) prior to surgery Group 2 (Reference group): Two weeks brushing (toothpaste containing sodium fluoride)only prior to surgery All subjects were provided with a standard toothpaste and toothbrush for brushing once (as a supervised brush following the dental prophylaxis), and for use twice daily at home throughout the study. Subjects randomised to the Group 1 then had a supervised product rinse (mouthwash containing 0.2% w/v Chlorhexidine digluconate) as a preprocedural (dental prophylaxis) rinse immediately prior to undergoing the procedure (subjects were monitored for up 1

2 to 20 minutes post-rinse during the dental prophylaxis to monitor any adverse events (AEs) or any hypersensitivity to treatment product). Thirty (30) minutes before the subjects had their dental prophylaxis, a total of 5 bacterial settle plates with lids removed were placed at set positions around the dental surgery. The lids were replaced on the plates after 30 minutes. Prior to starting the dental prophylaxis, 5 fresh settle plates were placed at the same set positions around the dental surgery. When the dental prophylaxis commenced, the lids were taken off the plates to allow bacteria to settle. After 30 minutes (regardless of whether the prophylaxis procedure had completed or not) the plates had their lids replaced. All plates were incubated at 37 C for 3 days aerobically and inspected daily to assess growth (check for overgrowth) and after 3 days removed and stored at 4 c for subsequent colony enumeration and colony forming unit/ml (CFU/ml) calculation. There was a minimum 14 day (maximum 16 day) treatment period using the supplied product(s) between the Baseline visit and implant surgery visit. Prior to the implant surgery visit (Visit 3), subjects abstained from brushing over a 12 hour period (-2 hours, +5 hours). At this visit subjects were asked to return their study products and underwent OST examination. Plaque samples at the specified locations and a 1mL unstimulated saliva sample were taken prior to a pre-surgery rinse of Chlorhexidine digluconate mouthrinse. All subjects were then provided with a single dose of 0.2% w/v Chlorhexidine digluconate mouthrinse to use for one timed minute immediately prior to undergoing the surgery. Repeat plaque samples were then taken immediately prior to surgery commencing, during surgery (immediately after the implant(s) had been placed), and immediately post surgery completion (once the surgical site has been closed using sutures). In addition, a 1mL unstimulated saliva sample was collected immediately prior to surgery commencing and immediately post surgery completion. All subjects were then provided with 0.2% w/v Chlorhexidine digluconate mouthrinse and standard toothpaste to be used for the remainder of the study. Subjects were asked to return to site after 1 day (Visit 4), 3 days (Visit 5) and 7 days (Visit 6) post surgery. They were asked to abstain from brushing over a 12 hour period (-2 hours, + 5 hours) prior to each study visit. At each visit subjects provided plaque samples and a 1mL saliva sample, and underwent an OST examination. At the end of all study procedures at the final visit (Visit 6), subjects were offered optional dental prophylaxis to remove any extrinsic stain caused by product use. Subjects were asked to return all study products at the final visit. AEs were recorded throughout the study, and incidents from the start of surgery at visit 3. Centre: 1, United Kingdom Indication: Dental Plaque Treatments: Test Product: Mouthwash containing 0.2% (weight/volume) w/v Chlorhexidine digluconate. Supervised use at site: Subjects rinsed for one timed minute with 10mL of mouthwash. No brushing took place prior to using the mouthwash. Home use: Subjects applied a strip of toothpaste to cover the head of the toothbrush and brushed in their usual manner for two timed minutes twice daily (morning and evening). After 5 timed minutes, subjects rinsed their mouth for one timed minute with 10mL of mouthwash. Reference Product: Standard toothpaste containing sodium fluoride Subjects applied a strip of toothpaste to cover the head of the toothbrush and brushed in their usual manner for two timed minutes twice daily (morning and evening). They then rinsed their mouth thoroughly with water after brushing. Objectives: Primary Objective: To evaluate and compare the effect of two week pre-surgical rinsing with an antimicrobial mouthrinse containing 0.2% weight/volume w/v Chlorhexidine digluconate in addition to brushing, versus brushing alone on the total number of plaque bacteria in the mouth 3 days post implant surgery. Primary Outcome (Endpoint): Total number of detectable plaque bacteria sampled 3 days post implant surgery Secondary Outcome (Endpoint): 2

3 1. Total number of detectable plaque bacteria sampled at implant surgery (at pre, mid and post implant) and post implant surgery (at Day 1 and 7) 2. Area under the curve (AUC) for the total number of plaque bacteria in the mouth post implant surgery 3. Total Number of recoverable viable bacteria in the aerosol generated during dental prophylaxis Statistical Methods: The primary population for efficacy assessment was the intent-to-treat (ITT) population. The total number of detectable bacteria in the mouth were log-transformed and then analysed using analysis of covariance (ANCOVA) at each assessment time around implant surgery and post-implant surgery with treatment regimen as factor and baseline level as covariate. The (AUC) of detectable bacteria in the mouth post implant surgery was calculated (including immediately postsurgery sample, 1 day, 3 days and 7 days post-surgery samples). Log scale AUC was analysed using ANCOVA with treatment regimen, as factor and baseline level as covariate. Adjusted means (log scale) of the two treatment regimens and the standard errors were provided. Treatment difference together with the 95% CI (confidence internal) and p-value were presented. The level of recoverable viable bacteria in the aerosol generated during dental prophylaxis at Baseline visit (aggregate across all settle plates) was log transformed and analysed using ANCOVA with treatment and dental room as factors and the level prior to dental prophylaxis (settle plate aggregate) and subjects baseline preprophylaxis bacterial level as covariates. Study Population: Subject Disposition (All randomized Subjects: N=38) Subjects Randomized, N 19 (100.0) 19 (100.0) Subjects completed study, n 19 (100.0) 17 ( 89.5) (%) Subject did not complete the 0 2 ( 10.5) study, n (%) Other (reason not specified) 0 2 ( 10.5) Demographics (Safety Population, N=38) Treatments Sex, n (%) Females: Males 9 (47.4): 10 (52.6) 10 (52.6): 9 (47.4) Mean Age, years (SD) 27.5(8.74) 28.4(12.23) Race n (%) Asian 1 (5.3) 1 (5.3) Black or African American 0 4 (21.1) White 18 (94.7) 14 (73.7) Primary outcome Results (ITT population, N=38) Table 1: Analysis of Plaque Bacteria Counts (log-scale) at Day 3 Treatments N=19 Reference Product N=19 Day 3 n* Mean (SD) 7.63 (0.501) 7.43 (0.598) Treatment Comparison [1] ( (vs.) ) Difference (CI) [2] 0.20 ( ) p-value [1] From ANCOVA analysis on log-transformed data with treatment as factor and baseline as covariate. 2] Difference is first named treatment minus second named treatment such that a negative difference favors the first named treatment. 3

4 Secondary Outcome Results (ITT, N=38) Table 2: Analysis of Plaque Bacteria Counts (log-scale) at implant surgery ( pre, mid and post implant) and post implant surgery (Day 1 and 7) Treatments At Day 0, Pre-Implant n* Mean (SD) 7.65 (0.375) 8.01(0.381) Treatment Comparison [1] ( vs.- ) Difference (CI) [2] (-0.62, -0.11) p-value At Day 0, Mid-Implant n* Mean (SD) 7.58(0.449) 7.84(0.597) Treatment Comparison [1 ( vs. )) Difference (CI) [2] (-0.61, 0.10) p-value At Day 0, Post- Implant n* Mean (SD) 7.58(0.429) 7.81(0.433) Treatment Comparison [1] ( vs. ) Difference (CI) [2] (-0.52, 0.06) p-value Day 1 n* Mean (SD) 7.44(0.409) 7.06(0.470) Treatment Comparison [1] ( vs. ) Difference (CI) [2] 0.39 (0.09, 0.69) p-value Day 7 n* Mean (SD) 7.72(0.335) 7.38(0.512) Treatment Comparison [1] ( vs. ) Difference (CI) [2] 0.34 (0.05, 0.63) p-value [1] From ANCOVA analysis on log-transformed data with treatment as factor and baseline as covariate. [2] Difference is first named treatment minus second named treatment such that a negative difference favors the first named treatment. Table 3: Analysis of Post-Surgery Bacteria Counts area AUC (log-scale) Treatments n* Mean (SD) 8.57(0.319) 8.37(0.356) Treatment Comparison [1] ( vs. ) Difference (CI) [2] 0.20 (-0.02, 0.43) p-value [1] From ANCOVA analysis on log-transformed data with treatment as factor and baseline as covariate. [2] Difference is first named treatment minus second named treatment such that a negative difference favors the first named treatment. Table 4: Analysis of Aerosol Bacteria Counts (log-scale) Treatments Pre Prophylaxis n*

5 Mean (SD) 0.94 (0.435) 0.91 (0.606) Post Prophylaxis n* Mean (SD) 1.31 (0.201) 1.33 (0.326) Treatment Comparison [1] ( vs. ) Difference (CI) [2] 0.00 (-0.18, 0.18) p-value [1] From ANCOVA with treatment and dental room as factors and pre-prophylaxis count and baseline plaque bacteria count as covariates. [2] Difference is first named treatment minus second named treatment such that a negative difference favors the first named treatment. Table 5: Adverse Events (AE s) Number of subjects with at least 17 ( 89.5) 18 ( 94.7) one AE, n(%) Number of subjects with No AE, n(%) 2 ( 10.5) 1 ( 5.3) Injury, poisoning and procedural complications Post procedural discomfort 16 ( 84.2) 15 ( 78.9) Procedural pain 2 ( 10.5) 1 ( 5.3) Post procedural complication 1 ( 5.3) 0 Post procedural haemorrhage 1 ( 5.3) 0 Eye contusion 0 1 ( 5.3) Incision site complication 0 1 ( 5.3) Incision site haemorrhage 0 1 ( 5.3) Mouth injury 0 1 ( 5.3) Post procedural swelling 0 3 ( 15.8) Thermal burn 0 1 ( 5.3) Nervous System Disorders Headache 5 ( 26.3) 1 ( 5.3) Ageusia 1 ( 5.3) 0 Dizziness 0 1 ( 5.3) Tongue biting 0 1 ( 5.3) Gastrointestinal disorders Abdominal pain upper 1 ( 5.3) 1 ( 5.3) Dry mouth 1 ( 5.3) 0 Gingival bleeding 1 ( 5.3) 0 Lip exfoliation 1 ( 5.3) 0 Tongue discolouration 1 ( 5.3) 0 Gingival pain 0 1 ( 5.3) Gingival swelling 0 1 ( 5.3) Lip dry 0 1 ( 5.3) Lip swelling 0 1 ( 5.3) Lip ulceration 0 1 ( 5.3) Nausea 0 1 ( 5.3) Oral mucosal erythema 0 1 ( 5.3) Toothache 0 1 ( 5.3) Infections and Infestations Nasopharyngitis 1 ( 5.3) 1 ( 5.3) Oral herpes 1 ( 5.3) 0 Angular cheilitis 0 1 ( 5.3) Tonsillitis 0 1 ( 5.3) General disorders and administration site conditions Injury associated with device 1 ( 5.3) 0 Asthenia 0 1 ( 5.3) 5

6 Fatigue 0 1 ( 5.3) Implant site erythema 0 2 ( 10.5) Implant site haemorrhage 0 1 ( 5.3) Implant site pain 0 1 ( 5.3) Implant site swelling 0 2 ( 10.5) Musculoskeletal And Connective Tissue Disorders Musculoskeletal pain 1 ( 5.3) 0 Pain in jaw 0 1 ( 5.3) Reproductive system and breast disorders Dysmenorrhoea 1 ( 5.3) 1 ( 5.3) Immune System Disorders Seasonal Allergy 0 1 ( 5.3) Renal And Urinary Disorders Urine odour abnormal 0 1 ( 5.3) Respiratory, Thoracic And Mediastinal Disorders Oropharyngeal Pain 0 2 ( 10.5) Skin And Subcutaneous Tissue Disorders Ecchymosis 0 1 ( 5.3) Rash 0 1 ( 5.3) Swelling face 0 3 ( 15.8) Surgical and medical procedures Pain prophylaxis 0 1 ( 5.3) Serious Adverse Events (SAEs) - On-Therapy There were no serious adverse events. 6