(ii) Control Strip- Placebo nasal strip to be applied for up to two hours in either of the first two scans only.

Transcription

1 GSK Medicine: Nasal strip Study Number: Title: A Magnetic Resonance Imaging Study of Nasal strips in Subjects with Nasal Congestion Rationale: The aim of the study was to evaluate the effect of the test nasal strip (relative to the placebo strip) on the nasal passages using anatomical magnetic resonance imaging (MRI) scans and to demonstrate the effect of the strip on breathing correlated cortical activity, using interoceptive functional MRI (fmri) task and analysis techniques derived from physiological data collected during scanning. Phase: IV Study Period: 05-Aug-2013 to 30- Oct-2013 Study Design: This was a single-centre, evaluator-blind (blinded to the person analysing the MRI data), and crossover exploratory study assessing the effect of the application of test nasal strip with structural and fmri. The study also investigated the effect of administering a decongestant prior to application of the test nasal strip by structural MRI. The study consisted of a screening period followed up by an evaluation period within 14 days of the screening period. The Evaluation visit consisted of three MRI scanning sessions on the same day. The order of the two initial MRI scanning sessions (participants were randomized to receive either test nasal strip or placebo strip for the first scan and then reversed for the second scan) and the third scanning session (Decongestant + test strip for all participants) was evaluator-blinded. Centres: 1, UK Indication: Nasal congestion Treatment: (i) Test Strip- Marketed Nasal Strip to be applied for up to two hours, and during the third scanning session for approximately 20 minutes (mins). (ii) Control Strip- nasal strip to be applied for up to two hours in either of the first two scans only. (iii) Decongestant spray- Nasal decongestant was administered (one spray per nostril) by the participants 20 mins (+/- 5mins) prior to the third MRI scanning session The nasal strips either test or placebo were applied to the participants by the investigator/designee, ensuring that the strips were placed correctly for the whole measurement period. Objectives (s): Primary objective: To demonstrate the effect of the test nasal strip (relative to the placebo nasal strip) on the nasal passages using anatomical magnetic resonance imaging (MRI) scans. To demonstrate the effect of the test nasal strip (relative to the placebo nasal strip) on breathing-correlated cortical activity, using an interoceptive functional MRI (fmri) task and analysis techniques derived from physiological data collected during scanning. Secondary objective: To demonstrate the effect of the test nasal strip (relative to the placebo nasal strip) on interactions within and between the brain s major networks, using resting-state fmri and analysis techniques derived from physiological data collected during scanning. To demonstrate the adjunctive effect of the decongestant and test nasal strip (relative to the placebo nasal strip) on the nasal passages using anatomical MRI scans. 1

2 Primary Outcome/Efficacy Variable: Anatomical Measures : Area Functional brain activity Secondary Outcome/Efficacy Variable(s): Breathing-related cortical activity Brain functional connectivity Physiological measures Statistical Methods: All participants who were dispensed with the study treatment were considered evaluable for the safety population. The analysis population was the per protocol (PP), and included all sessions (session or period level) that were successfully completed with no protocol violations, on the single visit day. Efficacy of the test nasal strip was demonstrated by significant differences in comparison with a placebo nasal strip based on MRI data. A mixed model analysis of variance (ANOVA) with treatment and period as fixed effects and participants and random effect was used for anatomical measures (Area and Volume); cerebral blood flow using arterial-spin labelling (CBF_ASL); blood oxygen level dependent in functional connectivity (BOLD_RS_FC); blood oxygen level dependent using interceptive actions (standard analysis (BOLD_IA) and psychophysiological interactive analysis. The significance level for all tests was the 2-sided 5% (P 0.05). Ninety five percent confidence intervals (CI) were constructed for adjusted means and differences (Adj diff.) between them. Study Population: Overall Number of Subjects Screened: 35 Randomized, N 28 Completed, n (%) 26 (92.9) Total Number Subjects Withdrawn, N (%) 2 (7.1) Withdrawal of consent, n (%) 1 (3.6) Withdrawn for other reasons, n (%) 1 (3.6) Demographics N (Safety Population) 28 Females: Males 9 (32.1): 19 (67.9) Mean Age, years (SD) 33.0 (10.98) Race, n (%) Asian Black or African American White 9 (32.1) 7 (25.0) 12 (42.9) 2

3 Primary Efficacy Results: Table 1. Anatomical Measures (Area and Volume)-PP Population MRI variable Test nasal strip CSA* (mm 2 ) (28.946) (31.468) Adj diff (95%CI) (12.32, 18.25) P- value 2 < Decongestant (29.103) Decongestant + Test nasal strip (29.370) VOL_S* (mm 3 ) ( ) ( ) Adj diff (95%CI) (794.16, ) P- value VOL_M* (mm 3 ) (399.95) (406.76) Adj diff (95%CI) (-78.62, ) ( ) (449.52) ( ) ( ) P- value *CSA=Cross Sectional Area, VOL_S=Single volume reading, VOL_M = multiple volume readings, mm= millimeter [1] ADJ DIFF is the Treatment difference defined as the Adjusted Mean of BRNS minus Adjusted Mean of. [2] Obtained from ANOVA model with Treatment and Period as fixed effects and subject as a random effect. Table 2. Cerebral Blood Flow Using Arterial-Spin Labeling: PP Population Cerebral Blood Flow (ml/100g/min) (23.351) Adj diff (95%CI) (-3.06, 2.14) (20.079) P- value [1] Adj Diff is the treatment difference defined as the adjusted mean of test nasal strip minus adjusted mean of placebo. 3

4 Table 3. Blood Oxygen Level Dependent-Interoceptive Actions (BOLD_IA) (All ROI): PP Population BOLD_IA (% signal Change) 7.39 (9.858) 7.92 (8.246) Treatment difference Adj diff (95%CI) (-6.43, 4.57) P- value BOLD_IA_PPI 0.13 (0.12) 0.12 (0.16) Adj diff (95%CI) (-0.03, 0.07) P- value [1] Adj diff is the Treatment difference defined as the adjusted mean of test nasal strip minus adjusted mean of placebo. ROI: Region of interest PPI: Psychophysiological interactive Secondary Outcome Results Table 4. Blood Oxygen Level Dependent-Interoceptive Actions (All ROI): PP Population BOLD_RS_FC 0.42 (0.261) 0.33 (0.249) Adj diff (95%CI) (-0.00, 0.17) P- value BOLD_RS_ER (% signal Change) (40.038) (43.793) Adj diff (95%CI) (-1.71, 31.96) P- value [1] Adj diff is the Treatment difference defined as the adjusted mean of test nasal strip minus adjusted mean of placebo. RS: Resting state FC: Functional connectivity ER: Event related 4

5 Table 5. Summary of Verbal Numerical Response (VNR) Over Time (study part 1) Baseline VNR 5.08 (1.495) 4.82 (1.492) Immediate Change (1.067) Change from Baseline 2 P= Adj diff (95%CI) (-0.76, 0.03) P- value Minute Change (1.296) Change from Baseline 2 P= Adj diff (95%CI) (-1.47, 0.35) (0.900) P= (1.629) P= P- value [1] P-value is for testing the treatment difference between test nasal strip and placebo strip [2] Immediate change from baseline was after application of test nasal strip /placebo and 30 minute change from baseline was 30 minutes after application of test nasal strip /placebo All values are in mean (SD) Table 6. Summary of Verbal Numerical Response (VNR) Over Time (study part 2) Decongestant + Mean (SD) Baseline VNR (before decongestant spray) 4.27 (1.888) Immediate change (from Baseline) (20 minutes after decongestant spray) change (from Baseline) (after test nasal strip was added to decongestant spray) Safety Results: There were no reported adverse events in this study (1.522) (1.436) 5