HSC Section 6 Nov2016 Green Book

Reichel et al Double-blind, placebo-controlled trial with . . .

exclusion criteria included age younger than 18 years, a history of laryngeal malignancy or gastrointestinal surgery, and the need for continuous therapy with warfarin, couma- rin, or acetylsalicylacid. No patient with a clinically signif- icant condition that could put the patient at risk, affect the patient’s ability to participate in the study, influence the trial results, or necessitate surgery during the study was in- cluded. Patients with a contraindication to esomeprazole (eg, known or suspected hypersensitivity or allergy to es- omeprazole or other PPIs) or participants of another inves- tigational drug study in the past 30 days were excluded from participation. No pregnant or lactating women were en- rolled, and in case of childbearing potential, effective con- traception had to be maintained. Finally, patients with drug or alcohol addiction or with any psychiatric disease were not allowed to participate in the study. Study Procedures Patients passing all inclusion and exclusion criteria were then sequentially randomized in a 1:1 ratio to receive either coated tablets of esomeprazole 20 mg (twice daily, 30 min- utes before meals) or a placebo tablet indistinguishable from the esomeprazole tablet ( Fig 1 ). Both esomeprazole and placebo were given for a total of three months and were supplied in four small plastic bottles, each containing 48 tablets. Esomeprazole and placebo were provided by Astra- Zeneca (Wedel, Germany), and Astra-Zeneca also per- formed the randomization. Patients and investigators were blinded as to the medication randomization. Enrolled pa- tients did not receive any instructions regarding lifestyle modifications to reduce acid reflux like avoidance of fatty meals or caffeine. However, all included subjects were explicitly instructed to take the medication with water at least 30 minutes before morning and evening meals. The RFS was readministered six weeks and three months after the start of treatment by the same otolaryngologist by la- ryngoscopy and each patient filled in the RSI questionnaire on these two follow-up visits. The primary objective of the study was the comparison of the total RSI and RFS after a treatment period of three months. At the final visit all patients completing the trial were additionally asked if they thought that therapy had completely resolved their com- plaints (possible answers were “yes” or “no”). In order to check for compliance with treatment, pill counting was performed at each visit. It was considered adequate if 75% or more of the treatment medication was taken. If one or more study medication bottles were not returned, compli- ance was not calculated. Statistical Analysis For sample size calculation we assumed that a typical LPR- associated subscore (eg, posterior commissure hypertrophy) would improve by at least one point in 65% of the PPI group and in 30% of the placebo group. For comparison of those two proportions in independent samples, a sample size of 31

patients per treatment group was calculated (two-tailed z test with alpha 0.05, power 80%, and accounting for a 10% drop-out rate). Baseline characteristics of both groups were reported as mean values and standard deviations (SD) or proportions and compared using the Mann-Whitney U test for continuous variables and the 2 test for categorical variables ( Table 1 ). Treatment or placebo effects after six weeks and three months were reported as mean differences and standard errors (SEM) from baseline and were tested using Wilcoxon signed rank tests ( Tables 2 and 3 ). Differ- ences in mean changes between esomeprazole and placebo were additionally tested using Mann-Whitney U test ( Tables 2 and 3 ). In order to compare the subjective estimation of the therapeutic drug effect between the two study groups, again the 2 test was used. A P value 0.05 was considered statistically significant. The statistical analyses were done with SPSS 14.0 for windows (version 14.0.1; SPSS Inc, Chicago, IL). Role of the Funding Source Astra-Zeneca had no involvement in the study design, col- lection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publi- cation. RESULTS Fifty-eight patients completed the study; the drop-out rate was low with 6.5%. Thirty patients received esomeprazole and the control group consisted of 28 individuals ( Fig 1 , Table 1 ). Baseline characteristics between the two study groups were comparable. This was also true for all respec- tive subscores of both RSI and RFS. Compared to baseline, the total RSI and RFS were sig- nificantly reduced in both study groups after a treatment period of six weeks ( Table 2 ). However, differences in total scores between the esomeprazole and placebo group were not statistically significant. The only symptom with a sta- tistically significant decrease for the esomeprazole group was heartburn ( P 0.05). When the differences in laryn- geal findings found after six weeks of treatment were com- pared for the two study groups, only diffuse laryngeal edema showed a significantly stronger improvement with esomeprazole ( P 0.05). For ventricular obliteration and laryngeal erythema a nonsignificant trend for better im- provement in the esomeprazole group was found. At the final visit, patients of both study groups again reported on an improvement of symptoms, reflected by a highly significant reduction from baseline of the total RSI ( P 0.001) ( Table 3 ). However, the total improvement was significantly stronger in the esomeprazole group ( P 0.05). While in esomeprazole recipients a highly significant reduc- tion for each single item of the RSI was evident, no signif- icant improvement from baseline for swallowing difficul- ties, coughing after meals, or heartburn was found in the

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