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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

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

test for continuous variables and the

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

test

( Tables 2

and

3 )

. In order to compare the subjective estimation of

the therapeutic drug effect between the two study groups,

again the

test was used. A

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 (

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 (

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

(

0.001)

( Table 3 )

. However, the total improvement was

significantly stronger in the esomeprazole group (

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

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

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