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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
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 2and
3 ). Differ-
ences in mean changes between esomeprazole and placebo
were additionally tested using Mann-Whitney
U
test
( Tables 2and
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
Reichel et al Double-blind, placebo-controlled trial with . . .
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