ADULT UROLOGY

EFFICACY AND SAFETY OF TADALAFIL 5, 10, AND 20 mg

IN JAPANESE MEN WITH ERECTILE DYSFUNCTION:
RESULTS OF A MULTICENTER, RANDOMIZED,
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
KOICHI NAGAO, YASUSUKE KIMOTO, KEN MARUMO, AKIRA TSUJIMURA, G. MATTHEW VAIL,
STEVEN WATTS, NOBUHISA ISHII, AND SADAO KAMIDONO

ABSTRACT
Objectives. To investigate the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in
Japanese men with erectile dysfunction (ED).
Methods. This multicenter, randomized, double-blind, placebo-controlled, 12-week study enrolled 343 Japa-
nese men with ED. The men were stratified into those with mild, moderate, or severe ED and then randomly
assigned 1:1:1:1 to placebo and 5 mg, 10 mg, and 20 mg tadalafil. Co-primary outcomes were the International
Index of Erectile Function erectile function domain score, the percentage of “yes” responses to the Sexual
Encounter Profile Diary Questions 2 and 3, and tolerability. Secondary outcomes included the International Index
of Erectile Function intercourse satisfaction and overall satisfaction domain scores and the percentage of “yes”
responses to a global assessment question.
Results. The least square mean change from baseline was 7.5, 9.1, and 9.4 for 5, 10, and 20 mg tadalafil versus 2.1
for placebo for the International Index of Erectile Function erectile function domain; 28.5, 36.0, and 36.5 for 5, 10,
and 20 mg tadalafil versus 8.6 for placebo for Sexual Encounter Profile question 2; and 34.3, 47.3, and 50.8 for 5,
10, and 20 mg tadalafil versus 12.3 for placebo for Sexual Encounter Profile question 3, respectively (P ⬍0.001 for
all doses and all measures). Patients taking tadalafil had significantly greater changes from baseline for the intercourse
satisfaction and overall satisfaction domains compared with patients taking placebo (P ⬍0.001). Also, 76.5%, 81.4%,
and 83.7% of patients taking 5, 10, and 20 mg tadalafil, respectively, reported improved erections (global assessment
question) versus 31.4% of patients taking placebo (P ⬍0.001). Most (98%) treatment-emergent adverse events were
mild or moderate in severity. One patient (tadalafil 5 mg) discontinued because of an adverse event (ureteral calculus).
Of the 343 patients, 302 (88%) completed the study. No deaths were reported.
Conclusions. All doses of tadalafil studied were efficacious and well tolerated in Japanese men with ED. UROLOGY
68: 845–851, 2006. © 2006 Elsevier Inc.

E rectile dysfunction (ED) is defined as the in-

ability to achieve and maintain an erection ad-
equate for satisfactory sexual performance,1 and
about 150 million men worldwide, including 11
million men in Japan, have ED.2,3 Among Japanese
men 31 to 70 years old, 1.74 million have complete
ED and 8 million have moderate ED.2
The understanding of ED changed in 1992 with
the discovery that the nitric oxide-cyclic guanosine
monophosphate pathway plays a key role in erec-

This study was supported by Lilly Research Laboratories, Eli Lilly
and Company (Study identifier H6D-MC-LVDI).
K. Nagao and K. Marumo are study investigators partially funded by,
and members of the medical advisory board for, the sponsor; and are
study investigators partially funded by Pfizer and Bayer. Y. Kimoto is a
study investigator partially funded by, and is a member of the medical
advisory board for, the sponsor; is a study investigator partially funded
by Pfizer; and is a paid consultant to Pfizer and Bayer. A. Tsujimura is a
study investigator partially funded by the sponsor and Bayer and is a
paid consultant to Pfizer and Bayer. G. M. Vail and S. D. Watts are
employees of, and hold stock in, the sponsor. N. Ishii is a member of the
medical advisory board for the sponsor; and is a paid consultant to, and
study investigator partially funded by, Pfizer and Bayer. S. Kamidono is
a member of the medical advisory board for the sponsor; is a paid con-
sultant to Pfizer; and is a study investigator partially funded by Bayer.
From the Department of Urology, Toho University School of Medi-
cine, Tokyo; Department of Urology, Spinal Injuries Center, Fukuoka;
Department of Urology, Tokyo Dental College, Ichikawa General Hos-
pital,Chiba;DepartmentofUrology,OsakaUniversityGraduateSchool
of Medicine, Osaka, Japan; Lilly Research Laboratories, Indianapo-
lis, Indiana; and Kobe University, Hyogo, Japan
Reprint requests: G. Matthew Vail, M.D., Lilly Corporate Center,
Drop Code 6063, Eli Lilly and Company, Indianapolis, IN 46285. E-
mail: vailge@lilly.com
Submitted: December 15, 2005, accepted (with revisions): May
1, 2006

© 2006 ELSEVIER INC. 0090-4295/06/$32.00

ALL RIGHTS RESERVED doi:10.1016/j.urology.2006.05.001 845
tile function and defects in the pathway may cause
ED.4,5 This discovery triggered the development of
oral inhibitors of phosphodiesterase type 5 for ED,
including sildenafil citrate, tadalafil, and vardenafil
HCl.6 – 8
Tadalafil is approved for ED in more than 90
countries worldwide, including France, the United
States, Brazil, and China. Tadalafil is unaffected by
food intake and has a mean plasma half-life of 17.5
hours.9,10 Tadalafil 10 and 20 mg is efficacious in
men of different ethnicities with mild to severe or-
ganic, psychogenic, and mixed ED for up to 36
hours after administration.11–13
The purpose of the present study was to charac-
terize the efficacy and safety of tadalafil in Japanese
men with ED when taken on demand at doses of 5,
10, and 20 mg for 12 weeks.
MATERIAL AND METHODS
PATIENTS
Men aged 20 years or older, who were in a monogamous
relationship with a female partner, and had a 3-month or
longer history of ED, were enrolled at 34 investigation sites in
Japan. The men entered a 4-week run-in period, agreeing to
make at least four intercourse attempts and to not use any
other ED therapy. All patients provided written informed con-
sent before enrollment in compliance with the International
Conference on Harmonization Guidelines on Good Clinical
Practice. In addition, the appropriate institutional ethical re-
view boards approved the protocol.
The exclusion criteria were as follows: ED caused by other
primary sexual disorders, including premature ejaculation or
untreated endocrine disease; a history of radical prostatec-
tomy, pelvic surgery, penile implantation, or clinically sig-
nificant penile deformity; clinically significant renal insuf-
ficiency; human immunodeficiency virus infection; clinically
significant chronic heart disease, cardiac failure, or conduc-
tion defect, or a recent history of myocardial infarction or
coronary artery bypass graft surgery, malignant hypertension,
stroke, angina, or life-threatening arrhythmia; severe hepatobili-
ary disease (glutamic-oxaloacetic transaminase or glutamic-
pyruvic transaminase more than three times the upper limit of
normal); hemoglobin A1c of more than 13%; a recent history of
drug, alcohol, or substance abuse; systolic blood pressure
greater than 170 or less than 90 mm Hg or diastolic blood
pressure greater than 100 or less than 50 mm Hg; current
treatment with nitrates, alpha-blockers (except tamsulosin),
cancer chemotherapy, or antiandrogens; a recent history of
significant central nervous system injuries; and previous un-
responsiveness to sildenafil.
STUDY DESIGN
This multicenter, randomized, double-blind, parallel-group,
placebo-controlled study (Eli Lilly study identifier H6D-MC-
LVDI) included a 4-week, treatment-free, run-in period to
collect erectile function baseline data followed by a 12-week,
double-blind, treatment period. Patients were stratified by se-
verity according to their baseline International Index of Erec-
tile Function erectile function (IIEF EF) domain score.14 The
IIEF EF domain possesses favorable statistical properties as a
diagnostic tool and for classifying ED severity.15 The IIEF has
been validated for Japanese populations.16 Patients were ran-
domly allocated 1:1:1:1 to placebo and 5, 10, and 20 mg
tadalafil using a dynamic allocation method.17,18 All patients
846
and study personnel were unaware of the treatment assign-
ment. Patients were instructed to take one dose of medication
as needed before sexual activity, not more than once daily.
Food and alcohol consumption were unrestricted.
EFFICACY VARIABLES
The primary efficacy variables were the IIEF EF domain
score and patient Sexual Encounter Profile diary questions 2
(“Were you able to insert your penis into your partner’s va-
gina?”) and 3 (“Did your erection last long enough for you to
have successful intercourse?”). The secondary efficacy vari-
ables included the IIEF intercourse satisfaction and overall
satisfaction domain scores, and a global assessment question
(GAQ): “Has the treatment you have been taking during this
study improved your erectile function?” A post hoc analysis
was done to determine the changes from baseline in the EF
domain scores for each ED severity subgroup.
SAFETY PARAMETERS
Safety was evaluated by recording all patient-reported ad-
verse events and any changes in clinical laboratory values,
vital signs, and electrocardiogram results. Treatment-emer-
gent adverse events (TEAEs) were defined as any adverse
event that first occurred or worsened after randomization. Pa-
tients voluntarily reported TEAEs throughout the study.
STATISTICAL ANALYSIS
Efficacy measures based on the 5-mg dose were not consid-
ered primary endpoints of the study. However, the 5-mg dose
was considered in the power calculation. A sample size of
approximately 300 patients, 75 patients per treatment group,
provided 80% power to detect a significant treatment effect
between placebo and tadalafil 5 mg on SEP question 2. The
other treatment groups were powered to more than 99% for all
three primary efficacy variables.
All patients with a baseline and at least one postbaseline
observation were included in the efficacy analyses. Missing
postbaseline data points were imputed with the most recent
nonmissing postbaseline value (last observation carried for-
ward method). Primary and secondary analyses were per-
formed on an intent-to-treat basis.
Least squares mean changes from baseline to endpoint were
tested using an analysis of covariance model with effects for
baseline, treatment group, and site. Additionally, the baseline-
by-treatment interaction term was included if significant at the
0.10 level. Treatment group differences were tested within the
framework of the analysis of covariance by contrasting model-
based least square means. Before analysis of covariance of SEP
responses, the proportion of “yes” responses was determined
for each patient and used in the primary analyses. All tests
were two-tailed, and the reported P values incorporated a
Dunnett’s adjustment for multiple comparisons.
Logistic regression analysis was used to assess treatment
group differences for dichotomous GAQ responses. The
model included effects for the baseline IIEF EF domain score,
treatment, and site. Reported P values were based on likeli-
hood ratio tests.
Adverse events were assigned according to the Medical Dic-
tionary for Regulatory Activities low-level terms and summa-
rized at the preferred term in version 7.0. Fisher’s exact tests
were used to analyze the TEAE rates.
RESULTS
Of the 382 patients entered in the study, 343
were randomly assigned to a treatment group and
302 (88%) completed the study (Fig. 1).
UROLOGY 68 (4), 2006
 FIGURE 1. Progress of patients through study.
DEMOGRAPHICS
The baseline characteristics among the treatment
groups were similar (Table I). The mean age was
approximately 55 years, 88% of men had had ED
for at least 1 year, and approximately one half had
had prior experience with sildenafil. Hyperten-
sion, diabetes mellitus, benign prostatic hyper-
plasia, and hyperlipidemia were common comor-
bid conditions.
EFFICACY
As shown in Figures 2 and 3, patients treated with
tadalafil reported significantly greater changes from
baseline for all three co-primary efficacy measures
versus placebo (P ⬍0.001). Post hoc analyses of
severity subgroups showed a significantly greater
change from baseline to endpoint compared with
placebo for nearly all treatment groups (P ⬍0.05).
The 5-mg dose failed to reach significance in pa-
tients with severe ED.
The change from baseline to endpoint on the IIEF
intercourse satisfaction domain (maximal score 15)
was 3.2, 3.8, and 4.1 for 5, 10, and 20 mg tadalafil,
respectively, versus 1.4 for placebo. The change
from baseline to endpoint for the IIEF overall sat-
isfaction domain (maximal score 10) was 2.1, 2.6,
and 2.8 for 5, 10, and 20 mg, respectively, versus
0.5 for placebo. At endpoint, 76.5%, 81.4%, and
83.7% of those taking 5, 10, and 20 mg, respec-
tively, reported improved erections (GAQ) versus
31.4% of placebo-treated patients (P ⬍0.001 for all
measures and all doses versus placebo).
UROLOGY 68 (4), 2006
TOLERABILITY
Table II shows the TEAEs reported by at least 3%
of patients. Most TEAEs were reported as moderate
(14.5%) or mild (83.8%). Three patients experi-
enced serious adverse events: hospitalization for
concomitant acute prostatitis and pyelonephritis
(10 mg); hospitalization because of a mental disor-
der (20 mg); and hospitalization because of a ure-
teral calculus (5 mg), with subsequent discontinu-
ation. No serious adverse events were assessed by
the study investigator as treatment related. No
cases of myocardial infarction, priapism, nonarte-
rial ischemic optic neuropathy, or abnormalities in
color vision (“blue vision”) occurred.
COMMENT
This is the first study to investigate tadalafil ex-
clusively in Japanese men with ED. Similar to the
results in men with ED from European, North
and South American, and Asian countries,11,19 –22
tadalafil is well tolerated and efficacious in Japa-
nese men with ED. Tadalafil significantly improved
erectile function according to all three co-primary
measures, and the intercourse and overall satisfac-
tion scores were significantly greater in men taking
tadalafil versus placebo.
This study enrolled patients with comorbid con-
ditions often associated with ED, including diabe-
tes, benign prostatic hyperplasia, and cardiovascu-
lar disease. Previous studies have shown that
tadalafil is efficacious and well tolerated in these
847
 TABLE I. Demographic characteristics at baseline
Tadalafil
Placebo 5 mg 10 mg 20 mg All
Characteristic (n ⴝ 86) (n ⴝ 85) (n ⴝ 86) (n ⴝ 86) (n ⴝ 343)
Mean age (yr) 57.2 54.1 55.6 53.6 55.1
Mean weight (kg) 68.6 69.7 68.8 68.1 68.8
ED history (ⱖ1 yr) 80 (93.0) 72 (84.7) 75 (87.2) 76 (88.4) 303 (88.3)
ED severity* (IIEF EF)
Mild (17–30) 32 (37.2) 32 (37.6) 32 (37.2) 32 (37.2) 128 (37.3)
Moderate (11–16) 21 (24.4) 20 (23.5) 21 (24.4) 21 (24.4) 83 (24.2)
Severe (1–10) 33 (38.4) 33 (38.8) 33 (38.4) 33 (38.4) 132 (38.5)
Mean IIEF EF domain score 13.9 13.6 14.1 14.1 13.9
ED etiology
Psychogenic 24 (27.9) 21 (24.7) 24 (27.9) 29 (33.7) 98 (28.6)
Organic 31 (36.0) 23 (27.1) 29 (33.7) 28 (32.6) 111 (32.4)
Mixed 31 (36.0) 41 (48.2) 33 (38.4) 29 (33.7) 134 (39.1)
Prior sildenafil therapy 48 (55.8) 54 (63.5) 48 (55.8) 44 (51.2) 194 (56.6)
Smoking 34 (39.5) 38 (44.7) 28 (32.6) 36 (41.9) 136 (39.7)
Alcohol 59 (68.6) 67 (78.8) 62 (72.1) 71 (82.6) 259 (75.5)
Comorbid conditions
Hypertension 24 (27.9) 20 (23.5) 19 (22.1) 27 (31.4) 66 (25.7)
Diabetes mellitus 17 (19.8) 16 (18.8) 14 (16.3) 23 (26.7) 53 (20.6)
Benign prostatic hyperplasia 9 (10.5) 10 (11.8) 14 (16.3) 11 (12.8) 35 (13.6)
Hyperlipidemia 19 (22.1) 10 (11.8) 11 (12.8) 13 (15.1) 34 (13.2)
KEY: ED ⫽ erectile dysfunction; IIEF ⫽ International Index of Erectile Function; EF ⫽ erectile function.
Data presented as number of patients, with percentages in parentheses.
* Measured by IIEF EF14; a modification of the severity categories was used for this study; at baseline, 16 patients (4.7%) had an IIEF EF domain score of 26 –30 (“no ED”)—for
efficacy analyses, these patients were placed in the mild subgroup.

FIGURE 2. Treatment with tadalafil improved erectile function as measured by IIEF EF domain showing per-patient
least square mean change from baseline to endpoint in IIEF EF domain score for all randomized patients by
treatment group and severity and IIEF EF domain endpoint scores (maximal possible score 30). Solid lines indicate
baseline IIEF EF domain scores. Numbers above the bars are endpoint values. Numbers below are number of
patients in treatment group. Primary endpoints reported in “All Patients” bars (P ⬍0.001 for all tadalafil doses
versus placebo). Severity subgroup analyses were done post hoc. Severity classifications were based on IIEF EF
domain scores at baseline and were mild (score 17 to 30), moderate (score 11 to 16), and severe (score 1 to 10).

groups. In an analysis of patients with diabetes and
ED,23 the mean per-patient SEP question 3 rate was
53% for 20 mg versus 22% for placebo (P ⬍0.001).
Furthermore, the GAQ score was 75% for 20 mg
versus 30% for placebo (P ⬍0.001). Analyses of
subpopulations with various comorbidities and
ED24 demonstrated that tadalafil also improved
erectile function in patients with hypertension,
cardiovascular disease, hyperlipidemia, depression,
and benign prostatic hyperplasia.
Patients in the present study took tadalafil as
needed before sexual activity, with no restriction

848 UROLOGY 68 (4), 2006

FIGURE 3. Treatment with tadalafil improved ability to achieve vaginal penetration as measured by SEP question
2 (A) and ability to maintain erection to complete successful intercourse as measured by SEP question 3 (B). Least
square mean per-patient percentage of successful penetration attempts (A) and successful intercourse attempts (B)
during 12-week treatment period for all randomized patients by treatment group and severity. Solid lines indicate
per-patient means at baseline. Numbers above bars are per-patient mean endpoint values. Numbers below bar are
number of patients in treatment group. Primary endpoints reported in “All Patients” bars (P ⬍0.001 all tadalafil
doses versus placebo). Severity subgroup analyses were done post hoc. Severity classifications were based on IIEF
EF domain scores at baseline and were mild (score 17 to 30), moderate (score 11 to 16), and severe (score 1 to 10).

on the interval between dosing and intercourse.
Previously, tadalafil has been shown to improve
erectile function quickly after dosing12 and for up
to 36 hours.13 In an analysis of 11 integrated stud-
ies,11 50% of men attempted intercourse at least
once between 12 and 24 hours after the dose, and
33% attempted intercourse at least once between
24 and 36 hours after the dose. The SEP question 3
rates during the 36-hour period for men taking
tadalafil were significantly greater than those for
placebo. Thus, men take advantage of the duration
of efficacy of tadalafil.
Tadalafil has been shown to be safe and well tol-
erated. The discontinuation rate due to adverse
events ranges from about 3% (12-week studies)11
to about 6% (18 to 24-month study).25 Daily ad-
ministration for 6 months had no adverse effects
on spermatogenesis or reproductive hormones in

UROLOGY 68 (4), 2006 849

 TABLE II. Treatment-emergent adverse events reported by at
least 3% of patients in any treatment group, listed by
decreasing frequency overall
Tadalafil (n)
Placebo 5 mg 10 mg 20 mg
Adverse Event (n ⴝ 86) (n ⴝ 85) (n ⴝ 86) (n ⴝ 86)
Headache 5 (5.8) 5 (5.9) 10 (11.6) 16 (18.6)
Nasopharyngitis 7 (8.1) 5 (5.9) 3 (3.5) 5 (5.8)
Flushing 1 (1.2) 4 (4.7) 4 (4.7) 5 (5.8)
Hot flush 1 (1.2) 0 6 (7.0) 3 (3.5)
Back pain 3 (3.5) 3 (3.5) 1 (1.2) 3 (3.5)
Diarrhea 3 (3.5) 1 (1.2) 2 (2.3) 2 (2.3)
Dyspepsia 0 1 (1.2) 1 (1.2) 4 (4.7)
Pyrexia 1 (1.2) 0 1 (1.2) 4 (4.7)
Malaise 0 1 (1.2) 3 (3.5) 2 (2.3)
Nasal congestion 0 1 (1.2) 1 (1.2) 3 (3.5)
Abdominal pain 3 (3.5) 1 (1.2) 0 0
Contact dermatitis 0 3 (3.5) 0 0
Ocular hyperemia 0 0 0 3 (3.5)
Data in parentheses are percentages.

men older than 45 years.26 In 35 trials, the rate of
myocardial infarction was 0.33 per 100 patient-years
in tadalafil-treated patients, comparable to that in
placebo-treated patients (0.41 per 100 patient-
years) and age-standardized male population (0.6
per 100 patient-years). In the present study, the
profile and rate of TEAEs were very similar to those
seen in previous studies.11
In the present study, the results for the 20-mg
dose were numerically greater for several end-
points, and the 5-mg dose failed to reach statistical
significance, especially in patients with severe ED.
ED severity can be affected by diabetes, hyperten-
sion, and age. Therefore, additional exploration of
Japanese men with these conditions may help deter-
mine whether tadalafil 20 mg can provide clinically
meaningful benefit beyond the 5 and 10-mg doses.
CONCLUSIONS
In this study of tadalafil for the treatment of ED
in Japanese men, up to 84% of Japanese men re-
ported some improvement in their erections and
about 98% of adverse events were reported to be
mild or moderate in severity. The results of this
study indicate that tadalafil 5, 10, and 20-mg doses
are efficacious and well tolerated in Japanese men
with ED.
ACKNOWLEDGMENT. To the other investigators who took part
in this study (see Appendix) and to Diane R. Stothard, Ph.D.,
Lilly Research Laboratories, Indianapolis, IN, for writing and
editorial support.
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APPENDIX
The other investigators were as follows: Hiroki Horita, Hok-
kaido Saiseikai Otaru Hospital; Toru Ujiie, Ebetsu Urology
Clinic; Hiroaki Seino, Ohta General Hospital, Ohta Nishinou-
chi Hospital; Koichi Nagao, Toho University School of Medi-
cine, Omori Hospital; Masaharu Takanami, Toho University
School of Medicine and Sakura Hospital; Ken Marumo, Keio
University Hospital; Yoshihito Atsumi, Saiseikai Central Hos-
pital; Kuniaki Otsuka, Tokyo Women’s Medical University
Daini Hospital; Hitoshi Hirakata, Surugadai Nihon University
Hospital; Haruaki Sasaki, Showa University Northern Yoko-
hama Hospital; Michitaka Yajima, Yajima Urology Clinic;
Mikio Namiki, Kanazawa University School of Medicine;
Toshiyasu Amano, Nagano Red Cross Hospital; Toshikazu
Otani, Chubu-Rosai Hospital; Harunori Narita, Narita Clinic;
Yuichi Sai, Sai Urology and Dermatology Clinic; Masami Kawa-
hara, Kawahara Clinic; Kiyomi Matsumiya and Akira Tsujimura,
Osaka University Hospital; Minoru Koga, Kenporen Osaka Cen-
tral Hospital; Ryoji Yasumoto, Osaka City Juso Hospital; Atsushi
Iwasa, Iwasa Clinic; Masahisa Ikegami, Ikegami Clinic; Yuji
Yamada, Kobe University Hospital; Koji Sawada, Sansei Hos-
pital; Terufumi Fujiwara, Fujiwara Urological Clinic; Atsushi
Nagai, Okayama University Hospital; Akito Terai, Kurashiki
Central Hospital; Hitoshi Takamoto, Kurashiki Medical Cen-
ter; Toru Araki, Araki Urological Clinic; Yasuo Kawanishi,
Takamatsu Red Cross Hospital; Yasusuke Kimoto, Spinal In-
juries Center; Mineo Takei, Hara Sanshin General Hospital;
Kazuhiro Yoshida, Hakujyujikai Hakujyuji Hospital; and Mit-
suhiro Hachida, Ooimachi Medical Clinic.
851