SANOFI-SYNTHELABO

SL770499\
(ALFUZOSIN)

**BRIEFING PACKAGE**

**Date:** 29 April 2003

EXECUTIVE SUMMARY

Alfuzosin is a selective α~1~--adrenergic blocker developed by
Sanofi-Synthelabo Inc. for the treatment of benign prostatic hyperplasia
(BPH). It was first approved for this indication in Europe in 1987, and
it is now approved in 108 countries worldwide.

The benefits of alfuzosin treatment in symptomatic BPH include
primarily: effective symptomatic relief of BPH; convenient once-daily
(od) dosing; low incidence of class adverse reactions (e.g., dizziness
and postural hypotension); treatment initiation at the therapeutic dose
(i.e., no dose titration required); and no risk for sexual disturbances
(e.g., impotence, libido decrease) observed with hormone-related
treatment.

A phase III program using the 10 mg od regimen of alfuzosin was
performed and a New Drug Application (NDA) was submitted to the FDA in
December 2000 for the treatment of the signs and symptoms of BPH.

In October 2001, the FDA issued an "Approvable" letter indicating only
2 outstanding issues: 1) How to interpret results of the PKD4532 study,
which assessed the effect of alfuzosin on QT interval using the Holter
method and 2) The need to assess the possible interaction of alfuzosin
with maximum doses of ketoconazole. No other issue was raised in the
Approvable letter.

The FDA has focused this Advisory Committee meeting on the first issue.
Therefore, this document focuses on the development program performed to
assess the effect of alfuzosin on cardiac repolarization, specifically
the evaluation of QT interval prolongation and methods used in this
evaluation. The safety of alfuzosin relevant to cardiac QT interval
prolongation is also documented.

Alfuzosin belongs to a drug class not suspected to cause ventricular
arrhythmias. As an α~1~‑adrenergic blocker, alfuzosin is expected to
increase heart rate (HR) in a dose‑dependent manner. This HR increase
confounds assessment of a possible drug effect on QT interval, because
QT interval is highly dependent on HR. The question, then, is how to
correct for increased HR when assessing a possible effect on QT
interval. The most widely used correction formulae (Bazett\'s \[QTcB\]
and Fridericia\'s \[QTcF\]) attempt to normalize QT intervals to the
values they would have if HR were 60 beats/min (bpm). These formulae
over‑correct the QT interval when HR increases. Population and
subject‑specific correction methods (QTcN and QTcNi, respectively)
([^1],[^2]) more precisely reflect the HR‑dependency of ventricular
repolarization. Although not optimal, these methods more accurately
predict the effect on QT interval of drugs that increase HR.

In studies assessing the effect of alfuzosin on QT interval that were
submitted in the NDA (PKD4532 and PDY5105), the Holter monitoring
method, specifically the Holter Bin method, was used. The Holter
monitoring method, a recognized method for the assessment of QT interval
([^3],[^4]), was reported to be a valuable method in the recent
preliminary concept paper for the clinical evaluation of QT/QTc interval
prolongation and proarrhythmic potential for non‑arrhythmic
drugs ([^5]). This method permits a direct comparison of QT intervals
over a large range of HRs without need for correction. For this reason,
Holter monitoring was used in these trials with alfuzosin.

For the alfuzosin dossier, 2 studies using both the Holter monitoring
method and standard 12‑lead electrocardiograms (ECGs) were performed to
thoroughly assess a possible effect of alfuzosin on QT interval. In both
studies (PKD4532 and PDY5105), the Holter Bin method was applied to
12-lead ECG data and QTcB, QTcF, QTcN, QTcNi corrections were applied to
ECG data. The first study (PKD4532) was a 4-way crossover study
assessing 3 doses of alfuzosin (10 mg --- i.e., the proposed therapeutic
dose, 20 mg, and 40 mg) *versus* placebo in 24 healthy male volunteers.
In this study, a 2 msec increase in QT interval according to the Holter
Bin method was observed, whatever the dose of alfuzosin.

The second study (PDY5105) was subsequently designed after discussion
and concurrence with the FDA. This study included a positive control,
that induced modest increase in QT interval (\>5‑10 msec) in order to
validate both the study and the Holter Bin method. It was a 4-way
crossover study conducted in 48 healthy volunteers. It assessed 2 doses
of alfuzosin (10 mg and 40 mg) and a positive control, moxifloxacin
(400 mg, the therapeutic dose) *versus* placebo. The 40 mg dose of
alfuzosin was chosen to evaluate a possible effect on QT interval at a
dose that covers the maximum plasma exposure anticipated to be
encountered in clinical practice in patients with BPH, even when
alfuzosin is co‑administered with ketoconazole. Moxifloxacin was
selected as the positive control because it is known to induce a modest
prolongation of the QT interval ([^6]), but, to our knowledge, not to be
associated with ventricular arrhythmias.

> The design of PDY5105 was in agreement with the methodological
> recommendations underlined in the recent preliminary concept paper for
> the clinical evaluation of QT/QTc interval prolongation and
> proarrhythmic potential for non‑arrhythmic drugs (5). In particular,
> in addition to inclusion of a positive control (moxifloxacin), a 1‑day
> assessment of QT interval under placebo allowed a time-matching of the
> comparative periods for drugs and placebo. The main criterion for
> evaluation in this study was QT interval assessed with the Holter Bin
> method (variation *versus* time‑matched baseline in comparison with
> placebo) over a 4‑hour period during which maximum plasma
> concentrations for both drugs were effectively achieved. The main
> results of this study are as follows:

-   Moxifloxacin 400 mg produced a clear and statistically significant
    (p\<0.0001) increase in QT/QTc interval, regardless of the
    assessment method used. This increase was in the range of those
    previously reported (6). The mean increase in QT interval compared
    to placebo was +7 msec with the Holter Bin method at a HR of 60 bpm.

-   Alfuzosin 10 mg (the therapeutic dose) did not induce significant
    changes in QT interval, regardless of the assessment method used.
    The mean change in QT interval compared to placebo was +0.1 msec
    with the Holter Bin method at a HR of 60 bpm.

-   Alfuzosin 40 mg (4 times the therapeutic dose) induced a weak,
    albeit statistically significant, increase in QT interval compared
    to placebo (mean equal to +2.9 msec) with the Holter Bin method at a
    HR of 60 bpm. This increase was half of that observed with
    moxifloxacin at its therapeutic dose.

-   As expected, alfuzosin increased HR in a dose-dependent manner. In
    addition, moxifloxacin also slightly increased HR. The HR increase
    with alfuzosin 40 mg explains the over-correction observed with QTcB
    and QTcF. A similar observation can be made for alfuzosin 10 mg and
    moxifloxacin, although the differences are less pronounced. QTcN and
    QTcNi approaches showed values intermediate between those recorded
    with the QTcB and QTcF and the Holter method.

These results are consistent with those from the PKD4532 study. The
minor differences in results, which are within the range of the
sensitivity of the method, are attributed to an improved study design in
the second study.

From the results of these 2 studies, it is concluded that:

-   The Holter Bin method, which allows comparison of direct QT interval
    measurements, is reproducible, sensitive, capable of demonstrating a
    statistically significant change in QT interval as small as 2 to
    3 msec, and is appropriate to assess drugs that modify HR.

-   The ≤2.9 msec mean increase in QT interval recorded with alfuzosin
    at 4 times the therapeutic dose is less than that observed with
    moxifloxacin at its therapeutic dose. This small increase in QT
    interval is below the range suspected to be associated with torsades
    de pointes \[preliminary concept paper (5)\].

> These conclusions are corroborated by the large clinical experience on
> the safety profile of alfuzosin in patients with BPH, a population of
> male patients, generally older than 65 years-of-age and suffering in
> more than 40% of cases from associated cardiovascular diseases.
> Specifically:

-   No signal regarding cardiac arrhythmia related to QT/QTc interval
    prolongation with alfuzosin was detected in the clinical trials
    safety database (more than 2000 patients treated with alfuzosin in
    phase II/III controlled trials).

-   A strong confirmation of this statement is provided by the large
    post‑marketing experience with alfuzosin (more than 130,000 patients
    in cohort observational surveys and a number of days of therapy
    superior to 1350 millions). No arrhythmogenic signal is detected in
    a population unrestricted for prescription.

> In conclusion:

-   The Holter Bin method is confirmed as a valuable method to assess
    the effect on QT interval of a drug that affects HR.

-   Thorough clinical assessment of the effect of alfuzosin on QT
    interval is not indicative of a prolongation of QT interval that
    could be associated with ventricular arrhythmia. This conclusion is
    corroborated by the absence of a signal of ventricular arrhythmia in
    a large clinical and post‑marketing experience.

TABLE OF CONTENTS

## Title page 1 {#title-page-1 .Table-of-Figures}

## Executive summary 2 {#executive-summary-2 .Table-of-Figures}

## Table of contents 5 {#table-of-contents-5 .Table-of-Figures}

## List of tables 7 {#list-of-tables-7 .Table-of-Figures}

## List of figures 8 {#list-of-figures-8 .Table-of-Figures}

## List of abbreviations 9 {#list-of-abbreviations-9 .Table-of-Figures}

##  {#section .Table-of-Figures}

# 1. introduction 10 {#introduction-10 .TOC-1 .unnumbered}

# 2. preclinical and pharmacokinetic characteristics 12 {#preclinical-and-pharmacokinetic-characteristics-12 .TOC-1 .unnumbered}

## 2.1 Preclinical data (HERG channel) 12 {#preclinical-data-herg-channel-12 .TOC-2}

## 2.2 Relevant pharmacokinetic data 12 {#relevant-pharmacokinetic-data-12 .TOC-2}

# 3. methods for qt evaluation 15 {#methods-for-qt-evaluation-15 .TOC-1 .unnumbered}

## 3.1 Bazett and Fridericia correction formulae 15 {#bazett-and-fridericia-correction-formulae-15 .TOC-2}

## 3.2 Population and subject specific formulae 16 {#population-and-subject-specific-formulae-16 .TOC-2}

## 3.3 Holter-monitoring method 18 {#holter-monitoring-method-18 .TOC-2}

## 3.3.1 Data acquisition 18 {#data-acquisition-18 .TOC-3}

## 3.3.2 Data processing 18 {#data-processing-18 .TOC-3}

## 3.3.3 Holter Bin method validation 20 {#holter-bin-method-validation-20 .TOC-3}

## 3.4 Use of a positive control 21 {#use-of-a-positive-control-21 .TOC-2}

# 4. Intensive ECG monitoring studies (pkd4532 and pdy5105) 21 {#intensive-ecg-monitoring-studies-pkd4532-and-pdy5105-21 .TOC-1 .unnumbered}

## 4.1 Study design (PDY5105) 21 {#study-design-pdy5105-21 .TOC-2}

## 4.1.1 Rationale for the choice of the alfuzosin 40 mg dose 22 {#rationale-for-the-choice-of-the-alfuzosin-40-mg-dose-22 .TOC-3}

## 4.1.2 Primary method for QT assessment (Holter Bin method) 23 {#primary-method-for-qt-assessment-holter-bin-method-23 .TOC-3}

## 4.1.3 Secondary method for QT assessment (12-lead ECG) 24 {#secondary-method-for-qt-assessment-12-lead-ecg-24 .TOC-3}

## 4.1.4 Sample size calculation and statistical method 24 {#sample-size-calculation-and-statistical-method-24 .TOC-3}

## 4.2 Results 25 {#results-25 .TOC-2}

## 4.2.1 Baseline HR and QT values 26 {#baseline-hr-and-qt-values-26 .TOC-3}

## 4.2.2 Heart rate results 27 {#heart-rate-results-27 .TOC-3}

## 4.2.3 QT/QTc interval results 27 {#qtqtc-interval-results-27 .TOC-3}

## 4.2.3.1 Moxifloxacin 28 {#moxifloxacin-28 .TOC-4}

## 4.2.3.2 Alfuzosin 28 {#alfuzosin-28 .TOC-4}

## 4.2.3.3 PKD4532 QT results 29 {#pkd4532-qt-results-29 .TOC-4}

## 4.2.4 Outliers 30 {#outliers-30 .TOC-3}

## 4.2.5 PK/PD relationship 31 {#pkpd-relationship-31 .TOC-3}

## 4.3 Conclusion 32 {#conclusion-32 .TOC-2}

# 5. clinical sAFETY 32 {#clinical-safety-32 .TOC-1 .unnumbered}

## 5.1.1 Methodology 32 {#methodology-32 .TOC-3}

## 5.1.2 Clinical trials 33 {#clinical-trials-33 .TOC-3}

## 5.1.3 Post-marketing experience 33 {#post-marketing-experience-33 .TOC-3}

## 5.1.3.1 Cohort observational surveys 34 {#cohort-observational-surveys-34 .TOC-4}

## 5.1.3.2 Spontaneous reporting 34 {#spontaneous-reporting-34 .TOC-4}

## 5.1.3.3 Post-marketing experience conclusion 35 {#post-marketing-experience-conclusion-35 .TOC-4}

## 5.1.4 Overall clinical safety conclusion 35 {#overall-clinical-safety-conclusion-35 .TOC-3}

# 6. Overall interpretation 35 {#overall-interpretation-35 .TOC-1 .unnumbered}

## 6.1 Validity of the approach 35 {#validity-of-the-approach-35 .TOC-2}

## 6.1.1 Approaches to the correction of QT interval for drugs that affect HR 35 {#approaches-to-the-correction-of-qt-interval-for-drugs-that-affect-hr-35 .TOC-3}

## 6.1.2 Clinical trial design for the assessment of QT interval prolongation 36 {#clinical-trial-design-for-the-assessment-of-qt-interval-prolongation-36 .TOC-3}

## 6.2 The risk of cardiac arrhythmia associated with these results 37 {#the-risk-of-cardiac-arrhythmia-associated-with-these-results-37 .TOC-2}

# 7. Supportive information 38 {#supportive-information-38 .TOC-1 .unnumbered}

## 7.1 Summaries of study reports 38 {#summaries-of-study-reports-38 .TOC-2}

## 7.1.1 Summary of INT5056 38 {#summary-of-int5056-38 .TOC-3}

## 7.1.2 Summary of PKD4532 41 {#summary-of-pkd4532-41 .TOC-3}

## 7.1.3 Summary of PDY5105 45 {#summary-of-pdy5105-45 .TOC-3}

## 7.2 Preclinical safety 51 {#preclinical-safety-51 .TOC-2}

## 7.3 Study design 51 {#study-design-51 .TOC-2}

## 7.4 QT interval assessment 53 {#qt-interval-assessment-53 .TOC-2}

## 7.5 Clinical safety 57 {#clinical-safety-57 .TOC-2}

# 8. references 58 {#references-58 .TOC-1 .unnumbered}

##  {#section-1 .TOC-2}

LIST OF TABLES

##  {#section-2 .TOC-3}

## Table (4.2.1) 1 - Baseline HR and QT interval values (mean ± SEM) for each treatment group (Study PDY5105) 26 {#table-4.2.1-1---baseline-hr-and-qt-interval-values-mean-sem-for-each-treatment-group-study-pdy5105-26 .TOC-3}

## Table (4.2.2) 2 - 12-lead ECG: HR change from baseline for alfuzosin 10 and 40 mg and moxifloxacin 400 mg *versus* placebo, pairwise comparisons (Study PDY5105) 27 {#table-4.2.2-2---12-lead-ecg-hr-change-from-baseline-for-alfuzosin-10-and-40-mg-and-moxifloxacin-400-mg-versus-placebo-pairwise-comparisons-study-pdy5105-27 .TOC-3}

## Table (4.2.3.1) 1 - QT interval change from baseline for moxifloxacin 400 mg compared to placebo (Study PDY5105) 28 {#table-4.2.3.1-1---qt-interval-change-from-baseline-for-moxifloxacin-400-mg-compared-to-placebo-study-pdy5105-28 .TOC-3}

## Table (4.2.3.2) 1 - QT interval change from baseline for alfuzosin 10 mg compared to placebo (Study PDY5105) 29 {#table-4.2.3.2-1---qt-interval-change-from-baseline-for-alfuzosin-10-mg-compared-to-placebo-study-pdy5105-29 .TOC-3}

## Table (4.2.3.2) 2 - QT interval change from baseline for alfuzosin 40 mg compared to placebo (Study PDY5105) 29 {#table-4.2.3.2-2---qt-interval-change-from-baseline-for-alfuzosin-40-mg-compared-to-placebo-study-pdy5105-29 .TOC-3}

## Table (4.2.3.3) 1 - QT interval change for alfuzosin 10 mg, 20 mg, and 40 mg compared to placebo (Study PKD4532) 30 {#table-4.2.3.3-1---qt-interval-change-for-alfuzosin-10-mg-20-mg-and-40-mg-compared-to-placebo-study-pkd4532-30 .TOC-3}

## Table (7.2) 1 - Inhibition of HERG potassium current expressed in CHO cells 51 {#table-7.2-1---inhibition-of-herg-potassium-current-expressed-in-cho-cells-51 .TOC-3}

## Table (7.3) 1 - Study details of PDY5105 and PKD4532 52 {#table-7.3-1---study-details-of-pdy5105-and-pkd4532-52 .TOC-3}

## Table (7.4) 1 - Holter‑monitoring method -- 4 hour-period: QT interval change from baseline of alfuzosin 10 mg, alfuzosin 40 mg, and moxifloxacin 400 mg, in comparison with placebo - primary endpoints (Study PDY5105) 53 {#table-7.4-1---holtermonitoring-method-4-hour-period-qt-interval-change-from-baseline-of-alfuzosin-10-mg-alfuzosin-40-mg-and-moxifloxacin-400-mg-in-comparison-with-placebo---primary-endpoints-study-pdy5105-53 .TOC-3}

## Table (7.4) 2 - 12‑lead ECG: change from baseline to C~max~: moxifloxacin 400 mg *versus* placebo, pairwise comparisons (Study PDY5105) 53 {#table-7.4-2---12lead-ecg-change-from-baseline-to-cmax-moxifloxacin-400-mg-versus-placebo-pairwise-comparisons-study-pdy5105-53 .TOC-3}

## Table (7.4) 3 - 12‑lead ECG: change from baseline to C~max~: alfuzosin 10 mg and 40 mg *versus* placebo, pairwise comparisons (Study PDY5105) 54 {#table-7.4-3---12lead-ecg-change-from-baseline-to-cmax-alfuzosin-10-mg-and-40-mg-versus-placebo-pairwise-comparisons-study-pdy5105-54 .TOC-3}

## Table (7.4) 4 - Individual data of subjects with QTcB\>450 msec and/or delta QTcB\>60 msec (Study PDY5105) 56 {#table-7.4-4---individual-data-of-subjects-with-qtcb450-msec-andor-delta-qtcb60-msec-study-pdy5105-56 .TOC-3}

## Table (7.5) 1 - Number (%) of patients experiencing AEs that are potentially suggestive of a proarrhythmic effect in double‑blind controlled phase II/III studies in BPH patients -- alfuzosin all formulations 57 {#table-7.5-1---number-of-patients-experiencing-aes-that-are-potentially-suggestive-of-a-proarrhythmic-effect-in-doubleblind-controlled-phase-iiiii-studies-in-bph-patients-alfuzosin-all-formulations-57 .TOC-3}

## Table (7.5) 2 - Number of SAEs that are potentially suggestive of a proarrhythmic effect collected in cohort observational surveys or spontaneously reported with alfuzosin, displayed by MedDRA preferred terms 57 {#table-7.5-2---number-of-saes-that-are-potentially-suggestive-of-a-proarrhythmic-effect-collected-in-cohort-observational-surveys-or-spontaneously-reported-with-alfuzosin-displayed-by-meddra-preferred-terms-57 .TOC-3}

##  {#section-3 .TOC-3}

LIST OF FIGURES

## Figure (2.2) 1 - Mean (SD) alfuzosin plasma concentration-time profile obtained in healthy male volunteers after a single administration of 10 mg alfuzosin 13 {#figure-2.2-1---mean-sd-alfuzosin-plasma-concentration-time-profile-obtained-in-healthy-male-volunteers-after-a-single-administration-of-10-mg-alfuzosin-13 .TOC-3}

## Figure (2.2) 2 - Representation of increases in alfuzosin C~max~ and AUC related to various intrinsic and extrinsic factors after administration of 10 mg alfuzosin 14 {#figure-2.2-2---representation-of-increases-in-alfuzosin-cmax-and-auc-related-to-various-intrinsic-and-extrinsic-factors-after-administration-of-10-mg-alfuzosin-14 .TOC-3}

## Figure (3.1) 1 - 12-lead ECG: relationship between QTcB and QTcF change from baseline and RR change from baseline on placebo data (Study PKD4532) 16 {#figure-3.1-1---12-lead-ecg-relationship-between-qtcb-and-qtcf-change-from-baseline-and-rr-change-from-baseline-on-placebo-data-study-pkd4532-16 .TOC-3}

## Figure (3.2) 1 - 12-lead ECG: relationship between QTcN (study population-specific) and QTcNi (subject-specific) change from baseline and RR change from baseline on placebo data (Study PKD4532) 17 {#figure-3.2-1---12-lead-ecg-relationship-between-qtcn-study-population-specific-and-qtcni-subject-specific-change-from-baseline-and-rr-change-from-baseline-on-placebo-data-study-pkd4532-17 .TOC-3}

## Figure (3.3.2) 1 - Holter‑monitoring analysis of ECG complexes 19 {#figure-3.3.2-1---holtermonitoring-analysis-of-ecg-complexes-19 .TOC-3}

## Figure (4.1.1) 1 - Alfuzosin C~max~ and AUC values after alfuzosin 10 mg tablet according to intrinsic and extrinsic factors 23 {#figure-4.1.1-1---alfuzosin-cmax-and-auc-values-after-alfuzosin-10-mg-tablet-according-to-intrinsic-and-extrinsic-factors-23 .TOC-3}

## Figure (4.2) 1 - Mean alfuzosin and moxifloxacin plasma concentrations *versus* time profiles observed after a single administration of alfuzosin 10 mg, alfuzosin 40 mg, or moxifloxacin 400 mg (Study PDY5105) 26 {#figure-4.2-1---mean-alfuzosin-and-moxifloxacin-plasma-concentrations-versus-time-profiles-observed-after-a-single-administration-of-alfuzosin-10-mg-alfuzosin-40-mg-or-moxifloxacin-400-mg-study-pdy5105-26 .TOC-3}

## Figure (4.2.5) 1 - Relationship between QTcNi change from baseline and mean plasma concentration using data from alfuzosin 10 mg and 40 mg and placebo (Study PDY5105) 31 {#figure-4.2.5-1---relationship-between-qtcni-change-from-baseline-and-mean-plasma-concentration-using-data-from-alfuzosin-10-mg-and-40-mg-and-placebo-study-pdy5105-31 .TOC-3}

## Figure (7.4) 1 - 12-lead ECG: relationship between QTcB and QTcF change from baseline and RR change from baseline on placebo data (Study PDY5105) 54 {#figure-7.4-1---12-lead-ecg-relationship-between-qtcb-and-qtcf-change-from-baseline-and-rr-change-from-baseline-on-placebo-data-study-pdy5105-54 .TOC-3}

## Figure (7.4) 2 - 12-lead ECG: relationship between QTcN and QTcNi change from baseline and RR change from baseline on placebo data (Study PDY5105) 55 {#figure-7.4-2---12-lead-ecg-relationship-between-qtcn-and-qtcni-change-from-baseline-and-rr-change-from-baseline-on-placebo-data-study-pdy5105-55 .TOC-3}

##  {#section-4 .TOC-3}

LIST OF ABBREVIATIONS

  ----------- -----------------------------------------------------------
  5ARIs       5α-reductase inhibitors

  AE          adverse event

  ANOVA       analysis of variance

  AUC         area under the plasma concentration *versus* time curve
              extrapolated to infinity

  AUC~last~   area under the plasma concentration *versus* time curve
              calculated using the trapezoidal method from time zero to
              the real time t~last~

  bid         twice daily

  BMI         body mass index

  BPH         benign prostatic hyperplasia

  CHO         Chinese hamster ovary

  CI          confidence interval

  C~max~      maximum plasma concentration

  C~trough~   plasma concentration observed before treatment
              administration during repeated dosing

  CYP3A4      cytochrome P450 3A4

  DBP         diastolic blood pressure

  ECG         electrocardiogram

  FDA         Food and Drug Administration

  HERG        human ether-a-go-go-related gene

  HPLC        high performance liquid chromatography

  HR          heart rate

  IC~20~      concentration inducing a 20% inhibition

  IC~50~      half maximal inhibitory concentration

  ISHNE       International Society for Holter and Noninvasive
              Electrocardiology

  LC-MS/MS    liquid chromatography tandem mass spectrometry

  LUTS        lower urinary tract symptoms

  NDA         new drug application

  od          once daily

  PCSA        potentially clinically significant abnormality

  SAE         serious adverse event

  SBP         systolic blood pressure

  SD          standard deviation

  SEM         standard error of the mean

  TEAE        treatment emergent adverse event

  tid         three times a day

  t~1/2z~     elimination half-life

  t~max~      first time to reach C~max~

  ULN         upper limit of normal

  US          United States

  UV          ultraviolet
  ----------- -----------------------------------------------------------

#  000introduction

> Alfuzosin hydrochloride is a selective α~1~‑adrenergic blocker
> developed by Sanofi‑Synthelabo Inc. for the treatment of BPH.
>
> Lower urinary tract symptoms (LUTS), resulting from bladder outlet
> obstruction associated with BPH, are common in older men and have a
> significant impact on their daily lives ([^7]). Medical treatment is
> the first-line option for symptomatic and uncomplicated BPH. The
> 2 principal options for the medical management of BPH are
> α~1~‑adrenergic blockers and 5α‑reductase inhibitors (5ARIs). 5ARIs
> block the conversion of testosterone to dihydrotestosterone, resulting
> in a reduction in prostate volume. α~1~‑adrenergic blockers act on the
> dynamic component of obstruction by decreasing the sympathetically
> controlled tone of prostatic smooth muscle. The latter are
> characterized by a rapid onset of action, with evidence of efficacy
> from the first dose. Thus, α~1~‑adrenergic blockers have a first‑line
> role in the pharmacotherapeutic management of BPH patients who are
> symptomatic but who are not candidates for surgery.

Alfuzosin was first approved for use in Europe for the BPH indication in
1987 at a dose of 2.5 mg three times a day (tid). Subsequently, 5 mg
twice daily (bid) and 10 mg once daily (od) regimens were developed and
approved. Alfuzosin is now approved in 108 countries worldwide,
including all of Europe, Canada, and Australia. It has provided over
1350 million therapy days of treatment for BPH from the first marketing
through December 2002. Alfuzosin has never been marketed for
hypertension.

The therapeutic value of alfuzosin for treatment of LUTS in BPH has been
well established ([^8],[^9],[^10],[^11],[^12],[^13]). In addition, its
therapeutic interest in the management of acute urine retention related
to BPH has also been reported ([^14])*.* The benefits of alfuzosin
treatment in symptomatic BPH include primarily: effective symptomatic
relief of BPH; convenient od regimen; low incidence of class adverse
reactions (e.g., dizziness and postural hypotension); dose initiation
with the therapeutic dose (i.e., no titration required); no risk for the
sexual disturbance (impotence, libido decrease) observed with
hormone‑related treatment.

There are 3 other α~1~‑adrenergic blockers approved for BPH treatment in
the United States (US): Hytrin (terazosin) for BPH and hypertension was
first approved in 1987 ([^15]); Cardura (doxazosin) for BPH and
hypertension was first approved in 1990 ([^16]); and Flomax
(tamsulosin) for BPH was first approved in 1997 ([^17]). NDA data
concerning the effect of these drugs on cardiac repolarization is not
known to the authors of this document.

In 1996, Sanofi-Synthelabo Inc. began a separate stand-alone phase III
clinical development program for the od regimen to support an NDA in the
US. While the phase III program was in progress, it became apparent to
the company that a high‑dose ECG study, to demonstrate the lack of
effect of drug on cardiac repolarization, was becoming a requirement for
all drugs submitted for NDAs in the US. An earlier clinical pharmacology
ECG study, however, suggested that the effect of the HR increase
produced by alfuzosin on the calculation of the QT interval length
(using the Bazett or Fridericia traditional universal formulae) was
confounding the ability to clearly assess the potential of alfuzosin to
affect cardiac repolarization. To avoid this confounding influence of
HR, a method based on Holter monitoring was chosen to assess the effect
of alfuzosin on QT interval. The Holter Bin method, used in the trial,
permits the direct comparison of treatments at the same HR, avoiding the
need for arbitrary correction formulae.

An NDA for the use of 10 mg od alfuzosin was submitted to the FDA in
December 2000 for the treatment of the signs and symptoms of BPH. The
NDA provided the results of the ECG study (PKD4532) that used the Holter
Bin method to assess effects on QT interval‑length prolongation. This
study compared placebo to the therapeutic dose (10 mg) and to
supra-therapeutic doses (20 mg and 40 mg). The FDA declared this NDA
"Approvable" in October 2001 and, in a subsequent meeting in
January 2002, clarified the following issues that were presented in the
Approvable letter:

-   The interpretation of the results of the PKD4532 study that assessed
    the effect of alfuzosin on QT interval using the Holter Bin method.

-   The assessment of the possible interaction of alfuzosin with maximum
    doses of ketoconazole.

No other issue was raised in the Approvable letter.

Both issues were subsequently addressed by developing a complementary
clinical program that comprised 2 studies (INT5056 and PDY5105). These
studies were designed and conducted with FDA concurrence to address the
outstanding concerns.

-   A new interaction study used the maximum permitted dose of
    ketoconazole (INT5056).

-   A new high-dose ECG study (PDY5105) compared placebo to the
    therapeutic (10 mg) and the supra-therapeutic (40 mg) doses of
    alfuzosin and to the US‑approved therapeutic dose (400 mg) of
    moxifloxacin as a positive control. Moxifloxacin is known to
    modestly increase QT interval length when assessed using correction
    formulae. This study was similar in design to the previous ECG study
    (PKD4532), except that the assessment of moxifloxacin by 12-lead ECG
    and the Holter Bin method allowed comparison of the signal from both
    the Holter method and correction formulae for moxifloxacin, bridging
    the 2 methods. The study design complied with the FDA requirement
    --- i.e., adequately powered with positive control and placebo
    capable of demonstrating small QT effects (at least 5 msec). The
    study design received FDA concurrence in May 2002.

Related to the assessment of alfuzosin on QT interval, the FDA has
convened the Advisory Committee meeting 29 May 2002 to discuss: 1)
clinical trial designs for assessment of QT prolongation, 2) approaches
to the correction of QT interval for drugs that affect HR, and 3) risks
of cardiac arrhythmia associated with different degrees of QT
prolongation.

Therefore, this document focuses on the development program performed to
assess the effect of alfuzosin on cardiac repolarization, specifically
the evaluation of QT interval prolongation and the methods used for this
evaluation. The safety of alfuzosin relevant to cardiac QT prolongation
is also documented.

# 000preclinical and pharmacokinetic characteristics

## 000Preclinical data (HERG channel)

The effects of alfuzosin and other reference drugs that belong to the
same therapeutic class were evaluated on human ether-a-go-go-related
gene (HERG) potassium channels, which are stably expressed in Chinese
hamster ovary (CHO) cells.

Alfuzosin has a negligible inhibitory effect on the HERG potassium
current, with an IC~50~=83.3±16.6 µmol/L \[Table (7.2) 1\]. The first
observed inhibition (IC~20~) occurred at 10 µmol/L. In human, alfuzosin
is 90% bound to plasma protein, so the free fraction is around 1.4 ng/mL
at maximum plasma concentration (C~max~) (i.e., 3.6 nmol/L). This
concentration is 2,800 times lower than the IC~20~.

## 000Relevant pharmacokinetic data

Figure (2.2) 1 displays the plasma concentration *versus* time profile
for alfuzosin 10 mg after single dose administration.

![](media/image1.wmf){width="5.280555555555556in"
height="4.415277777777778in"}

Figure (2.2) 1 - Mean (SD) alfuzosin plasma concentration-time profile
obtained in healthy male volunteers after a single administration of
10 mg alfuzosin

Alfuzosin is slowly absorbed for up to 20 hours. Peak plasma
concentrations reach a plateau from 5 to 12 hours after administration.
The elimination half-life of alfuzosin after the administration of a
10 mg tablet is approximately 10 hours. There is only a small
accumulation of exposure as a result of repeated administration
(approximately a 1.1‑fold increase) and steady state is observed after
the second day of administration.

Alfuzosin is eliminated primarily by metabolism, with only 11% of the
administered dose excreted in the urine as unchanged compound.
Cytochrome P450 3A4 (CYP3A4) is the principle hepatic enzyme involved in
the metabolism of alfuzosin. The elimination half‑life of total
radioactivity after ^14^C-alfuzosin administration is similar to the
elimination half-life of alfuzosin itself. This indicates that
metabolites should not accumulate after repeated administration. The
metabolites are rapidly excreted, resulting in alfuzosin being the major
circulating compound in the plasma. Alfuzosin and its metabolites are
excreted in feces (69% of dose) and urine (24% of dose).

The FDA Approvable letter (05 October 2001) requested a study to assess
the possible interaction between the therapeutic dose of alfuzosin
(10 mg) and the highest recommended dose of ketoconazole (400 mg).

The results of this study (INT5056) indicate that repeated
administration of 400 mg ketoconazole once daily over 8 days under fed
conditions resulted in a 2.3‑ and 3.0‑fold increase in alfuzosin C~max~
and area under the plasma concentration *versus* time curve extrapolated
to infinity (AUC), respectively (see study summary in Section 7.1.1).

Figure (2.2) 2 presents intrinsic (repeat administration, age, renal
impairment, hepatic impairment) and extrinsic (inhibition of its
metabolism) factors that increase exposure of alfuzosin (see
Section 4.1.1).

![](media/image2.wmf){width="6.002083333333333in"
height="4.177083333333333in"}

\* (estimated from C~trough~ values in BPH patients) \*\* (estimated
from changes in clearance)

Figure (2.2) 2 - Representation of increases in alfuzosin C~max~ and AUC
related to various intrinsic and extrinsic factors after administration
of 10 mg alfuzosin

# 000methods for qt evaluation

## 000Bazett and Fridericia correction formulae

Alfuzosin and all other α~1‑~adrenergic blocker drugs are expected to
increase HR. The HR increase observed after administration of an
α~1~‑adrenergic blocker is the consequence of a primary vasodilatory
effect followed by a neural sympathetic stimulation. The magnitude of
this baroreflex response is subject to large inter-individual
variability. Increases in mean HR, as well as large inter-individual HR
variability, were in fact observed following alfuzosin administration
during the 2 completed phase I ECG studies.

Because the QT interval is HR-dependent, an evaluation of drug-induced
QT interval changes must always accommodate for the underlying changes
in HR. Many general HR correction formulae have been proposed to
normalize the QT interval to a HR of 60 bpm, using several mathematical
functions to correct for HR changes \[please see review in (1,[^18])\].
The value of these "universal" (i.e., the same correction is applied to
every individual) correction formulae has been discredited ([^19]),
because they substantially over‑correct or under-correct the QT interval
when HR moves away from normal resting ranges ([^20],[^21]). This is
particularly true for the most widely used correction formula proposed
by Bazett (QTcB=QT/RR^0.5^) and, to a lesser extent, for the Fridericia
formula (QTcF=QT/RR^0.33^). With the Bazett correction formula, QT
interval is clearly under‑corrected when HR is under 60 bpm and
over-corrected when HR is higher than 60 bpm ([^22]). Moreover, this
over-correction increases as HR moves away from 60 bpm ([^23]). Using
the placebo data from the PKD4532 study, the problems associated with
the Bazett and Fridericia formulae when HR changes are illustrated in
Figure (3.1) 1. This figure shows that the corrected QT interval remains
strongly HR dependent, because the regression line of the changes in QTc
interval as a function of changes in HR would have been expected to be
horizontal for an adequate correction. A similar relationship using
placebo data was also shown for the PDY5105 study, as illustrated in
Figure (7.4) 1.

QTcB QTcF

![](media/image3.wmf){width="2.995833333333333in"
height="3.0902777777777777in"}![](media/image4.wmf){width="3.0034722222222223in"
height="3.0902777777777777in"}

Figure (3.1) 1 - 12-lead ECG: relationship between QTcB and QTcF change
from baseline and RR change from baseline on placebo data (Study
PKD4532)

Therefore, the Bazett\'s and Fridericia\'s correction formulae confound
efforts to evaluate an increase in QT interval in the presence of HR
increases.

## 000Population and subject specific formulae

Malik and co-authors proposed a study population-specific correction
formula to better correct for HR variation for the population studied
(1,2). This population‑specific correction formula (QTcN) is based on a
simple parabolic model in which the exponent is estimated from the model
fit to the population. Baseline or placebo QT/RR data are used to
produce the exponent α, leading to a correction formula of generic form
QTcN=QT/RR^α^ (1). This study population-specific QT correction formula
was recently proposed to the FDA during 2 Advisory Committee meetings
\[ziprazidone ([^24]) and telithromycin ([^25])\].

The study population-specific QT interval correction formula (QTcN) does
not adequately fit all subjects (1,2,18,[^26]), so the concept of a
subject-specific correction formula (QTcNi) was subsequently proposed
(26) in order to minimize the correction error. This method is based on
several ECG recordings at different HRs in the same individual that are
used to determine the specific QT/RR relationship for that individual.

Population- and subject-specific correction formulae were generated and
used in the 2 thorough ECG studies (PKD4532 and PDY5105) using multiple,
resting, 12‑lead ECGs recorded during the placebo period.

In the subject-specific approach, data were fitted to a parabolic model
that yielded individual exponential factors ranging from 0.188 to 0.278.
These formulae allow a better correction of QT intervals for HR changes
\[Figure (3.2) 1\] compared with the Bazett or Fridericia formulae
\[Figure (3.1) 1\]. In some subjects, however, the observed QT/RR values
deviate from the parabolic fit, in agreement with the findings of Malik
and co‑authors (26). Thus, although performing better than previous
formulae, the subject‑specific correction (Ni) still does not fully
account for changes in HR. A similar relationship using placebo data was
also shown for the PDY5105 study, as illustrated in Figure (7.4) 2.

QTcN QTcNi

> ![](media/image5.wmf){width="2.995833333333333in"
> height="3.0902777777777777in"}![](media/image6.wmf){width="2.995833333333333in"
> height="3.0902777777777777in"}

Figure (3.2) 1 - 12-lead ECG: relationship between QTcN (study
population-specific) and QTcNi (subject-specific) change from baseline
and RR change from baseline on placebo data (Study PKD4532)

## 000Holter-monitoring method

As none of the correction formulae provide optimal ways for QT interval
assessment for drugs that increase HR, other approaches based on
continuous Holter monitoring have been developed. Continuous ECG
recordings allow:

-   To build individualized QT/RR relationships for each subject,

-   To perform, within each subject, a direct comparison of the
    uncorrected QT interval, between baseline placebo and drug treatment
    at identical HR.

This latter approach, hereafter referred to as the Holter Bin method,
does not require a correction over a large range of HRs and was
therefore chosen as the primary method used in the thorough ECG studies
with alfuzosin (PKD4532 and PDY5105).

The Holter Bin method of analysis of QT interval complies with the
recommendations of the International Society for Holter and Noninvasive
Electrocardiology (ISHNE) Task Force ([^27]) and has been previously
used to assess QT intervals in clinical pharmacology studies
(3,4,[^28]).

A description of the data acquisition, data processing, and method
validation for the Holter Bin method is provided below.

### 000Data acquisition

Continuous Holter recordings were obtained during a placebo run-in day
and an under‑treatment day. The procedures used to evaluate each subject
were as follows:

-   Continuous ECGs (over approximately 24 hours) were recorded using a
    3‑lead Holter digital device (Syneflash Digital Recorder, Ela
    Medical),

-   Electrodes were positioned at the same place on the chest wall
    (positions were identified and marked),

-   Digital storage of the information was obtained on computer CD-ROM
    that was transferred to an expert cardiologist.

### 000Data processing

The expert cardiologist performed all readings in a blinded manner
through the use of validated software (WinAtrec^®^). Per period, about
98% of the recorded complexes were readable and were retained for
classification and averaging. Test protocols with acceptance conditions
were applied to validate the various steps of data processing and
analysis (Section 3.3.3).

Data processing was performed in 3 steps:

1)  RR interval measurements,

2)  Classification of all sinus cardiac ECG complexes into 10 msec
    RR groups ("bins"),

3)  Averaging of complexes within each RR bin and measurement of QT
    intervals.

The QT interval length of the averaged complex was the value for each
subject in each treatment group (or baseline) used in the analysis.

A schematic diagram of the data processing is presented in
Figure (3.3.2) 1.

![](media/image7.wmf){width="5.976388888888889in"
height="7.131944444444445in"}

Figure (3.3.2) 1 - Holter‑monitoring analysis of ECG complexes

The result of the blinded data processing was the average QT interval
for each RR bin, and each treatment period, by subject.

### 000Holter Bin method validation

The systems used in the implementation of the Holter Bin monitoring
method have been the subject of extensive validation. The goal was to
ensure that all computer systems used in the process meet
state-of-the-art international requirements, in terms of specifications,
operational qualification, documentation, traceability, security, and
audit trails. The objective of the validation plan was to ensure proper
functionality and accuracy of methodology embedded in the application.
To achieve this objective, a dedicated simulated ECG was designed to
replicate most important conditions.

The data acquisition systems used in the study (Syneflash Digital
recorder, ELA Medical) and standard 12-lead ECGs (MAC 5000, Marquette)
were validated systems compliant with international norms and Good
Clinical Practice standards, and were approved by the FDA. The key
software equipment used for the method was WinAtrec v4.0 (AMPS LLC). It
was intended that this software provide a tool to build templates for QT
interval analyses from the Holter recordings.

Specifically, the following critical points were qualified:

-   Verification of data access authorization at all stages of use,

-   Presence of audit trails,

-   Verification of production of the data bins,

-   Verification of detection of abnormal ECGs,

-   Verification of calculations and associated documentation.

Validation of the algorithm used to obtain averaged ECG templates has
been previously described (3). Only at the end of the qualification
phases and after examination of the full and satisfactory validation
dossier was the form documenting final acceptance of the system
signed‑off. Beyond system validation, several other requirements were
necessary for a complete validation of the method, including the
determination of accuracy, precision, limit of detection, specificity,
reproducibility, and robustness. From previously published studies using
this approach (4,[^29]) and from the first alfuzosin ECG
placebo‑controlled study (PKD4532), the precision and robustness of the
method were demonstrated. In order to demonstrate accuracy, specificity,
and reproducibility, however, a carefully designed placebo‑controlled
study with inclusion of a positive control was needed. This was one of
the goals of study PDY5105.

## 000Use of a positive control

The preliminary concept paper (5) encourages use of a concurrent
positive control group to evaluate the effect of a drug on QT interval
and to support the use of novel correction approaches, like the
Holter-based correction. Use of a positive control demonstrates the
ability of the experiment to detect relevant effects on QT/QTc intervals
(i.e., validates the study design, assesses the sensitivity of the
approach used, and avoids false negatives). Moreover the positive
control chosen should be one that consistently produces a mean QT/QTc
interval effect in the range of 5-10 msec, without inducing a large
increase in HR. Another important requirement for proper use of the
positive control is to conduct the study in a double-blind manner, and
to ensure that the QT intervals are measured in a blinded manner by an
expert cardiologist.

Moxifloxacin was a good positive control candidate because it induces a
consistent and modest increase in QT/QTc intervals after administration
of a single dose of 400 mg (6). Following FDA concurrence with the
choice of moxifloxacin as an adequate positive control, the
specifications of the criterion to be met to validate the Holter Bin
method, as requested in the October 2001 approvable letter, were agreed
with FDA. The prospective goal of detecting a statistically significant
increase in QT intervals of at least 5 msec in the moxifloxacin group
was established as a basis of the PDY5105 study design.

# 000Intensive ECG monitoring studies (pkd4532 and pdy5105)

Two studies (PKD4532 and PDY5105) were performed to thoroughly assess
the effect of alfuzosin on QT interval. A summary and study design
details for these 2 studies are provided in Section 7.1.2,
Section 7.1.3, and Table (7.3) 1, respectively. The first study,
PKD4532, was a four‑way, double‑blind, crossover study assessing
3 single doses of alfuzosin (10 mg, 20 mg, and 40 mg) *versus* placebo
in 24 healthy volunteers. The following sections will primarily focus on
the second study (PDY5105).

## 000Study design (PDY5105)

The second study, PDY5105, was designed with the FDA's concurrence. This
study was a 4‑way crossover study assessing 2 single doses of alfuzosin
(10 mg and 40 mg) and a single dose of the positive control (400 mg
moxifloxacin) *versus* placebo in 48 healthy volunteers. The study was a
single-center, randomized, double‑dummy and placebo‑controlled, and used
standard 12‑lead ECG as well as Holter monitoring. Each period consisted
of a 2-day run-in placebo followed by a single-dose day, with a washout
of 5 to 9 days between successive periods. A thorough pharmacokinetic
assessment was carried out with blood samples collected at the same time
as ECG recordings. The 12‑lead ECG reading was performed in a blinded
centralized manner by qualified cardiologists. The Holter monitoring was
analyzed blindly and independently of the 12‑lead ECG reading, which was
analyzed by another qualified cardiologist.

A significant difference between the 2 studies was the use in PDY5105 of
a 2‑day placebo run-in period (Day 1 and Day 2) preceding the day of
drug administration (Day 3), whereas in PKD4532 each period consisted of
a single day of treatment. Thus in PDY5105, Holter recording performed
at Day 2 was considered as the baseline for the Holter recording
performed on the day of dosing. The only available baseline in study
PKD4532 is the Holter recorded at the day of screening. This substantial
improvement in PDY5105 study design allowed a more relevant and
time-matched baseline, increasing the sensitivity of the trial.

### 000Rationale for the choice of the alfuzosin 40 mg dose

A high dose of 40 mg alfuzosin (i.e., 4 times the therapeutic dose) was
utilized in PDY5105 as well as in the previous PKD4532 study. This dose
gives exposure greater than that achieved at the therapeutic dose
(10 mg) with any identified intrinsic (age, renal impairment, hepatic
impairment) or extrinsic (inhibition of its metabolism) factors that
increase the exposure of alfuzosin \[Figure (4.1.1) 1\]. In addition, at
a dose of 40 mg, the mean C~max~ and the upper 95% confidence interval
(CI) for C~max~ were equivalent to or greater than those predicted in
BPH patients who are more than 75 years old or who have moderate renal
insufficiency and who are also administered ketoconazole. Therefore, the
40 mg dose utilized in PDY5105 and PDY4532 evaluates alfuzosin exposure
at the upper limits of what might be observed in the target population.

![](media/image8.wmf){width="5.5368055555555555in"
height="4.121527777777778in"}

Figure (4.1.1) 1 - Alfuzosin C~max~ and AUC values after alfuzosin 10 mg
tablet according to intrinsic and extrinsic factors

### Primary method for QT assessment (Holter Bin method)

Holter recordings for the primary analysis were made for moxifloxacin,
alfuzosin, and placebo during a 4‑hour period when the highest drug
concentrations were anticipated (i.e., T7 through T11 hours). The
baseline was defined for each period as the time‑matched interval
(T7-T11 h) of the Day 2 placebo run‑in.

Changes in QT intervals were calculated for each subject and for each RR
bin between the treatment period and the baseline (placebo run-in) to
generate the following primary endpoints:

-   1000 msec RR bin (QT~1000~) corresponding to 60 bpm HR,

-   Largest sample size RR bin: for the RR bin containing the largest
    total number of complexes,

-   Average of all RR bins.

### Secondary method for QT assessment (12-lead ECG)

The conditions of recording and measurements were as follows:

Standard 12-lead ECGs were digitally recorded using a MAC 5000
(Marquette, USA) electrocardiographic machine after the subject had
rested for at least 10 minutes. The ECGs (each consisting of a 10 sec
recording) were performed at specific time points corresponding to the
PK sampling times. A computer-assisted, manual, on-screen measurement of
digitized ECG wave-forms was performed from the digital records, using a
standard methodology: on either lead II (preferably) or V2 to V5 (same
lead for a given subject) the QT interval was determined by the tangent
method ([^30]). RR (msec), PR (msec), QRS intervals (msec), and QT
interval duration (msec) were measured on 3 consecutive complexes and
averaged.

HR, QTcB, QTcF, QTcN and QTcNi were derived from the mean values of the
measured parameters.

The analysis variable was change from baseline for HR, QT and QTcB,
QTcF, QTcN, and QTcNi at the time of individual C~max~ and at hours 7
through 11 (period corresponding to the same period of Holter monitoring
analysis). The baseline value for these analyses was the mean of the
3 measures on Day 3-T0 of each period.

### Sample size calculation and statistical method

Study PDY5105 was designed to provide sufficient power to evaluate both
primary (Holter Bin method) and secondary (standard 12-lead ECG)
pharmacodynamic endpoints. As indicated in the first study (PKD4532),
the statistical power to detect a given difference with the Holter Bin
method is much greater than that with the standard 12‑lead ECG.
Therefore, the sample size calculation is driven by the 12-lead ECG.

Estimates of SD for both endpoints were obtained from the previous
study, PKD4532. For standard 12‑lead ECGs, it was determined that a
minimum of 36 completed subjects would be required to provide 80% power
to detect a 5 msec difference in QTc interval from baseline between
active treatment and placebo, assuming a within-subject standard
deviation of 7.5 msec (the SD~within~ obtained for QTcN in PKD4532 was
7.8 msec). A sample size of 45** **subjects would provide 80% power to
detect a 7.5 msec difference from baseline between active treatment and
placebo assuming a standard deviation of 12.5 msec (the SD~within~
obtained for QTcB in PKD4532 was 12 msec).

For the Holter Bin method primary endpoint, a sample size of at least 36
subjects would provide 88% power to detect a 3 msec difference in QT
interval between active treatment and placebo, assuming a 4 msec
SD~within~ for change from baseline in QT interval at RR=1000 ms (the
SD~within~ obtained for QT interval change from baseline at in PKD4532
was 3.6 msec).

A sample size of 45 subjects would provide 80% power to detect a 3 msec
difference in QT interval between active treatment and placebo, assuming
a 5 msec SD~within~ for change from baseline in QT interval at RR
=1000 ms (upper bound of the 95% CI for SD~within~).

The primary statistical method was prospectively defined as follows:

Mean QT interval change from baseline for each endpoint was analyzed by
a mixed linear‑effects model including terms for subject as random
effect, and sequence, period, and treatment as fixed effects. Pairwise
comparisons were performed using linear contrasts as follows:
moxifloxacin 400 mg *versus* placebo, alfuzosin 10 mg *versus* placebo,
and alfuzosin 40 mg *versus* placebo.

Results from these comparisons are presented as the mean difference
*versus* placebo with its 95% CI.

## 000Results

The primary focus of the results presented below is PDY5105, as this
confirmatory study had an improved design, a larger sample size (48
subjects *versus* 24) and included a positive control. A summary table
of the core results of PKD4532 study is also provided.

Forty-eight male subjects (mean age 27 years; range 19-45 years) were
included in the study and analyzed for safety. Three subjects withdrew
for personal reasons (not safety related) after receiving 1 or 2 doses
of run‑in placebo. Forty‑five subjects received an active treatment,
completed the study, and were evaluated for the pharmacodynamic and
pharmacokinetic analyses.

Figure (4.2) 1 presents the PK profile for alfuzosin 10 mg and 40 mg and
moxifloxacin 400 mg. It confirms that the Holter Bin method and 12-lead
ECG analyses were performed at the time of C~max~ for both drugs, as
prospectively planned.

![](media/image9.wmf){width="4.134027777777778in"
height="3.890972222222222in"}

Figure (4.2) 1 - Mean alfuzosin and moxifloxacin plasma concentrations
*versus* time profiles observed after a single administration of
alfuzosin 10 mg, alfuzosin 40 mg, or moxifloxacin 400 mg (Study PDY5105)

### 000Baseline HR and QT values

Table (4.2.1) 1 shows that pre-dose baseline values of HR and QT were
comparable across treatment groups.

Table (4.2.1) 1 - Baseline HR and QT interval values (mean ± SEM) for
each treatment group (Study PDY5105)

+--------------+---------+----------+----------+----------+-----------+
| **Baseline** | **Para  | **P      | **Alf    | **Alf    | **Mox     |
|              | meter** | lacebo** | uzosin** | uzosin** | ifloxacin |
|              |         |          |          |          | 400 mg**  |
|              |         |          | **10     | **40     |           |
|              |         |          | mg**     | mg**     |           |
+--------------+---------+----------+----------+----------+-----------+
| Holter Bin   | HR      | 60.9 ±   | 60.4 ±   | 61.8 ±   | 61.6 ±    |
| method       | (bpm)   | 1.2      | 1.2      | 1.2      | 1.2       |
|              |         |          |          |          |           |
| Run-in       |         |          |          |          |           |
| placebo      |         |          |          |          |           |
|              |         |          |          |          |           |
| 7 to         |         |          |          |          |           |
| 11 hours     |         |          |          |          |           |
+--------------+---------+----------+----------+----------+-----------+
|              | Q       | 398.9 ±  | 404.0 ±  | 403.5 ±  | 404.7 ±   |
|              | T~1000~ | 3.2      | 3.5      | 3.5      | 3.1       |
|              | (msec)  |          |          |          |           |
+--------------+---------+----------+----------+----------+-----------+
| 12‑lead ECG  | HR      | 54.7 ±   | 54.8 ±   | 55.0 ±   | 54.3 ±    |
| data         | (bpm)   | 1.4      | 1.4      | 1.2      | 1.2       |
|              |         |          |          |          |           |
| pre-dose     |         |          |          |          |           |
| (H0)         |         |          |          |          |           |
+--------------+---------+----------+----------+----------+-----------+
|              | Unco    | 407.1 ±  | 407.4 ±  | 405.7 ±  | 408.9 ±   |
|              | rrected | 4.3      | 4.2      | 4.1      | 4.3       |
|              | QT      |          |          |          |           |
|              | (msec)  |          |          |          |           |
+--------------+---------+----------+----------+----------+-----------+

Baseline values should not be directly compared between methods (Holter
Bin method and 12‑lead ECG) as they were evaluated at different periods
of time.

### Heart rate results

Table (4.2.2) 2 presents the differences *versus* placebo in HR changes
from baseline for the 3 treatment groups, as assessed from 12-lead ECG,
either during the \[7-11h\] time window or at time of individual C~max~.

Moxifloxacin 400 mg increased mean HR by 1.5 to 2.8 bpm *versus*
placebo. Alfuzosin 10 and 40 mg increased HR by 1.5 to 5.2 bpm and 3.7
to 5.8 bpm, respectively, *versus* placebo.

Table (4.2.2) 2 - 12-lead ECG: HR change from baseline for alfuzosin 10
and 40 mg and moxifloxacin 400 mg *versus* placebo, pairwise comparisons
(Study PDY5105)

+-------------------+----------------+------+---------+-------+------+
| **Assessment      | **Treatment**  | **P  | *       | **95% |      |
| Period**          |                | -Val | *Mean** | CI**  |      |
|                   |                | ue** |         |       |      |
|                   |                |      | **Dif   |       |      |
|                   |                |      | ference |       |      |
|                   |                |      | *vs*    |       |      |
|                   |                |      | Placebo |       |      |
|                   |                |      | (bpm)** |       |      |
+-------------------+----------------+------+---------+-------+------+
|                   |                |      |         | **Lo  | *    |
|                   |                |      |         | wer** | *Upp |
|                   |                |      |         |       | er** |
|                   |                |      |         | **Bo  |      |
|                   |                |      |         | und** | *    |
|                   |                |      |         |       | *Bou |
|                   |                |      |         |       | nd** |
+-------------------+----------------+------+---------+-------+------+
| \[H7, H8, H9,     | Alfuzosin 10   | 0.   | 1.5     | -0.0  | 3.0  |
| H10, H11\]        | mg             | 0569 |         |       |      |
+-------------------+----------------+------+---------+-------+------+
|                   | Alfuzosin 40   | 0.   | 3.7     | 2.1   | 5.2  |
|                   | mg             | 0001 |         |       |      |
+-------------------+----------------+------+---------+-------+------+
|                   | Moxifloxacin   | 0.   | 1.5     | -0.1  | 3.0  |
|                   | 400 mg         | 0594 |         |       |      |
+-------------------+----------------+------+---------+-------+------+
| At time of        | Alfuzosin 10   | 0.   | 5.2     | 2.2   | 8.3  |
| individual C~max~ | mg             | 0013 |         |       |      |
+-------------------+----------------+------+---------+-------+------+
|                   | Alfuzosin 40   | 0.   | 5.8     | 3.2   | 8.4  |
|                   | mg             | 0001 |         |       |      |
+-------------------+----------------+------+---------+-------+------+
|                   | Moxifloxacin   | 0.   | 2.8     | 1.3   | 4.2  |
|                   | 400 mg         | 0005 |         |       |      |
+-------------------+----------------+------+---------+-------+------+

Although, these mean changes *versus* placebo appear not to be very
large, there is clearly a larger increase with alfuzosin 40 mg than with
alfuzosin 10 mg. There is also a modest HR increase observed with
moxifloxacin.

In addition, the proportion of subjects with an increase in HR (from
baseline) over 10 bpm was 20%, 14%, 27%, and 47% for placebo,
moxifloxacin, alfuzosin 10 mg and alfuzosin 40 mg, respectively. The
proportion of subjects with an increase over 15 bpm was 33% in the
alfuzosin 40 mg group, as compared to 9% in the placebo group.

These results indicate that, because alfuzosin induces a marked HR
increase in a substantial number of subjects, there is a real potential
for traditional correction formulae (especially QTcB and QTcF, to a
lesser extent QTcN and QTcNi) to result in biased overestimation of QT
changes.

### QT/QTc interval results

For the Holter Bin method, the focus will be mainly on the results
corresponding to the RR=1000 msec (QT~1000~ corresponding to a HR of
60 bpm), as the usual correction formulae (QTcB, QTcF, QTcN and QTcNi)
also use the HR of 60 bpm as the reference for QT correction. The
results for the 2 other Holter Bin endpoints are essentially similar and
are presented in Table (7.4) 1.

Results are presented as QT changes from baseline for alfuzosin 10 mg,
alfuzosin 40 mg, and moxifloxacin 400 mg, in comparison with placebo
over the 7-11 hours time window.

For the standard 12‑lead ECGs, results from the 7 to 11 hour time window
are presented below. The results obtained at the time of C~max~ for each
individual are presented in Table (7.4) 2 and Table (7.4) 3.

#### 000Moxifloxacin

Moxifloxacin 400 mg (the therapeutic dose) produced a clear and highly
statistically significant (p\<0.0001) increase in QT interval,
regardless of the method used \[Table (4.2.3.1) 1\]. These results are
within the range of published data (6).

Moxifloxacin slightly increased mean HR *versus* placebo by 1.5 bpm,
thereby explaining the over‑correction observed with the Bazett and
Fridericia formulae.

Table (4.2.3.1) 1 - QT interval change from baseline for moxifloxacin
400 mg compared to placebo (Study PDY5105)

+--------------------+---------+-------------------+---------+-------+
| **Method**         | **Endp  | **Mean Difference | **95%   | **P   |
|                    | oints** | Between           | CI**    | va    |
|                    |         | Moxifloxacin      |         | lue** |
|                    |         | 400 mg and        |         |       |
|                    |         | Placebo (msec)**  |         |       |
+--------------------+---------+-------------------+---------+-------+
| **Holter Bin       | Q       | \+ 7.0            | 4.4 ;   | 0     |
| method**           | T~1000~ |                   | 9.6     | .0001 |
|                    |         |                   |         |       |
| 7 to 11 hours      |         |                   |         |       |
+--------------------+---------+-------------------+---------+-------+
| **12-lead ECG**    | QTcNi   | \+ 9.4            | 6.9 ;   | 0     |
|                    |         |                   | 11.8    | .0001 |
| \[H7, H8, H9, H10, |         |                   |         |       |
| H11\]              |         |                   |         |       |
+--------------------+---------+-------------------+---------+-------+
|                    | QTcN    | \+ 9.4            | 6.9 ;   | 0     |
|                    |         |                   | 11.9    | .0001 |
+--------------------+---------+-------------------+---------+-------+
|                    | QTcF    | +10.3             | 7.7 ;   | 0     |
|                    |         |                   | 13.0    | .0001 |
+--------------------+---------+-------------------+---------+-------+
|                    | QTcB    | +11.9             | 8.3 ;   | 0     |
|                    |         |                   | 15.6    | .0001 |
+--------------------+---------+-------------------+---------+-------+

#### 000Alfuzosin 

-   Alfuzosin 10 mg (i.e., the therapeutic dose) did not induce any
    statistically significant change in the QT interval, regardless of
    the method used \[Table (4.2.3.2) 1\]. The mean HR increase of
    1.5 bpm compared to placebo during the 7 to 11 hour time window
    explains the over‑correction observed with the Bazett and Fridericia
    formulae.

Table (4.2.3.2) 1 - QT interval change from baseline for alfuzosin 10 mg
compared to placebo (Study PDY5105)

+---------------------+--------+--------------------+--------+--------+
| **Method**          | *      | **Mean Difference  | **95%  | **P    |
|                     | *Endpo | Between Alfuzosin  | CI**   | v      |
|                     | ints** | 10 mg and Placebo  |        | alue** |
|                     |        | (msec)**           |        |        |
+---------------------+--------+--------------------+--------+--------+
| **Holter Bin        | QT     | \+ 0.1             | -2.5 ; | 0.97   |
| method**            | ~1000~ |                    | 2.6    |        |
|                     |        |                    |        |        |
| 7 to 11 hours       |        |                    |        |        |
+---------------------+--------+--------------------+--------+--------+
| **12-lead ECG**     | QTcNi  | \+ 0.5             | -2.0 ; | 0.70   |
|                     |        |                    | 2.9    |        |
| \[H7, H8, H9, H10,  |        |                    |        |        |
| H11\]               |        |                    |        |        |
+---------------------+--------+--------------------+--------+--------+
|                     | QTcN   | \+ 0.5             | -2.0 ; | 0.71   |
|                     |        |                    | 3.0    |        |
+---------------------+--------+--------------------+--------+--------+
|                     | QTcF   | \+ 1.6             | -1.1 ; | 0.24   |
|                     |        |                    | 4.3    |        |
+---------------------+--------+--------------------+--------+--------+
|                     | QTcB   | \+ 3.3             | -0.3 ; | 0.07   |
|                     |        |                    | 6.9    |        |
+---------------------+--------+--------------------+--------+--------+

-   Alfuzosin 40 mg (i.e., 4 times the therapeutic dose) induced a weak,
    albeit statistically significant, QT increase of 2.9 msec when
    assessed with the Holter Bin method \[Table (4.2.3.2) 2\]. However,
    this increase was half of that induced by moxifloxacin at its
    therapeutic dose.

The mean HR increase of 3.7 bpm compared to placebo during the 7 to
11 hour time window, which was associated with the substantial number of
subjects (33%) experiencing an HR increase by more than 15 bpm, explains
the large over‑correction observed with the Bazett and Fridericia
formulae.

Table (4.2.3.2) 2 - QT interval change from baseline for alfuzosin 40 mg
compared to placebo (Study PDY5105)

+---------------------+--------+-------------------+---------+-------+
| **Method**          | *      | **Mean difference | **95%   | **P   |
|                     | *Endpo | Between Alfuzosin | CI**    | va    |
|                     | ints** | 40 mg and Placebo |         | lue** |
|                     |        | (msec)**          |         |       |
+---------------------+--------+-------------------+---------+-------+
| **Holter Bin        | QT     | \+ 2.9            | 0.3 ;   | 0.03  |
| method**            | ~1000~ |                   | 5.5     |       |
|                     |        |                   |         |       |
| 7 to 11 hours       |        |                   |         |       |
+---------------------+--------+-------------------+---------+-------+
| **12-lead ECG**     | QTcNi  | \+ 4.7            | 2.2 ;   | 0     |
|                     |        |                   | 7.1     | .0003 |
| \[H7, H8, H9, H10,  |        |                   |         |       |
| H11\]               |        |                   |         |       |
+---------------------+--------+-------------------+---------+-------+
|                     | QTcN   | \+ 4.6            | 2.1 ;   | 0     |
|                     |        |                   | 7.0     | .0004 |
+---------------------+--------+-------------------+---------+-------+
|                     | QTcF   | \+ 6.9            | 4.2 ;   | 0     |
|                     |        |                   | 9.5     | .0001 |
+---------------------+--------+-------------------+---------+-------+
|                     | QTcB   | +10.8             | 7.2 ;   | 0     |
|                     |        |                   | 14.4    | .0001 |
+---------------------+--------+-------------------+---------+-------+

#### 000PKD4532 QT results

Results from study PDY5105 are consistent with those obtained in the
previous ECG study (PKD4532). In PKD4532, a 2 msec increase for QT~1000~
(Holter Bin method used for primary analysis) was observed, whatever the
dose of alfuzosin (10, 20, and 40 mg) \[Table (4.2.3.3) 1\].

Table (4.2.3.3) 1 - QT interval change for alfuzosin 10 mg, 20 mg, and
40 mg compared to placebo (Study PKD4532)

+-----------------+-------+------------+---------------+------+-------+
| **Method**      | **E   | **T        | **Mean        | *    | **P   |
|                 | ndpoi | reatment** | Difference    | *95% | va    |
|                 | nts** |            | (msec)**      | CI** | lue** |
+-----------------+-------+------------+---------------+------+-------+
| **Holter Bin    | QT~   | Alfuzosin  | \+ 2.0        | \- ; | 0     |
| method**        | 1000~ | 10 mg      |               | 3.2  | .0110 |
|                 |       |            |               |      |       |
| 7 to 11 hours   |       |            |               |      |       |
+-----------------+-------+------------+---------------+------+-------+
|                 | QT~   | Alfuzosin  | \+ 1.9        | \- ; | 0     |
|                 | 1000~ | 20 mg      |               | 3.6  | .0664 |
+-----------------+-------+------------+---------------+------+-------+
|                 | QT~   | Alfuzosin  | \+ 1.7        | \- ; | 0     |
|                 | 1000~ | 40 mg      |               | 3.2  | .0590 |
+-----------------+-------+------------+---------------+------+-------+

[]{.mark}

[]{.mark}

The slight numerical differences observed between the 2 studies are in
the range of variability that can be seen between 2 studies, reaching
also the limit of sensitivity of the method. They are also likely due to
differences in design (no run-in placebo in PKD4532) leading to analyses
with different baselines in the 2 studies. This improvement in the
design of study PDY5105, associated with the use of a positive control
and the larger sample size, resulted in increased precision for this
study.

### 000Outliers

Outlier subjects were analyzed according to standard categorical
analyses of QTc interval data (absolute values QTc\>450 msec and changes
from baseline QTcB\>60 msec).

In total, 7 subjects had a value of QTcB over 450 msec at some point
during the study (maximum value observed was 458 msec). These 7 subjects
experienced this increased (in the range of 450-458 msec) QTcB while on
placebo (2 subjects), moxifloxacin (1 subject), alfuzosin 10 mg
(1 subject), and alfuzosin 40 mg (3 subjects).

Four subjects had delta QTcB intervals over 60 msec (3 on alfuzosin
40 mg and 1 on alfuzosin 10 mg).

In the alfuzosin-treated group, all subjects having either
QTcB\>450 msec or delta QTcB\>60 msec had large HR increases *versus*
baseline (17 to 49 bpm). For these subjects, at the corresponding RR bin
(when available), the absolute QT values assessed by the Holter Bin
method were not higher than 423 msec, and QT changes from baseline were
no more than 5 msec \[Table (7.4) 4\].

No QTcF value over 450 msec or delta QTcF over 60 msec was recorded,
whatever the treatment.

No QTcN or QTcNi value over 450 msec or a delta QTcF over 60 msec was
recorded, whatever the treatment.

Furthermore, the arrhythmia analysis performed on the 24-hour Holter
recording did not show the presence of any ventricular ectopic beat,
including in the alfuzosin 40 mg group at the time of maximal plasma
concentration.

### 000PK/PD relationship

PK/PD relationship for alfuzosin was explored by using data from 12-lead
ECG measured at the time of blood sample collection. As QTcNi has been
shown earlier to be the QT interval correction formula that best
accounts for HR, it will be used as the pharmacodynamic variable.

All data points are used in this analysis, resulting in
1470 observations in the alfuzosin figure (including placebo data).

It is apparent from Figure (4.2.5) 1 that there is a large intrinsic
variability of QTcNi, as shown by the placebo data (0 concentration).
Furthermore, it is noteworthy that there is no increase of more than
35 msec in QTcNi. The relationship between QTcNi and alfuzosin plasma
concentration appears very shallow. At the highest concentrations
obtained in the study (above 80 ng/mL, i.e., the mean C~max~ of
alfuzosin 40 mg), there appears to be no QTcNi increase.

> ![](media/image10.wmf){width="4.223611111111111in"
> height="3.2631944444444443in"}

Figure (4.2.5) 1 - Relationship between QTcNi change from baseline and
mean plasma concentration using data from alfuzosin 10 mg and 40 mg and
placebo (Study PDY5105)

## 000Conclusion

From this confirmatory study (PDY5105), the following conclusions can be
drawn:

-   Using the 12‑lead ECG, moxifloxacin produced statistically
    significant increases of more than 9 msec in QTc interval (range
    from 9.4 to 11.9 msec), regardless of the correction formula. The
    values observed with Bazett's and Fridericia's formulae are
    comparable to values reported in the literature and validate the
    study.

-   Using the Holter Bin method, moxifloxacin (400 mg) produced a
    statistically significant QT~1000~ increase of about 7 msec.

-   Using the same method, the therapeutic dose of alfuzosin produced no
    significant change in the QT interval. At 4 times the therapeutic
    dose, alfuzosin produced a mean QT~1000~ change of 2.9 msec, less
    than half what is observed with moxifloxacin.

-   This study indicates that the Holter Bin method can detect a
    statistically significant change in QT interval as small as 3 msec.
    This demonstrates that the Holter Bin method is sensitive and can
    detect moderate drug‑induced increases of QT interval.

# 000clinical sAFETY

In controlled phase II/III clinical trials conducted in Europe and the
US, 2104 patients suffering from BPH received alfuzosin: 1012 patients
received alfuzosin od, 685 patients received alfuzosin 2.5 mg tid, and
407 patients received alfuzosin 5 mg bid. Post‑marketing experience
including cohort observational surveys (more than 130,000 patients) and
spontaneous reporting (nearly 1350 million therapy‑days of commercial
use) since the launch in Europe in 1988 have provided a very substantial
source of information for the assessment of a potential signal of an
arrhythmogenic risk.

### 000Methodology

Adverse events (AEs) that are potentially suggestive of a proarrhythmic
effect have been quoted in the preliminary concept paper *"The clinical
evaluation of QT/QTc interval prolongation and proarrhythmic potential
for non-antiarrhythmic drugs\" dated 15 November 2002, revised
28 January and 06 February 2003"*. The concept paper distinguishes AEs
reported in clinical studies and in post‑marketing:

-   In clinical trials, the rate of some rare AEs is to be compared to
    the control group (torsades de pointes, ventricular tachycardia,
    ventricular arrhythmia, ventricular ectopy, ventricular fibrillation
    and flutter, cardiac arrest, sudden death, syncope, dizziness,
    palpitations, and seizures).

-   In post‑marketing, the available data should be examined for
    evidence of QT/QTc interval prolongation and torsades de pointes and
    for AEs possibly related to QT/QTc interval prolongation, such as
    cardiac arrest, sudden cardiac death, ventricular arrhythmias (e.g.,
    ventricular tachycardia and ventricular fibrillation). A
    well‑characterized episode of torsades de pointes has a high
    probability of being related to drug use, whereas the other events
    that are reported more commonly may be of significance if seen in a
    population at low risk for them (e.g., young men experiencing sudden
    death).

Therefore, the safety database was reviewed accordingly:

-   In controlled clinical studies, all AEs possibly related to QT/QTc
    interval prolongation were reviewed, whatever the causal
    relationship to study drug and whatever the seriousness criterion.

-   In the post-marketing experience, serious adverse events (SAEs)
    reported to Sanofi‑Synthelabo Pharmacovigilance up to
    31 December 2002 were reviewed, whatever the causal relationship.

### 000Clinical trials

The characteristics of the BPH population included in phase II/III
controlled clinical studies were: men with a mean age of 64±7 (≥65:
47%), 25% suffering from concomitant hypertension, 46% reporting having
a coronary artery disease at baseline, and 48.5% of whom had a
creatinine clearance at baseline below 80 mL/mn (12.5% below 60 mL/mn).

No cases of torsades de pointes, ventricular fibrillation, or
ventricular tachycardia have been reported during the clinical
development of alfuzosin, regardless of the formulation or dose used.
The most frequently reported AEs potentially suggestive of a
proarrhythmic effect, as identified in the preliminary concept paper,
were dizziness (3.5%) and syncope (0.3%) \[Table (7.5) 1\]. These events
are well known to be due to the vasodilatory effect of the
α~1~‑adrenergic blocker class of drugs (15,16,17,[^31]).

In other studies (phase I, extension studies, phase IV, and studies in
non‑BPH indication), including 7084 volunteers or patients, no cases of
torsades de pointes or ventricular fibrillation were reported. Two
elderly volunteers experienced asymptomatic, non‑polymorphic, transient
non-sustained ventricular tachycardia (14 and 17 beat run, 12 and
17 hours post 15 mg od dosing, respectively), a common ECG finding in
elderly volunteers ([^32]). The only fatal case (i.e., sudden death in a
73 year‑old patient receiving 5 mg bid) was reported in a phase IV
non-placebo controlled study. He had been recently diagnosed with angina
pectoris and left ventricular hypertrophy requiring nitrates.

### 000Post-marketing experience

As the first launch of alfuzosin occurred in 1988, an extensive
post‑marketing experience was recorded from cohort observational surveys
and from post‑marketing surveillance. Taking into account the treated
population, i.e., men 65 years-of-age and over in 68% of the cases
(European IMS data, Jan-Dec 2002), having co-morbidity in 68.5% of
cases, including 40% underlying cardiovascular diseases, such as
hypertension (23%) or coronary artery disease (8.5%), and taking
concomitant drugs in 67% of cases ([^33]), the recording of
cardiovascular events was expected. The interpretation of these events
should always take into consideration the medical context and the age of
the treated population.

#### 000Cohort observational surveys

More than 130,000 patients were exposed up to 3 years (mean duration
9 months) to different alfuzosin formulations in cohort observational
surveys up to 31 December 2002. The surveys were not designed to
specifically monitor safety. The number of SAEs involving ventricular
rhythm disorders or which might be related to QT/QTc interval
prolongation according to the preliminary concept paper and recorded by
Sanofi-Synthelabo Pharmacovigilance are presented in Table (7.5) 2.

These data show:

-   No cases of torsades de pointes, ventricular tachycardia, or QT/QTc
    interval prolongation were reported.

-   One case of ventricular fibrillation (possibly related to a
    myocardial infarction) in a patient with risk factors for coronary
    heart disease was reported.

-   Seventeen fatalities related to a cardiac disorder (cardiac arrest,
    sudden cardiac death) were reported in observational surveys. In 14
    out of the 17 patients, a medical history of cardiovascular
    disorders was mentioned (coronary heart disease, myocardial
    infarction, hypertension, or cardiac failure).

-   Twenty-three other reports of death, for which either no specific
    cause or circumstances were noted.

In conclusion, taking into account the elderly population treated with
alfuzosin in general practice, we detected no signal of a potential
arrhythmogenic risk.

> []{.mark}

#### 000Spontaneous reporting

Spontaneously reported SAEs recorded in the Sanofi‑Synthelabo
Pharmacovigilance database transmitted by either the health professional
or health authorities or published in the literature from launch up to
31 December 2002 were reviewed. The estimated number of therapy days
with alfuzosin (all formulations) up to 31 December 2002 is about
1350 million.

-   Neither torsades de pointes nor QT interval prolongation was
    reported.

-   Seven cases of ventricular arrhythmias (ventricular tachycardia:
    N=3, ventricular fibrillation: N=4) were reported. In 1 case, the
    role of alfuzosin was excluded (the AE occurred 16 days after the
    last intake of alfuzosin) and in the remaining 6 reports, all
    patients were suffering from pre-existing cardiac disorders.

-   Cardiac arrests following the first intake of a 2.5 mg tablet of
    alfuzosin were reported in 2 patients (71 and 79 years-of-age)
    treated with concomitant antihypertensive and vasodilatory drugs.
    Both patients recovered.

-   Five cases of sudden death in patients aged between 56 and 83 years
    were noted. In all cases except 1, either a family history of sudden
    death or medical history of cardiac disorder or myocardial
    infarction were reported by the notifiers.

Overall, the reporting rate of spontaneous cases of events potentially
related to QT/QTc interval prolongation is estimated to be 1 per
100 million therapy days, and the rate of fatality (N=7) is estimated to
be 0.6 per 100 million therapy days. This low rate clearly does not
provide a signal for an arrhythmogenic potential of alfuzosin,
especially in a middle-aged/elderly male population frequently
presenting concomitant risk factors.

#### 000Post-marketing experience conclusion

Post-marketing information has been gathered on alfuzosin since the
first launch in 1988. Alfuzosin is marketed in 108 countries worldwide,
with an experience of nearly 1350 million therapy days. From this vast
experience, no arrhythmogenic signal has been detected:

-   from cohort observational surveys (more than 130,000 patients),

-   from spontaneous notification from health professionals,

-   from reports from national health authorities, or

-   from cases in the literature.

### 000Overall clinical safety conclusion

-   No signal regarding cardiac arrhythmia related to QT/QTc interval
    prolongation with alfuzosin was detected in the clinical trials
    safety database.

-   Furthermore, a strong confirmation of this statement is provided by
    the large post‑marketing experience with alfuzosin in a population
    unrestricted for prescription.

# 000Overall interpretation

## 000Validity of the approach

The validity of our approach on the potential effects of alfuzosin on
cardiac repolarization can be critically reviewed in light of the recent
preliminary concept paper issued by the FDA on "The clinical evaluation
of QT/QTc interval prolongation and proarrhythmic potential for
non‑antiarrhythmic drugs".

### 000Approaches to the correction of QT interval for drugs that affect HR

In both studies evaluating the effects of alfuzosin on QT interval, the
magnitude of HR changes is not compatible with the use of Bazett's and
Fridericia's formulae, which over‑correct at increased HRs.

The inability of the Bazett's and Fridericia's correction factors to
fully compensate for the effects of HR on the QT interval was
demonstrated by the strong correlation between QT and RR interval
established using the placebo data from PKD4532 and PDY5105.

The Holter Bin method, on which our primary analyses is based, allows a
direct comparison between QT interval under treatment and QT interval
under placebo at similar HR, thereby avoiding the use of a correction
factor.

The QT variations obtained for both the positive control (moxifloxacin)
and the 2 doses of alfuzosin using the Holter Bin method are in closer
agreement with those obtained using population-specific (QTcN) and
individual-specific (QTcNi) correction methods, which are other methods
developed to accommodate for changes in HR.

### 000Clinical trial design for the assessment of QT interval prolongation

The design of study PDY5105 was developed with the help of experts and
with concurrence from the FDA. The design of this study was in agreement
with the methodology recommendations proposed in the recent concept
paper (5).

***Main features of the study design***

PDY5105 was a 4‑way crossover, single-dose, randomized, double-dummy,
and placebo‑controlled study. The 4 treatments were placebo, alfuzosin
at 10 and 40 mg, and moxifloxacin (400 mg). A 1-day assessment of QT
interval under placebo allowed a time matching of the comparative
periods for treatment and placebo. In addition, blood samples were
collected at the time of ECG recordings.

***Positive controls***

Moxifloxacin was a good positive control candidate because it induces a
consistent and modest increase in QT/QTc intervals after administration
of a single dose of 400 mg. In PDY5105, moxifloxacin provided increases
in QTcB and QTcF in line with previously published studies using
standard ECG techniques.

***Statistical power***

This study was powered to detect QT interval changes of 3 msec and of
5 msec (Holter Bin method and standard resting ECG analysis,
respectively).

***Dose selection***

In study PDY5105 a potential dose effect was investigated by
administering alfuzosin doses of 10 mg and 40 mg.

The 40 mg dose (4 times the therapeutic dose) allowed the exploration of
concentrations higher than those achieved following therapeutic dose
administration. This dose produced plasma concentrations greater than
any factor shown to increase exposure to alfuzosin at therapeutic doses.
A single dose was chosen because there is little accumulation of
alfuzosin after repeated administration.

The maximum dose of alfuzosin used was close to the maximum tolerated
dose and was agreed upon with the FDA. The administration of doses
higher than 40 mg could have led to major vasodilatory effects in some
healthy volunteers.

The design of the first study (PKD4532) was essentially similar to
PDY5105, although it did not include a positive control and a 1-day
placebo run-in. According to current methodological standards, the
design of these 2 studies is appropriate for the thorough assessment of
QT interval variations.

## 000The risk of cardiac arrhythmia associated with these results

Data from the 2 studies discussed in this document consistently show
that the effect on QT interval assessed using the Holter Bin method was
in the range of 2 to 3 msec, even at doses up to 4 times the therapeutic
dose of alfuzosin. Using the same Holter Bin method, moxifloxacin at the
therapeutic dose of 400 mg increased QT interval by 7 msec.

It is recognized by the recent concept paper that drugs that produce a
maximum effect on QT interval of less than 5 msec have not at this time
been associated with torsades de pointes. This fact has recently been
reported in a paper published by Shah ([^34]).

Study PDY5105 demonstrates that the increase in QT interval for
alfuzosin was less than for moxifloxacin, a drug already approved.
Further, this 2 to 3 msec QT increase for alfuzosin was below the 5 msec
threshold quoted in the concept paper as being without repolarization
risk.

The results of the Holter Bin method were robust and in the same range
as results using the subject-specific correction method (QTcNi).

The large safety experience with alfuzosin corroborates the lack of
signal of arrhythrogenic risk seen in the ECG studies performed. No
signal regarding cardiac arrhythmia related to QT/QTc interval
prolongation with alfuzosin was detected in the clinical trials safety
database. Furthermore, a strong confirmation of this statement is
provided by the large post‑marketing experience with alfuzosin.

In conclusion, thorough clinical assessment of the effect of alfuzosin
on QT interval is not indicative of a prolongation of QT interval that
could be associated with ventricular arrhythmia. This conclusion is
corroborated by the absence of a signal of ventricular arrhythmia in a
large clinical and post‑marketing experience

# 000Supportive information

## 000Summaries of study reports

### 000Summary of INT5056

+----------------+-----------------------------------------------------+
| **Title of the | Assessment of pharmacokinetic drug interaction      |
| study:**       | between alfuzosin 10 mg od formulation and          |
|                | ketoconazole 400 mg per day in healthy male         |
|                | subjects. (INT5056)                                 |
+----------------+-----------------------------------------------------+
| *              | The purpose of this study was:                      |
| *Objectives:** |                                                     |
|                | -   To assess the effect of repeated oral doses of  |
|                |     400 mg ketoconazole on the pharmacokinetic      |
|                |     profile of a single oral dose 10 mg alfuzosin   |
|                |     once daily (od) formulation.                    |
|                |                                                     |
|                | -   To assess the clinical and biological safety    |
|                |     and tolerability of 10 mg alfuzosin od          |
|                |     formulation given alone and co‑administered     |
|                |     with 400 mg ketoconazole after repeated daily   |
|                |     doses of ketoconazole.                          |
+----------------+-----------------------------------------------------+
| **             | This was a single-center, open-labeled,             |
| Methodology:** | non-randomized, two‑period study performed in       |
|                | 12 healthy male subjects.                           |
+----------------+-----------------------------------------------------+
| **Number of    | Planned: 12 Randomized: 13 Treated: 13              |
| subjects:**    |                                                     |
+----------------+-----------------------------------------------------+
| **Evaluated:** | Pharmacokinetics: 12 Safety: 13                     |
+----------------+-----------------------------------------------------+
| **Diagnosis    | Healthy male Caucasian aged between 18 and 40 years |
| and criteria   | with a body mass index between 18 and 25.           |
| for            |                                                     |
| inclusion:**   |                                                     |
+----------------+-----------------------------------------------------+
| **Test         | alfuzosin hydrochloride                             |
| product:**     |                                                     |
+----------------+-----------------------------------------------------+
| Dose:          | 1 alfuzosin 10 mg tablet od                         |
+----------------+-----------------------------------------------------+
| A              | oral route with 200 mL of non‑carbonated water in   |
| dministration: | fed conditions                                      |
+----------------+-----------------------------------------------------+
| **Interaction  | ketoconazole                                        |
| drug:**        |                                                     |
+----------------+-----------------------------------------------------+
| Dose:          | 2 ketoconazole 200 mg tablets od (i.e., 400 mg)     |
+----------------+-----------------------------------------------------+
| A              | oral route with 200 mL of non-carbonated water in   |
| dministration: | fed conditions                                      |
+----------------+-----------------------------------------------------+
| **Criteria for |                                                     |
| evaluation:**  |                                                     |
+----------------+-----------------------------------------------------+
| Pha            | Plasma concentrations:                              |
| rmacokinetics: |                                                     |
|                | -   alfuzosin concentrations were assessed in       |
|                |     samples collected before dosing and 0.5, 1, 2,  |
|                |     3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 48, 72 and 96 |
|                |     hours after alfuzosin od administration on      |
|                |     Day 1 Period 1 and on Day 7 Period 2.           |
|                |                                                     |
|                | -   ketoconazole concentrations were assessed in    |
|                |     samples collected in Period 2: before treatment |
|                |     on Day 1, before dosing on Day 7, then 0.5, 1,  |
|                |     2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 24 hours    |
|                |     after ketoconazole administration on Day 7, and |
|                |     24 hours after ketoconazole administration on   |
|                |     Day 8.                                          |
|                |                                                     |
|                | Plasma pharmacokinetic parameters:                  |
|                |                                                     |
|                | -   alfuzosin: t~lag~, C~max~, t~max~, AUC~last~,   |
|                |     t~1/2Z~ and AUC on Day 1 Period 1 and on Day 7  |
|                |     Period 2.                                       |
|                |                                                     |
|                | -   Ketoconazole: C~max~, t~max~, AUC~0-24~ on      |
|                |     Day 7 Period 2.                                 |
+----------------+-----------------------------------------------------+
| Pha            | Not applicable.                                     |
| rmacodynamics: |                                                     |
+----------------+-----------------------------------------------------+
| Safety:        | -   Adverse events spontaneously reported by the    |
|                |     subject or observed by the investigator.        |
|                |                                                     |
|                | -   Laboratory parameters: routine blood tests.     |
|                |                                                     |
|                | -   Vital signs: heart rate, blood pressure.        |
|                |                                                     |
|                | -   Electrocardiogram (ECG) parameters (ECG         |
|                |     automatic reading).                             |
+----------------+-----------------------------------------------------+

(continued)

*(INT5056 continued)*

+----------------+-----------------------------------------------------+
| *              | Plasma concentrations of alfuzosin were assayed by  |
| *Bioanalytical | a validated high-performance liquid chromatography  |
| methods**      | (HPLC) method with spectrofluorometric detection;   |
|                | the limit of quantification was 0.5 ng/mL           |
|                | (DOH0212).                                          |
|                |                                                     |
|                | Plasma concentrations of ketoconazole were assayed  |
|                | by a validated HPLC method with spectrofluorometric |
|                | detection; the limit of quantification was 10 ng/mL |
|                | (Cephac/SOP No. 834 version b).                     |
+----------------+-----------------------------------------------------+
| **Statistical  |                                                     |
| methods:**     |                                                     |
+----------------+-----------------------------------------------------+
| Pha            | -   Alfuzosin: Pharmacokinetic parameters t~lag~,   |
| rmacokinetics: |     C~max~, t~max~, AUC~last~, t~1/2Z~ and AUC were |
|                |     summarized by descriptive statistics on Day 1   |
|                |     Period 1 (alfuzosin alone) and Day 7 Period 2   |
|                |     (alfuzosin + ketoconazole). Prior to the        |
|                |     analyses described below, C~max~, AUC~last,~    |
|                |     and AUC values were log‑transformed, t~max~ was |
|                |     rank transformed and t~1/2Z~ values were        |
|                |     replaced by the constant rate λ~z~. To compare  |
|                |     treatment periods, all pharmacokinetic          |
|                |     parameters were analyzed by analysis of         |
|                |     variance (ANOVA) using a model with a fixed     |
|                |     term for treatment and a random term for        |
|                |     subject. For C~max~, AUC~last~ and AUC the      |
|                |     magnitude of treatment differences was          |
|                |     estimated with 90% confidence intervals (CIs)   |
|                |     by first computing estimates with CIs for the   |
|                |     differences between treatment means in the      |
|                |     ANOVA framework, and then converting to ratios  |
|                |     of geometric means using antilogarithm          |
|                |     transformation. The magnitude of the effect of  |
|                |     ketoconazole on alfuzosin od formulation        |
|                |     pharmacokinetics was based on the estimated     |
|                |     ratios and 90% CIs.                             |
|                |                                                     |
|                | -   Ketoconazole: The pharmacokinetic parameters    |
|                |     C~max~, t~max~ and AUC~0-24h~ were summarized   |
|                |     by descriptive statistics on Day 7 Period 2     |
|                |     (alfuzosin + ketoconazole).                     |
+----------------+-----------------------------------------------------+
| Pha            | Not applicable.                                     |
| rmacodynamics: |                                                     |
+----------------+-----------------------------------------------------+
| P              | Not applicable.                                     |
| harmacokinetic |                                                     |
| /              |                                                     |
| p              |                                                     |
| harmacodynamic |                                                     |
| relationship:  |                                                     |
+----------------+-----------------------------------------------------+
| Safety:        | The clinical safety analysis was descriptive and    |
|                | focused on treatment emergent adverse events        |
|                | (TEAEs). Analyses on laboratory parameters, vital   |
|                | signs and ECG parameters were based on the          |
|                | definitions of potentially clinically significant   |
|                | abnormalities (PCSA). The main analysis focused on  |
|                | the alfuzosin administrations: comparison of        |
|                | Period 1 Day 1 (alfuzosin alone) and Period 2 Day 7 |
|                | (co‑administration alfuzosin and ketoconazole). The |
|                | secondary safety analysis included the entire       |
|                | ketoconazole administration period (Period 2 Day 1  |
|                | to Day 8).                                          |
+----------------+-----------------------------------------------------+

(continued)

*(INT5056 continued)*

+----------------+-----------------------------------------------------+
| **Summary:**   |                                                     |
+----------------+-----------------------------------------------------+
| P              | Mean (standard deviation \[SD\]) alfuzosin          |
| harmacokinetic | pharmacokinetic parameters obtained after a single  |
| results:       | oral administration, in fed conditions, of          |
|                | alfuzosin 10 mg od alone or co‑administered on      |
|                | Day 7 over an 8‑day repeated 400 mg ketoconazole    |
|                | administration are presented in the table below:    |
|                |                                                     |
|                | +-----------+-----------+-----------+-----------+   |
|                | | **Mean    | **Al      | **        | **Ratio   |   |
|                | | (SD)**    | fuzosin** | Alfuzosin | \[90%     |   |
|                | |           |           | +**       | CI\]**    |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | **Par     | **alone   | **ket     | **or p    |   |
|                | | ameters** | (n=12)**  | oconazole | value**   |   |
|                | |           |           | (n=12)**  |           |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | t~lag~    | 0.5 \[0.0 | 0.0 \[0.0 | \-        |   |
|                | | (h)^a^    | -- 2.0\]  | -- 1.0\]  |           |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | C~max~    | 13.5      | 28.8      | 2.31      |   |
|                | | (ng/mL)   | (6.6)     | (6.8)     | \[1.90 -- |   |
|                | |           |           |           | 2.80\]    |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | t~max~    | 8.0 \[3.0 | 10.0      | p = 0.33  |   |
|                | | (h)^a^    | -- 12.0\] | \[6.0 --  |           |   |
|                | |           |           | 12.0\]    |           |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | t~last~   | 24.0      | 48.0      | \-        |   |
|                | | (h)^a^    | \[24.0 -- | \[24.0 -- |           |   |
|                | |           | 48.0\]    | 48.0\]    |           |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | AUC~last~ | 175.2     | 517.9     | 3.18      |   |
|                | | (ng.h/mL) | (83.3)    | (130.1)   | \[2.68 -- |   |
|                | |           |           |           | 3.76\]    |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | t~1/2z~   | 7.6^b^    | 8.8 (2.7) | p =       |   |
|                | | (h)       | (3.0)     |           | 0.02^b^   |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | AUC       | 189.9^b^  | 543.3     | 2.97      |   |
|                | | (ng.h/mL) | (85.6)    | (138.6)   | \[2.54 -- |   |
|                | |           |           |           | 3.48\]^b^ |   |
|                | +-----------+-----------+-----------+-----------+   |
|                | | a: median |           |           |           |   |
|                | | values    |           |           |           |   |
|                | | \[min --  |           |           |           |   |
|                | | max\]     |           |           |           |   |
|                | |           |           |           |           |   |
|                | | b: n=11   |           |           |           |   |
|                | +-----------+-----------+-----------+-----------+   |
|                |                                                     |
|                | The statistical analysis performed on alfuzosin     |
|                | pharmacokinetic parameters showed that the 8-day    |
|                | repeated administration of ketoconazole 400 mg      |
|                | daily increased C~max~ of alfuzosin by 2.3-fold.    |
|                | For t~max~ no statistically significant difference  |
|                | was found, the t~max~ being unchanged. The 8-day    |
|                | repeated administration of ketoconazole 400 mg      |
|                | daily increased AUC~last~ and AUC of alfuzosin by   |
|                | 3.2 and 3.0, respectively. t~1/2z~ was              |
|                | statistically different after ketoconazole          |
|                | co-administration (p=0.02) with a slight mean       |
|                | increase of 1.16-fold.                              |
+----------------+-----------------------------------------------------+
| Safety         | The most frequent observed TEAE during the study    |
| results:       | was headache, which was most frequently reported    |
|                | after co‑administration of ketoconazole and         |
|                | alfuzosin (6 cases). No headache was reported after |
|                | single administration of alfuzosin. Two cases of    |
|                | nausea, 1 case of vomiting and 1 case of hot        |
|                | flushes were reported after co‑administration of    |
|                | ketoconazole and alfuzosin. One case of vagal       |
|                | malaise was reported 4 hours after single           |
|                | administration of alfuzosin (Day 1 Period 1). One   |
|                | case of thrombocytopenia (90 Giga/L) was reported   |
|                | after single administration of alfuzosin (Day 1     |
|                | Period 1). The thrombocytopenia was of mild         |
|                | intensity and lead to study discontinuation. This   |
|                | case was considered to be not related to study      |
|                | treatment due to preexisting low platelet count     |
|                | before study drug intake (119 Giga/L). There were   |
|                | no deaths or serious adverse events during the      |
|                | study.                                              |
|                |                                                     |
|                | No clinically relevant abnormalities in laboratory  |
|                | tests were noted at the end of the study period     |
|                | except 1 subject who had a creatinine kinase value  |
|                | above the PCSA limit (i.e., 793 U/L -- 4.17 ULN) at |
|                | the end‑of‑study visit, 5 days after the            |
|                | co‑administration of ketoconazole and alfuzosin.    |
|                | Values returned to normal after the study.          |
|                |                                                     |
|                | No subjects with orthostatic hypotension or         |
|                | decrease in blood pressure were identified on Day 1 |
|                | Period 1 and Day 7 Period 2.                        |
|                |                                                     |
|                | No QTc\>450 ms or change from baseline in           |
|                | QTc\>60 ms were observed.                           |
+----------------+-----------------------------------------------------+

(continued)

*(INT5056 continued)*

+----------------+-----------------------------------------------------+
| Conclusions:   | In fed conditions, repeated administration of       |
|                | 400 mg ketoconazole once daily over 8 days resulted |
|                | in a 2.3‑, 3.2‑ and 3.0‑fold increase in alfuzosin  |
|                | C~max~, AUC~last~, and AUC, respectively, observed  |
|                | after a single administration of alfuzosin 10 mg    |
|                | od. Under these study conditions, there were no     |
|                | safety issues associated with laboratory results,   |
|                | hemodynamic parameters and ECGs.                    |
|                |                                                     |
|                | A slight increase in frequency of adverse events,   |
|                | mainly headache, was observed with the              |
|                | co‑administration of ketoconazole and alfuzosin.    |
+----------------+-----------------------------------------------------+

### 000Summary of PKD4532

+----------------+-----------------------------------------------------+
| **Title of the | Effects of supratherapeutic doses of alfuzosin      |
| study:**       | 10 mg OD formulation on ECG parameters (PKD4532)    |
+----------------+-----------------------------------------------------+
| *              | **Primary**                                         |
| *Objectives:** |                                                     |
|                | -   To assess the effect of supratherapeutic doses  |
|                |     of alfuzosin administered as a once daily (OD)  |
|                |     formulation on electrocardiogram (ECG)          |
|                |     parameters.                                     |
|                |                                                     |
|                | **Secondary**                                       |
|                |                                                     |
|                | -   To assess the pharmacokinetic profile of        |
|                |     alfuzosin (OD formulation) given at doses of    |
|                |     10, 20, and 40 mg/day.                          |
|                |                                                     |
|                | -   To assess the clinical safety (including blood  |
|                |     pressure and heart rate) and tolerability of    |
|                |     single supratherapeutic doses of the alfuzosin  |
|                |     OD formulation                                  |
+----------------+-----------------------------------------------------+
| **             | Single-center, placebo-controlled, double-blind,    |
| Methodology:** | single-dose, randomized, crossover study. Subjects  |
|                | were randomized to 1 of 24 unique sequences after   |
|                | which they were treated with a single dose and      |
|                | observed over 48 hours for each of the 4 dose       |
|                | periods.                                            |
+----------------+-----------------------------------------------------+
| **Number of    | Planned: 24                                         |
| subjects:**    |                                                     |
|                | Treated: 24                                         |
|                |                                                     |
|                | Evaluable: 24                                       |
+----------------+-----------------------------------------------------+
| **Diagnosis    | Healthy Caucasian male subjects aged 18-40 years    |
| and criteria   | with body mass index (BMI) between 18.5 and 28 and  |
| for            | body weight between 50 and 90 kg.                   |
| inclusion:**   |                                                     |
+----------------+-----------------------------------------------------+
| **Test         | Alfuzosin hydrochloride 10 mg tablets OD            |
| product:**     |                                                     |
+----------------+-----------------------------------------------------+
| Dose:          | 10, 20, or 40 mg                                    |
+----------------+-----------------------------------------------------+
| A              | Four tablets (alfuzosin and/or placebo) were        |
| dministration: | administered orally 5 minutes after a standardized  |
|                | high fat breakfast with 200 mL of non-carbonated    |
|                | water with subjects in a semi-recumbent position.   |
+----------------+-----------------------------------------------------+

*(continued)*

(PKD4532 *continued*)

+----------------+-----------------------------------------------------+
| **Reference    |                                                     |
| therapy (dose, |                                                     |
| route of       |                                                     |
| administratio  |                                                     |
| n):**Identical |                                                     |
| placebo        |                                                     |
| tablets OD     |                                                     |
+----------------+-----------------------------------------------------+
| **Criteria for |                                                     |
| evaluation:**  |                                                     |
+----------------+-----------------------------------------------------+
| Ph             | **Primary**                                         |
| armacodynamic: |                                                     |
|                | -   Manual ECG reading \[Heart rate (HR), QRS       |
|                |     duration, PR, QT intervals, QTcB, QTcF\]        |
|                |                                                     |
|                | -   Holter analysis (selective beat averaging)      |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   Mean of Delta *versus* Screening QT interval at |
|                |     RR overlap                                      |
|                |                                                     |
|                | -   Mean of Delta *versus* Placebo QT interval at   |
|                |     RR overlap                                      |
|                |                                                     |
|                | **Secondary**                                       |
|                |                                                     |
|                | -   Manual ECG reading \[raw data and delta         |
|                |     *versus* baseline\]                             |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   Emax~(H0.5-12)~, (HR, QTcB, QTcF) and T~max~    |
|                |                                                     |
|                | -   Emax~(H0.5-24)~ (HR, QTcB, QTcF) and T~max~     |
|                |                                                     |
|                | -   Emean~(H0.5-12)~ (HR, QTcB, QTcF)               |
|                |                                                     |
|                | -   Emean~(H0.5-24)~ (HR, QTcB, QTcF)               |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   Automatic ECG reading \[delta *versus*          |
|                |     baseline\]                                      |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   (HR, QRS duration, PR, QT, QTc intervals)       |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   Holter analysis (selective beat averaging)      |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   Mean of Delta *versus* Screening QT interval at |
|                |     maximum RR overlap                              |
|                |                                                     |
|                | -   Mean of Delta *versus* Placebo QT interval at   |
|                |     maximum RR overlap                              |
|                |                                                     |
|                | -   Mean of Delta *versus* Screening QT interval at |
|                |     fixed RR                                        |
|                |                                                     |
|                | -   Mean of Delta *versus* Placebo QT interval at   |
|                |     fixed RR                                        |
+----------------+-----------------------------------------------------+
| Ph             | -   C~max~, t~max~, t~1/2z~, AUC~last~, and AUC     |
| armacokinetic: |                                                     |
+----------------+-----------------------------------------------------+
| Safety:        | **Primary**                                         |
|                |                                                     |
|                | -   Vital signs \[HR, systolic blood pressure       |
|                |     (SBP), diastolic blood pressure (DBP)\]         |
|                |                                                     |
|                | **Secondary**                                       |
|                |                                                     |
|                | -   Adverse events                                  |
|                |                                                     |
|                | -   Biochemistry, hematology, and urinalysis        |
|                |                                                     |
|                | -   Vital signs - Emax~(H0.5-24)~ (HR, SBP, DBP)    |
|                |     and T~max~                                      |
|                |                                                     |
|                | -   Holter analysis (heart rate variability and     |
|                |     descriptive analysis)                           |
+----------------+-----------------------------------------------------+
| **Statistical  | Specific pharmacodynamics based on ECG, and safety  |
| methods:**     | based on hemodynamic parameters were analyzed. Mean |
|                | post-dose treatment effects were tested on absolute |
|                | changes from baseline. Analysis for repeated        |
|                | measurement using a mixed linear effects model      |
|                | (SAS PROC MIXED) included terms for subject as a   |
|                | random effect, for period, time and treatment as    |
|                | fixed effects, and for treatment\*time as an        |
|                | interaction. If the treatment\*time interaction was |
|                | significant, separate analysis at each time point   |
|                | was performed. If the treatment effect was          |
|                | significant, pairwise treatment comparisons         |
|                | *versus* placebo were done using linear contrasts.  |
|                | Results from the relevant comparisons were          |
|                | presented as mean differences with one-sided 95%    |
|                | confidence intervals (CI).                          |
|                |                                                     |
|                | Holter analysis was based on QT analysis of         |
|                | selectively averaged beats. Comparisons of mean     |
|                | absolute changes from screening were performed for  |
|                | each of 2 circadian conditions (Peak, Night) using  |
|                | a mixed linear model with terms for subject as      |
|                | random effect, period and treatment as fixed        |
|                | effects. If a significant treatment effect was      |
|                | detected, pairwise comparisons were done and        |
|                | presented as in the analysis of ECGs.               |
+----------------+-----------------------------------------------------+

*(continued)*

(PKD4532 *continued*)

<table>
<colgroup>
<col style="width: 3%" />
<col style="width: 15%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 28%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 3%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="3"><p><strong>Statistical methods:</strong></p>
<p><em>(continued)</em></p></td>
<td colspan="7"><p>Comparison <em>versus</em> the null hypothesis was
performed on change in QT <em>versus</em> placebo for each circadian
condition and for each treatment. Results were expressed as means with
one‑sided 95% confidence intervals. All Holter parameters were
summarized by descriptive statistics.</p>
<p>Pharmacokinetic parameters were summarized using descriptive
statistics.</p>
<p>The tolerability evaluations were based upon the review of the
individual values and descriptive statistics.</p></td>
</tr>
<tr class="even">
<td colspan="3"><p><strong>Summary:</strong></p>
<p>Pharmacodynamic results:</p></td>
<td colspan="7"><p><u>ECG</u></p>
<p>The population consisted of healthy males aged 22 to 40 years of
average body mass index (20.9 to 27.3). Their ECG profiles were
statistically comparable at baseline.</p>
<p>There were no significant increases in the PR or QT intervals in the
pairwise comparisons <em>versus</em> placebo at any dose level of
alfuzosin. There was a statistically significant increase of +0.6 ms
[upper boundary of 95% CI (UB): +1.0] in delta QRS duration at only the
10 mg dose.</p>
<p>Individual alfuzosin <em>versus</em> placebo treatment contrasts
identified statistically significant differences between both the 20 mg
and 40 mg doses and placebo treatment for HR, QTcB and QTcF with respect
to delta baseline values (see following table). Analyses of Emean on
delta baseline values supported this outcome while analyses of Emax
showed a similar effect for delta HR only. These effects were not seen
with the 10 mg alfuzosin dose.</p></td>
</tr>
<tr class="odd">
<td colspan="3"></td>
<td colspan="7">The increase in delta HR and QTc occurred in a
dose-dependent fashion (see table below).</td>
</tr>
<tr class="even">
<td></td>
<td colspan="8"><strong>Analysis of Absolute ECG Changes from Baseline
(H0.5 to H24)</strong></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td><strong>Parameter</strong></td>
<td colspan="2"><strong>Fixed Effect</strong></td>
<td><strong>P‑value</strong></td>
<td><strong>Pairwise Comparison</strong></td>
<td><strong>P‑value</strong></td>
<td><strong>Mean Difference</strong></td>
<td><p><strong>95% CI</strong></p>
<p><strong>UB</strong></p></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Delta HR (bpm)</td>
<td colspan="2">Treatment</td>
<td>0.0001</td>
<td><p>SL770499 10 mg <em>vs</em> PLACEBO</p>
<p>SL770499 20 mg <em>vs</em> PLACEBO</p>
<p>SL770499 40 mg <em>vs</em> PLACEBO</p></td>
<td><p>0.1011</p>
<p>0.0001*</p>
<p>0.0001*</p></td>
<td><p>+0.6</p>
<p>+4.6</p>
<p>+5.8</p></td>
<td><p>+1.3</p>
<p>+5.4</p>
<p>+6.5</p></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>Delta QTcB (ms)</td>
<td colspan="2">Treatment</td>
<td>0.0001</td>
<td><p>SL770499 10 mg <em>vs</em> PLACEBO</p>
<p>SL770499 20 mg <em>vs</em> PLACEBO</p>
<p>SL770499 40 mg <em>vs</em> PLACEBO</p></td>
<td><p>0.1416</p>
<p>0.0001*</p>
<p>0.0001*</p></td>
<td><p>+1.2</p>
<p>+8.5</p>
<p>+13.2</p></td>
<td><p>+3.0</p>
<p>+10.3</p>
<p>+15.0</p></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Delta QTcF (ms)</td>
<td colspan="2">Treatment</td>
<td>0.0001</td>
<td><p>SL770499 10 mg <em>vs</em> PLACEBO</p>
<p>SL770499 20 mg <em>vs</em> PLACEBO</p>
<p>SL770499 40 mg <em>vs</em> PLACEBO</p></td>
<td><p>0.2673</p>
<p>0.0001*</p>
<p>0.0001*</p></td>
<td><p>+0.5</p>
<p>+3.4</p>
<p>+7.1</p></td>
<td><p>+1.8</p>
<p>+4.7</p>
<p>+8.4</p></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="8">(*) = Statistically significant at a comparisonwise
one-sided error rate of 0.05</td>
<td></td>
</tr>
</tbody>
</table>

*(continued)*

(PKD4532 *continued*)

<table>
<colgroup>
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 12%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 6%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="3"><p><strong>Summary:</strong></p>
<p>Pharmacodynamic results:</p>
<p><em>(continued)</em></p></td>
<td colspan="11"><p><u>Holter Monitoring</u></p>
<p>Holter monitoring provided a method for analyzing QT interval that
was subject‑specific and independent of HR, by selective beat averaging
(SBA). The QT intervals analyzed were those around the time of
C<sub>max</sub> (Peak H7 to H11) and during the night (H16 to H20).</p>
<p>In the comparison <em>versus</em> the null hypothesis performed on QT
differences between alfuzosin and placebo, statistically significant
effects were observed during Peak (approximate time of C<sub>max</sub>),
see table below. Mean differences were approximately +2 ms regardless of
the RR interval analyzed, and no upper boundary values of the 95% CI
exceeded +4 ms. The observed treatment effects did not appear to be
dose-related. The difference observed is in the same range of magnitude
as spontaneous changes over time under placebo.</p>
<p>No significant changes were observed during the night.</p>
<p>There was no modification of T‑wave morphology by any treatment
groups. No notable changes in PR interval or QRS duration were
observed.</p></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="12"><strong>Mean (One-Sided 95% CI) QT Differences (ms)
from Placebo</strong></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td colspan="5"></td>
<td colspan="3"><strong>Alfuzosin 10 mg</strong></td>
<td><strong>Alfuzosin 20 mg</strong></td>
<td colspan="3"><strong>Alfuzosin 40 mg</strong></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="12"><strong>Peak [C<sub>max</sub>] (H7 - H11)</strong></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td colspan="5">Average QT (ms) at RR overlap</td>
<td colspan="3">1.7 [-, 2.9]*</td>
<td>2.1 [-, 3.3]**</td>
<td colspan="3">1.8 [-, 3.3]*</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="5">QT at fixed RR [RR=1000 ms] = QT<sub>1000</sub></td>
<td colspan="3">2.0 [-, 3.2]*</td>
<td>1.9 [-, 3.6]</td>
<td colspan="3">1.7 [-, 3.2]</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td colspan="12"><strong>Night (H16 - H20)</strong></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="5">Average QT (ms) at RR overlap</td>
<td colspan="3">-0.5 [-, 1.0]</td>
<td>-1.6 [-, 0.1]</td>
<td colspan="3">-1.5 [-, -0.2]</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td colspan="5">QT at fixed RR [RR=1000 ms] = QT<sub>1000</sub></td>
<td colspan="3">-0.7 [-, 0.6]</td>
<td>-1.8 [-, 0.4]</td>
<td colspan="3">-1.4 [-, 0.0]</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="8"><p>*: p-value &lt;0.05</p>
<p>**: p-value &lt;0.01</p></td>
<td></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="4">Pharmacokinetic results:</td>
<td colspan="10"><ul>
<li><p>Mean C<sub>max</sub> and AUC both increased with dose. The data
are consistent with dose proportionality and linear pharmacokinetics.
For both parameters, there was a high level of inter-subject variability
[(coefficient of variation (CV) in the region of 40%].</p></li>
<li><p>Median t<sub>max</sub> ranged from 6.5 to 8.5 hours with
individual values ranging from 2 to 18 hours.</p></li>
<li><p>The mean (SEM) terminal elimination half-life (t<sub>½z</sub>)
ranged from 9.5 ± 0.56 h to 13.9 ± 1.3 h.</p></li>
</ul></td>
</tr>
<tr class="even">
<td></td>
<td colspan="14"><p><strong>Plasma pharmacokinetic parameters after
single administration of 10, 20 and 40 mg Alfuzosin OD</strong></p>
<p><strong>[Mean (SEM) - CV%, n=24]</strong></p></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td colspan="3"><strong>C<sub>max</sub></strong><br />
(ng/mL)</td>
<td colspan="2"><strong>t<sub>max</sub> <sup>a<br />
</sup></strong>(h)</td>
<td><strong>AUC<sub>last</sub><br />
</strong>(ng.h/mL)</td>
<td colspan="3"><strong>AUC</strong><br />
(ng.h/mL)</td>
<td><strong>t<sub>½z</sub></strong><br />
(h)</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td><strong>10 mg</strong></td>
<td colspan="3">8.9<br />
(0.68) - 38%</td>
<td colspan="2">6.5<br />
(2.0 - 18.0)</td>
<td>129<br />
(10.6) - 40%</td>
<td colspan="3">169<sup>c</sup><br />
(11.4) - 27%</td>
<td>13.9<sup>b</sup><br />
(1.30) - 42%</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td><strong>20 mg</strong></td>
<td colspan="3">18.3<br />
(1.64) - 44%</td>
<td colspan="2">6.5<br />
(3.0 - 16.0)</td>
<td>289<br />
(26.5) - 45%</td>
<td colspan="3">343<sup>d</sup><br />
(32.1) - 41%</td>
<td>12.3<br />
(0.94) - 37%</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td><strong>40 mg</strong></td>
<td colspan="3">38.9<br />
(3.18) - 40%</td>
<td colspan="2">8.5<br />
(3.0 - 12.0)</td>
<td>664<br />
(57.1) - 42%</td>
<td colspan="3">702<br />
(55.9) - 39%</td>
<td>9.5<br />
(0.56) - 29%</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td colspan="13"><blockquote>
<p><sup>a</sup> Median (range)</p>
<p><sup>b</sup> n=21 : <sup>c</sup> n=16 : <sup>d</sup> n=19</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td colspan="4">Safety results:</td>
<td colspan="10">Clinical, vital signs and laboratory safety were
satisfactory in this study and consistent with the safety profile
already known for alfuzosin.</td>
</tr>
</tbody>
</table>

*(continued)*

(PKD4532 *continued*)

+----------------+-----------------------------------------------------+
| Conclusions:   | Increases in QTcB and QTcF were seen with the       |
|                | higher doses of alfuzosin, which were likely        |
|                | related to the inability of these correction rate   |
|                | formulae to appropriately compensate for increased  |
|                | HR. Selective beat averaging in Holter analysis     |
|                | eliminated this inadequacy and showed that          |
|                | alfuzosin had no clinically significant effect in   |
|                | terms of QT prolongation up to 4 times the          |
|                | therapeutic dose (approximately +2ms *versus*       |
|                | placebo with an upper bound \< +4 ms).              |
|                |                                                     |
|                | There was a dose proportional increase in C~max~    |
|                | and AUC, indicating linear pharmacokinetic          |
|                | behavior. There were no apparent dose-dependent     |
|                | differences in t~max~ (median 6.5 to 8.5 h) or in   |
|                | t~½z~ (mean 9.5 to 13.9 h).                         |
+----------------+-----------------------------------------------------+

### 000Summary of PDY5105

+----------------+-----------------------------------------------------+
| **Title of the | Effect of supra‑therapeutic doses of alfuzosin ER   |
| study:**       | on QT interval, using a rate‑independent method,    |
|                | compared to placebo and to moxifloxacin in healthy  |
|                | volunteers (PDY5105)                                |
+----------------+-----------------------------------------------------+
| **Objectives** |                                                     |
+----------------+-----------------------------------------------------+
| > Primary:     | The purpose of the present study was to assess the  |
|                | effect on the QT interval of the ECG using the      |
|                | Holter‑monitoring method following the              |
|                | administration of alfuzosin 10 and 40 mg, placebo,  |
|                | and moxifloxacin 400 mg (positive control).         |
+----------------+-----------------------------------------------------+
| > Secondary:   | The secondary objectives of this study were as      |
|                | follows:                                            |
|                |                                                     |
|                | -   To evaluate the change from baseline of QTc,    |
|                |     corrected by Bazett (QTcB), Fridericia (QTcF),  |
|                |     a population specific formula (QTcN), and a     |
|                |     subject‑specific formula (QTcNi) with alfuzosin |
|                |     10 mg and 40 mg, and with moxifloxacin 400 mg,  |
|                |     at the time of maximum drug concentration       |
|                |                                                     |
|                | -   To document the systemic exposure after a       |
|                |     single oral dose of alfuzosin 10 mg, alfuzosin  |
|                |     40 mg, and moxifloxacin 400 mg                  |
|                |                                                     |
|                | -   To assess safety                                |
+----------------+-----------------------------------------------------+
| **             | This was a single‑center, 4‑way crossover,          |
| Methodology:** | randomized, double‑dummy placebo‑controlled study.  |
|                | Each period consisted of a 2‑day run‑in placebo,    |
|                | followed by a single‑dose day, with a washout of    |
|                | 5 to 9 days between successive periods.             |
+----------------+-----------------------------------------------------+
| **Number of    | Planned: 45 Randomized: 48 Treated: 48              |
| subjects:**    |                                                     |
+----------------+-----------------------------------------------------+
| **Evaluated:** | Pharmacokinetics: 45 Pharmacodynamics: 45 Safety:   |
|                | 48                                                  |
+----------------+-----------------------------------------------------+
| **Diagnosis    | Healthy male Caucasian aged between 18 and 50 years |
| and criteria   | with a body mass index between 18 and 30 (kg/m^2^). |
| for            |                                                     |
| inclusion:**   |                                                     |
+----------------+-----------------------------------------------------+
| **Test         | alfuzosin hydrochloride                             |
| product:**     |                                                     |
+----------------+-----------------------------------------------------+
| Dose:          | 10 mg tablets                                       |
+----------------+-----------------------------------------------------+
| A              | Oral                                                |
| dministration: |                                                     |
+----------------+-----------------------------------------------------+
| *(continued)*  |                                                     |
+----------------+-----------------------------------------------------+

(PDY5105 *continued*)

+----------------+-----------------------------------------------------+
| **Comparative  | moxifloxacin hydrochloride                          |
| therapy:**     |                                                     |
+----------------+-----------------------------------------------------+
| Dose:          | 400 mg capsules                                     |
+----------------+-----------------------------------------------------+
| A              | Oral                                                |
| dministration: |                                                     |
+----------------+-----------------------------------------------------+
| **Reference    | Placebo                                             |
| therapy:**     |                                                     |
+----------------+-----------------------------------------------------+
| Dose:          | matching tablets for alfuzosin and matching         |
|                | capsules for moxifloxacin                           |
+----------------+-----------------------------------------------------+
| A              | oral                                                |
| dministration: |                                                     |
+----------------+-----------------------------------------------------+
| **Criteria for |                                                     |
| evaluation:**  |                                                     |
+----------------+-----------------------------------------------------+
| Pha            |                                                     |
| rmacodynamics: |                                                     |
+----------------+-----------------------------------------------------+
| > Primary:     | **Holter‑monitoring method:**                       |
|                |                                                     |
|                | To assess the effect of alfuzosin 10 mg, alfuzosin  |
|                | 40 mg, and moxifloxacin 400 mg compared to placebo  |
|                | on QT interval with the Holter‑monitoring method    |
|                | the following 3 endpoints were used:                |
|                |                                                     |
|                | -   1000 msec RR bin                                |
|                |                                                     |
|                | -   Largest sample-size RR bin                      |
|                |                                                     |
|                | -   Average of all RR bins                          |
+----------------+-----------------------------------------------------+
| > Secondary:   | **12‑lead ECG:**                                    |
|                |                                                     |
|                | To assess the effect of alfuzosin 10 mg, alfuzosin  |
|                | 40 mg, and moxifloxacin 400 mg compared to placebo  |
|                | on corrected QT interval with manual 12-lead ECGs   |
|                | the following correction formulae were used:        |
|                |                                                     |
|                | -   Bazett's (QTcB)                                 |
|                |                                                     |
|                | -   Fridericia's (QTcF)                             |
|                |                                                     |
|                | -   Population‑specific (QTcN)                      |
|                |                                                     |
|                | -   Subject‑specific (QTcNi)                        |
+----------------+-----------------------------------------------------+
| Pha            | The following pharmacokinetic parameters of         |
| rmacokinetics: | alfuzosin once-daily formulation and of             |
|                | moxifloxacin using the following standard           |
|                | noncompartmental techniques were determined:        |
|                |                                                     |
|                | -   Maximum plasma concentration (C~max~)           |
|                |                                                     |
|                | -   Observed time of C~max~ (t~max~)                |
|                |                                                     |
|                | -   Area under the curve from time 0 to the last    |
|                |     measurement (AUC~last~)                         |
|                |                                                     |
|                | -   Area under the curve from time 0 extrapolated   |
|                |     to infinity (AUC)                               |
|                |                                                     |
|                | -   Elimination half-life (t~1/2z~)                 |
+----------------+-----------------------------------------------------+
| Safety:        | -   Assessment of adverse events                    |
|                |                                                     |
|                | -   Physical examination including weight           |
|                |                                                     |
|                | -   Vital signs                                     |
|                |                                                     |
|                | -   Laboratory safety:                              |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   Hematology                                      |
|                |                                                     |
|                | -   Blood chemistry                                 |
|                |                                                     |
|                | -   Urinalysis                                      |
|                |                                                     |
|                | ```{=html}                                          |
|                | <!-- -->                                            |
|                | ```                                                 |
|                | -   12-lead ECG and Holter monitoring               |
+----------------+-----------------------------------------------------+
| *              | Plasma concentrations of alfuzosin were assayed by  |
| *Bioanalytical | a validated method following a solid phase          |
| methods**      | extraction and liquid chromatography--tandem mass   |
|                | spectrometry (LC‑MS/MS) detection (DOH0252). The    |
|                | limit of quantification was 0.5 ng/mL.              |
|                |                                                     |
|                | Plasma concentrations of moxifloxacin were assayed  |
|                | by a validated high performance liquid              |
|                | chromatography (HPLC) with an ultraviolet (UV)      |
|                | detection method. The limit of quantification was   |
|                | 25 ng/mL.                                           |
+----------------+-----------------------------------------------------+

*(continued)*

(PDY5105 *continued*)

+----------------+-----------------------------------------------------+
| **Statistical  |                                                     |
| methods:**     |                                                     |
+----------------+-----------------------------------------------------+
| Pha            | ***Holter‑monitoring data: primary variable***      |
| rmacodynamics: |                                                     |
|                | **Analysis**                                        |
|                |                                                     |
|                | The prospectively defined period of this analysis   |
|                | is 7‑11 hours after alfuzosin administration and    |
|                | 1‑5 hours after moxifloxacin administration,        |
|                | corresponding to the periods of maximal drug        |
|                | concentration. The run‑in placebo (Day 2, T7--T11h) |
|                | assessment was considered as baseline for           |
|                | comparison with Day 3 within each period. Change    |
|                | from baseline of QT interval for each common HR was |
|                | computed, using the following formula:              |
|                |                                                     |
|                | Change from baseline in QT interval                 |
|                | (msec) = QT~treatment~ (msec) -                     |
|                | QT~Baseline~ (msec).                                |
|                |                                                     |
|                | Mean change from baseline in QT interval (msec) at  |
|                | the 1000 msec RR bin corresponding to a HR          |
|                | of 60 bpm, the change from baseline in QT interval  |
|                | (msec) at the largest sample size RR bin, and the   |
|                | change from baseline in QT interval (msec) over all |
|                | of the common HRs were analyzed by a mixed linear   |
|                | effects model including terms for subject as random |
|                | effect, and sequence, period, and treatment as      |
|                | fixed effects.                                      |
|                |                                                     |
|                | Results were presented as mean difference *versus*  |
|                | placebo with its 95% confidence intervals.          |
|                |                                                     |
|                | **Descriptive analysis**                            |
|                |                                                     |
|                | Change from baseline in QT interval (msec) of the   |
|                | Holter‑monitoring data on Day 3 was summarized by   |
|                | treatment using mean, SEM, minimum, maximum, and n. |
|                |                                                     |
|                | ***12-lead ECG data: secondary variables***         |
|                |                                                     |
|                | The analysis variable was change from baseline for  |
|                | HR, QT and QTcB, QTcF, QTcN, and QTcNi at 1)        |
|                | C~max~, and 2) at hours T7 through T11h (period     |
|                | corresponding to the same period of                 |
|                | Holter‑monitoring analysis). The baseline value for |
|                | these analyses was the mean of the 3 measures on    |
|                | Day 3-T0 of each period.                            |
|                |                                                     |
|                | **[Analysis at C~max~]{.underline}**                |
|                |                                                     |
|                | HR, and intervals QT, QTcB, QTcF, QTcN, and QTcNi   |
|                | were analyzed by a mixed linear effects model       |
|                | including terms for subject as random effect, and   |
|                | sequence, period, and treatment as fixed effects.   |
|                |                                                     |
|                | Results were presented as mean difference *versus*  |
|                | placebo with its 95% confidence intervals.          |
+----------------+-----------------------------------------------------+

*(continued)*

(PDY5105 *continued*)

+----------------+-----------------------------------------------------+
| Pha            | **[Analysis from T7 through T11h (time-averaged QTc |
| rmacodynamics: | intervals)]{.underline}**                           |
| *(continued)*  |                                                     |
|                | Change from baseline at T7, T8, T9, T10 and T11h of |
|                | HR, QT, QTcB, QTcF, QTcN, and QTcNi interval were   |
|                | subjected to an analysis of variance using a mixed  |
|                | linear effects model using restricted maximum       |
|                | likelihood estimates of random effects. The model   |
|                | included terms for subject as random effect, and    |
|                | sequence, period, treatment, and time as fixed      |
|                | effects.                                            |
|                |                                                     |
|                | Results from these comparisons were presented as    |
|                | mean difference *versus* placebo with its           |
|                | 95% confidence intervals.                           |
|                |                                                     |
|                | **Descriptive analysis**                            |
|                |                                                     |
|                | For all parameters obtained from manual reading,    |
|                | raw data, change from baseline were summarized      |
|                | using descriptive statistics, by parameter,         |
|                | treatment, visit, and time of measurement.          |
|                |                                                     |
|                | Graphs were provided for the evaluable population   |
|                | in order to describe evolution of the means         |
|                | (± S.E.M.) from pre‑dose (T0h) to T24h by treatment |
|                | and time using raw data and change *versus*         |
|                | baseline (T0h).                                     |
+----------------+-----------------------------------------------------+
| Pha            | Pharmacokinetic parameters of alfuzosin and         |
| rmacokinetics: | moxifloxacin were summarized using mean, SD,        |
|                | coefficient of variation, minimum, and maximum.     |
+----------------+-----------------------------------------------------+
| Safety:        | The clinical safety analysis was descriptive and    |
|                | focused on treatment‑emergent adverse events        |
|                | (TEAEs). Analysis of laboratory parameters, vital   |
|                | signs, and ECG parameters were based on specified   |
|                | criteria of potentially clinically significant      |
|                | abnormalities (PCSAs).                              |
+----------------+-----------------------------------------------------+

*(continued)*

(PDY5105 *continued*)

+----------------+-----------------------------------------------------+
| **Summary:**   |                                                     |
+----------------+-----------------------------------------------------+
| P              | **Holter‑monitoring results**                       |
| harmacodynamic |                                                     |
| results:       | The following results were obtained for the         |
|                | pairwise comparison of on‑drug period to placebo    |
|                | period for the 3 Holter‑monitoring endpoints:       |
|                |                                                     |
|                | +----------+------------+----+-----+----+----+      |
|                | | **H      | **T        | *  | **M | *  |    |      |
|                | | olter‑mo | reatment** | *P | ean | *9 |    |      |
|                | | nitoring |            | -V | Di  | 5% |    |      |
|                | | End      |            | al | ffe | CI |    |      |
|                | | points** |            | ue | ren | ** |    |      |
|                | |          |            | ** | ce\ |    |    |      |
|                | |          |            |    | *   |    |    |      |
|                | |          |            |    | vs* |    |    |      |
|                | |          |            |    | P   |    |    |      |
|                | |          |            |    | lac |    |    |      |
|                | |          |            |    | ebo |    |    |      |
|                | |          |            |    | (m  |    |    |      |
|                | |          |            |    | sec |    |    |      |
|                | |          |            |    | )** |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          |            |    |     | *  | *  |      |
|                | |          |            |    |     | *L | *U |      |
|                | |          |            |    |     | ow | pp |      |
|                | |          |            |    |     | er | er |      |
|                | |          |            |    |     | B  | ** |      |
|                | |          |            |    |     | ou |    |      |
|                | |          |            |    |     | nd | *  |      |
|                | |          |            |    |     | ** | *B |      |
|                | |          |            |    |     |    | ou |      |
|                | |          |            |    |     |    | nd |      |
|                | |          |            |    |     |    | ** |      |
|                | +----------+------------+----+-----+----+----+      |
|                | | 1        | Alfuzosin  | 0. | 0.1 | -2 | 2  |      |
|                | | 000 msec | 10 mg\     | 96 |     | .5 | .6 |      |
|                | | RR Bin   | (n = 36)   | 94 |     |    |    |      |
|                | |          |            |    |     |    |    |      |
|                | | (Q       |            |    |     |    |    |      |
|                | | T~1000~) |            |    |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          | Alfuzosin  | 0. | 2.9 | 0  | 5  |      |
|                | |          | 40 mg\     | 02 |     | .3 | .5 |      |
|                | |          | (n = 35)   | 78 |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          | Mo         | 0. | 7.0 | 4  | 9  |      |
|                | |          | xifloxacin | 00 |     | .4 | .6 |      |
|                | |          | 400 mg (n  | 01 |     |    |    |      |
|                | |          | = 37)      |    |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | | Largest  | Alfuzosin  | 0. | 0.4 | -1 | 2  |      |
|                | | Sam      | 10 mg\     | 70 |     | .8 | .6 |      |
|                | | ple‑size | (n = 41)   | 17 |     |    |    |      |
|                | | RR Bin   |            |    |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          | Alfuzosin  | 0. | 2.5 | 0  | 4  |      |
|                | |          | 40 mg\     | 01 |     | .4 | .7 |      |
|                | |          | (n = 45)   | 97 |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          | Mo         | 0. | 6.9 | 4  | 9  |      |
|                | |          | xifloxacin | 00 |     | .8 | .1 |      |
|                | |          | 400 mg (n  | 01 |     |    |    |      |
|                | |          | = 43)      |    |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | | Average  | Alfuzosin  | 0. | 0.1 | -1 | 2  |      |
|                | | of All   | 10 mg\     | 95 |     | .9 | .0 |      |
|                | | RR Bins  | (n = 42)   | 47 |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          | Alfuzosin  | 0. | 2.0 | 0  | 3  |      |
|                | |          | 40 mg\     | 04 |     | .0 | .9 |      |
|                | |          | (n = 45)   | 84 |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                | |          | Mo         | 0. | 6.6 | 4  | 8  |      |
|                | |          | xifloxacin | 00 |     | .6 | .6 |      |
|                | |          | 400 mg (n  | 01 |     |    |    |      |
|                | |          | = 43)      |    |     |    |    |      |
|                | +----------+------------+----+-----+----+----+      |
|                |                                                     |
|                | -   Alfuzosin 10 mg (i.e., the therapeutic dose)    |
|                |     did not induce any change in QT interval. Mean  |
|                |     differences were 0.1, 0.4, and 0.1 msec; these  |
|                |     were not statistically significant differences. |
|                |                                                     |
|                | -   Alfuzosin 40 mg (i.e., 4 times the therapeutic  |
|                |     dose) induced weak, albeit statistically        |
|                |     significant QT increase of 2.9, 2.5, and        |
|                |     2.0 msec. However, these increases were much    |
|                |     weaker than those induced by moxifloxacin at    |
|                |     therapeutic dose.                               |
|                |                                                     |
|                | -   Moxifloxacin 400 mg (i.e., the therapeutic      |
|                |     dose) produced a clear and consistent           |
|                |     QT interval length increase for each of the     |
|                |     3 endpoints. The magnitude of these effects was |
|                |     7.0, 6.9, and 6.6 msec; these differences were  |
|                |     all highly statistically significant            |
|                |     (p\<0.0001). These results demonstrate the      |
|                |     sensitivity of the method.                      |
+----------------+-----------------------------------------------------+

*(continued)*

(PDY5105 *continued*)

+----------------+-----------------------------------------------------+
| P              | **Manual 12‑lead ECG results**                      |
| harmacodynamic |                                                     |
| results:       | [Analysis at C~max~]{.underline}                    |
| *(continued)*  |                                                     |
|                | Moxifloxacin 400 mg (i.e., the therapeutic dose)    |
|                | produced statistically significant QT interval      |
|                | length increase in comparison with placebo with     |
|                | conventional correction formulae (Bazett: 15.7 msec |
|                | and Fridericia: 12.7 msec).                         |
|                |                                                     |
|                | Using QTcN and QTcNi, moxifloxacin still generated  |
|                | a strong QT interval increase compared to placebo   |
|                | (11 and 11.1 msec, respectively), although less     |
|                | than with Fridericia or Bazett.                     |
|                |                                                     |
|                | At the therapeutic dose of alfuzosin 10 mg, QTcN    |
|                | and QTcNi changes were less than 2 msec. At         |
|                | alfuzosin 40 mg, QTcN and QTcNi changes were        |
|                | approximately 4 msec. These much smaller QT changes |
|                | compared with QTcB and QTcF demonstrated that HR    |
|                | drove most of the apparent QTcB and QTcF changes,   |
|                | as alfuzosin 10 mg and 40 mg increased HR by 5 to   |
|                | 6 bpm.                                              |
|                |                                                     |
|                | [Analysis from T7 through T11h (time‑averaged QTc   |
|                | intervals)]{.underline}                             |
|                |                                                     |
|                | The change in QTc for the 4‑hour period exhibited   |
|                | the same trend with the correction factors as the   |
|                | data from C~max~.                                   |
|                |                                                     |
|                | No outliers using QTcN or QTcNi formulae were       |
|                | observed after treatment administration.            |
+----------------+-----------------------------------------------------+
| P              | Mean pharmacokinetic parameters for alfuzosin and   |
| harmacokinetic | moxifloxacin are presented in the following table.  |
| results:       |                                                     |
|                | +-----------+------+-------+------+-----+------+    |
|                | | **Dr      | *    |       |      |     |      |    |
|                | | ug/Dose** | *Pha |       |      |     |      |    |
|                | |           | rmac |       |      |     |      |    |
|                | |           | okin |       |      |     |      |    |
|                | |           | etic |       |      |     |      |    |
|                | |           | Para |       |      |     |      |    |
|                | |           | mete |       |      |     |      |    |
|                | |           | rs** |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | |           | **Me |       |      |     |      |    |
|                | |           | an** |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | |           | **(S |       |      |     |      |    |
|                | |           | D) - |       |      |     |      |    |
|                | |           | C    |       |      |     |      |    |
|                | |           | V%** |       |      |     |      |    |
|                | +-----------+------+-------+------+-----+------+    |
|                | |           | **C~ | **t   | **A  | **  | *    |    |
|                | |           | max~ | ~max~ | UC~l | t~1 | *AUC |    |
|                | |           | (    | ^a^** | ast~ | /2z | (ng  |    |
|                | |           | ng/m |       | (ng  | ~** | .h/m |    |
|                | |           | L)** | **    | .h/m |     | L)** |    |
|                | |           |      | (h)** | L)** | *   |      |    |
|                | |           |      |       |      | *(h |      |    |
|                | |           |      |       |      | )** |      |    |
|                | +-----------+------+-------+------+-----+------+    |
|                | | Alfuzosin | 11.2 | 7.0   | 176  | 1   | 193  |    |
|                | | 10 mg     |      |       |      | 1.7 | ^c^  |    |
|                | |           | (4.  | (2.0  | \(71 | ^b^ |      |    |
|                | | N = 44    | 5) - | --    | \) - |     | \(71 |    |
|                | |           | 40   | 16.0) | 40   | (   | \) - |    |
|                | |           |      |       |      | 4.4 | 37   |    |
|                | |           |      |       |      | ) - |      |    |
|                | |           |      |       |      | 38  |      |    |
|                | +-----------+------+-------+------+-----+------+    |
|                | | Alfuzosin | 48.6 | 9.0   | 747  | 1   | 898  |    |
|                | | 40 mg     |      |       |      | 2.3 | ^e^  |    |
|                | |           | (21. | (2.0  | \    | ^d^ |      |    |
|                | | N = 45    | 0) - | --    | (277 |     | \    |    |
|                | |           | 43   | 16.0) | \) - | (   | (375 |    |
|                | |           |      |       | 37   | 6.8 | \) - |    |
|                | |           |      |       |      | ) - | 42   |    |
|                | |           |      |       |      | 55  |      |    |
|                | +-----------+------+-------+------+-----+------+    |
|                | | Mox       | 3724 | 2.0   | 3    | 1   | 4    |    |
|                | | ifloxacin |      |       | 8267 | 1.6 | 5789 |    |
|                | | 400 mg    | \    | (0.97 |      |     | ^f^  |    |
|                | |           | (849 | --    | \(   | (   |      |    |
|                | | N = 44    | \) - | 5.0)  | 6105 | 1.5 | \(   |    |
|                | |           | 23   |       | \) - | ) - | 7708 |    |
|                | |           |      |       | 16   | 13  | \) - |    |
|                | |           |      |       |      |     | 17   |    |
|                | +-----------+------+-------+------+-----+------+    |
|                | | ^a^       |      |       |      |     |      |    |
|                | | Median    |      |       |      |     |      |    |
|                | | (range)   |      |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | | ^b^       |      |       |      |     |      |    |
|                | | n = 42;   |      |       |      |     |      |    |
|                | | Minimum   |      |       |      |     |      |    |
|                | | of 3      |      |       |      |     |      |    |
|                | | points    |      |       |      |     |      |    |
|                | | used for  |      |       |      |     |      |    |
|                | | the       |      |       |      |     |      |    |
|                | | e         |      |       |      |     |      |    |
|                | | stimation |      |       |      |     |      |    |
|                | | of λ~Z~   |      |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | | ^c^       |      |       |      |     |      |    |
|                | | n = 23;   |      |       |      |     |      |    |
|                | | Other     |      |       |      |     |      |    |
|                | | values    |      |       |      |     |      |    |
|                | | not       |      |       |      |     |      |    |
|                | | c         |      |       |      |     |      |    |
|                | | alculable |      |       |      |     |      |    |
|                | | or with   |      |       |      |     |      |    |
|                | | ext       |      |       |      |     |      |    |
|                | | rapolated |      |       |      |     |      |    |
|                | | portion   |      |       |      |     |      |    |
|                | | of AUC    |      |       |      |     |      |    |
|                | | \>30%     |      |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | | ^d^       |      |       |      |     |      |    |
|                | | n = 43;   |      |       |      |     |      |    |
|                | | Minimum   |      |       |      |     |      |    |
|                | | of 3      |      |       |      |     |      |    |
|                | | points    |      |       |      |     |      |    |
|                | | used for  |      |       |      |     |      |    |
|                | | the       |      |       |      |     |      |    |
|                | | e         |      |       |      |     |      |    |
|                | | stimation |      |       |      |     |      |    |
|                | | of λ~Z~   |      |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | | ^e^       |      |       |      |     |      |    |
|                | | n = 29;   |      |       |      |     |      |    |
|                | | Other     |      |       |      |     |      |    |
|                | | values    |      |       |      |     |      |    |
|                | | not       |      |       |      |     |      |    |
|                | | c         |      |       |      |     |      |    |
|                | | alculable |      |       |      |     |      |    |
|                | | or with   |      |       |      |     |      |    |
|                | | ext       |      |       |      |     |      |    |
|                | | rapolated |      |       |      |     |      |    |
|                | | portion   |      |       |      |     |      |    |
|                | | of AUC    |      |       |      |     |      |    |
|                | | \>30%     |      |       |      |     |      |    |
|                | |           |      |       |      |     |      |    |
|                | | ^f^       |      |       |      |     |      |    |
|                | | n = 15;   |      |       |      |     |      |    |
|                | | Other     |      |       |      |     |      |    |
|                | | values    |      |       |      |     |      |    |
|                | | not       |      |       |      |     |      |    |
|                | | c         |      |       |      |     |      |    |
|                | | alculable |      |       |      |     |      |    |
|                | | or with   |      |       |      |     |      |    |
|                | | ext       |      |       |      |     |      |    |
|                | | rapolated |      |       |      |     |      |    |
|                | | portion   |      |       |      |     |      |    |
|                | | of AUC    |      |       |      |     |      |    |
|                | | \>30%     |      |       |      |     |      |    |
|                | +-----------+------+-------+------+-----+------+    |
+----------------+-----------------------------------------------------+
| Safety         | Mild to moderate postural hypotension was observed  |
| results:       | with alfuzosin, due to the alpha~1~ blockade,       |
|                | exacerbated by the prolonged supine position        |
|                | required by the study. No deaths, serious adverse   |
|                | events (SAEs), or discontinuations due to AE were   |
|                | reported during the study.                          |
|                |                                                     |
|                | > No clinically significant abnormalities in        |
|                | > laboratory and vital sign parameters were         |
|                | > reported.                                         |
+----------------+-----------------------------------------------------+

*(continued)*

(PDY5105 *continued*)

+----------------+-----------------------------------------------------+
| Conclusions:   | The following conclusions were drawn:               |
|                |                                                     |
|                | -   An increase in QTc based on Bazett's and        |
|                |     Fridericia's formulae is found for moxifloxacin |
|                |     comparable to values reported in the            |
|                |     literature, thus demonstrating the sensitivity  |
|                |     of the trial.                                   |
|                |                                                     |
|                | -   A QT increase of about 7 msec by moxifloxacin,  |
|                |     at the therapeutic dose, is found using the     |
|                |     Holter‑monitoring method. This demonstrates     |
|                |     that the Holter‑monitoring method is sensitive  |
|                |     and can detect moderate drug‑induced increases  |
|                |     of QT interval.                                 |
|                |                                                     |
|                | -   Using the same method, the therapeutic dose of  |
|                |     alfuzosin produces no significant change in the |
|                |     QT interval. At 4 times the therapeutic dose,   |
|                |     alfuzosin produces QT changes of no more than   |
|                |     2.9 msec.                                       |
|                |                                                     |
|                | -   These results confirm that alfuzosin did not    |
|                |     produce meaningful increases in the             |
|                |     QT interval.                                    |
+----------------+-----------------------------------------------------+

## 000Preclinical safety

Table (7.2) 1 - Inhibition of HERG potassium current expressed in CHO
cells

  ---------------- --------------------------- ---------------------------
  **Drugs**        **Number of                 **IC~50~ µmol/L**
                   Cells/Concentration**       

  Alfuzosin        4-9                         83.3 ± 16.6

  Doxazosin        5                           3.0 ± 0.5

  Prazosin         1-6                         3.4 ± 0.4

  Tamsulosin       5                           104.8 ± 0.6

  Terazosin        3-6                         21.4 ± 2.9
  ---------------- --------------------------- ---------------------------

## 000Study design

Table (7.3) 1 - Study details of PDY5105 and PKD4532

+----+-------------+------+--------+--------------------------------+
| *  | **Design**  | *    |        | **Relevant Parameters**        |
| *S |             | *Tre |        |                                |
| tu |             | atme |        |                                |
| dy |             | nt** |        |                                |
| ** |             |      |        |                                |
+----+-------------+------+--------+--------------------------------+
|    |             | *    | **Con  |                                |
|    |             | *Alf | trol** |                                |
|    |             | uzos |        |                                |
|    |             | in** |        |                                |
+----+-------------+------+--------+--------------------------------+
| P  | 4-period    | 10   | M      | [24-hour Holter                |
| DY | randomized  | mg,  | oxiflo | recordings:]{.underline}       |
| 51 | crossover,  |      | xacin. |                                |
| 05 | do          | 40   |        | For each treatment period:     |
|    | uble-dummy, | mg,  | 400    |                                |
|    | placebo and | si   | mg,    | -   placebo run-in (Day 2,     |
|    | active      | ngle | single |     baseline)                  |
|    | controlled. | dose | dose   |                                |
|    |             | in   | in     | -   treatment (Day 3)          |
|    | Each period | mor  | aft    |                                |
|    | consisted   | ning | ernoon | Period for Holter Bin analysis |
|    | of:         | (T0) | (T6)   | was a 4-hour time period when  |
|    |             | a    |        | the maximal drug               |
|    | -   2 days  | fter | Pl     | concentrations were            |
|    |     of      | a    | acebo, | anticipated, i.e., 7h --11h    |
|    |     placebo | high | single | after alfuzosin administration |
|    |     run-in  | ‑fat | dose   | corresponding to 1h --5h after |
|    |     (Days   | b    | in     | moxifloxacin administration.   |
|    |     1-2)    | reak | m      |                                |
|    |             | fast | orning | [12-lead ECG                   |
|    | -   1 day   |      | (T0)   | recordings:]{.underline}       |
|    |     of      |      | after  |                                |
|    |             |      | a      | For each treatment period:     |
|    |   treatment |      | hi     |                                |
|    |     (Day 3) |      | gh-fat | -   placebo run-in (Day 2):    |
|    |             |      | bre    |                                |
|    | Washout of  |      | akfast | At T0 (mean of 3 successive    |
|    | 5 to 9 days |      |        | recordings done pre-dose at    |
|    | between     |      |        | 5‑minute intervals) and at T2, |
|    | successive  |      |        | T4, T6, T7, T8, T9, T10, T11,  |
|    | periods     |      |        | and T12.                       |
|    |             |      |        |                                |
|    |             |      |        | -   treatment (Day 3):         |
|    |             |      |        |                                |
|    |             |      |        | At T0 (mean of 3 successive    |
|    |             |      |        | recordings done pre-dose at    |
|    |             |      |        | 5‑minute intervals, baseline)  |
|    |             |      |        | and at T2, T4, T6, T7, T8, T9, |
|    |             |      |        | T10, T11, T12, T24 and T30h.   |
+----+-------------+------+--------+--------------------------------+
| P  | 4-period    | 10   | Pl     | [24-hour Holter                |
| KD | randomized, | mg,  | acebo, | recordings:]{.underline}       |
| 45 | do          |      | single |                                |
| 32 | uble-blind, | 20   | dose   | -   Study screening (baseline) |
|    | crossover,  | mg,  | in     |                                |
|    | placebo     |      | m      | -   treatment (Day 1 of each   |
|    | ‑controlled | 40   | orning |     period)                    |
|    |             | mg,  | (T0)   |                                |
|    | Each period | si   | after  | > Period for Holter Bin        |
|    | consisted   | ngle | a      | > analysis was a 4-hour time   |
|    | of:         | dose | hi     | > period when the maximal drug |
|    |             | in   | gh-fat | > concentrations were          |
|    | -   1 day   | mor  | bre    | > anticipated, i.e., 7h --11h  |
|    |     of      | ning | akfast | > (peak) and at night (i.e.,   |
|    |             | (T0) |        | > 16h --20h) after alfuzosin   |
|    |   treatment | a    |        | > administration               |
|    |     (Day 1) | fter |        |                                |
|    |             | a    |        | [12-lead ECG                   |
|    | Washout of  | high |        | recordings:]{.underline}       |
|    | at least 6  | ‑fat |        |                                |
|    | days        | b    |        | -   treatment (Day 1)          |
|    | between     | reak |        |                                |
|    | successive  | fast |        | > at T-1 (baseline) and at,    |
|    | periods     |      |        | > T0.5, T1, T2, T3, T4, T5,    |
|    |             |      |        | > T6, T7, T8, T9, T10, T11,    |
|    |             |      |        | > T12, T14, T16, T18, T24 and  |
|    |             |      |        | > T48h.                        |
+----+-------------+------+--------+--------------------------------+

## 000QT interval assessment

Table (7.4) 1 - Holter‑monitoring method -- 4 hour-period: QT interval
change from baseline of alfuzosin 10 mg, alfuzosin 40 mg, and
moxifloxacin 400 mg, in comparison with placebo - primary endpoints
(Study PDY5105)

+---------------+-------------------+------+------------+------+------+
| **Holt        | **Treatment**     | **P  | **Mean     | *    |      |
| er‑Monitoring |                   | -Val | D          | *95% |      |
| Endpoints**   |                   | ue** | ifference\ | CI** |      |
|               |                   |      | *versus*   |      |      |
|               |                   |      | Placebo    |      |      |
|               |                   |      | (msec)**   |      |      |
+===============+===================+======+============+======+======+
|               |                   |      |            | **L  | *    |
|               |                   |      |            | ower | *Upp |
|               |                   |      |            | Bou  | er** |
|               |                   |      |            | nd** |      |
|               |                   |      |            |      | *    |
|               |                   |      |            |      | *Bou |
|               |                   |      |            |      | nd** |
+---------------+-------------------+------+------------+------+------+
| Largest       | Alfuzosin 10 mg   | 0.   | 0.4        | -1.8 | 2.6  |
| sample-size   | (n=41)            | 7017 |            |      |      |
| RR bin        |                   |      |            |      |      |
+---------------+-------------------+------+------------+------+------+
|               | Alfuzosin 40 mg   | 0.   | 2.5        | 0.4  | 4.7  |
|               | (n=45)            | 0197 |            |      |      |
+---------------+-------------------+------+------------+------+------+
|               | Moxifloxacin      | 0.   | 6.9        | 4.8  | 9.1  |
|               | 400 mg (n=43)     | 0001 |            |      |      |
+---------------+-------------------+------+------------+------+------+
| Average of    | Alfuzosin 10 mg   | 0.   | 0.1        | -1.9 | 2.0  |
| all RR bins   | (n=42)            | 9547 |            |      |      |
+---------------+-------------------+------+------------+------+------+
|               | Alfuzosin 40 mg   | 0.   | 2.0        | 0.0  | 3.9  |
|               | (n=45)            | 0484 |            |      |      |
+---------------+-------------------+------+------------+------+------+
|               | Moxifloxacin      | 0.   | 6.6        | 4.6  | 8.6  |
|               | 400 mg (n=43)     | 0001 |            |      |      |
+---------------+-------------------+------+------------+------+------+
| 1000 msec RR  | Alfuzosin 10 mg   | 0.   | 0.1        | -2.5 | 2.6  |
| Bin           | (n=36)            | 9694 |            |      |      |
|               |                   |      |            |      |      |
| (QT~1000~)    |                   |      |            |      |      |
+---------------+-------------------+------+------------+------+------+
|               | Alfuzosin 40 mg   | 0.   | 2.9        | 0.3  | 5.5  |
|               | (n=35)            | 0278 |            |      |      |
+---------------+-------------------+------+------------+------+------+
|               | Moxifloxacin      | 0.   | 7.0        | 4.4  | 9.6  |
|               | 400 mg (n=37)     | 0001 |            |      |      |
+---------------+-------------------+------+------------+------+------+

Table (7.4) 2 - 12‑lead ECG: change from baseline to C~max~:
moxifloxacin 400 mg *versus* placebo, pairwise comparisons
(Study PDY5105)

+---------------------------+--------+------------+--------+--------+
| **ECG Parameter**         | **P-V  | **Mean**   | **95%  |        |
|                           | alue** |            | CI**   |        |
|                           |        | **D        |        |        |
|                           |        | ifference\ |        |        |
|                           |        | *versus*   |        |        |
|                           |        | Placebo**  |        |        |
+---------------------------+--------+------------+--------+--------+
|                           |        |            | *      | *      |
|                           |        |            | *Lower | *Upper |
|                           |        |            | B      | B      |
|                           |        |            | ound** | ound** |
+---------------------------+--------+------------+--------+--------+
|                           |        |            |        |        |
+---------------------------+--------+------------+--------+--------+
| HR (bpm)                  | 0.0005 | 2.8        | 1.3    | 4.2    |
+---------------------------+--------+------------+--------+--------+
| QT interval (msec)        | 0.0045 | 6.9        | 2.3    | 11.5   |
+---------------------------+--------+------------+--------+--------+
| Bazett QTc (msec)         | 0.0001 | 15.7       | 10.8   | 20.6   |
+---------------------------+--------+------------+--------+--------+
| Fridericia QTc (msec)     | 0.0001 | 12.7       | 8.6    | 16.8   |
+---------------------------+--------+------------+--------+--------+
| QTcN (msec)               | 0.0001 | 11.0       | 7.0    | 15.0   |
+---------------------------+--------+------------+--------+--------+
| QTcNi (msec)              | 0.0001 | 11.1       | 7.2    | 15.0   |
+---------------------------+--------+------------+--------+--------+

Table (7.4) 3 - 12‑lead ECG: change from baseline to C~max~: alfuzosin
10 mg and 40 mg *versus* placebo, pairwise comparisons (Study PDY5105)

+------------------+----------------+-------+---------+------+-------+
| **ECG            | **Treatment**  | *     | *       | *    |       |
| Parameters**     |                | *P-Va | *Mean** | *95% |       |
|                  |                | lue** |         | CI** |       |
|                  |                |       | **Diff  |      |       |
|                  |                |       | erence\ |      |       |
|                  |                |       | *       |      |       |
|                  |                |       | versus* |      |       |
|                  |                |       | Pl      |      |       |
|                  |                |       | acebo** |      |       |
+------------------+----------------+-------+---------+------+-------+
|                  |                |       |         | **L  | **    |
|                  |                |       |         | ower | Upper |
|                  |                |       |         | Bou  | Bo    |
|                  |                |       |         | nd** | und** |
+------------------+----------------+-------+---------+------+-------+
|                  |                |       |         |      |       |
+------------------+----------------+-------+---------+------+-------+
| HR (bpm)         | Alfuzosin 10   | 0     | 5.2     | 2.2  | 8.3   |
|                  | mg             | .0013 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
|                  | Alfuzosin 40   | 0     | 5.8     | 3.2  | 8.4   |
|                  | mg             | .0001 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
| QT interval      | Alfuzosin 10   | 0     | -5.8    | -    | -1.4  |
| (msec)           | mg             | .0115 |         | 10.2 |       |
+------------------+----------------+-------+---------+------+-------+
|                  | Alfuzosin 40   | 0     | -4.2    | -8.5 | 0.2   |
|                  | mg             | .0590 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
| Bazett QTc       | Alfuzosin 10   | 0     | 10.2    | 3.9  | 16.6  |
| (msec)           | mg             | .0023 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
|                  | Alfuzosin 40   | 0     | 13.9    | 5.8  | 22.0  |
|                  | mg             | .0012 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
| Fridericia QTc   | Alfuzosin 10   | 0     | 4.9     | 0.9  | 8.8   |
| (msec)           | mg             | .0171 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
|                  | Alfuzosin 40   | 0     | 7.7     | 1.9  | 13.5  |
|                  | mg             | .0102 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
| QTcN (msec)      | Alfuzosin 10   | 0     | 1.8     | -1.4 | 5.0   |
|                  | mg             | .2709 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
|                  | Alfuzosin 40   | 0     | 4.2     | -0.6 | 9.0   |
|                  | mg             | .0819 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
| QTcNi (msec)     | Alfuzosin 10   | 0     | 1.8     | -1.3 | 5.0   |
|                  | mg             | .2456 |         |      |       |
+------------------+----------------+-------+---------+------+-------+
|                  | Alfuzosin 40   | 0     | 4.3     | -0.5 | 9.2   |
|                  | mg             | .0804 |         |      |       |
+------------------+----------------+-------+---------+------+-------+

[]{.mark}

[]{.mark}

QTcB QTcF

![](media/image11.wmf){width="3.0555555555555554in"
height="3.0930555555555554in"}![](media/image12.wmf){width="3.0034722222222223in"
height="3.0930555555555554in"}

Figure (7.4) 1 - 12-lead ECG: relationship between QTcB and QTcF change
from baseline and RR change from baseline on placebo data
(Study PDY5105)

QTcN QTcNi

![](media/image13.wmf){width="3.015972222222222in"
height="3.0930555555555554in"}![](media/image14.wmf){width="3.015972222222222in"
height="3.0930555555555554in"}

Figure (7.4) 2 - 12-lead ECG: relationship between QTcN and QTcNi change
from baseline and RR change from baseline on placebo data
(Study PDY5105)

Table (7.4) 4 - Individual data of subjects with QTcB\>450 msec and/or
delta QTcB\>60 msec (Study PDY5105)

<table style="width:100%;">
<colgroup>
<col style="width: 8%" />
<col style="width: 17%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td colspan="3"><strong>Holter Bin method</strong></td>
</tr>
<tr class="even">
<td><strong>Subject</strong></td>
<td><strong>Treatment</strong></td>
<td><p><strong>Time</strong></p>
<p><strong>(h)</strong></p></td>
<td><p><strong>HR</strong></p>
<p><strong>(bpm)</strong></p></td>
<td><p><strong>Delta</strong></p>
<p><strong>HR</strong></p>
<p><strong>(bpm)</strong></p></td>
<td><p><strong>QTcB</strong></p>
<p><strong>(msec)</strong></p></td>
<td><p><strong>Delta</strong></p>
<p><strong>QTcB</strong></p>
<p><strong>(msec)</strong></p></td>
<td><p><strong>QTcF</strong></p>
<p><strong>(msec)</strong></p></td>
<td><p><strong>Delta</strong></p>
<p><strong>QTcF</strong></p>
<p><strong>(msec)</strong></p></td>
<td><p><strong>RR bin</strong></p>
<p><strong>(msec)</strong></p></td>
<td><p><strong>QT</strong></p>
<p><strong>(msec)</strong></p></td>
<td><p><strong>Delta</strong></p>
<p><strong>QT</strong></p>
<p><strong>(msec)</strong></p></td>
</tr>
<tr class="odd">
<td>045</td>
<td>Alfuzosin 10 mg</td>
<td>T4</td>
<td>110</td>
<td>49</td>
<td><strong>458</strong></td>
<td><strong>83.3</strong></td>
<td>414</td>
<td>40.3</td>
<td>550</td>
<td colspan="2">ND</td>
</tr>
<tr class="even">
<td>013</td>
<td>Alfuzosin 40 mg</td>
<td>T7</td>
<td>83</td>
<td>17</td>
<td><strong>456</strong></td>
<td>42.7</td>
<td>432</td>
<td>25</td>
<td>720</td>
<td>395</td>
<td>2</td>
</tr>
<tr class="odd">
<td>015</td>
<td>Alfuzosin 40 mg</td>
<td>T11</td>
<td>77</td>
<td>37</td>
<td>441</td>
<td><strong>86.3</strong></td>
<td>424</td>
<td>44.3</td>
<td>780</td>
<td colspan="2">ND</td>
</tr>
<tr class="even">
<td>022</td>
<td>Alfuzosin 40 mg</td>
<td>T24</td>
<td>69</td>
<td>20.3</td>
<td><strong>452</strong></td>
<td>54.7</td>
<td>442</td>
<td>30.7</td>
<td>870</td>
<td>423</td>
<td>5</td>
</tr>
<tr class="odd">
<td>034</td>
<td>Alfuzosin 40 mg</td>
<td>T10</td>
<td>82</td>
<td>31</td>
<td>443</td>
<td><strong>61.7</strong></td>
<td>421</td>
<td>29</td>
<td>730</td>
<td>383</td>
<td>-2</td>
</tr>
<tr class="even">
<td>037</td>
<td>Alfuzosin 40 mg</td>
<td>T2</td>
<td>79</td>
<td>18.7</td>
<td><strong>457</strong></td>
<td>48.3</td>
<td>436</td>
<td>28</td>
<td>760</td>
<td>385</td>
<td>0</td>
</tr>
<tr class="odd">
<td>108</td>
<td>Alfuzosin 40 mg</td>
<td>T8</td>
<td>68</td>
<td>18.3</td>
<td>437</td>
<td><strong>67.7</strong></td>
<td>428</td>
<td>47</td>
<td>880</td>
<td>393</td>
<td>-2</td>
</tr>
<tr class="even">
<td>011</td>
<td>Moxifloxacin 400 mg</td>
<td>T7</td>
<td>69</td>
<td>5.7</td>
<td><strong>453</strong></td>
<td>44.7</td>
<td>443</td>
<td>38</td>
<td>870</td>
<td>415</td>
<td>15</td>
</tr>
<tr class="odd">
<td>023</td>
<td>Placebo</td>
<td>T24</td>
<td>75</td>
<td>10.3</td>
<td><strong>451</strong></td>
<td>40</td>
<td>434</td>
<td>28.3</td>
<td>800</td>
<td>415</td>
<td>0</td>
</tr>
<tr class="even">
<td>104</td>
<td>Placebo</td>
<td>T4</td>
<td>88</td>
<td>17.7</td>
<td><strong>452</strong></td>
<td>27.7</td>
<td>424</td>
<td>11</td>
<td>680</td>
<td>363</td>
<td>0</td>
</tr>
<tr class="odd">
<td>104</td>
<td>Placebo</td>
<td>T9</td>
<td>82</td>
<td>11.7</td>
<td><strong>455</strong></td>
<td>30.7</td>
<td>432</td>
<td>19</td>
<td>730</td>
<td>370</td>
<td>0</td>
</tr>
<tr class="even">
<td colspan="12">ND = No data available (treatment and/or baseline data
missing in this RR bin)</td>
</tr>
</tbody>
</table>

## 000Clinical safety

Table (7.5) 1 - Number (%) of patients experiencing AEs that are
potentially suggestive of a proarrhythmic effect in double‑blind
controlled phase II/III studies in BPH patients -- alfuzosin all
formulations

+-------------------------------+----------------+---------------------+
| **AE Suggestive of            | **Placebo**    | **Alfuzosin^a^**    |
| Proarrhythmic Effect**        |                |                     |
|                               | N= 1440 (%)    | N = 2104            |
|                               |                |                     |
|                               |                | (%)                 |
+-------------------------------+----------------+---------------------+
| Torsades de pointes           | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Ventricular tachycardia       | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Ventricular arrhythmia        | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Ventricular ectopy            | 2 (0.3)        | 3 (0.1%)            |
+-------------------------------+----------------+---------------------+
| Ventricular fibrillation      | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Ventricular flutter           | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Cardiac arrest                | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Sudden death                  | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| Syncope^b^                    | 0              | 6 (0.3%)            |
+-------------------------------+----------------+---------------------+
| Dizziness^b^                  | 26 (1.8)       | 74 (3.5%)           |
+-------------------------------+----------------+---------------------+
| Palpitations                  | 6 (0.4)        | 10 (0.5%)           |
+-------------------------------+----------------+---------------------+
| > Seizures                    | 0              | 0                   |
+-------------------------------+----------------+---------------------+
| ^a^ All formulations: od,     |                |                     |
| bid, tid                      |                |                     |
|                               |                |                     |
| ^b^ Dizziness and syncope are |                |                     |
| part of the pharmacodynamic   |                |                     |
| effect of α‑blockers          |                |                     |
+-------------------------------+----------------+---------------------+

Table (7.5) 2 - Number of SAEs that are potentially suggestive of a
proarrhythmic effect collected in cohort observational surveys or
spontaneously reported with alfuzosin, displayed by MedDRA preferred
terms

  ------------------------------------------------------------------------
                                 **Alfuzosin**         
  ------------------------------ --------------------- -------------------
  **Exposure up to 31 Dec 2002** **Cohort              **Spontaneous
                                 Observational         Reports**
                                 Surveys**             

  **AE Suggestive of             **More than 130,000   **1,350 Million
  Proarrhythmic Effect**         Patients, up to 3     Days of Treatment**
                                 years**               

  QT/QTc interval prolongation   0                     0

  Torsades de pointes            0                     0

  Ventricular tachycardia        0                     3

  Ventricular arrhythmia         0                     0

  Ventricular fibrillation or    1                     4
  flutter                                              

  Cardiac arrest, sudden cardiac 17                    7
  death                                                
  ------------------------------------------------------------------------

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