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2.0 SYNOPSIS Name of Sponsor: Takeda Global Research & Development Center, Inc. Name of Finished Product: Lu AA21004 Investigator: Stuart Harris, MD Publication Based on the Study: None Study Period: 14 July 2008 to 05 January 2009 OBJECTIVES Study Center: SeaView Research, Inc. 3898 NW 7th St Miami, FL 33126 USA Phase of Development: Phase 1 Primary: The primary objective of this study was to evaluate the effects of Lu AA21004 relative to placebo on cardiac repolarization following multiple oral doses in healthy adult male subjects. Secondary: The secondary objectives of the study were as follows: To characterize the pharmacokinetic profiles of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835 associated with the 10 and 40 mg once daily (QD) doses in healthy adult male subjects. To evaluate the safety and tolerability of Lu AA21004 10 and 40 mg QD in healthy adult male subjects. To establish assay sensitivity to the response in the QT/heart rate-corrected QT (QTc) interval following a single dose of 400 mg moxifloxacin in healthy adult male subjects. METHODS This was a phase 1, double-blind, randomized study featuring a 4-treatment parallel-group design to evaluate the effect of multiple doses of Lu AA21004 and a single dose of moxifloxacin on QTc intervals recorded in healthy adult male subjects. The study planned to enroll and randomize 340 male subjects, aged 18 to 45 years, inclusive, to 4 treatment groups (85 subjects per treatment group).
Sequence of Events for Each Treatment Group Screening Check- In Baseline Placebo Dosing Study Medications (1 or 2 or 3 or 4) (a) Days -28 to -3 Day -2 Day -1 Days 1-14 Days 15-22 ECG PK + ECG PK confinement to study clinic Washout Final Assessment /ET Follow-up (b) Days 22-27 Day 28 Day 44 Outpatient Visit Phone Call ECG=electrocardiogram; ET=early termination; PK=pharmacokinetics. (a) Study medications: (1) Lu AA21004 10 mg QD, (2) Lu AA21004 40 mg QD, (3) placebo, (4) placebo on Days 1 to 13 and moxifloxacin 400 mg on Day 14. (b) At 30 days following the last dose, a phone call was made to inquire about adverse events/serious adverse events (SAEs) and concomitant medications since final dose of study medication. The study consisted of Screening (Days -28 to -3), Check-in (Day -2), a Treatment Period (Day -1 and Days 1 to 14), Final Assessment/Early Termination (Day 28), and a follow-up phone call on Day 44. Subjects reported to the clinic on the morning of Day -2 (Check-in) and remained confined until the final pharmacokinetic blood sampling was completed on Day 22. Subjects returned to the clinic on the morning of Day 28 as an outpatient visit for the completion of the Final Assessment/Early Termination procedures. A follow-up phone call was made 30 days after administration of the last dose of study medication (Day 44). Number of Subjects (Planned and Analyzed): Planned: 340 subjects. Analyzed: Electrocardiogram (ECG) population 327 subjects; Pharmacokinetic population (excluding placebotreated subjects) 246 subjects; Safety population 340 subjects. Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been healthy males; aged 18 to 45 years, inclusive; weighing at least 50 kg and with a body mass index of 19 to 32 kg/m 2, inclusive; with a resting pulse and heart rate between 45 and 100 bpm; in good health as determined by the investigator per medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluations (hematology, blood biochemistry, and urinalysis); testing negative for hepatitis B surface antigen and hepatitis C virus antibody; and willing to sign the informed consent form, and comply with the protocol requirements. Test Product, Dose and Mode of Administration, Lot Number: Drug Dose Form Route Lot No. Lu AA21004 10 mg Overencapsulated tablet Oral E05486-004E01 Lundbeck tablet: 2129770 Lu AA21004 placebo N/A Capsule Oral E05486-002E01 Avelox (moxifloxacin) 400 mg Tablet Oral BXC9481 N/A=not applicable. Duration of Treatment: The total duration of the study was approximately 72 days, consisting of Screening (Days -28 to -3), Check-in (Day -2), a Treatment Period (Day -1 and Days 1 to 14), Final Assessment/Early Termination (Day 28), and a follow-up phone call on Day 44.
Reference Therapy, Dose and Mode of Administration, Lot Number: None. Criteria for Evaluation: ECG: The following ECG parameters were derived: The largest time-matched, baseline-adjusted least squares (LS) means difference in QT/QTc intervals: QT, QT interval corrected by Fridericia formula (QTcF), QT interval corrected by Bazett s formula (QTcB), QT interval corrected by Framingham formula (QTcFm), QT interval corrected by individual linear formula (QTcNi[Linear]), and QT interval corrected by individual log-linear formula (QTcNi[Nonlinear]) between Lu AA21004 and placebo. Time-matched, baseline-adjusted LS means difference in the absolute ECG interval measurements (heart rate, PR and QRS intervals) between the treatments. Time-matched, baseline-adjusted LS means difference in average of 3 QT/QTc measurements around the time at which the maximum observed plasma concentration (Cmax) occurred (Tmax) (including Tmax) for Lu AA21004, Lu AA34443, and Lu AA39835 between Lu AA21004 and placebo group. The average of the 3 measurements for the placebo group was the corresponding time points to those that constituted the 3 measurements around Tmax for the Lu AA21004 group. The same corresponding time points were used at Baseline for both the Lu AA21004 and placebo groups. Number and percentage of subjects with absolute QTc intervals above 450, 480, and 500 ms and the number and percentage of subjects with increases from Baseline above 30 and 60 ms. Number and percentage of subjects with abnormal T-wave morphology and presence of U-waves (ECG). Outliers for heart rate, PR interval, and QRS duration. Pharmacokinetic: For each subject the following plasma pharmacokinetic parameters of Lu AA21004, its metabolites Lu AA34443 and Lu AA39835, and moxifloxacin were derived on Day 14 of each treatment group: Cmax, observed minimum plasma concentration (Cmin), time at which Cmax occurred (Tmax), area under the plasma concentration-time curve from time 0 to 24 hours postdose (AUC[0-24]), oral clearance (CL/F) for Lu AA21004 only, and apparent volume of distribution at steady state (Vss/F) for Lu AA21004. Safety: Safety variables included adverse events, clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital sign measurements, weight, physical examination results, and 12-lead ECG findings. Genotype Analysis: Subjects were genotyped for common cytochrome P450 (CYP) 2C9, CYP2C19, and CYP2D6 allelic variants associated with drug disposition. Statistical Methods: ECG Measures The following QT correction methods were used for ECG analysis: Mean QTcF: QT QTcF 3 RR (RR is expressed in units of seconds)
Mean QTcB: QT QTcB 2 RR (RR is expressed in units of seconds) Mean QTcFm: QTcFm QT 0.154(1 RR) (RR and QT expressed in units of seconds) An individual correction was generated by using the slope of each subject s predose QT/RR relationship to normalize the data to a zero correlation coefficient between QT and RR. The slope for correction was calculated from the algebraic constant from the line of best fit (LS) for the QT/RR relationship for all values of QT/RR from predose and baseline ECG for each subject, where the equation for the linear fit was in the form: QT=Intercept + slope RR The following formula for QT correction was used: QTcNi=QT + slope (1 RR) The planned primary endpoint for ECG analysis was the largest time-matched baseline-adjusted LS means difference for QTcNi between Lu AA21004 and placebo at posttreatment ECG collection times. The original raw ECG data consisting of triplicate measurements at each timepoint was averaged. The averaged values were used to derive corrected values of QTcNi as well as QTcF, QTcB, and QTcFm. The secondary endpoints for ECG analysis included the largest time-matched baseline-adjusted LS means difference in QT/QTc intervals (QT, QTcF, QTcB, and QTcFm) between Lu AA21004 and placebo at post treatment ECG collection times. An additional analysis using the heart-rate correction method of QTcNi (Nonlinear) (derived as QTcNi=QT/RR, where was obtained from the log[rr]) was performed. As a post-hoc analysis, the accuracy of each QTc method (QTcNi[Linear], QTcF, QTcB, QTcFm and QTcNi[Nonlinear] for heart rate correction was assessed using on-drug values. For this evaluation, each subject s QTc/RR slope on-drug was estimated and the average of the squared slopes was calculated. The QTc method that generated an average slope closest to zero (ie, a flat slope demonstrating no relation between RR and QTc) was deemed to be the most appropriate for heart rate correction. Mixed effects models with treatment, time, treatment-by-time interaction as fixed effects, baseline QT/QTc as covariate and repeated measure analysis with AR(1) covariance structure and subject as a random effect were used to model change from Baseline in QT/QTc on Day 14. Within the framework of the analyses of variance LS mean estimates and their corresponding 90% confidence intervals (CIs) of Lu AA21004 treatments to placebo difference were presented at each time of measurement on Day 14. To assess the assay sensitivity a 90% CI for the difference in LS means between moxifloxacin and placebo treatments was also presented. An analysis similar to the one described above was performed on QT/QTc based on the average of 3 measurements around Tmax for Lu AA21004, Lu AA34443, and Lu AA39835; this analysis included only the Lu AA21004 treatment groups and placebo. In addition the time-matched, baseline-adjusted LS means difference in the absolute ECG interval measurements (heart rate; PR and QRS intervals) between the treatments were analyzed. Categorical analysis of the number and percentage of subjects meeting threshold of QTc intervals is provided and the number and percent subjects of abnormal T-wave morphology and presence of U-waves (ECG). The number and percentage of subjects with absolute QTc interval>450 ms, 480 ms, and >500 ms and is provided for each treatment group. Similar summary information is provided for QT and QTc interval increases from Baseline of >30 ms and >60 ms. The percentage of subjects who show abnormal T and U waves was summarized by treatment. Outlier analysis was performed for PR interval, QRS duration, and heart rate.
Outlier analysis of the PR interval and the QRS duration for each treatment was performed by presenting the number and percentage of subjects who have a greater than 25% change from Baseline. Results were tabulated by treatment. In addition, the mean change and 2-sided 90% CI in PR and QRS intervals from placebo after baseline-adjustment was computed. Outlier analysis of heart rate for each treatment was performed by presenting the number and percentage of subjects who have a greater than 25% decrease from Baseline or a heart rate of less than 50 bpm (bradycardia) or a greater than 25% increase from Baseline or with a heart rate greater than 110 bpm (tachycardia). The relationship between Lu AA21004 plasma concentrations and time-matched placebo and baseline-corrected QT/QTc measurements was assessed as an exploratory analysis using a mixed effects modeling approach with linear terms alone and also with a linear and quadratic term of plasma and its 2-sided 90% CI at Cmax of Lu AA21004 was provided. Plots of change from baseline QT/QTc at each time point versus plasma concentration were provided for each treatment group. Pharmacokinetic Measures: Descriptive statistics (number of subjects, mean, SD, percent coefficient of variation, minimum, and maximum) is provided at each sampling time for plasma concentrations and plasma pharmacokinetic parameters of Lu AA21004, Lu AA34443, Lu AA39835, and moxifloxacin. Assessments of the achievement of steady-state conditions for plasma concentrations of Lu AA21004, Lu AA34443, and Lu AA39835 were also performed. Safety Measures: All safety assessments, including adverse events, clinical laboratory evaluations, vital signs,12-lead ECG results, and physical examination was summarized with descriptive statistics, where appropriate, and presented in the data listings. SUMMARY OF RESULTS Subject Disposition: A total of 340 men (mean age of 32.6 years) were enrolled into the study and equally randomized to 1 of the 4 treatment groups: placebo only, Lu AA21004 10 mg, Lu AA21004 40 mg, and placebo/moxifloxacin (placebo on Days 1 to 13 and moxifloxacin 400 mg on Day 14). Of these, 328 subjects (96.5%) completed the study and 12 subjects (3.5%) were prematurely discontinued and did not complete the study as planned (2 subjects placebo only, 4 subjects Lu AA21004 10 mg, 3 subjects Lu AA21004 40 mg, and 3 subjects placebo/moxifloxacin). The reasons for subject withdrawal included: adverse events (8 subjects, 2 subjects in each treatment group), withdrawal of consent (5 subjects, 1 subject Lu AA21004 10 mg, 2 subjects Lu AA21004 40 mg, and 2 subjects placebo/moxifloxacin), and other reasons (2 subjects, 1 subject Lu AA21004 10 mg and 1 subject Lu AA21004 40 mg). Pharmacodynamic (QTc) Results: Summary of Baseline-Adjusted, Time-matched Change for Heart Rate and QT/QTc Interval Results The mean time-matched, baseline-adjusted change in heart rate observed on Day 14 in the placebo and moxifloxacin 400 mg treatment groups ranged from 5.5 (at 1 hour postdose) to 8.9 bpm (at 12 hours postdose) and 7.5 (at 23.5 hours postdose) to 11.1 bpm (at 12 hours postdose), respectively. The mean time-matched, baseline-adjusted changes in heart rate in the Lu AA21004 10 mg and Lu AA21004 40 mg treatment groups ranged from 2.9 (at 8 hours postdose) to 5.6 bpm (at 3 hours postdose) and from 1.3 (at 1 hour postdose) to 5.1 bpm (at 7 hours postdose), respectively. This heart rate increase observed after multiple doses of Lu AA21004 10 or 40 mg QD was on average 3 to 4 bpm, and was smaller than that observed in the placebo or single dose moxifloxacin 400 mg group. This mild heart rate reduction was not considered clinically significant. The baseline-adjusted, time-matched differences between active treatment and placebo for QTc intervals using QTcNi (Linear) correction method are summarized in the table below. The upper bound of the 2-sided 90% CI around the LS mean difference from placebo for baseline-adjusted QTcNi (Linear) did not exceed 10 ms at any time point after administration of Lu AA21004 10 mg or 40 mg QD; values ranged from 3.0 to 4.9 ms for Lu AA21004
10 mg and 5.6 to 8.4 ms for the supratherapeutic dose of Lu AA21004 40 mg. The lower bound of the 2-sided 90% CI around the LS mean difference from placebo for baseline-adjusted QTcNi (Linear) exceeded 5 ms from 2 to 4 hours postdose after administration of a single dose of moxifloxacin 400 mg on Day 14, thereby demonstrating assay sensitivity. Moxifloxacin 400 mg single ECG Lu AA21004 10 mg QD vs Lu AA21004 40 mg QD vs dose vs Placebo QTcNi Collection Placebo QTcNi (Linear) (ms) Placebo QTcNi (Linear) (ms) (Linear) (ms) Time Postdose LS Mean 90% CI for LS Mean 90% CI for LS Mean 90% CI for (hrs) Difference Difference Difference Difference Difference Difference Predose 0.4 (-3.1, 3.9) 4.9 (1.4, 8.4) 1.7 (-1.8, 5.2) 1-0.4 (-3.9, 3.1) 4.0 (0.5, 7.5) 7.2 (3.7, 10.7) 2 0.7 (-2.8, 4.2) 3.8 (0.3, 7.3) 10.1 (6.6, 13.6) 3 1.0 (-2.5, 4.5) 3.8 (0.3, 7.3) 11.0 (7.5, 14.6) 4 1.4 (-2.1, 4.9) 4.4 (0.9, 7.9) 10.6 (7.1, 14.1) 5 0.5 (-3.0, 4.0) 3.1 (-0.4, 6.6) 7.6 (4.1, 11.1) 6 0.8 (-2.7, 4.3) 3.2 (-0.3, 6.7) 7.8 (4.3, 11.3) 7 0.5 (-3.0, 4.0) 2.2 (-1.3, 5.7) 6.8 (3.3, 10.3) 8-0.4 (-3.9, 3.1) 2.4 (-1.1, 5.9) 5.6 (2.1, 9.1) 9-0.0 (-3.5, 3.5) 2.1 (-1.4, 5.6) 6.1 (2.6, 9.6) 10 0.3 (-3.2, 3.8) 3.8 (0.3, 7.3) 7.9 (4.4, 11.4) 12 1.3 (-2.2, 4.8) 4.4 (0.9, 7.9) 6.0 (2.5, 9.5) 16-0.3 (-3.8, 3.2) 3.3 (-0.2, 6.8) 6.2 (2.7, 9.7) 23.5-0.6 (-4.1, 3.0) 4.4 (0.9, 7.9) 5.6 (2.1, 9.1) Note: Statistical model used was a mixed effects model with treatment, time, treatment-by-time interaction as fixed effects, baseline QT/QTc as a covariate and repeated measure analysis with AR(1) covariance structure. The results of the primary endpoint of QTcNi (Linear) and the secondary endpoints of QTcF, QTcFm, and QTcB as well as from the post hoc analysis using QTcNi (Nonlinear) were consistent, and they indicated that Lu AA21004 had no clinically meaningful effect on cardiac repolarization based on the following observations: The upper bound of the 2-sided 90% CI around the LS mean difference from placebo for baseline-adjusted QTcNi (Linear), QTcF, QTcB, QTcFm, and QTcNi (Nonlinear) did not exceed 10 ms at any time point after administration of Lu AA21004 10 mg or 40 mg QD for 14 days. The lower bound of the 2-sided 90% CI around the LS mean difference from placebo for baseline-adjusted QTcNi (Linear), QTcF, QTcB, QTcFm, and QTcNi (Nonlinear) exceeded 5 ms at at least 3 times points between 1 to 6 hours after administration of a single dose of moxifloxacin 400 mg on Day 14. The peak and time curve of the effect were consistent with those observed in similar thorough QT (TQT) studies in healthy volunteers and the study s ability to capture a small QT prolongation could thereby be demonstrated in compliance with International Conference on Harmonisation E14 guidance. Summary of ECG Outlier Events No notable treatment-related differences in the proportion of subjects with predefined outlier events for QTcNi (Linear), QTcF, QTcB, QTcFm, QTcNi (Nonlinear) were observed.
No clear treatment-related differences in the proportion of subjects with predefined outlier events for PR interval, QRS duration, or heart rate were noted. No positive U-waves were reported during the study. The percentage of subjects with T-wave morphology described as inverted, biphasic, and flat was small and equally distributed among all treatment groups at Baseline and after 14 days of dosing. Pharmacokinetic Results: The pharmacokinetic results for Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835 were consistent with those observed in previous studies (see table below). Analyte Parameter (units) (a) n (b) Lu AA21004 10 mg N=82 Arithmetic Mean (%CV) Geometric Mean n (b) Lu AA21004 40 mg N=82 Arithmetic Mean (%CV) Geometric Mean Lu AA21004 AUC(0-24) (ng hr/ml) 82 316.85 (46.04) 290.01 82 1177.80 (33.65) 1114.55 Cmax (ng/ml) 82 16.84 (44.36) 15.47 82 63.35 (35.19) 59.79 Cmin (0) (ng/ml) 82 10.23 (47.20) 9.31 82 37.13 (38.25) --- Tmax (hr) (c) 82 8.10 (0.00, 16.10) --- 82 8.10 (4.10, 23.60) --- T1/2 (hr) 77 58.58 (47.93) --- 82 56.41 (36.19) --- CL/F (L/hr) 82 37.42 (40.52) --- 82 37.94 (33.97) --- Vss/F (L) 80 2710.50 (26.50) --- 82 2752.83 (18.54) --- Lu AA34443 AUC(0-24) (ng hr/ml) 82 290.73 (36.84) 271.30 82 1180.80 (27.11) 1133.77 Cmax (ng/ml) 82 17.86 (43.70) 16.25 82 73.27 (32.57) 69.41 Cmin (0) (ng/ml) 82 8.32 (35.17) 7.83 82 33.06 (28.64) --- Tmax (hr) (c) 82 5.10 (3.10, 16.10) --- 82 4.10 (3.10, 8.10) --- T1/2 (hr) 78 60.83 (43.63) --- 82 56.13 (33.90) --- Lu AA39835 AUC(0-24) (ng hr/ml) 82 10.29 (29.66) 9.89 82 47.12 (26.08) 45.62 Cmax (ng/ml) 82 0.53 (33.98) 0.50 82 2.46 (27.09) 2.38 Cmin (0) (ng/ml) 82 0.36 (27.86) 0.34 82 1.56 (30.99) --- Tmax (hr) (c) 82 7.10 (0.00, 16.10) --- 82 7.10 (3.10, 12.10) --- T1/2 (hr) 76 64.71 (40.94) --- 82 61.85 (36.85) --- --=not applicable, AUC(0-24)=area under the plasma concentration-time curve from time 0 to 24 hours, CV=coefficient of variance. (a) All PK parameters are presented for Day 14. (b) Several subjects did not have a complete dataset for specific pharmacokinetic parameters of at least 1 of the analytes Lu AA21004, Lu AA34443, and Lu AA39835. (c) Tmax is presented as median (minimum, maximum).
The pharmacokinetic results for moxifloxacin were also consistent with those observed in previous similar studies (see table below). Parameter (units) Placebo/Moxifloxacin 400 mg N=82 Arithmetic n Mean (%CV) AUC(0-24) (ng hr/ml) 82 20716 (14) 20531 Cmax (ng/ml) 82 1703 (16) 1682 Tmax (hr) (a) 82 2.10 (1.10, 5.10) --- T1/2 (hr) 82 16.69 (26.08) --- ---=not applicable. (a) Tmax is presented as median (minimum, maximum). Geometric Mean Safety Results: Overall, 238 subjects (70.0%) experienced at least 1 treatment-emergent adverse event during the study. The incidence of subjects experiencing adverse events was highest for the Lu AA21004 40 mg group (74.1%), 70.6% for the Lu AA21004 10 mg group, 68.2% for the placebo only group, and 67.1% for the placebo/moxifloxacin group. One subject in the Lu AA21004 10 mg treatment group experienced a treatment-emergent adverse event considered severe; all other treatment-emergent adverse events were considered mild or moderate in intensity. A total of 98 subjects (28.8%) experienced treatment-emergent adverse events considered at most possibly related to the study drug (22.4% placebo only, 31.8% Lu AA21004 10 mg, 40.0% Lu AA21004 40 mg, and 21.2% placebo/moxifloxacin) and 14 subjects (4.1%) experienced treatment-emergent adverse events considered probably related to study drug (3.5% placebo only, 4.7% Lu AA21004 10 mg, 5.9% Lu AA21004 40 mg, and 2.4% placebo/moxifloxacin). Eight subjects (2.4%), 2 in each treatment group experienced treatment-emergent adverse events that led to study drug discontinuation. There were no deaths or other SAEs during this study. The most common adverse event during the study was contact dermatitis (42.9% of subjects overall), occurring with similar incidence across the 4 treatment groups, as a reaction to the application of the electrodes during the ECG procedure. The most frequent drug related adverse events (in greater than 10 subjects overall) were, in decreasing order of incidence: headache, diarrhea, nausea, increased blood pressure, sinus tachycardia, and dizziness. The incidence of these adverse events was generally higher for the Lu AA21004 supratherapeutic dose (40 mg) compared with the other 3 treatment groups. Four Lu AA21004-treated subjects (2 Lu AA21004 10 mg and 2 Lu AA21004 40 mg) experienced single episodes of vasovagal syncope, which the investigator assessed as nonserious and secondary to vasomotor instability rather than to hemodynamically significant arrhythmias. Two cases were directly associated with venipuncture; the triggering event was not identified in the other 2 cases. For one of the 4 subjects (Lu AA21004 10 mg treatment group), the adverse event of vasovagal syncope (considered severe and possibly related to study drug) led to study drug discontinuation; the subject s treatment was unblinded. Several subjects had clinical laboratory values meeting the potentially clinically significant criteria, but none of them were considered as adverse events or led to study drug discontinuation. One subject in the placebo/moxifloxacin experienced an adverse event of increased alanine aminotransferase (ALT) (104 IU/L on Day 14), however this elevation was not considered potentially clinically significant; the subject recovered (33 IU/L on Day 28) and completed the study as planned.
Several subjects had vital sign or ECG parameters measurements that met the criteria for being potentially clinically significant. Seventeen subjects (4 placebo only, 4 Lu AA21004 10 mg, 6 Lu AA21004 40 mg, and 3 placebo/moxifloxacin) experienced adverse events of increased blood pressure and for 2 of these subjects (from the placebo only and Lu AA21004 10 mg treatment groups) the events led to study drug discontinuation. Additionally, 1 subject from the placebo/moxifloxacin treatment group experienced an adverse event of orthostatic hypotension that resulted in study drug discontinuation. Two subjects experienced ECG-related adverse events in the system organ class (SOC) of investigations, namely ECG T-wave inversion (in a Lu AA21004 10 mg-treated subject) and ECG St-T change (in a placebo/moxifloxacintreated subject); both completed the study. CONCLUSIONS: In this TQT study, administration of Lu AA21004 10 or 40 mg QD for 14 days to healthy male subjects had no clinically significant effect on cardiac repolarization. Administration of Lu AA21004 10 or 40 mg QD for 14 days was well tolerated in healthy male subjects in this study. Date of Report: 15 July 2010