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Atomoxetine

Phase 3

Attention Deficit Hyperactivity Disorder | Small molecule | Other |Eli Lilly and Company|Last Updated: Jun 26, 2014

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
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Trial Design
RandomizedDouble-BlindACTIVE_CONTROLLEDBiomarker
Total Trials24
Total Enrollment7,508
FDA Designations
No designations recorded
Clinical Trials (24)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT00969618A Long Term Follow-Up Study for Asian Adult Patients With Attention Deficit Hyperactivity DisorderPHASE3 COMPLETED 211Nov 1, 2009Jan 1, 2012Dec 12, 201212 Japan
NCT00962104Atomoxetine to Treat Asian Adult Patients With Attention-Deficit/Hyperactivity DisorderPHASE3 COMPLETED 391Aug 1, 2009Feb 1, 2011Sep 11, 201224 Japan, South Korea +1
NCT00700427A Long Term Study of a Medication for Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)PHASE3 COMPLETED 2,017Jun 1, 2008Oct 1, 2013Jun 26, 201456 Austria, Belgium +10
NCT00568685Atomoxetine to Treat Korean Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD)PHASE3 COMPLETED 153Nov 1, 2007Nov 1, 2008Jan 26, 20103 South Korea
NCT00447278A Study Comparing the Effect of Atomoxetine Versus Other Standard Care Therapy on the Long Term Functioning in Attention-Deficit/Hyperactivity Disorder (ADHD) Children and AdolescentsPHASE3 COMPLETED 399Mar 1, 2007Jul 1, 2009Apr 27, 201035 Belgium, France +7
NCT00191945Efficacy and Safety of Atomoxetine in Children With Recent Diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD)PHASE3 COMPLETED 151May 1, 2005Feb 1, 2008Feb 2, 201011 Spain
NCT00191386Long-Term Study of Atomoxetine in Children With Attention-Deficit/Hyperactivity Disorder (AD/HD)PHASE3 COMPLETED 228May 1, 2005Aug 1, 2009Dec 28, 201024 Japan
NCT00191542Atomoxetine vs Placebo in the Treatment of ADHD in Swedish Children and AdolescentsPHASE3 COMPLETED 100Mar 1, 2005Aug 1, 2006Oct 11, 20069 Sweden
NCT00191737An Open-Label Study of Atomoxetine in Adolescents With Attention-Deficit/Hyperactivity DisorderPHASE3 COMPLETED 147Oct 1, 2004Feb 1, 2006Jan 26, 20072 Germany
NCT00192023An Italian Study of the Efficacy of Atomoxetine in the Treatment of Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD) and Comorbid Oppositional Defiant Disorder (ODD).PHASE3 COMPLETED 139Oct 1, 2004May 1, 2008Jan 18, 201012 Italy
NCT00191516An Open-Label Study of Atomoxetine in Children With Attention-Deficit/Hyperactivity DisorderPHASE3 COMPLETED 257Oct 1, 2004Feb 1, 2006Jan 26, 20071 Germany
NCT00191659Study of Broader Efficacy of Atomoxetine in the Treatment of ADHD in Children/AdolescentsPHASE3 COMPLETED 200Jun 1, 2004Apr 1, 2006Mar 2, 20071 United Kingdom
NCT00191880Open-Label Trial of Atomoxetine to Evaluate Academic Outcome in Children Ages 8-11 Years With Attention Deficit/Hyperactivity DisorderPHASE3 COMPLETED 100May 1, 2004Jun 1, 2006Aug 29, 20068 Canada
NCT00485459Atomoxetine Hydrochloride Versus Placebo in Taiwanese Children and Adolescents With ADHDPHASE3 COMPLETED 106Feb 1, 2004Nov 1, 2004Jun 13, 20071 Taiwan
NCT00485550Comparison of Atomoxetine Plus Either Comparator or Placebo in Children With ADHD Who Haven't Responded to Stimulant TherapyPHASE3 COMPLETED 14Jan 1, 2004Mar 1, 2005Jun 13, 20071 United States
NCT00191698Comparison of Atomoxetine and Placebo in Children and Adolescents With ADHD and ODDPHASE3 COMPLETED 226Dec 1, 2003Nov 1, 2007Oct 31, 200816 Australia, Belgium +6
NCT00486083Comparison Atomoxetine Hydrochloride and Comparator in Pediatric Outpatients With ADHDPHASE3 COMPLETED 330Dec 1, 2003Oct 1, 2004Jun 13, 20073 China, Mexico +1
NCT00485407Guiding Dose Increases in Patients Incompletely Responsive to Usual Doses of AtomoxetinePHASE3 COMPLETED 377Jul 1, 2003Jun 1, 2005Nov 1, 20072 United States, Canada
NCT00190684Long-Term, Open Label Atomoxetine StudyPHASE3 COMPLETED 1,553Aug 1, 2000Oct 1, 2009Jan 17, 2011100 United States, Australia +12
NCT00636818Atomoxetine Asian Study in Adult Subjects With Attention-Deficit/Hyperactivity Disorder (ADHD)PHASE2 COMPLETED 45Mar 1, 2008Oct 1, 2008Nov 4, 201011 China, South Korea +1
NCT00530335Atomoxetine Phase 2 Study in Japanese Adult Patients With Attention Deficit/Hyperactivity Disorder (ADHD)PHASE2 COMPLETED 45Sep 1, 2007Apr 1, 2008Jul 27, 201112 Japan
NCT00191295Atomoxetine Versus Placebo in Children With Attention Deficit/Hyperactivity Disorder (ADHD)PHASE2 COMPLETED 240Feb 1, 2005Sep 1, 2006Nov 6, 200724 Japan
NCT00485628Safety Study in Outpatient Japanese Children With ADHDPHASE2 COMPLETED 37Apr 1, 2003Oct 1, 2003Jun 13, 20071 Japan
NCT01177943A Bioequivalence (BE) Study in Healthy SubjectsPHASE1 COMPLETED 42Aug 1, 2010Oct 1, 2010Oct 27, 20111 Japan
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Study Endpoints
Primary Endpoints
Number of Participants With Adverse Events Leading to Discontinuation
Baseline through 48 weeks
Change From Baseline in the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) 18-Item Total Attention-Deficit/Hyperactivity Disorder (ADHD) Symptom Score up to 10 Weeks
Baseline, up to 10 weeks

CAARS-Inv:SV is a scale that assesses symptom severity over past week. Total ADHD symptom score consisted of 18 items (sum of inattention \[9 items, range: 0-27\] and hyperactivity-impulsivity \[9 items, range: 0-27\] subscales) using a 4-point scale (0=not at all/never to 3=very much/very frequently) for total score range of 0 to 54. Higher scores indicate greater impairment.

Percentage of Participants Who Maintain a Satisfactory Response During the Double-Blind Maintenance/Randomized Withdrawal Period
Baseline (Week 24) up to Week 49

Conners' Adult ADHD Rating Scale-Investigator Rated:Screening Version (CAARS-Inv:SV); 30-item scale (3 subscales): inattention, hyperactivity/impulsivity (9 items each), ADHD Index (12 items). Each item is scored 0 (not at all/never) to 3 (very much/very frequently). Total ADHD symptoms score (SS)=inattention+hyperactivity/impulsivity (range:0-54). Higher score=more impairment. Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) measures participant's overall severity of ADHD symptoms and scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Maintenance of response during the randomized withdrawal phase was a reduction of ≥30% in the baseline CAARS-Inv:SV Total ADHD SS and a CGI-ADHD-S score ≤3. Participants had to continuously meet the response criteria, except for 1 excursion after assessment at Week 24 through Week 37 and 1 other excursion after assessment at Week 37 through Week 49. Excursions were not permitted at 2 consecutive visits.

Change From Baseline to Day 42 Endpoint in Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) Total Score
Baseline, Day 42

Measures the 18 symptoms contained in the DSM-IV diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 none/never or rarely) to 3 (severe/very often). Total scores range from 0 (no symptoms) to 54 (highly symptomatic).

Change From Baseline to 6 Month Endpoint in Child Health and Illness Profile - Child Edition, Parent Report Form (CHIP-CE PRF), Achievement Domain
Baseline, 6 months

CHIP-CE PRF: parent rated assessment of a child's health status/level of functioning. The achievement domain describes developmentally appropriate role functioning in school and with peers. The majority of items assess frequency of activities or feelings using a 5-point response format (1=never, 5=always). Standard scores (T-scores) were established, with all domains and subdomains having a mean score of 50 and standard deviation of 10. Normative range is 40 to 60. Higher scores indicate better health and lower scores indicate worse health.

Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version:Investigator Administered and Scored (ADHDRS-IV-Parent:Inv) Total Score at 12 Week Endpoint
Week 12

Measures the 18 symptoms contained in the DSM-IV diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total Scores range from 0 to 54.

Number of Participants With Adverse Events for Long Term Safety and Tolerability
Baseline through 4 years

Details on the actual adverse events are presented in the Reported Adverse Events Section.

To test the hypothesis that atomoxetine and psychoeducation given for 10 weeks is superior to placebo and psychoeducation in improving overall
functioning of patients with ADHD as measured by the mean change in the total score of the Child Health and Illness Profile-Child Edition-Parent form (CHIP-CE-Parent form) domain Achievement.
Global Impression of Perceived Difficulties (GIPD) scale at baseline, Week 8 and Week 24
Change From Baseline to 8 Week Endpoint in Swanson, Nolan and Pelham Questionnaire (SNAP-IV): Attention-Deficit/Hyperactivity Disorder (ADHD) Subscale
Visit 8 (baseline) and Visit 14 (8 weeks)

Items from the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for ADHD are included for the two subsets of symptoms: inattention (items #1-#9) and hyperactivity/impulsivity (items #11-#19). The SNAP-IV is based on a 0 (not at all) to 3 (very much) rating scale. Total subscale scores range from 0 to 54.

To test whether atomoxetine given for 10 weeks is superior to standard current therapy as measured by CHIP-CE (Child Health and Illness Profile - Child Edition)
The primary objective of this study is to assess the correlation of change from baseline to one year in ADHD symptoms as measured by the Attention Deficit/Hyperactivity Disorder Rating Scale- IV-
Parent Version: Investigator Administered and Scored,
total score, with change from baseline in academic achievement of medication-naive patients treated with atomoxetine at one year as measured by the total
of the composite scores of the broad reading, broad math, and broad language subtests of the Woodcock-Johnson Tests of Achievement (WJII)
Test the hypothesis that atomoxetine administered as a single-daily dose provides superior efficacy compared with placebo in Taiwanese children and adolescents with ADHD
Assess the safety of atomoxetine and placebo compared to atomoxetine and methylphenidate in children aged 6 through 12 years with ADHD who have been identified as stimulant non-responders and have been exposed to acute treatment of atomoxetine.
Mean reduction in ODD symptoms using the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP-IV), atomoxetine vs placebo
over 8 weeks
Test the hypothesis that atomoxetine hydrochloride is non-inferior to methylphenidate hydrochloride in improving ADHD symptoms following an approximately 8-week period of double blind treatment as assessed by a comparison of response rates
Test whether patients treated with atomoxetine 1.2 mg/kg/day who have sub-optimal clinical responses and peak plasma atomoxetine levels no higher than 800 ng/mL will benefit from a dose increase to 2.4 mg/kg/day
Categorical Changes in Vital Signs (Blood Pressure [BP], Pulse, Weight, Temperature) During the Study
Baseline through 5 years

Vital signs were assesed categorically using the term high for BP, high and low for pulse and temperature, or decreased for weight. For BP, high was an increase to a value above the 95th percentile of the National Institute of Health (NIH) values. For pulse, high was an increase of at least 25 beats per minute to at least 110, and low was a decrease of at least 20 beats per minute to at most 65 beats per minute. For temperature, high was an increase of at least 1 to 37.7 and low was a decrease of at least 1.3 to at most 35.6. Decrease in weight was marked by a reduction of at least 3.5%.

Change From Baseline to 5 Year Endpoint in BP
baseline, 5 years
Change From Baseline to 5 Year Endpoint in Pulse
baseline, 5 years
Change From Baseline to 5 Year Endpoint in Body Weight
baseline, 5 years
Change From Baseline to 5 Year Endpoint in Height
baseline, 5 years
Change From Baseline to 5 Year Endpoint in Weight, Height, and Body Mass Index (BMI) Percentile Stratified by Baseline Quartile
baseline, 5 years

Patients were assessed for changes in weight, height, and BMI. BMI is an estimate of body fat based on body weight divided by height squared.

Change From Baseline to 5 Year Endpoint in Electrocardiogram (ECG)
baseline, 5 years

Patients were assessed for changes in ECG. The RR interval is the time duration between two consecutive R waves of the ECG. The QRS interval is the beginning of Q to the end of the S wave. The QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate. A corrected QT interval (QTc) has been corrected in order to aid interpretation. QTbz is the QT interval using Bazett's correction formula. QTfr is the QT interval using Fridericia's correction formula.QTdat is the QT interval using a data specific correction method for children.

Change From Baseline to 5 Year Endpoint in Heart Rate
baseline, 5 years

Patients were assessed for changes in heart rate using electrocardiogram.

Number of Patients Meeting Committee for Proprietary Medicinal Products (CPMP) Categorical QTc Interval Criteria Part I (Numerical Increase)
baseline through 5 years

QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate. A corrected QT interval (QTc) has been corrected in order to aid interpretation. QTbz is the QT interval using Bazett's correction formula. QTfr is the QT interval using Fridericia's correction formula. QTdat is the QT interval using a data specific correction method for children.

Number of Patients Meeting CPMP Categorical QTc Interval Criteria Part II (Interpretation at Baseline and Endpoint)
baseline through 5 years

QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate. A corrected QT interval (QTc) has been corrected in order to aid interpretation. QTbz is the QT interval using Bazett's correction formula. QTfr is the QT interval using Fridericia's correction formula. QTdat is the QT interval using a data specific correction method for children. For Males: Normal is \<430 ms, Borderline is \>=430 ms and \<450 ms, Prolonged is \>=450 ms. For Females: Normal is \<450 ms, Borderline is \>=450 ms and \<470 ms, Prolonged is \>=470 ms.

Number of Participants With Abnormal Laboratory Analytes During the Study
baseline through 5 years

Standard reference ranges from Covance Laboratories were used in the determination of abnormal high and low values based on age and gender, where appropriate. Aspartate aminotransferase (AST); serum glutamic oxaloacetic transaminase (SGOT); units/liter (U/L); alanine aminotransferase (ALT); serum glutamic pyruvic transaminase (SGPT); millimoles/liter (mmol/L); grams/liter (g/L); micromoles/liter (umol/L); millimoles/liter-iron (mmol/L-Fe); trillion/liter (TI/L)or 10\^12 units/liter; Giga/liter (GI/L)or 10\^9 units/liter; femtoliters (fL); urinalysis (UA)

Number of Participants in Each Tanner Stage (Pubic Hair) by Age Group
1 year through 5 years

Tanner Stage: I: no pubic hair at all (prepubertal Dominic state) II: small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females) III: hair becomes more coarse and curly, and begins to extend laterally IV: adult-like hair quality, extending across pubis but sparing medial thighs V: hair extends to medial surface of the thighs Age Groups: 1. age\<11.0 (female) and age\<12 (male) 2. 11=\<age\<12 (female) or 12\<=age\<13 (male) 3. 12=\<age\<15 (female) or 13=\<age\<15 (male) 4. age\>=15 (female and male)

Discontinuations Due to Adverse Events (AE)
Baseline to 8 Weeks

The definition of a study adverse event was any unfavorable medical event, newly emerged or a deterioration of a preexisting condition, in other words any untoward medical occurrence in a patient administered a pharmaceutical product, without regard to the possibility of a causal relationship, that occurred after the visit for informed consent and up to the visit for completion of administration, or discontinuation.

Change of total score on ADHD RS-IV-JParent Version: Investigation-Administered and Scored
The primary objective of the study is to assess whether treatment with 1.8 mg/kg/day of atomoxetine will be safe and tolerable in a population of Japanese pediatric patients aged 6 through 18 years.
Maximum Observed Plasma Concentration (Cmax)
Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 8, 12, 18, and 24 hours post dose

The Cmax values are based on the atomoxetine plasma concentration. The Least Squares (LS) Mean Value was based on treatment, period, group, and subject.

Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-tlast)]
Predose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 8, 12, 18, and 24 hours post dose

The AUC (0-tlast) is the area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (tlast) and is based on the atomoxetine plasma concentration. The Least Squares (LS) Mean Value was based on treatment, period, group, and subject.

Secondary Endpoints
Mean Change From Baseline to 48 Weeks Endpoint in the Conners' Adult Attention-Deficit Hyperactivity Disorder Rating Scale-Investigator Rated: Screening Version-Japanese (CAARS-Inv:SV-J)
Baseline, 48 weeks
Mean Change From Baseline to 48 Weeks Endpoint in the Adult Attention-Deficit/Hyperactivity Disorder Quality of Life (AAQoL)-29 Scores
Baseline, 48 weeks
Mean Change From Baseline to 48 Weeks Endpoint in the Behavior Rating Inventory of Executive Function -Adult (BRIEF-A) Version: Self Report (BRIEF-A:Self Report )
Baseline, 48 weeks
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Study Design & Arms
AllocationNA
MaskingNONE
ModelSINGLE_GROUP
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
AtomoxetineEXPERIMENTAL -
PlaceboPLACEBO_COMPARATOR -
Atomoxetine 0.2 milligram per kilogram per day (mg/kg/day)ACTIVE_COMPARATOR -
Atomoxetine 0.5 mg/kg/dayACTIVE_COMPARATOR -
Atomoxetine 1.2 mg/kg/dayACTIVE_COMPARATOR -
OESTACTIVE_COMPARATOROther Early Standard Treatment (OEST): any treatment for ADHD as prescribed by investigator, 6 months, up to an additional 6 months extension
AEXPERIMENTALAtomoxetine is administered at 1.2 mg/kg/day, PO for 8 weeks, followed by 1.2 or 2.4 mg/kg/day, PO for 4 weeks, open label administration can continue for up to one year
BPLACEBO_COMPARATORPlacebo is administered by mouth, daily for 8 weeks. After 8 weeks, those randomized to placebo may be titrated to 1.2 mg/kg/day atomoxetine for the remainder of the study up to one year
Atomoxetine Oral SolutionEXPERIMENTAL -
Atomoxetine Capsule FormulationACTIVE_COMPARATOR -
Interventions
NameTypeDescription
AtomoxetineDRUG40-120 milligrams/day (mg/day) taken by mouth, once a day for 48 weeks
PlaceboDRUGTaken by mouth, once daily for 10 weeks.
atomoxetine hydrochlorideDRUGOral 40-100 mg/day
Other standard therapy for ADHDDRUGAny treatment for ADHD as prescribed by investigator, 6 months, up to an additional 6 months extension
atomoxetine 0.5 mg/kg/dayDRUGatomoxetine 0.5 milligrams per kilogram per day (mg/kg/day) daily (QD), by mouth (PO)
atomoxetine 1.2 mg/kg/dayDRUGatomoxetine 1.2 mg/kg/day QD, PO
atomoxetine 1.2-1.4 mg/kg/dayDRUGatomoxetine 1.2 - 1.4 mg/kg/day QD, PO
Methylphenidate HydrochlorideDRUG -
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Eligibility Criteria
Age Range18 Years — N/A
SexALL
Healthy VolunteersNo
Study Sites12

Inclusion Criteria: * Patients who have completed the B4Z-JE-LYEE study (NCT00962104) and signed the Informed Consent Document (ICD). * Patients must have been judged by the investigator to be reliable to keep appointments for clinic visits and all tests, including venipuncture and examinations, re...

Countries:JapanSouth KoreaTaiwanAustriaBelgiumFinlandFranceGermanyItalyNetherlandsPortugalSpainSwedenSwitzerlandUnited KingdomIrelandMexicoNorwayTurkey (Türkiye)CanadaUnited StatesAustraliaDenmarkChinaIsraelPuerto RicoSouth Africa
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