A Study to Evaluate the Efficacy and Safety of Two Doses of PF-03654746 in Adults With Attention Deficit Hyperactivity Disorder (ADHD).

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether PF-03654746 is effective in the treatment of Adult Attention Deficit Hyperactivity Disorder (ADHD). This will be a randomized, double-blind, crossover study in which adults with ADHD will receive 3 weeks of treatment with PF-03654746, either a low dose (1 mg), or flexible dose (0.50 mg titrated up to 2 mg), and 3 weeks of placebo. A washout period will separate the 2 treatment periods. Participants will be required to washout of prior ADHD medication before entering the study. Participants will be required to come to the site for 10 visits over approximately a 10-week period.

Official Title
-----------------
A Phase Iia, Randomized, Double Blind, Placebo Controlled, Three-treatment, Two-period Crossover Study Of The Efficacy And Safety Of Two Doses Of Pf-03654746 In Adults With Attention Deficit Hyperactivity Disorder

Conditions
-----------------
Attention Deficit Hyperactivity Disorder

Intervention / Treatment
-----------------
* Drug: PF-03654746
* Drug: Placebo capsules
* Drug: PF-03654746


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with a diagnosis of Attention Deficit Hyperactivity Disorder, based on clinical assessment and interview. Male and female outpatients. Subjects with a diagnosis of Attention Deficit Hyperactivity Disorder, based on clinical assessment and interview. Female subjects must be of non-childbearing potential. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including hypertension), hepatic, neurologic, or allergic disease. Current or lifetime history of psychosis or bipolar disorder; any current anxiety disorder (with the exception of social or specific phobia), or substance abuse or dependence in the past 6 months. Current episode of Major Depression or episode within the last 6 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flexible Dose<br> | Drug: PF-03654746<br>* Dosage Form: 0.5 mg capsules of PF-03654746 Dosage: 0.5 mg QD for Days 1-7, then 1.0 mg QD Days 8-14, then 2.0 mg QD Days 15-21<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo capsules<br>* Dosage Form: matching placebo capsules Dosage: Subjects will take two placebo capsules each morning throughout the 3 week double-blind treatment placebo treatment period.<br>|
| Experimental: Fixed Dose<br> | Drug: PF-03654746<br>* Dosage Form: 0.5 mg capsules of PF-03654746 Dosage: 1 mg (2 x 0.5 mg capsules) of PF-03654746 given daily for three weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Adult Attention Deficit Hyperactivity Disorder (ADHD) Investigator Symptom Rating Scale (AISRS) Total Score at Week 3 | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). AISRS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher score corresponded to a worse severity of ADHD. | Baseline, Week 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Adult Attention Deficit Hyperactivity Disorder (ADHD) Investigator Symptom Rating Scale (AISRS) Total Score at Week 1 and 2 | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). AISRS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher score corresponded to a worse severity of ADHD. | Baseline, Week 1, 2 | 
| Percentage of Participants With at Least 30 Percent Decrease From Baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). AISRS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher score corresponded to a worse severity of ADHD. | Week 1, 2, 3 | 
| Percentage of Participants With 1 or 2 Score on Clinical Global Impression-Severity Scale (CGI-S) | CGI-S: 7-point clinician rated scale to assess severity of participant's current illness state; range: 1 (normal - not ill at all) to 7 (among the most extremely ill patients). Higher score = more affected. Participants with a score of 1 (normal - not ill at all) or 2 (borderline mentally ill) are reported. | Week 1, 2, 3 | 
| Percentage of Participants With Less Than or Equal to 18 Score on Adult ADHD Investigator Symptom Rating Scale (AISRS) | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). AISRS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher score corresponded to a worse severity of ADHD. | Week 1, 2, 3 | 
| Percentage of Participants With Sustained Response of at Least 30 Percent Decrease From Baseline in Time-Sensitive ADHD Symptom Scale (TASS) Total Score | TASS: a time sensitive 18-item questionnaire completed by the participant that measured the severity of current ADHD symptoms. It included 9 items that evaluate symptoms of inattention sub-scale and 9 items that evaluate symptoms of impulsivity and hyperactivity sub-scale. Each item was rated from 0 (none) to 3 (severe). TASS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher total score corresponds to a worse severity of ADHD. TASS was administered each day from Day 1 to 14 and on Day 21 in each intervention period. Participants with sustained response were those who had at least 30 percent decrease from baseline in TASS total score, which was maintained at all visits up to the time of assessment. Sustained responders at Day 7, 14 and 21 were analyzed. | Day 7, 14, 21 | 
| Change From Baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) Subscale Scores at Week 1, 2 and 3 | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). The AISRS inattention and hyperactive/impulsive total subscale score range from 0 to 27. A higher total subscale score corresponded to a worse severity of ADHD inattention or hyperactivity/impulsivity. | Baseline, Week 1, 2, 3 | 
| Change From Baseline in Time-Sensitive ADHD Symptom Scale (TASS) Total Score on Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 21 | TASS: a time sensitive 18-item questionnaire completed by the participant that measured the severity of current ADHD symptoms. It included 9 items that evaluate symptoms of inattention sub-scale and 9 items that evaluate symptoms of impulsivity and hyperactivity sub-scale. Each item was rated from 0 (none) to 3 (severe). TASS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher total score corresponded to a worse severity of ADHD. TASS was administered each day from Day 1 to 14 and on Day 21 in each intervention period. | Baseline, Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21 | 
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Week 3 | The MADRS scale measures the depression level of a participant. It is administered as a semi-structured clinician interview. The total score is derived by adding the scores of the following 10 items: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; (5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; (9) Pessimistic thoughts; (10) Suicidal thoughts. Each item is scored using a 6-point scale which ranges from 0 to 6 (a higher score indicates increased severity). The total score range was 0 to 60 where 0 indicates no depression and 60 indicates severely depressed. | Baseline, Week 3 | 
| Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Week 3 | HAM-A is a clinician-rated 14 item scale that provides an overall measure of global anxiety, including psychic (mental agitation and psychological distress) and somatic (physical complaints related to anxiety) symptoms. Each item was scored on a scale ranging from 0 (not present) to 4 (very severe) with a total score range of 0 to 56, where higher score indicates greater anxiety. | Baseline, Week 3 | 
| Change From Baseline in ADHD Impact Module - Adults (AIM-A) Subscale Score at Week 3 | AIM-A: 66 item questionnaire completed by the participant to assess the impact of ADHD on the participant's quality of life. It is comprised of 4 global quality of life (QoL) items (current quality of life item [CQoLI], range:1 to 10; global limitation item [GLI]: range:1 to 4, on the right track item [RTI], range:1 to 3, more good days [GD] than bad days [BD], range:1 to 5, higher scores indicate a better QoL for all the 4 QoL items) and 6 multi-item subscales (living with ADHD, general well-being, performance and daily functioning [PDF], relationships and communication [R/C], Impact of symptoms-bother/concern [IS-B/C] scale, and impact of symptoms-interference [IS-I] scale). Participants responded to each item of multi-item subscale using a likert scale ranging from 1 (strongly agree) to 5 (strongly disagree). Multi-item subscale scores were calculated as an average of scores for the contributing items and transformed into 0 to 100 score where higher scores indicate a better QoL. | Baseline, Week 3 | 
| Change From Baseline in Adult ADHD Quality of Life Scale (AAQOL) Subscale Score at Week 3 | AAQoL is a 29-item questionnaire consisting of 4 subscales: life productivity (11 items), psychological health ([PH] 6 items), life outlook (7 items) and relationships (5 items). Participants rated each item on a scale ranging from 1 (not at all/never) to 5 (extremely/very often). The scores of each item were then transformed to a 0 to 100 point scale, higher scores indicating better quality of life. The score for each subscale was calculated as the sum of the corresponding item scores. Total score ranges were: life productivity (0 to 1100), psychological health (0 to 600), life outlook (0 to 700) and relationships (0 to 500), where higher subscale score indicates better quality of life for each subscale. | Baseline, Week 3 | 
| Change From Baseline in Sheehan Disability Scale (SDS) Subscale Scores at Week 3 | SDS was a participant-rated questionnaire assessing the effect of the participant's symptoms on the 3 domains/subscales: work/school, social life/leisure activities, and family/home management. Each domain was rated on visual analog scale ranges from 0 to 10 where 0=not at all impaired and 10=extremely impaired, and total SDS score was calculated as a sum of all the domains with a score range of 0=not at all impaired to 30=extremely impaired. Disability scores were reported for each of the domains/subscales. Higher scores reflect greater impairment. | Baseline, Week 3 |