POC Study in Partially Responsive Generalized Anxiety Disorder

Study Overview
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Brief Summary
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This study aims to evaluate whether PF-06372865 is safe and effective in the treatment of sub-optimally controlled symptoms of generalized anxiety disorder during two 4-week treatment periods using a Sequential Parallel Comparison Design (SPCD). The study will use the Hamilton Anxiety Rating Scale (HAM-A) to measure change in symptoms from baseline for two doses of PF-06372865 compared to placebo.

Official Title
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An 8-week, Randomized, Phase 2, Double-blind, Sequential Parallel-group Comparison Study Of Two Dose Levels Of Pf 06372865 Compared To Placebo As An Adjunctive Treatment In Outpatients With Inadequate Response To Standard Of Care For Generalized Anxiety Disorder

Conditions
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Generalized Anxiety Disorder

Intervention / Treatment
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* Drug: PF-06372865.


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Outpatient males and females 18 65 years of age (inclusive). Diagnostic and Statistical Manual of Mental Disorders Fourth edition Text Revised (DSM IV TR) diagnosis of GAD (DSM IV TR, 300.02), confirmed as primary diagnosis by the Mini international neuropsychiatric interview (MINI) structured interview. All subjects must have a total HAM A (via SIGH A) score 22 at screening. In addition, scores at the baseline visit must also be within 20% of scores at screening. Subjects must also have a Covi Anxiety Scale score of 9 and a Raskin Depression Scale score 7 at the Screening (Visit 1) visit to ensure predominance of anxiety symptoms over depression symptoms. Taking an FDA approved GAD treatment (escitalopram 10 to 20 mg total daily dose, paroxetine 20 to 50 mg total daily dose, duloxetine 60 to 120 mg total daily dose, or venlafaxine 75 to 225 mg total daily dose) at a stable FDA approved dosage for at least the two consecutive months in the current episode immediately prior to the screening visit. Sertraline or citalopram are also permitted as background treatment for GAD at doses of 50 to 200 mg total daily dose and 20 to 40 mg total daily dose, respectively. Exclusion criteria: Subjects with a history of daily benzodiazepine use within one month of the screening visit. Recent (defined as meeting disorder diagnostic criteria during the last 6 months) of a DSM IV TR Axis I diagnosis other than generalized anxiety disorder, with the following exceptions: a. Subjects with recent (in the last 2 months) major depressive disorder may be enrolled if the anxiety symptoms are predominant over the depressive symptoms, as judged by the Covi/Raskin criteria listed above and confirmed GAD as the primary diagnosis by the MINI structured interview. b. Comorbid social phobia and/or specific phobias are permitted as long as the anxiety symptoms due to these disorders are clinically less significant than the anxiety symptoms due to GAD and GAD is confirmed as the primary diagnosis by the MINI structured interview. Recent (defined as meeting disorder diagnostic criteria during the last 6 months) of a DSM IV TR Axis I of panic disorder with or without agoraphobia, Post Traumatic Stress Disorder (PTSD), dissociative disorder, obsessive compulsive disorder, attention deficit disorder. If a subject has a past misdiagnosis of any of these disorders, or if the subject has another psychiatric disorder that in the opinion of the investigator affects the suitability of a subject for this study based on safety or other considerations, the investigator will need to contact the sponsor prior to screening. Past and/or current DSM IV TR diagnosis of schizophrenia, schizoaffective disorder, other psychotic disorders, bipolar disorders (I or II), factitious disorder or cognitive disorder (including delirium, dementia, and amnestic disorder). Presence of comorbid personality disorders (Axis II) based on DSM IV TR. Subjects who meet DSM IV TR defined diagnostic criteria for psychoactive substance dependence (excluding nicotine dependence) within 12 months of screening or DSM IV TR defined substance abuse within 3 months prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF 06372865 2.5 mg BID then placebo.<br>PF 06372865 2.5 mg tablet 2 times daily for 4 weeks (Stage 1), followed by placebo 2 times daily for 4 weeks (Stage 2). | Drug: PF-06372865.<br>* Blinded PF 06372865 and matching placebo will be provided as tablets for oral administration.<br>|
| Experimental: PF 06372865 7.5 mg BID then placebo.<br>PF 06372865 2.5 mg tablet 2 times daily for one week, then PF 06372865 7.5 mg tablet 2 times daily for 3 weeks (Stage 1), followed by placebo (2 times daily) for 4 weeks (Stage 2). | Drug: PF-06372865.<br>* Blinded PF 06372865 and matching placebo will be provided as tablets for oral administration.<br>|
| Experimental: Placebo then PF 06372865 2.5 mg BID.<br>Placebo 2 times daily for 4 weeks (Stage 1), followed by PF 06372865 2.5 mg tablet 2 times daily for 4 weeks | Drug: PF-06372865.<br>* Blinded PF 06372865 and matching placebo will be provided as tablets for oral administration.<br>|
| Experimental: Placebo then PF 06372865 7.5 mg BID.<br>Placebo 2 times daily for 4 weeks (Stage 1), followed by PF 06372865 2.5 mg tablet 2 times daily for one week, then PF 06372865 7.5 mg tablet 2 times daily for 3 weeks (Stage 2). | Drug: PF-06372865.<br>* Blinded PF 06372865 and matching placebo will be provided as tablets for oral administration.<br>|
| Placebo Comparator: Placebo followed by placebo.<br>Placebo 2 times daily for 4 weeks (Stage 1) followed by Placebo 2 times daily for 4 weeks (Stage 2). | Drug: PF-06372865.<br>* Blinded PF 06372865 and matching placebo will be provided as tablets for oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Anxiety Rating Scale (HAM-A) Total Scores at Baseline: Stage 1 and 2 | The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. | Stage 1: Baseline (Day 1 ), Stage 2: Baseline (Day 28) | 
| Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Scores at Week 4: Stage 1 | The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. | Week 4 | 
| Hamilton Anxiety Rating Scale (HAM-A) Total Scores at Week 4 During Stage 1 and at Week 8 During Stage 2 | The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. | Stage 1: Week 4, Stage 2: Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Scores at Week 5, Week 6, Week 7 and Week 8: Stage 2 | The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. | Week 5, 6, 7, 8 | 
| Sheehan Disability Scale (SDS) Total Score and Social, Work, Family Subscale Scores at Baseline: Stage 1 and Stage 2 | SDS was a copyrighted, three question instrument designed to assess functional impairment associated with mental disorders in three domains: work impairment, social impairment, and impairment of family life or home responsibilities. Disability scores were reported for each of the questions (subscale scores range from 0 to 10) and a total disability score was calculated as the sum of scores for each question (total scores range from 0 to 30). Higher scores reflect greater impairment. | Stage 1: Baseline (Day 1 ), Stage 2: Baseline (Day 28) | 
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score and Social, Work, Family Subscale Scores: Stage 1 and Stage 2 | SDS was a copyrighted, three question instrument designed to assess functional impairment associated with mental disorders in three domains: work impairment, social impairment, and impairment of family life or home responsibilities. Disability scores were reported for each of the questions (subscale scores range from 0 to 10) and a total disability score was calculated as the sum of scores for each question (total scores range from 0 to 30). Higher scores reflect greater impairment. | Stage 1: Week 4, Stage 2: Week 8 | 
| Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Scores at Week 1, Week 2 and Week 3: Stage 1 | The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. | Week 1, 2, 3 | 
| Percentage of Responders of Total Hamilton Anxiety Rating Scale (HAM-A): Stage 1 and Stage 2 | A responder was defined as a participant with >= to 50 percent decrease in their total HAM-A score from baseline to the last week in the stage (Week 4 in Stage 1, Week 8 in Stage 2). The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. Percentage of responders of total HMA scale were reported. | Stage 1: Week 4, Stage 2: Week 8 | 
| Change From Baseline in Clinical Global Impression - Improvement (CGI-I) Scale Score at Week 1, 2, 3, 4 in Stage 1 and Week 5, 6, 7, 8 in Stage 2 | CGI-I was a 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Improvement was defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse) or 7 (very much worse) on the scale. Higher score indicated more affected. Change is equal to score at observation minus score at baseline. | Stage 1 (S1): Baseline (Day 1), Week 1 (W1), 2 (W2), 3 (W3), 4 (W4) and Stage 2 (S2): Baseline (Day 28), Week 5 (W5), 6 (W6), 7 (W7), 8 (W8) | 
| Change From Baseline in Clinical Global Impression -Severity (CGI-S) Scale Score at Week 1, 2, 3, 4 in Stage 1 and Week 5, 6, 7, 8 in Stage 2 | The CGI-S consisted of a single 7-point rating score of illness severity, was completed by a clinician. Raters selected one response based on the following question, Considering your total clinical experience with that particular population, how mentally ill was your participant at that time? Scores were: 1 (normal, not ill at all), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill) 6 (severely ill) or 7 (among the most severely ill participants). Higher scores indicate more severity. | Stage 1 (S1): Baseline (Day 1), Week 1 (W1), 2 (W2), 3 (W3), 4 (W4) and Stage 2 (S2): Baseline (Day 28), Week 5 (W5), 6 (W6), 7 (W7), 8 (W8) | 
| Plasma Concentration Versus Time Summary of PF-06372865: Stage 1 | Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLOQ =0.0100 nanogram per milliliter (ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) = 0. | Pre-dose (0 hour), 2, 4, 10 hours post dose on Day 1 of Week 2, 3, 4 | 
| Plasma Concentration Versus Time Summary of PF-06372865: Stage 2 | Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLOQ =0.0100 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0. | Pre-dose (0 hour), 2, 4, 10 hours post dose on Day 1 of Week 6, 7, 8 | 
| Change From Baseline in the Hamilton Anxiety Rating Scale (HAM-A): Psychic Subscale Score at Week 1, 2, 3, 4, 5, 6, 7, 8 | The HAM-A scale was a clinician interview-administered scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Psychic subscale of the HAM-A was the sum of 7 items. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 28 (very severe), where lower scores indicates less anxiety. | Stage 1 (S1): Baseline (Day 1), Week 1 (W1), 2 (W2), 3 (W3), 4 (W4) and Stage 2 (S2): Baseline (Day 28), Week 5 (W5), 6 (W6), 7 (W7), 8 (W8) | 
| Change From Baseline in the Hamilton Anxiety Rating Scale (HAM-A): Somatic Subscale Score at Week 1, 2, 3, 4, 5, 6, 7, 8 | The HAM-A scale was a clinician interview-administered scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Somatic subscale of the HAM-A was the sum of 7 items. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 28 (very severe), where lower scores indicates less anxiety. | Stage 1 (S1): Baseline (Day 1), Week 1 (W1), 2 (W2), 3 (W3), 4 (W4) and Stage 2 (S2): Baseline (Day 28), Week 5 (W5), 6 (W6), 7 (W7), 8 (W8) | 
| Percentage of Participants With Remission of Total Hamilton Anxiety Rating Scale (HAM-A) Scores | Percentage of participants with HAM-A total score less than or equal to 7 in the last week of the Stage (Week 4 in Stage 1, Week 8 in Stage 2). The HAM-A scale was a clinician rated interview scale designed to measure the signs and symptoms of anxiety. It had 14-items to rate the intensity of psychic and somatic anxiety on a 5-point severity scale. Each item ranging from 0 (not present) to 4 (very severe) were summed up to give a total possible score of 0 (not present) to 56 (very severe), where lower scores indicates less anxiety. | Stage 1: Week 1 up to Week 4 and Stage 2: Week 5 up to Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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outpatient, safety, efficacy, suboptimal response, PF 06372865, generalized anxiety disorder