Org 25935 Versus Placebo as Augmentation to Cognitive-behavioral Therapy to Treat Panic Disorder (P05705)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of Org 25935 vs. placebo given in combination with cognitive-behavioral therapy (CBT) to reduce the symptoms of panic disorder. It is hypothesized that treatment with Org 25935 at a dose of 4 mg or 12 mg will differ significantly from placebo with respect to the Panic Disorder Severity Scale (PDSS) total score over 3 weeks of therapy.

Official Title
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A Multi-center, Double-blind, Fixed Dose Trial Examining the Efficacy and Safety of Org 25935 Versus Placebo as Augmentation to Cognitive Behavioral Therapy in Subjects With Panic Disorder

Conditions
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Panic Disorder

Intervention / Treatment
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* Behavioral: Cognitive-behavioral therapy
* Drug: Org 25935
* Drug: Org 25935
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: is a male, or a female who is not of childbearing potential or who is non-pregnant, non-lactating and using a medically accepted method of contraception. is between the ages of 18 and 65, inclusive; signed written informed consent after the scope and nature of the investigation have been explained to them before Screening evaluations; is fluent in English; is diagnosed at Screening with current panic disorder, with or without agoraphobia; has a Clinical Global Impressions (CGI)-Severity score at Screening of >= 4 and <= 6; is currently taking no psychotropic medications or is able and willing to discontinue these medications prior to the first CBT session. Anti-depressant and anxiolytic medications are acceptable only if they are stabilized for at least 8 weeks prior to Screening; is able to complete all scheduled assessment and treatment visits and is willing to comply with the requirements of the study protocol. Exclusion Criteria: is diagnosed with a primary Axis I disorder other than panic disorder; has a Screening Montgomery-Asberg Depression Rating Scale (MADRS) score of >= 35 (severe depression); has any history of bipolar disorder, psychotic disorder, or obsessive compulsive disorder; has a diagnosis of post traumatic stress disorder, eating disorder, or substance abuse or dependence (excluding nicotine) within the past six months; is known or suspected to have significant personality dysfunction that could, in the investigator's opinion, interfere with trial participation. Participants with known borderline or avoidant personality disorder are excluded; are at imminent risk of self-harm or harm to others, in the investigator's opinion based on clinical interview and responses provided on the Columbia Suicide Severity Rating Scale (C-SSRS). Participants must be excluded if they report suicidal ideation of Type 4 or 5 in the past 3 months or suicidal behavior in the past 12 months as measured by the C-SSRS at Screening; is currently a psychiatric inpatient or has been hospitalized for a psychiatric condition within the past year; has ever been diagnosed with organic brain syndrome, mental retardation, or other cognitive dysfunction that could interfere with their capacity to participate in CBT or to complete safety and efficacy assessments; has any history of head trauma causing ongoing cognitive impairment; has any history of seizures (apart from childhood febrile seizures); has an uncontrolled, unstable clinically significant medical condition (e.g., renal, endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic or cerebrovascular disease, or malignancy) that may interfere with the interpretation of safety and efficacy evaluations in the opinion of the investigator; has a clinically relevant visual disturbance, such as cataract, color blindness, macular degeneration, glaucoma, or retinal disease; has clinically significant abnormal laboratory, vital sign, physical examination, or electrocardiogram (ECG) findings at Screening that may interfere with the interpretation of safety or efficacy assessments in the opinion of the investigator; has a Corrected QT interval (QTc) value >450 milliseconds at Screening using Bazett's QTc formula; for females, has a positive result on serum pregnancy test (at Screening), or plan to become pregnant during the course of the trial; has a positive urine drug or alcohol breath test at Screening, unless the positive finding can be accounted for by documented prescription use; is unable or unwilling to comply with the investigator's instructions regarding drug and alcohol use during the trial period; has a history of sensitivity/idiosyncrasy to glutamatergic drugs or chemically related compounds or excipients which may be employed in the trial or to any other unknown drug used in the past; are receiving concurrent psychotherapy for the treatment of panic disorder [general supportive psychotherapy is acceptable if therapy was initiated at least 3 months prior to Screening] or have received a prior adequate trial of CBT for panic disorder; has been exposed to an investigational drug within 6 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4 mg Org 25935<br>Participants took a total of 3 doses of 4 mg Org 25935 prior to therapy sessions over a 2-week period. | Behavioral: Cognitive-behavioral therapy<br>* Participants underwent 5 weekly CBT session (sessions were 60-90 minutes in duration).<br>Drug: Org 25935<br>* 4 mg Org 25935 is given in tablet form, a single dose 2 hours prior to 3 CBT sessions. A total of 3 doses of trial medication is given over a 2-week period.<br>|
| Experimental: 12 mg Org 25935<br>Participants took a total of 3 doses of 12 mg Org 25935 prior to therapy sessions over a 2-week period. | Behavioral: Cognitive-behavioral therapy<br>* Participants underwent 5 weekly CBT session (sessions were 60-90 minutes in duration).<br>Drug: Org 25935<br>* 12 mg Org 25935 is given in tablet form, a single dose two hours prior to 3 CBT sessions. A total of 3 doses of trial medication is given over a two-week period.<br>|
| Placebo Comparator: Placebo<br>Participants took a total of 3 doses of placebo matched to Org 25935 prior to therapy sessions over a 2-week period. | Behavioral: Cognitive-behavioral therapy<br>* Participants underwent 5 weekly CBT session (sessions were 60-90 minutes in duration).<br>Drug: Placebo<br>* Placebo is given in tablet form, a single dose 2 hours prior to 3 CBT sessions. A total of 3 doses of trial medication is given over a 2-week period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Panic Disorder Severity Scale (PDSS) Score From Baseline to End-of-Treatment (EOT) | The mean change in PDSS score from baseline (Screening) to EOT (Day 36) was calculated for each arm. The PDSS is a 7-item clinician-rated scale that assesses multiple dimensions of panic disorder severity (e.g., frequency of panic attacks). Each item is scored on a 5-point Likert scale (0 to 4) with the total score ranging from a minimum of 0 to a maximum of 28 (higher scores indicate greater panic disorder severity). | Screening and Day 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PDSS Score From Baseline to Visit 4 | The mean change in PDSS score from baseline (Screening) to Visit 4 (Day 22) was calculated for each arm. The PDSS is a 7-item clinician-rated scale that assesses multiple dimensions of panic disorder severity (e.g., frequency of panic attacks). Each item is scored on a 5-point Likert scale (0 to 4) with the total score ranging from a minimum of 0 to a maximum of 28 (higher scores indicate greater panic disorder severity). | Screening and Visit 4 (Day 22) | 
| Change in PDSS Score From Baseline to Follow-Up | The mean change in PDSS score from baseline (Screening) to Follow-Up (Day 59) was calculated for each arm. The PDSS is a 7-item clinician-rated scale that assesses multiple dimensions of panic disorder severity (e.g., frequency of panic attacks). Each item is scored on a 5-point Likert scale (0 to 4) with the total score ranging from a minimum of 0 to a maximum of 28 (higher scores indicate greater panic disorder severity). | Screening and Follow-Up (Day 59) | 
| Structured Clinical Interview for DSM-IV-TR Axis 1 Disorders, Patient Edition With Psychotic Screen (SCID-I/P With Psy Screen) Score at Screening | The SCID-I/P with Psy Screen, Panic Disorder Module was used to score participants' PD (with [w] or without [w/o] AGP) as being current (full criteria for the disorder met), in full remission (IFR) [there are no longer any symptoms or signs of the disorder, but it is still clinically relevant to note the disorder], or in partial remission (IPR) [full criteria for the disorder were previously met, but currently only some of the symptoms or signs of the disorder remain] at baseline (Screening). The SCID-I/P is a diagnostic exam used to assess for Axis-1 mental disorders. | Screening | 
| SCID-I/P With Psy Screen Score at EOT | The SCID-I/P with Psy Screen, Panic Disorder Module, was used to score participants' PD (w or w/o AP) as being current (full criteria for the disorder are met), IFR (there are no longer any symptoms or signs of the disorder, but it is still clinically relevant to note the disorder), or IPR (full criteria for the disorder were previously met, but currently only some of the symptoms or signs of the disorder remain) at EOT (Day 36). The SCID-I/P is a diagnostic exam used to assess for Axis-1 mental disorders. | Day 36 | 
| Change in Clinical Global Impression-Severity (CGI-S) Score | The mean change in CGI-S score from baseline (Screening) to EOT (Day 36) was calculated for each arm. The CGI-S is a clinician-rated instrument used to assess global severity of general anxiety symptoms. The instrument consists of a 7-point scale that the clinician uses to rate the severity of the patient's illness, from 1 (normal, not at all ill) to 7 (extremely ill). | Screening and Day 36 | 
| Change in Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) Score | The mean change in SIGH-A score from baseline (Screening) to EOT (Day 36) was calculated for each arm. The SIGH-A is a 14-item scale to assess anxiety in a clinical population. Each item is scored on a 5-point Likert scale (0 to 4) with the total score ranging from a minimum of zero to a maximum of 56 (higher scores indicate greater anxiety severity). | Screening and Day 36 | 
| Change in Anxiety Sensitivity Index (ASI) Score | The mean change in ASI score from baseline (Screening) to EOT (Day 36) was calculated for each arm. The ASI is a 16-item self-report questionnaire that assesses fear of anxiety sensations. Each item is scored on a 5-point Likert scale (0 to 4) with total score ranging from a minimum of 0 to a maximum of 64 (higher scores indicate greater fear of anxiety sensations). | Screening and Day 36 | 
| Change in Montgomery-Asberg Rating Scale for Depression (MADRS) Score | The mean change in MADRS score from baseline (Screening) to EOT (Day 36) was calculated for each arm. The MADRS is a 10-item clinical-administered scale designed to assess severity of depression. Each item is rated from 0 to 6, with total score ranging from 0 to 60 (higher MADRS scores indicate more severe depression). | Screening and Day 36 | 
| Change in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Score | The mean change in Q-LES-Q score from baseline (Screening) to EOT (Day 36) was calculated for each arm. The Q-LES-Q is a self-report questionnaire rating 16 aspects of quality of life, including physical health and mood. Scores range from 0 (very poor) to 5 (very good), with total score ranging from 0 to 80 (higher O-LES-Q scores indicate greater quality of life). | Screening and Day 36 | 
| Number of Participants Experiencing an Adverse Event (AE) | The number of participants experiencing one or more AEs throughout the study period was determined. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 59 days | 
| Number of Participants Discontinuing Study Therapy Due to AEs | The number of participants withdrawing from study treatment during the treatment period was determined. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 2 weeks |