Clinical Evaluation of BRL29060A (Paroxetine Hydrochloride Hydrate) in Posttraumatic Stress Disorder (PTSD)

Study Overview
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Brief Summary
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This is a single-blind, placebo-controlled, parallel group study to evaluate the efficacy of BRL29060A (paroxetine hydrochloride hydrate, hereafter paroxetine) administered orally over the dose range of 20 mg to 50 mg once daily after supper for 12 weeks in Japanese patients with posttraumatic stress disorder (PTSD) as assessed by the change from baseline in CAPS-SX total score. Also the effect of paroxetine on regional cerebral blood flow (rCBF) induced by subthreshold emotional arousing (or symptom stimulating) tasks will be determined using functional magnetic resonance imaging (fMRI) for exploratory assessment of the correlation between the change in rCBF and the efficacy. The sample size is 30 subjects. The study period consists of 4 weeks of run-in phase, 12 weeks of treatment phase, 0-3 weeks of taper phase and follow-up examination at 2 weeks after the last dose, for a total of 18-21 weeks. Subjects will visit the clinic at the start of run-in phase, Week -2, the start of treatment phase, Weeks 2, 4, 6, 8 and 12 of treatment, and follow-up examination.

Official Title
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Clinical Evaluation of BRL29060A (Paroxetine Hydrochloride Hydrate) in Posttraumatic Stress Disorder (PTSD) - A Placebo-controlled, Single-Blind Comparative Study -

Conditions
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Post-Traumatic Stress Disorder, Stress Disorders, Post-Traumatic

Intervention / Treatment
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* Drug: paroxetine
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are primarily diagnosed with PTSD (Posttraumatic Stress Disorder: 309.81) using DSM-IV-TR criteria. The CAPS-DX (Clinician-Administered PTSD Scale-DX) and M.I.N.I. (The Mini International Neuropsychiatric Interview, Japanese version 5.0.0. [2003]) will be used for diagnosis Pathologic condition: Patients who experienced a motor vehicle accident (MVA) with severe or potential severe physical injury more than 3 months ago but less than 12 months ago Patients aged 20 and <65 at the time of signing the Informed consent Male and female patients Inpatient/outpatient status: Both are permitted Patients who are able to give written informed consent in person (i.e., patients who are capable of giving written informed consent on their own) Patients whose combined score of the CAPS-SX standard B, C, and D is over 50 Exclusion Criteria: Patients primarily diagnosed with a DSM-IV-TR Axis I disorder other than PTSD (e.g. major depressive disorder, dysthymic disorder, specific phobia [simple phobia], obsessive-compulsive disorder, panic disorder, etc.) within 6 months of week -4 (start of baseline phase) Patients presenting with a current major depressive episode that preceded the diagnosis of PTSD Patients receiving disability payments due to PTSD or other psychiatric diseases Patients currently engaged in compensation litigation whereby personal gain would be achieved from prolonged symptoms of PTSD or any other psychiatric disorders Patients who meet the DSM-IV-TR criteria for substance abuse or dependence (alcohol or drugs) within 6 months of Week -4 (start of baseline phase) Patients with history of a suicide attempt within 6 months before Week -4 (start of baseline phase), or have, in the opinion of the investigator, C. high risk of suicide according to the MINI at Week -4 Patients who are pregnant, lactating or of childbearing potential and are likely to become pregnant Patients receiving electro-convulsive therapy (ECT) prior to Week -4 (start of baseline phase) Patients receiving another investigational product within 12 weeks before Week -4 (start of baseline phase) Patients with a history or complication of manic psychosis Patients with a history or complication of convulsive disorder (epilepsy, etc.) Patients with a diagnosis or complication of a cognitive disorder (MMSE <=24 points) Patients with a history and complication of serious cerebral organic disorder. (e.g. cerebrovascular disorder, meningitis, degenerative disease and other neurological disorders and seizures; however, bleeding in the upper arachnoid membrane should not be excluded) Patients unable or unwilling to undergo the fMRI procedure (e.g., cerebrovascular clipping surgery, pacemaker, any internal metals with magnetism, and claustrophobia) Patients with glaucoma Patients with a known tendency for bleeding or those with predisposing conditions Patients with a history of hypersensitivity to paroxetine Patients with serious physical symptoms (cardiac, hepatic and renal dysfunction, or hematopoietic dysfunction, etc.). For seriousness, Grade 3 of Criteria for seriousness of adverse reactions to drugs, etc. (Yakuan No.80) is used as an index Patients with a history or complication of cancer or malignant tumour Patients with chronic hepatitis type B and/or C which is positive of hepatitis B surface antigen (HBsAg) and/or hepatitis C antibody Others whom the investigator or sub-investigator considers ineligible for or unable to participate in the investigation Criteria at Week 0 (start of Treatment Phase): Subjects whose drug compliance rate for Drug 1 (Run-in Phase placebo) is <80% between Week -4 and Week 0; Subjects whose CAPS-SX total score of the standard B, C, and D at Week 0 varied by 25% or more compared with those at Week -2

Ages Eligible for Study
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Minimum Age: 20 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: paroxetine<br>Drug 2 (20 mg/day or placebo) will be administered once daily after supper for the first two weeks after the run-in phase. If the investigator/subinvestigator judges that a sufficient response is achieved, Drug 2 will be continued for the remaining period. If a sufficient response is not achieved with Drug 2 but treatment is well tolerated, the dose will be titrated to one step higher level until a sufficient response is achieved [i.e., Drug 3 (30 mg/day or placebo) → Drug 4 (40 mg/day or placebo) → Drug 5 (50 m/day or placebo)] at intervals of at least two weeks by once daily administration after supper. Once a sufficient response is achieved, that dose will be continued. | Drug: paroxetine<br>* BRL29060A (paroxetine hydrochloride hydrate, hereafter paroxetine) administered orally over the dose range of 20 mg to 50 mg once daily after supper for 12 weeks in Japanese patients with posttraumatic stress disorder (PTSD)<br>|
| Placebo Comparator: placebo<br>placebo | Other: placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Change From Baseline in CAPS-SX (Clinician-Administered Post Traumatic Stress Disorder (PTSD) Scale One Week Symptom Status Version) Total Score at Week 12 | The Clinical-Administered PTSD Scale (CAPS) is a structured interview for assessing PTSD diagnostic status and symptom severity. The CAPS assesses both the frequency and intensity of individual PTSD symptoms on separate five-point (0-4) rating scales, and these ratings can be summed to create a nine-point (0-8) severity score for each symptom. The total CAPS score can range from 0 to 136, with a higher value indicating increased severity. A minus value for change from baseline indicates an improvement of symptom severity. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Week 0 and Week 12 Z-scores for Regional Blood Flow Using Functional Magnetic Resonance Imaging (fMRI) in the Left Amygdala (LA), Right Amygdala (RA), and the Medial Prefrontal Cortex (MPFC) | Change in regional blood flow (rCBF) measured by fMRI represents altered neuronal responses in PTSD patients and is considered to be the biomarker for treatment response. fMRI measures are provided as blood oxygeneration level-dependent (BOLD) signals (z-score). To trigger neuronal activation, 2 visual stimuli were used: MVA-task (consisting of MVA-related and unpleasant pictures) and face-task (consisting of a variety of facial expressions [e.g., neutral, happy, fear]). Week 0 and 12 rCBF data from 1 participant were invalid (involuntary movement in the fMRI machine); no analysis was done. | Baseline and Week 12 | 
| Number of Participants With the Indicated Change From Baseline in CAPS-SX (Clinician-Administered Post Traumatic Stress Disorder [PTSD] Scale One Week Symptom Status Version) Total Score at Weeks 4 and 8 | The Clinical-Administered PTSD Scale (CAPS) is a structured interview for assessing PTSD diagnostic status and symptom severity. The CAPS assesses both the frequency and intensity of individual PTSD symptoms on separate five-point (0-4) rating scales, and these ratings can be summed to create a nine-point (0-8) severity score for each symptom. The total CAPS score can range from 0 to 136, with a higher value indicating increased severity. A minus value for change from baseline indicates an improvement of symptom severity. | Baseline and Weeks 4 and 8 | 
| Number of Participants With the Indicated Change From Baseline in CAPS-SX (Clinician-Administered Post Traumatic Stress Disorder [PTSD] Scale One Week Symptom Status Version) Relating Re-experiencing at Weeks 4, 8, and 12 | The Clinical-Administered PTSD Scale (CAPS) is a structured interview for assessing PTSD diagnostic status and symptom severity. The CAPS assesses both the frequency and intensity of individual PTSD symptoms on separate five-point (0-4) rating scales, and these ratings can be summed to create a nine-point (0-8) severity score for each symptom. The total CAPS score can range from 0 to 136, with a higher value indicating increased severity. A minus value for change from baseline indicates an improvement of symptom severity. | Baseline and Weeks 4, 8, and 12 | 
| Number of Participants With the Indicated Change From Baseline in CAPS-SX (Clinician-Administered Post Traumatic Stress Disorder [PTSD] Scale One Week Symptom Status Version) Relating Avoidance and Numbing at Weeks 4, 8, and 12 | The Clinical-Administered PTSD Scale (CAPS) is a structured interview for assessing PTSD diagnostic status and symptom severity. The CAPS assesses both the frequency and intensity of individual PTSD symptoms on separate five-point (0-4) rating scales, and these ratings can be summed to create a nine-point (0-8) severity score for each symptom. The total CAPS score can range from 0 to 136, with a higher value indicating increased severity. A minus value for change from baseline indicates an improvement of symptom severity. | Baseline and Weeks 4, 8, and 12 | 
| Number of Participants With the Indicated Change From Baseline in CAPS-SX (Clinician-Administered Post Traumatic Stress Disorder [PTSD] Scale One Week Symptom Status Version) Relating Increased Arousal Symptom at Weeks 4, 8, and 12 | The Clinical-Administered PTSD Scale (CAPS) is a structured interview for assessing PTSD diagnostic status and symptom severity. The CAPS assesses both the frequency and intensity of individual PTSD symptoms on separate five-point (0-4) rating scales, and these ratings can be summed to create a nine-point (0-8) severity score for each symptom. The total CAPS score can range from 0 to 136, with a higher value indicating increased severity. A minus value for change from baseline indicates an improvement of symptom severity. | Baseline and Weeks 4, 8, and 12 | 
| Number of Participants With the Indicated Change From Baseline in CGI (Clinical Global Impression) Severity of Illness Scores at Weeks 2, 4, 6, 8, 10, and 12 | The participant's status was assessed using the following 8-point scale: 0, Not assessed; 1, Normal, not at all ill; 2, Borderline mentally ill; 3, Mildly ill; 4, Moderately ill; 5, Markedly ill; 6, Severely ill; 7, Among the most extremely ill patients. | Baseline and Weeks 2, 4, 6, 8, 10, and 12 | 
| Number of Participants With a Clinical Global Impression (CGI) Global Improvement of 4 at Week 12 | The participant's status was assessed using the following 8-point scale: 0, Not assessed; 1,Very much improved; 2, Much Improved; 3, Minimally improved; 4, No change; 5, Minimally worse; 6, Much worse; 7, Very much worse. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD (Posttraumatic Stress Disorder), CAPS, fMRI, Paroxetine