Summary ID#236 Clinical Study Summary: Study B1Y-MC-HCCJ

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1 CT Registry ID#236 Page 1 Summary ID#236 Clinical Study Summary: Study B1Y-MC-HCCJ Title of Study: Fluoxetine: Fluoxetine versus Placebo in Adolescent Depressed Patients Investigator(s): This single-center study included one principal investigator. Study Center(s): This study was conducted at one study center in one country. Length of Study: 2 years Phase of Development: 3 Date first patient enrolled: March 1984 Date last patient completed: March 1986 Objectives: To evaluate the safety and efficacy of fluoxetine in adolescent patients with major depressive disorder comparing fluoxetine with placebo. Study Design: This was a single center, randomized, double-blind, parallel study of adolescent patients with major depressive disorder comparing fluoxetine with placebo. All patients received placebo on a single-blind basis for approximately one week, but not less than four days nor more than ten days (Study Period 1), to eliminate placebo-reactors from the study group. The study drug, ie fluoxetine or placebo, was administered on a double-blind basis for six weeks (Study Period 2). The study included 40 patients who had not responded to placebo during Study Period 1. Responses were assessed by analyzing the following psychiatric scales: Hamilton Psychiatric Rating Scale for Depression (HAMD), Clinical Global Impressions (CGI), Raskin Depression Scale, Covi Anxiety Scale, Self-Rating Symptom Scale (SCL-58), Patient s Global Impressions (PGI), Efficacy Index, and Adverse Experience Form. Patients who had not experienced a serious adverse event during the main study were included in a twelve week open-label extension period. Patients within the Fluoxetine group continued to receive study drug. Administration of study drug to patients within the placebo group was discontinued. Long term efficacy and safety were evaluated for patients in both groups. Responses were assessed based on the criteria listed above. Number of Patients: Planned: 50 patients Randomized: 21 fluoxetine (males 9, females 12), 19 placebo (males 9, females 10) Completed: 15 fluoxetine, 15 placebo Enrollment was discontinued before 50 patients were enrolled due to slow rate of recruitment Diagnosis and Main Criteria for Inclusion: All patients satisfied the criteria for major depressive disorder according to DSM III (Diagnostic and Statistical Manual of Mental Disorder [3 rd Edition]), HAMD score was at least 20, the Raskin Depression Scale was at least 8, and the Raskin Depression Scale exceeded the Covi Anxiety Scale score. The patients were male and female outpatients or inpatients, 12 to 17 years of age with an educational level and degree of understanding such that they could communicate intelligently with the investigator and nurse. Test Product, Dose, and Mode of Administration: Fluoxetine hydrochloride mg/day, given orally twice daily as fluoxetine 10 mg capsules. Duration of Treatment: Fluoxetine: 6 weeks, plus 12 week extension period (if applicable) Placebo: 6 weeks Reference Therapy, Dose, and Mode of Administration: Placebo capsules given orally twice daily (Study Periods 1 and 2 only)

2 CT Registry ID#236 Page 2 Variables: Efficacy: Change in psychiatric test score served as the primary efficacy criterion. Efficacy was determined by comparing baseline (Visit 1) HAMD, CGI, Raskin, Covi Anxiety Scale, and SCL-58 scores with scores obtained at the end of the active medication periods (Study Period 2) or those obtained at termination from the study. Study Period 1 was an initial wash-out period to eliminate placebo-responders from the study and to establish baseline values. Study Period 2 was a six-week, double-blind treatment period. Subsequent evaluations were scheduled at one week intervals and concluded at Visit 8. The HAMD, CGI, Raskin Depression Scale, Covi Anxiety Scale, and SCL-58 were evaluated at admission and at all follow-up visits. PGI, Efficacy Index and Adverse Experiences were evaluated at all follow-up visits. Safety: Clinical laboratory tests (hematology, urinalysis and clinical chemistry), an electrocardiogram and a physical examination were performed at the admission visit and within 48 hours following the end of study drug therapy. Fluoxetine and desmethylfluoxetine levels were quantitated from plasma samples collected at admission and at visit 8. Pulse, temperature, blood pressure, and weight were recorded at each visit. Evaluation Methods: Statistical: Analysis of Variance (ANOVA) was used to assess significant treatment effects for continuous efficacy and safety data. Within-patient treatment efficacy was assessed using the Wilcoxan signed rank statistic. Treatment and investigator effects were tested at the a =.05 level of significance. Treatment-by-investigator interactions were tested at the a =.10 level of significance. Categorical efficacy and safety data were analyzed using the chi-squared tests with appropriate degrees of freedom. Summary: Patient Demographics: The majority of patients were female (55% [22/40]) and Caucasian (100% [40/40]). Mean patient age was years. Treatment groups were comparable at baseline with respect to demographics. Efficacy: There was no statistically significant difference in the mean change in HAMD-17 and HAMD-21 scores between fluoxetine-treated patients and placebo-treated patients. There was a statistically significant (p<.001) improvement in HAMD 17 and HAMD 21 total scores, measured from baseline to endpoint in the fluoxetine and placebo treatment groups (Table HCCJ.1 and Table HCCJ.2). There was no statistically significant difference in the mean change in CGI-Improvement and Raskin Total scores between fluoxetine-treated patients and placebo-treated patients. There was a statistically significant (p<.001) improvement in CGI-Improvement (Table HCCJ.3) and Raskin Total scores (Table HCCJ.4), measured from baseline to endpoint in the fluoxetine and placebo treatment groups. There was a statistically significant (p<.001) improvement in Covi Anxiety Scale Total scores (Table HCCJ.5), measured from baseline to endpoint in the fluoxetine treated group. There was also a significant (p=.001) improvement in Covi scores measured from baseline to endpoint in the placebo-treated group. There was no statistically significant difference in the mean change in Covi Anxiety Scale Total scores between fluoxetine-treated patients and placebo-treated patients. There was a statistically significant (p<.001) improvement in SCL Total 1-58 scores (Table HCCJ.6), measured from baseline to endpoint, in the fluoxetine treated group. There was no statistically significant improvement in SCL Total 1-58 scores in the placebo-treated group. There was no statistically significant difference in the mean change in SCL scores between fluoxetine-treated patients and placebo-treated patients.

3 CT Registry ID#236 Page 3 Safety: No deaths were reported among the patients enrolled in this study. Fluoxetine-treated patients had significantly higher rates of treatment emergent tremor (28.6% versus 0.0%), and insomnia (23.8% versus 0.0%) as compared to placebo-treated patients. Ten patients discontinued from the study (adverse event 2 [9.5%] fluoxetine, 0 [0.0%] placebo; lack of efficacy 1 [4.8%] fluoxetine, 3 [15.8] placebo; patient decision 1 [4.8%] fluoxetine, 1 [5.3%] placebo; protocol requirement 1 [4.8%] fluoxetine; 0 [0.0%] placebo; and physician decision 1 [4.8%] fluoxetine, 0 [0.0%] placebo). Table HCCJ.7 summarizes treatment-emergent adverse events by body system. Fluoxetine-treated patients had a statistically significant (p<.001) greater loss of weight than placebotreated patients during the main study. In summary, 40 adolescent patients with major depressive disorder were randomized in a double-blind, parallel study to evaluate the efficacy and safety of fluoxetine compared with placebo. On the basis of baseline to endpoint improvement in HAMD 17 and HAMD 21, CGI-Improvement, Raskin Total, and Covi Anxiety Scale Total scores, fluoxetine was no more effective than placebo in alleviating symptoms of depression in adolescents..

4 CT Registry ID#236 Page 4 Table HCCJ.1. Summary of Efficacy Changes from Baseline to Endpoint HAMD 17 Total Score Study B1Y-MC-HCCJ

5 CT Registry ID#236 Page 5 Table HCCJ.2. Summary of Efficacy Changes from Baseline to Endpoint HAMD 21 Total Score Study B1Y-MC-HCCJ

6 CT Registry ID#236 Page 6 Table HCCJ.3. Summary of Efficacy Changes from Baseline to Endpoint CGI-Improvement Study B1Y-MC-HCCJ

7 CT Registry ID#236 Page 7 Table HCCJ.4. Summary of Efficacy Changes from Baseline to Endpoint Raskin Total Score Study B1Y-MC-HCCJ

8 CT Registry ID#236 Page 8 Table HCCJ.5. Summary of Efficacy Changes from Baseline to Endpoint COVI Total Score Study B1Y-MC-HCCJ

9 CT Registry ID#236 Page 9 Table HCCJ.6. Summary of Efficacy Changes from Baseline to Endpoint SCL Total Score Study B1Y-MC-HCCJ

10 CT Registry ID#236 Page 10 Table HCCJ.7. Treatment-Emergent Adverse Events By Body System Study B1Y-MC-HCCJ

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