Prescription Drug Information: Zoloft (Page 6 of 7)

14 CLINICAL STUDIES

Efficacy of ZOLOFT was established in the following trials:

14.1 Major Depressive Disorder

The efficacy of ZOLOFT as a treatment for MDD was established in two randomized, double-blind, placebo-controlled studies and one double-blind, randomized-withdrawal study following an open label study in adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).

  • Study MDD-1 was an 8-week, 3-arm study with flexible dosing of ZOLOFT, amitriptyline, and placebo. Adult patients received ZOLOFT (N=126, in a daily dose titrated weekly to 50 mg, 100 mg, or 200 mg), amitriptyline (N=123, in a daily dose titrated weekly to 50 mg, 100 mg, or 150 mg), or placebo (N= 130).
  • Study MDD-2 was a 6-week, multicenter parallel study of three fixed doses of ZOLOFT administered once daily at 50 mg (N=82), 100 mg (N=75), and 200 mg (N=56) doses and placebo (N=76) in the treatment of adult outpatients with MDD.

Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. Study MDD-2 was not readily interpretable regarding a dose response relationship for effectiveness.

A third study (Study MDD-3) involved adult outpatients meeting the DSM-III criteria for MDD who had responded by the end of an initial 8-week open treatment phase on ZOLOFT 50–200 mg/day. These patients (n=295) were randomized to continuation on double-blind ZOLOFT 50–200 mg/day or placebo for 44 weeks. A statistically significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on placebo: ZOLOFT [n=11 (8%)] and placebo [n=31 (39%)]. The mean ZOLOFT dose for completers was 70 mg/day.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

14.2 Obsessive-Compulsive Disorder

Adults with OCD

The effectiveness of ZOLOFT in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult (age 18–65) non-depressed outpatients (Studies OCD-1, OCD-2, and OCD-3). Patients in all three studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score ranging from 23 to 25.

  • Study OCD-1 was an 8-week randomized, placebo-controlled study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day, titrated in 50 mg increments every 4 days to a maximally tolerated dose; the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT (N=43) experienced a mean reduction of approximately 4 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of 2 points in placebo-treated patients (N=44). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -3.79 (ZOLOFT) and -1.48 (placebo).
  • Study OCD-2 was a 12-week randomized, placebo-controlled fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. ZOLOFT (N=240) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the Y-BOCS total score, which were statistically significantly greater than the approximately 3 point reduction in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -5.7 (pooled results from ZOLOFT 50 mg, 100 mg, and 150 mg) and -2.85 (placebo).
  • Study OCD-3 was a 12-week randomized, placebo controlled study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. ZOLOFT (N=241) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of approximately 4 points in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was — 6.5 (ZOLOFT) and -3.6 (placebo).

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

The effectiveness of ZOLOFT was studied in the risk reduction of OCD relapse. In Study OCD-4, patients ranging in age from 18–79 meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on ZOLOFT 50–200 mg/day (n=224) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for analysis of discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the Y-BOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Insufficient clinical response during the double-blind phase indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and condition 3 being met at visit 3):

  • Condition 1: Y-BOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline;
  • Condition 2: CGI-I increased by ≥ one point; and
  • Condition 3: Worsening of the patient’s condition in the investigator’s judgment, to justify alternative treatment.

Patients receiving continued ZOLOFT treatment experienced a statistically significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

Pediatric Patients with OCD

The effectiveness of ZOLOFT for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (ages 6–17) (Study OCD-5). ZOLOFT (N=92) was initiated at doses of either 25 mg/day (pediatric patients ages 6–12) or 50 mg/day (adolescents, ages 13–17), and then titrated at 3 and 4 day intervals (25 mg incremental dose for pediatric patients ages 6–12) or 1 week intervals (50 mg incremental dose adolescents ages 13–17) over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score of 22. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 units on the CY-BOCS total score which was statistically significantly greater than the 3 unit reduction for placebo patients (n=95). Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

14.3 Panic Disorder

The effectiveness of ZOLOFT in the treatment of PD was demonstrated in three double-blind, placebo-controlled studies (Studies PD-1, PD-2, and PD-3) of adult outpatients who had a primary diagnosis of PD (DSM-III-R), with or without agoraphobia.

  • Studies PD-1 and PD-2 were 10-week flexible dose studies of ZOLOFT (N=80 study PD-1 and N=88 study PD-2) compared to placebo (N=176 study PD-1 and PD-2). In both studies, ZOLOFT was initiated at 25 mg/day for the first week, then titrated in weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies PD-1 and PD-2. In these studies, ZOLOFT was shown to be statistically significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. The difference between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.
  • Study PD-3 was a 12-week randomized, double-blind fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Patients receiving ZOLOFT (50 mg N=43, 100 mg N=44, 200 mg N=45) experienced a statistically significantly greater reduction in panic attack frequency than patients receiving placebo (N=45). Study PD-3 was not readily interpretable regarding a dose response relationship for effectiveness.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.

In Study PD-4, patients meeting DSM-III-R criteria for PD who had responded during a 52-week open trial on ZOLOFT 50–200 mg/day (n=183) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Insufficient clinical response in the double-blind phase indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits:

  • CGI-I ≥ 3;
  • meets DSM-III-R criteria for PD;
  • number of panic attacks greater than at baseline.

Patients receiving continued ZOLOFT treatment experienced a statistically significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

14.4 Posttraumatic Stress Disorder

The effectiveness of ZOLOFT in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies PSTD-1 and PSTD-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies PSTD-1 and PSTD-2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.

Studies PSTD-1 and PSTD-2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first week, and titrated in weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and tolerability. The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively, for Studies PSTD-1 and PSTD-2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS), which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES), which measures intrusion and avoidance symptoms. Patients receiving ZOLOFT (N=99 and N=94, respectively) showed statistically significant improvement compared to placebo (N=83 and N=92) on change from baseline to endpoint on the CAPS, IES, and on the Clinical Global Impressions (CGI-S) Severity of Illness and Global Improvement (CGI-I) scores.

In two additional placebo-controlled PTSD trials (Studies PSTD-3 and PSTD-4), the difference in response to treatment between patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies PSTD-1 and PSTD-2, while the second additional study was conducted in predominantly male veterans.

As PTSD is a more common disorder in women than men, the majority (76%) of patients in Studies PSTD-1 and PSTD-2 described above were women. Post hoc exploratory analyses revealed a statistically significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender effect is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.

In Study PSTD-5, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on ZOLOFT 50–200 mg/day (n=96) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits:

  • CGI-I ≥ 3;
  • CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and
  • worsening of the patient’s condition in the investigator’s judgment.

Patients receiving continued ZOLOFT treatment experienced statistically significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

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