An open-label, multicenter evaluation of the long-term safety and efficacy of risperidone in adolescents with schizophrenia

This open-label, multicenter study (NCT00246285) was conducted in 12 countries (Belgium, Bulgaria, Czech Republic, Estonia, Germany, India, Poland, Romania, Russia, Spain, Ukraine, and the United States) from May 29, 2001, to December 20, 2006. The study protocol and amendments were approved by institutional review boards or independent ethics committees before study initiation, and the study was conducted in accordance with the Declaration of Helsinki. All subjects gave consent to participate; their legal representatives provided written informed consent before any study procedures were initiated.

Changes to the study design were made to fulfill regulatory requirements. The changes consisted of a reduction in the planned duration of treatment and the dose range. The planned duration of treatment was initially 12 months but was subsequently changed to 6 months in a protocol amendment (amendment 3). Subjects who were enrolled before the amendment were treated for up to 12 months. Amendment 3 also changed the maximum dose from 4 to 6 mg/day and the dose range from 0.03 to 0.08 mg/kg/day to 2 to 6 mg/day.

Several sources of enrollment into the trial were possible. Adolescents with schizophrenia were enrolled directly into the open-label study; in addition, subjects were enrolled after completing their participation in one of two short-term, double-blind, controlled clinical studies (NCT00088075 and NCT00034749) assessing the short-term efficacy and safety of risperidone (Figure 1) [8, 9].

Inclusion and exclusion criteria for the previous double-blind studies have been described in detail [8, 9]. Subjects in the two double-blind studies were eligible for the open-label study if they had completed at least 24 days of previous double-blind treatment or discontinued because of tolerability issues, if they were expected to benefit from continuation of treatment, and if they had no other serious, unstable illnesses and were otherwise physically healthy.

Additional subjects were enrolled directly into the open-label study. Inclusion and exclusion for directly enrolled subjects were similar to those of the double-blind studies. Subjects were aged 13 to 17 years, of either sex, and in good physical health with no serious illnesses or neurologic conditions other than schizophrenia. Subjects were diagnosed with schizophrenia (according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition DSM-IV criteria) using the semistructured clinical interview for DSM-IV for children of the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version (K-SADS-PL). Training on the proper use of the K-SADS-PL was provided during investigator meetings and via Internet-based training sessions. Reliability was determined by independent review by an expert panel of the first K-SADS-PL completed after training. Additionally, subjects had to have a Positive and Negative Syndrome Scale (PANSS) [17] total score of 40 to 120 at screening and baseline. Subjects already receiving oral risperidone could be enrolled only if they were expected to benefit from continued treatment. Exclusion criteria included diagnosis of dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, or primary substance-induced psychotic disorder. Subjects were also excluded if they had mental retardation (intelligence quotient <70), if they had known or suspected substance dependence, or if they were considered at significant risk of suicide or violent behavior. Subjects were ineligible if more than 1 week had elapsed since completing or discontinuing from the short-term study.

Directly enrolled subjects and those who had taken study medication in tablet form during the 6-week, double-blind, placebo-controlled study [9] received an initial risperidone dose of 0.5 mg in tablet form on day 1 of the OL phase. Subjects who had taken an oral risperidone solution in the 8-week double-blind study [8] received an initial risperidone dose of 0.01 mL/kg in liquid form on day 1 of the OL phase.

By day 7, risperidone was titrated for all subjects to a minimum of 2 mg/day, followed by titration to a maximum tolerated dose between 2 and 6 mg/day. Dosage was under the control of each site’s investigators, who adjusted each subject’s dosage on the basis of their assessment of the efficacy and tolerability of the study medication. Once a stable dose was achieved, this dose was maintained for the rest of the study and adjusted only in the case of emergent tolerability or efficacy issues. Subjects who could not be maintained on a minimum of 2 mg/day were withdrawn from the study.

Except for other antipsychotics, the concomitant use of other psychotropic treatments, such as antidepressants, mood stabilizers, and anxiolytics, were allowed. These medications and respective dosing regimens were provided to patients per the local regulatory guidelines of the individual countries and per clinician judgment. The flexibility in concomitant therapy allows investigators to treat each individual to a level that is optimal for that subject.

Efficacy parameters assessed were PANSS total and factor scores for positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression [18]; clinical response (defined as ≥20% reduction from open-label baseline in mean PANSS total score), Clinical Global Impressions for Severity and Clinical Global Impressions for Improvement [19]; and the Children’s Global Assessment Scale (CGAS) [20]. Investigators received training and certification to ensure consistent administration and scoring of the PANSS. Certification of raters consisted of detailed instruction on the PANSS, including a focus on developmental adjustments. Following training, raters were tested by scoring a tape of adolescents with schizophrenia who demonstrated sufficient positive and negative symptoms. Rater candidates were certified by adequate scoring of this interview and by demonstrating appropriate credentials and experience. Retraining occurred at least annually. To the extent possible, assessments were made at approximately the same time of day and by the same clinician at all visits.

Safety and tolerability assessments included AE monitoring, laboratory tests, vital signs, body weight and height, physical examination, Tanner staging [21, 22], and electrocardiograms. EPS severity was assessed by the Abnormal Involuntary Movement Scale (AIMS) [23], the Simpson Angus Scale (SAS) [24], and the Barnes Akathisia Rating Scale (BARS) [25]. The sexual maturity of subjects was assessed by a qualified physician using Tanner staging which rates on a scale of 1 to 5 through the selection of one diagram (from a series of five) thought to most closely resemble the sexual maturity of the subject. AEs of potential clinical interest (including somnolence, fatigue, EPS-related AEs, potentially prolactin-related AEs, and glucose metabolism–related AEs) were grouped together in categories by the World Health Organization Adverse Reaction Terminology–preferred terms and examined separately.

Efficacy and safety were analyzed in the intent-to-treat population (all subjects who received at least one dose of risperidone).

For somnolence AEs, time to first event was assessed graphically using Kaplan-Meier curves. Weight and body mass index (BMI) were transformed to z scores based on the United States 2000 Centers for Disease Control and Prevention growth charts (http://​www.​cdc.​gov/​growthcharts). The z score indicates how many standard deviations (SDs) an observed value is away from the expected weight or BMI, based on a subject’s age (in months) and sex: no deviation from expected weight or BMI results in a z score change of 0 (SD = 1).

The intent-to-treat population consisted of 390 subjects (Figure 1). A total of 50 were directly enrolled (direct-enroll group); 136 entered from the double-blind, placebo-controlled, 6-week study (including 48 who had received placebo [PBO/RIS group] and 88 who had received risperidone) [9]; and 204 entered from the double-blind, 8-week study (all of whom had received risperidone, some at doses as low as 0.15 to 0.6 mg/day) [8]. The RIS/RIS group comprised the 292 subjects who had previously received risperidone. A total of 111 subjects in the RIS/RIS group enrolled for 12 months of treatment before the protocol change. These subjects had all been enrolled in the 8-week study.

Overall, 264 (67.7%) subjects completed the study per protocol (either 6 or 12 months); 42 subjects (88%) PBO/RIS; 186 subjects (64%) RIS/RIS; and 36 subjects (72%) direct-enroll. A total of 126 subjects discontinued the study: 6 subjects (13%) PBO/RIS, 106 subjects (36%) RIS/RIS, and 14 subjects (28%) direct-enroll. AEs were the most frequent reason for discontinuation in all groups (Figure 1). Of the 111 subjects enrolled for 12 months before the protocol amendment, 55 (50%) completed 12 months of treatment compared with 209 (75%) who enrolled after the protocol amendment and completed 6 months of treatment. The most common reason for discontinuation for the 12-month group was AEs (18 subjects [16.0%]).

Table 1 summarizes demographic parameters and baseline characteristics. Mean age was 15.5 years, and the majority of subjects were male (61%). The mean age at onset of first psychotic symptoms was 13.3 years, average age at diagnosis was 14.9 years, and mean age at the start of antipsychotic treatment was 14.5 years.

The median mode dose during open-label treatment was 3.8 mg/day (4.0 mg/day, 3.5 mg/day, and 4.0 mg/day in the PBO/RIS, RIS/RIS, and direct-enroll subjects, respectively). For subjects enrolled for 12 months, the median mode dose was 3.0 mg/day. The median duration of exposure was 176 days among subjects enrolled for 6 months, and 336 days for those enrolled for 12 months.

From open-label baseline, mean PANSS total scores improved in all three groups (Table 2). Analysis of mean change over time in PANSS total scores (Figure 2) for observed cases indicated that the magnitude of change was most pronounced within the first month of treatment, with maintained improvement over time. Mean score changes from open-label baseline to the 6-month end point indicated improvements in all five PANSS factor scores (Table 2). A clinical response (defined as ≥20% reduction from open-label baseline in PANSS total score) at the 6-month end point was achieved by 61.8% of subjects overall (84.8% of the PBO/RIS, 56.4% of the RIS/RIS, and 72.0% in the direct-enroll groups).

Of the total population, 62.7% of subjects were rated as having reduced overall illness severity on the Clinical Global Impressions for Severity at the 6-month end point compared with open-label baseline (Figure 3). Change in CGAS scores at the 6-month end point also showed that all groups experienced functional improvement relative to open-label baseline (Table 2).

As expected, mean symptom and global illness severity scores at the open-label baseline for the efficacy measures were lower for the RIS/RIS group because of significant improvements during double-blind treatment [8, 9]. Nevertheless, the majority of RIS/RIS subjects experienced further symptom and functional improvement with continued treatment.

Subjects enrolled for 12 months demonstrated continued efficacy, as determined by reductions in PANSS total (Figure 2) and PANSS factor scores, as well as improvement in global clinical status and overall functioning.

The open-label study design used here is known to be associated with potential bias when interpreting study results. Subjects were titrated to the maximum tolerated dose, which may have resulted in higher rates for some AEs. Previous treatment with risperidone in some subjects may have resulted in a lower frequency of certain AEs reported with subsequent exposure. Previously exposed subjects may have already experienced such events early on in their treatment (before the reporting period of this trial) or potentially may have discontinued. It is also possible that longer-term treatment (i.e., longer than 12 months) could be associated with additional AEs (e.g., metabolic parameters, growth or sexual maturation) that may not have been observed in the study.