This analysis used propensity score matching of subjects from randomized placebo-controlled schizophrenia studies to compare paliperidone ER 6-12 mg/day with risperidone 2-4 mg/day and risperidone 4-6 mg/day. Although the approved dose range of paliperidone ER is 3-12 mg/day, this analysis focused on 6-12 mg/day because comparisons between paliperidone ER 6-12 mg/day and risperidone 2-4 mg/day were expected to provide similar systemic drug exposure based on pharmacokinetic data [2
]. Comparisons between paliperidone ER 6-12 mg/day and risperidone 4-6 mg/day were performed as these dose ranges were expected to yield the most favorable risk/benefit ratios based on clinical data.
The significant difference in the mean PANSS total scores suggested that paliperidone ER 6-12 mg/day may be more efficacious than risperidone 2-4 mg/day. Consistent results were observed on PANSS factor scores, CGI-S scores, response rates and placebo-corrected discontinuation rates for lack of efficacy. Data further suggested that paliperidone ER 6-12 mg/day achieved good overall tolerability compared with risperidone 2-4 mg/day, except for increased rates for tachycardia and sinus tachycardia. Discontinuation rates due to AEs were comparable, and weight gain for the 2 groups was similar.
Changes in the mean PANSS total score suggested that paliperidone ER 6-12 mg/day may be similar to risperidone 4-6 mg/day in terms of efficacy. This result is consistent with PANSS factor score and response rate data; however, overall clinical status (CGI-S) improved significantly more with paliperidone ER. Also, these data suggest that with the exception of increased rates of insomnia and tachycardia, paliperidone ER 6-12 mg/day achieved good overall tolerability compared with risperidone 4-6 mg/day.
Because there is no control over treatment assignments, covariate differences between groups may lead to biased estimates of treatment effects, as treatment groups may not be comparable. The advantage of propensity score matching is that observed covariates between groups can be balanced, thereby reducing selection bias for treatment assignment [14
]. Further, this analysis used individual rather than group data, offering advantages over meta-analytic techniques such as the ability to identify the exact populations to be studied and to have access to individual data points. Notably, although studies were conducted at different times and in different countries, no significant differences were found in baseline-to-end point change on any efficacy measure between the placebo groups from the paliperidone ER and risperidone studies, suggesting that identification of analysis populations using this approach was viable for comparing paliperidone ER and risperidone.
However, propensity score analyses have several limitations. First, because this analysis relies on clinical trial databases, differences in trial design between the paliperidone ER and risperidone studies may have introduced additional bias in estimating treatment differences. The shorter duration of RIS-USA-72 (4 weeks vs 6-8 weeks for all other studies) (Table ) could have introduced a bias favoring risperidone, particularly with regard to completion rates and AE reports. Further, entry into open-label extensions of the paliperidone ER studies was permitted at week 3; in the RIS-INT-3 risperidone study, however, subjects could enter the open-label extension only if they completed the double-blind phase. This difference could have introduced a bias for completing the risperidone study. At the time the risperidone studies were conducted, regulations limited inclusion of women in phase III clinical trials, resulting in marked differences in the percentages of women included in the risperidone and paliperidone studies. Additionally, as patient-level data are necessary to perform propensity score analyses, this method can only be used if individual patient-level data are available.
A literature search (through December 31, 2009) identified 4 additional placebo-controlled studies of paliperidone ER monotherapy and 5 additional placebo-controlled studies of risperidone monotherapy that were not included in the present analysis. Individual patient-level data were available for the 4 paliperidone ER studies and for 1 of the risperidone studies, but their designs were inappropriate for inclusion. The study by Tzimos et al examined subjects that were >65 years old [15
]. The study by Luthringer et al was 2 weeks in duration and focused on the effect of paliperidone ER on sleep measurements [16
]. The study by Kramer et al focused on relapse prevention; it included subjects who were initially stabilized on paliperidone ER for 8 weeks prior to the double-blind phase [17
]. The paliperidone ER study by Canuso et al and the risperidone study by Potkin et al evaluated monotherapy for only 2 weeks, followed by a 4-week additive therapy phase during which additional psychotropics could be administered [18
]. For the remaining risperidone studies [20
], individual patient-level data for the propensity score analysis were not available.
Because the propensity score matching approach does not include all of the subjects from the original studies, differences can arise in the patient populations. The nonrandomized design of this study can limit the clinical interpretation of these results. One example is the significant difference in placebo completion rates—36.8% for the placebo (PALI) group vs 51.6% for the placebo (RIS) group—which influenced the placebo-adjusted response rate of the risperidone groups. Additionally, the risperidone 2-4 mg/day did not separate from placebo on PANSS total score change and therefore may not have been a valid active risperidone comparison for paliperidone ER 6-12 mg/day. However, the original risperidone study found that the 2 mg/day dose was superior to placebo [12
]. In fact, the p value (0.052) in this analysis only narrowly missed statistical significance. As a result, the significant differences in PANSS total scores between the paliperidone ER 6-12 mg/day and risperidone 2-4 mg/day groups will need to be confirmed using randomized controlled studies to establish their clinical relevance. Additionally, the dropout rates in studies need to be considered when interpreting the efficacy findings. Although it is easy to implement the LOCF methodology, this method may not be the most robust approach in estimating the true treatment differences and controlling type I error rates. Also, in this particular analysis these trials were of a short duration, as is generally found with placebo-controlled trials in schizophrenia, and long-term effectiveness of these dosage groups could therefore not be evaluated.
Comparison of risperidone and paliperidone ER prolactin levels was limited by the availability of data and differences in the timing of specimen collection and trial duration. Prolactin specimens were collected in only 1 risperidone study (RIS-INT-3) vs all 3 paliperidone ER trials. The blood samples in the paliperidone ER studies were obtained at Tmax
, whereas the timing of blood draws was not specified in the risperidone study. Further, prolactin data for risperidone were available only at baseline and at week 8 end point, prohibiting comparisons at the same time point (week 6) between risperidone and paliperidone ER. However, an analysis from a separate 6-day phase I study in stable subjects with schizophrenia found similar prolactin pharmacokinetic profiles (Cmax
and AUC) when subjects received the highest recommended dose of paliperidone ER (12 mg/day) compared with an average dose of risperidone (4 mg/day) [2
]. Finally, our ability to assess EPS severity was limited because the studies did not use the same movement disorder rating scales. With the exception of spontaneously reported akathisia, EPS-related AEs (parkinsonism, dystonia, tremor, hypertonia and hypokinesia) did not meet the criteria specified in the Methods section (AE differential ≥ 2%), which identified notable differences in AE rates between paliperidone ER and risperidone.