Association between prolactin increasing antipsychotic use and the risk of breast cancer: a retrospective observational cohort study in a United States Medicaid population.

Introduction: Results of retrospective studies examining the relationship between prolactin increasing antipsychotics and incident breast cancer have been inconsistent. This study assessed the association between use of high prolactin increasing antipsychotics (HPD) and the incidence of breast cancer using best practices in pharmacoepidemiology. Methods: Using administrative claims data from the MarketScan Medicaid database, schizophrenia patients initiating antipsychotics were identified. Those initiating HPD were compared with new users of non/low prolactin increasing drugs (NPD). Two definitions of breast cancer, two at-risk periods, and two large-scale propensity score (PS) adjustment methods were used in separate analyses. PS models included all previously diagnosed conditions, medication use, demographics, and other available medical history. Negative control outcomes were used for empirical calibration. Results: Five analysis variants passed all diagnostics for sufficient statistical power and balance across all covariates. Four of the five variants used an intent-to-treat (ITT) approach. Between 4,256 and 6,341 patients were included in each group for the ITT analyses, and patients contributed approximately four years of follow-up time on average. There was no statistically significant association between exposure to HPD and risk of incident breast cancer in any analysis, and hazard ratios remained close to 1.0, ranging from 0.96 (95% confidence interval 0.62 - 1.48) to 1.28 (0.40 - 4.07). Discussion: Using multiple PS methods, outcome definitions and at-risk periods provided robust and consistent results which found no evidence of an association between use of HPD and risk of breast cancer.

Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia: Results for the 6-Month Formulation From an Open-label Extension Study Compared to Real-World Data for the 1-Month and 3-Month Formulations.

BACKGROUND: The 3 paliperidone palmitate (PP) long-acting injectable antipsychotic formulations, PP 1-month (PP1M), PP 3-month (PP3M), and PP 6-month (PP6M), have shown to reduce the risk of relapse in schizophrenia. The current phase-4 study constructed external comparator arms (ECAs) using real-world data for PP3M and PP1M and compared relapse prevention rates with PP6M from an open-label extension (OLE) study in adult patients with schizophrenia. METHODS: PP6M data were derived from a single-arm, 24-month, OLE study (NCT04072575), which included patients with schizophrenia who completed a 12-month randomized, double-blind, noninferiority, phase-3 study (NCT03345342) without relapse. Patients in the PP3M and PP1M ECAs were identified from the IBM® MarketScan® Multistate Medicaid Database based on similar eligibility criteria as the PP6M cohort. RESULTS: A total of 178 patients were included in each cohort following propensity score matching. Most patients were men (>70%; mean age: 39-41 years). Time to relapse (primary analysis based on Kaplan-Meier estimates) was significantly delayed in the PP6M cohort (P < .001, log-rank test). The relapse rate was lower in the PP6M cohort (3.9%) vs PP3M (20.2%) and PP1M (29.8%) cohorts. Risk of relapse decreased significantly (P < .001) by 82% for PP6M vs PP3M (HR = 0.18 [95% CI = 0.08 to 0.40]), 89% for PP6M vs PP1M (HR = 0.11 [0.05 to 0.25]), and 35% for PP3M vs PP1M (HR = 0.65 [0.42 to 0.99]; P = .043). Sensitivity analysis confirmed findings from the primary analysis. Although the ECAs were matched to mimic the characteristics of the PP6M cohort, heterogeneity between the groups could exist due to factors including prior study participation, unmeasured confounders, variations in data capture and quality, and completeness of clinical information. CONCLUSIONS: In a clinical trial setting, PP6M significantly delayed time to relapse and demonstrated lower relapse rates compared with PP3M and PP1M treatments in real-world settings among adult patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

Comparative effectiveness study of paliperidone palmitate 6-month with a real-world external comparator arm of paliperidone palmitate 1-month or 3-month in patients with schizophrenia.

Background: The paliperidone palmitate 6-month (PP6M) long-acting injectable formulation is currently the longest dosing interval available for schizophrenia treatment. Objective: To compare treatment outcomes between a real-world external comparator arm (ECA; NeuroBlu database) and the PP6M open-label extension (OLE) clinical trial arm. Methods: The ECA comprised patients receiving PP 1-month (PP1M) or PP 3-month (PP3M) for ⩾12 months without a relapse. The PP6M OLE arm included patients with PP1M treatment prior to randomization who completed the 12-month double-blind PP6M study on either PP3M or PP6M relapse-free. Inverse probability treatment weighting (IPTW) was used to study time-to-relapse (primary outcome) and change in Clinical Global Impressions-Severity (CGI-S) score (secondary outcome). Results: At 24 months, 3.9% (7/178) of patients in the PP6M cohort experienced a relapse versus 15.6% (26/167) in the ECA. Time-to-relapse was longer in the PP6M cohort versus the ECA at 12-, 18-, and 24-months across the different weighting methods; median time-to-relapse was not reached in both cohorts. Hazard ratio (HR) for relapse was significantly lower for the PP6M cohort versus the ECA throughout the duration of the study [HR at 24 months: 0.18 (95% CI: 0.08-0.42), p < 0.001]. At 24 months, change in CGI-S score for the PP6M cohort was 0.76 points lower than the ECA (p < 0.001). Results were similar in a sensitivity analysis using propensity score matching (PSM); IPTW resulted in larger sample sizes in balanced dataset than PSM. Conclusion: Consistent findings across weighting and matching methods suggest PP6M efficacy in reducing and delaying relapses and long-term symptom control compared to PP1M/PP3M in usual-care settings. Additional confounds, such as greater illness severity and more frequent comorbidities and comedications in the ECA, were not fully controlled by the applied statistical methods. Future real-world studies directly comparing PP6M with PP3M/PP1M and adjusting for these confounders are warranted.

Long-Term Efficacy and Safety of Paliperidone 6-Month Formulation: An Open-Label 2-Year Extension of a 1-Year Double-Blind Study in Adult Participants With Schizophrenia.

BACKGROUND: Paliperidone palmitate 6-month (PP6M) demonstrated noninferiority to paliperidone palmitate 3-month in preventing relapse in patients with schizophrenia in a phase 3 double-blind (DB) study (NCT03345342). Here, we report long-term efficacy and safety results from a 2-year single-arm, open-label extension (OLE; NCT04072575) of this DB study. METHODS: Participants who completed the DB study without relapse were enrolled and followed-up every 3 months up to 2 years. Participants received 4 PP6M gluteal injections (700/1000 mg eq.) at baseline, 6-month, 12-month, and 18-month visits. Efficacy endpoints included assessment of relapse, Positive and Negative Syndrome Scale total score, Personal and Social Performance score, and Clinical Global Impression-Severity scale change from baseline. Safety was assessed by treatment-emergent adverse events (TEAEs), physical examinations, and laboratory tests. RESULTS: Of 178 participants enrolled, 154 (86.5%) completed the OLE (mean age: 40.4 years, men: 70.8%; mean duration of PP6M exposure during OLE: 682.1 days). Overall, 7/178 (3.9%) participants relapsed between 20 and 703 days after enrolment. Mean (SD) changes from baseline to endpoint were as follows: Positive and Negative Syndrome Scale total score, 0.7 (8.22); Clinical Global Impression-Severity, 0.0 (0.51); and Personal and Social Performance Scale, 0.5 (7.47). Overall, 111/178 participants (62.4%) reported ≥1 TEAE; most common (>5%) TEAEs were headache (13.5%) and increased blood prolactin/hyperprolactinemia (18.0%); 8/178 (4.5%) participants experienced serious TEAEs, and 6/178 (3.4%) participants withdrew due to TEAEs. No deaths were reported. CONCLUSIONS: The relapse rate observed with PP6M during the 2-year OLE was low (3.9%). Clinical and functional improvements demonstrated in the DB study were maintained during OLE, and no new safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

Efficacy and Safety of Paliperidone Palmitate 6-Month versus Paliperidone Palmitate 3-Month Long-Acting Injectable in European Patients with Schizophrenia: A Post Hoc Analysis of a Global Phase-3 Double-Blind Randomized Non-Inferiority Study.

Purpose: To examine efficacy and safety of paliperidone palmitate (PP) 6-month (PP6M) vs PP3-month (PP3M) long acting injectable (LAI) in patients with schizophrenia from European sites previously stabilized on PP3M or PP1-month (PP1M). Methods: This post-hoc subgroup analysis used data from a global phase-3 double-blind (DB) randomized non-inferiority study (NCT03345342). Patients were randomized (2:1, respectively) to receive dorsogluteal injections of PP6M (700 mg eq. or 1000 mg eq.) or PP3M (350 mg eq. or 525 mg eq.) in the 12-month DB phase. Primary endpoint was time-to-relapse during the DB phase, using a Kaplan-Meier cumulative survival estimate (non-inferiority margin 95% CI lower bound larger than prespecified as -10%). Treatment emergent adverse events (TEAEs), physical examinations, and laboratory tests were also evaluated. Results: A total of 384 patients who entered the DB phase were included in European sites (PP6M, n = 260; PP3M, n = 124) with a mean age similar in both groups (mean age [SD] years: PP6M, 40.0 [11.39]; PP3M, 38.8 [10.41]). Baseline characteristics were similar across both groups. The number of patients who experienced a relapse during DB phase were PP6M: 18 (6.9%) vs PP3M: 3 (2.4%) with percentage relapse-free difference of -4.9% (95% CI: -9.2%, -0.5%), thus achieving non-inferiority criteria. Secondary efficacy endpoints indicated comparable improvements. Incidence of TEAEs was similar between PP6M (58.8%) and PP3M (54.8%) groups. Nasopharyngitis, headache, increased weight, and injection-site pain were the most common TEAEs. Conclusion: The efficacy of PP6M was non-inferior to that of PP3M in preventing relapse in the European subgroup previously treated with PP1M or PP3M, which was consistent with the global study. No new safety signals were identified.

Stroke Risk Among Elderly Users of Haloperidol and Typical Antipsychotics Versus Atypical Antipsychotics: A Real-World Study From a US Health Insurance Claims Database.

BACKGROUND: We estimated stroke risk associated with new exposure to haloperidol, or any typical antipsychotic, versus atypical antipsychotic among patients aged ≥65 years regardless of dementia status. METHODS: IBM MarketScan Medicare Supplemental Database data (January 1, 2001 to December 31, 2017) were used. Stroke risk for new users of typical antipsychotics (T1 cohort) or haloperidol (T2 cohort) was compared with new users of atypical antipsychotics (C1 cohort) aged ≥65 years. Crude incidence rate (IR) and incidence proportion of stroke were estimated within each cohort and gender subgroup. Three propensity score (PS) matching strategies were employed: Unadjusted (crude), Sentinel PS replication, and a large-scale regularized regression model (adapted PS). RESULTS: Overall, 36,734 (T1), 24,074 (T2), and 226,990 (C1) patients were included. Crude IRs for stroke per 1000 person-years were 17.67 (T1), 23.74 (T2), and 14.17 (C1). In preplanned analyses, PS-matched calibrated hazard ratio (cHR) for stroke T1 versus C1 cohort was 1.08 (95% calibrated confidence interval [cCI] = 0.75, 1.55) with Sentinel PS strategy and 1.31 (95% cCI = 1.07, 1.60) with adapted PS strategy. The cHR for stroke in patients of T2 versus C1 was 1.69 (95% cCI = 1.08, 2.75) with Sentinel PS strategy and 1.45 (95% cCI = 1.17, 1.80) with adapted PS strategy. CONCLUSION: Stroke risk in elderly new users of haloperidol was elevated compared to new users of atypical antipsychotics and was elevated for typical antipsychotics using the adapted PS strategy.