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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 33  |  Issue : 4  |  Page : 198-203

Long-term safety, efficacy, treatment satisfaction, and impact on healthcare service use of paliperidone palmitate one-month intramuscular formulation in patients with recent-onset schizophrenia in taiwan: A subgroup analysis of an asia-pacific, 18-month, phase 3b study


1 Dr. Tang's Psychiatric Clinic, Kaohsiung, Taiwan
2 Department of Psychiatry, Chung Shan Medical University Hospital; Department of Psychiatry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3 Department of Psychiatry, National Taiwan University Hospital; Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
4 Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan
5 Department of Psychiatry, Chi-Mei Medical Center, Tainan, Taiwan
6 Medical Affairs, Janssen Pharmaceuticals of Johnson and Johnson, Cheng Hsin General Hospital, Taipei, Taiwan
7 Department of Psychiatry, Cheng Hsin General Hospital; Department of Psychiatry, Taipei Veterans General Hospital; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan

Date of Submission19-Jul-2019
Date of Decision09-Oct-2019
Date of Acceptance20-Oct-2019
Date of Web Publication23-Dec-2019

Correspondence Address:
Tung-Ping Su
No. 45, Cheng Hsin Street, Taipei 112
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TPSY.TPSY_39_19

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  Abstract 


Objectives: In this study, the authors intended to evaluate the efficacy and safety of paliperidone palmitate 1-month injection (PP1M) in patients with recent-onset schizophrenia (SCH). Methods: A subgroup analysis was done for patients enrolled in Taiwan in an Asia-Pacific, Phase 3b study (ClinicalTrials.gov identifier NCT01051531). Patients were switched from oral antipsychotics to intramuscular PP1M. Results: We included 61 patients (age: 31.2 ± 8.8 years). The Positive and Negative Syndrome Scale scores were significantly decreased, with the largest effect size observed in positive, disorganized, and depressive factors (Cohen's d = 0.52, 0.52, and 0.79, respectively). Most symptoms stabilized within six months, whereas stabilization of functional improvement required 1–1.5 years of PP1M treatment, especially for employment/academic status. PP1M treatment was well-tolerated, with over 70% of treatment satisfaction rate, and significantly reduced the average days of hospitalization (43.3–7.1/person-years). Conclusion: Switching to PP1M improved treatment outcome and satisfaction as well as reduced healthcare service use in patients with recent-onset SCH.

Keywords: clinical trial, employment status, long-acting injection, schizophrenia


How to cite this article:
Tang TC, Hsieh MH, Liu CC, Chiu NY, Jang FL, Chiang CL, Su TP. Long-term safety, efficacy, treatment satisfaction, and impact on healthcare service use of paliperidone palmitate one-month intramuscular formulation in patients with recent-onset schizophrenia in taiwan: A subgroup analysis of an asia-pacific, 18-month, phase 3b study. Taiwan J Psychiatry 2019;33:198-203

How to cite this URL:
Tang TC, Hsieh MH, Liu CC, Chiu NY, Jang FL, Chiang CL, Su TP. Long-term safety, efficacy, treatment satisfaction, and impact on healthcare service use of paliperidone palmitate one-month intramuscular formulation in patients with recent-onset schizophrenia in taiwan: A subgroup analysis of an asia-pacific, 18-month, phase 3b study. Taiwan J Psychiatry [serial online] 2019 [cited 2020 Jan 27];33:198-203. Available from: http://www.e-tjp.org/text.asp?2019/33/4/198/273860




  Introduction Top


Schizophrenia (SCH) is a chronic debilitating disease that impairs patients' emotion, cognition, and well-being [1], and imposes a substantial burden on the Healthcare system, with direct healthcare costs and productivity losses as the two main cost drivers [2]. The socioeconomic burden of SCH is also substantial in Taiwan, as shown through lifetime healthcare expenditures of up to US $53,000 per patient [3], total healthcare costs of up to $193,084 in New Taiwan dollars in the 1st year of diagnosis [4], a four-month readmission rate of 25% [5], and a four-year readmission rate of approximately 60% [6] after the first hospitalization.

Antipsychotic medications are the mainstay of SCH treatment [7], but about 30%–70% of patients with SCH are nonadherent to oral medications [8] for many reasons, including cognitive dysfunction and poor insight [9],[10]. Long-acting injectable (LAI) antipsychotic drugs have been developed to overcome challenges associated with adherence to oral antipsychotics, and their use is recommended by several guidelines, especially in the early stages of SCH [7, 11, 12].

Paliperidone palmitate one-month formulation (PP1M; Janssen Pharmaceutica N.V, Beerse, Belgium) is an intramuscular, second-generation LAI antipsychotic approved for the treatment of SCH. The efficacy and safety of PP1M in patients with SCH have been reported in several populations, including those previously treated with antipsychotics [13],[14],[15], but evidence for the efficacy, safety, treatment satisfaction, and impact on healthcare service use of PP1M is still limited in Taiwan. We did a subgroup analysis with data from patients enrolled in Taiwan in a multicenter, Asia-Pacific, Phase 3b study that assessed the safety and efficacy of PP1M in patients with recent-onset SCH (≤ 5 years) who switched from previous oral antipsychotics [14].


  Methods Top


Study design

The original single-arm, open-label, multicenter, 18-month, Asia-Pacific, Phase 3b study was conducted in nine countries (Australia, People's Republic of China, Hong Kong, Korea, Malaysia, New Zealand, the Philippines, Taiwan, and Thailand) from April 2010 to May 2013 (ClinicalTrials.gov identifier NCT01051531). The study consisted of an optional retrospective period (12 months before PP1M initiation) and an open-label prospective period (18 months after PP1M initiation) [14].

Study patients

Patients aged 18–50 years with recent-onset SCH (≤ 5 years, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4 th Edition (DSM-IV) criteria) treated in inpatient or outpatient settings and with suboptimal treatment response, intolerance, or noncompliance to oral antipsychotics (based on the investigator's clinical judgment) were eligible for study participation. Excluded from the study were patients who had a psychiatric diagnosis due to medication/substance abuse or medical conditions (e.g., hypothyroidism), treatment resistance (based on the investigator's clinical judgment or treatment with clozapine within three months prior to screening), DSM-IV-diagnosed substance dependence within 6 months before study entry, or treatment with an LAI antipsychotic within three injection cycles before baseline [14].

The study was approved by the institutional review board (IRB) at Changhua Christian Hospital with the requirement of obtaining informed consents from the study participants (protocol number = 100709, approval date = October 22, 2010). The IRBs of other hospitals at all participating sites also did the approval of the study.

Study treatment

The patients received a seven-day screening and washout period to discontinue oral antipsychotics and were treated for 18 months with intramuscular PP1M 150 mg eq on day 1 and 100 mg eq on day 8 ± 2 (both in the deltoid muscle), and then 50, 75, 100, or 150 mg eq once monthly in the deltoid or gluteal muscle at the investigator's discretion. No oral or depot antipsychotics other than PP1M were allowed. Details of the study treatment have been published previously [14].

Assessments and outcome measures

During the 18-month prospective period, symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total score and five factors (positive, negative, disorganized/concrete, excited, and depressed [16]) (baseline and days 38, 188, 368, and 548) and the Clinical Global Impression-SCH (CGI-SCH) overall severity score (baseline and days 8, 38, 98, 188, 278, 368, 458, and 548). Functional improvement was assessed using the Personal and Social Performance (PSP) total score (baseline and days 38, 188, 368, and 548). Employment status (full-time employment; part-time employment; casual employment; sheltered work; unemployed, seeking work; unemployed, not seeking work; homemaker or dependent husband; or student) was also captured at baseline and days 188, 368, and 548. Treatment satisfaction was assessed using the Medication Satisfaction Questionnaire (MSQ; l = extremely dissatisfied, 2 = very dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = very satisfied, and 7 = extremely satisfied) at baseline and days 8, 38, 98, 188, 278, 368, 458, and 548. The number of days of hospitalization per person-years during the retrospective and prospective periods (i.e., the total number of hospitalization days in the period/length of the period [year]) and hospitalization due to psychiatric reasons during the prospective period was captured. Safety was assessed throughout the study considering drug exposure and treatment-emergent adverse events (TEAEs).

Statistical analysis

The intent-to-treat (ITT) population comprised all patients who received ≥ 1 dose of PP1M. The healthcare resource use set comprised all ITT patients with any healthcare resource utilization data available during the prospective period. The mirror analysis set comprised all patients in the healthcare resource use set who had retrospective data (including hospitalization, emergency room visits, and outpatient visits) available in the 12 months before day 1.

At each visit, PANSS and CGI-SCH overall severity scores were summarized and represented as mean and standard deviation (SD). A paired t-test was done for change from baseline to each timepoint in PANSS scores. The effect size (Cohen's d) was calculated for the PANSS scores on days 38, 188, 368, and 548. The PSP scores were categorized as good (71–100), variable (31–70), or poor (≤ 30) functioning. The proportions of employees (full time or part time) or students and patients hospitalized due to psychiatric reasons during the prospective period were calculated. A mirror analysis was done to compare the average number of days of hospitalization (per person-years) during the retrospective and prospective periods.

We imput missing values with the last observation carried forward method. No imputation was done for missing baseline values. TEAEs were coded using the Medical Dictionary for Regulatory Activities version 13.0 (www.meddra.org).

Analyses were done using Statistical Analysis System version 9.1.3 or later version (SAS Institute Inc., Cary, North Carolina, USA). The differences between groups were considered significant if p values are < 0.05.


  Results Top


Patient disposition and baseline characteristics

We enrolled 66 patients at six participating sites in Taiwan. The ITT population, healthcare resource use set, and mirror analysis set included 61, 60, and 60 patients, respectively. Of the 61 patients, 46 (75.4%) completed the study. Reasons for early termination were adverse events (six patients [40.0%]), consent withdrawal (six [40.0%]), lack of efficacy (two [13.3%]), and protocol violation (one [6.7%]).

[Table 1] shows demographic and baseline characteristic data. The most commonly (≥ 5%) used previous oral antipsychotic medications were paliperidone (49.2%), risperidone (16.4%), amisulpride (8.2%), and haloperidol (6.6%). The most commonly (≥ 5%) prescribed concomitant medications that were tapered off within the 1st month of the study were paliperidone (29.5%) and quetiapine fumarate (6.6%).
Table 1. Demographics and baseline characteristics (intent-to-treat population)

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Symptom severity and functional improvement

During the prospective period, the mean PANSS score (total and five factors) and the mean CGI-SCH overall severity score was decreased from baseline to day 548 [Figure 1]. The effect size on day 548 was 0.69 for the PANSS total score, 0.52 for the positive factor, 0.31 for the negative factor, 0.52 for the disorganized/concrete factor, 0.42 for the excited factor, and 0.79 for the depressed factor. While improvement in other factors mostly occurred within the first 6 months, depressed factor was improved throughout the 18 months of PP1M treatment.
Figure 1. Change in mean ± SD PANSS scores for (a) total score, (b) positive factor, (c) negative factor, (d) disorganized/concrete factor, (e) excited factor, and (f) depressed factor and (g) change in mean ± SD CGI-SCH overall severity score during the 18-month prospective period (ITT population). *p < 0.05, **p < 0.01. Positive factor, PANSS P1, P3, P5, and G9; negative factor, PANSS N1, N2, N3, N4, N6, and G7; disorganized/concrete factor, PANSS P2, N5, and G11; excited factor, PANSS P4, P7, G8, and G14; depressed factor, PANSS G2, G3, and G6. CGI-SCH, Clinical Global Impression-Schizophrenia; CI, confidence interval; ITT, intent to treat; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation.

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The proportion of patients with good functioning (PSP total score 71–100) was 34.4% at baseline, 41.7% at day 38, 48.3% at day 188, and 58.3% at days 368 and 548. The proportion of employees (full time or part time) or students was 42.6% (26/61 patients) at baseline, 36.7% (18/49 patients) on day 188, 51.1% (24/47 patients) on day 368, and 56.5% (26/46 patients) on day 548. The results were similar when a sensitivity analysis was performed for patients who completed the study (n = 46, 43.2% at baseline, 37.0% on day 188, 52.2% on day 368, and 56.5% on day 548).

Treatment satisfaction

The treatment satisfaction rate (MSQ score ≥ 4) was improved continuously in the first six months (from 32.8% at baseline to 77.6% on day 188) and persisted at over 70% thereafter. Moreover, 53.3% of the patients with early withdrawal were neutral or satisfied with PP1M treatment.

Healthcare service use

The average days of hospitalization were decreased from the retrospective period to the prospective period (43.3–7.1/person-years). The proportion of patients hospitalized due to psychiatric reasons was 5% among all patients (n = 60) and was lower among those without a history of hospitalization (2.4% [n = 41]) compared with those with a history of hospitalization (10.5% [n = 19]), although the sample size was small to draw any definite conclusions.

Safety

Patients received 15.4 ± 6.5 (mean ± SD) doses of PP1M for 421.4 ± 190.1 (mean ± SD) days during the prospective period. The mean ± SD PP1M dose was 108.0 ± 21.5 mg eq in the overall prospective period and 101.9 ± 25.2 mg eq in the dose maintenance phase (after day 8). The last dose received was 50, 75, 100, and 150 mg eq in 3 (4.9%), 16 (26.2%), 25 (41.0%), and 17 (27.9%) patients, respectively.

Fifty-two (85.2%) patients reported TEAEs, of which 35 (57.4%) were mild in severity. Thirty-four (55.7%) patients experienced treatment-related TEAEs. Five serious TEAEs were reported in four (6.6%) patients (mania, SCH, suicide attempt, abdominal pain, and gastric banding), but no deaths were reported. Six (9.8%) patients experienced TEAEs leading to treatment discontinuation and study withdrawal (anxiety, psychotic disorder, suicide attempt, injection-site pain, akathisia, and hyperhidrosis).

The most common (> 5%) TEAEs were psychiatric disorders (anxiety [13.1%], insomnia [9.8%], and restlessness [6.6%]), nervous system disorders (akathisia [9.8%], headache [9.8%], poor quality sleep [8.2%], and tremor [8.2%]), gastrointestinal disorders (diarrhea [8.2%] and constipation [6.6%]), weight gain (weight increased [11.5%] and abnormal weight gain [8.2%]), injection-site pain (11.5%), and upper respiratory tract infection (11.5%). Extrapyramidal symptoms were reported in twenty (32.8%) patients, with the most commonly (> 5%) reported being akathisia (9.8%), tremor (8.2%), and restlessness (6.6%); most were mild to moderate in severity. Injection-site pain was reported in seven (11.5%) patients. But all events were mild in severity, and only one patient discontinued treatment because of it. Prolactin-related TEAEs (TEAEs associated with prolactin level changes) were reported in nine (14.8%) patients, most commonly hyperprolactinemia or blood prolactin abnormal (five patients), but none led to treatment discontinuation or study withdrawal.


  Discussion Top


We did a subgroup analysis using data from patients enrolled in Taiwan in an Asia-Pacific, Phase 3b study [14] characterized by a longer follow-up period (18 months) compared with similar previous studies (up to six months) [13],[15].

The changes in mean PANSS total and CGI-SCH overall severity scores, improvement in PSP functioning and employment status, reduction in days of hospitalization, and the safety of PP1M were generally comparable between our analysis and the original Asia-Pacific study [14],[17]. No new safety signals emerged in this study. Symptoms (PANSS or CGI-SCH scores) were generally stabilized within six months, whereas stabilization of functional improvement required one year (PSP score) to 1.5 years (employment/academic status) of PP1M treatment, highlighting the importance of long-term antipsychotic maintenance treatment in functional recovery among patients with recent-onset SCH.

In our subgroup, 49.2% and 16.4% of participants had taken oral paliperidone and risperidone, respectively, before initiating PP1M. As the current study excluded treatment-resistant patients, it is conceivable that the efficacy of PP1M was demonstrated more easily in our study. Moreover, these patients may have had covert nonadherence to oral paliperidone or risperidone, which could not be detected by the investigator. The reasons for a favorable response to PP1M in these patients deserve further investigation.

The effect size of the PANSS score on day 548 was moderate for improvements in all symptom domains and was numerically largest for the depressed factor (0.79). Moreover, all PANSS symptom domains improved over time with PP1M treatment, including depressive and anxiety symptoms (G2: anxiety; G3: guilt feelings; and G6: depression). Previous research has shown reduction [18] or relapse prevention [19] in depressive symptoms with PP1M, and a direct treatment effect of paliperidone on depressive symptoms, independent of its antipsychotic effects [20]. The mood-improving effects of paliperidone deserve further investigation.

The rehospitalization rate during the prospective period (5%) in our subgroup analysis was much lower than that observed in previous population-based studies in Taiwan (25% in four months [5] or 49%–54% in two years [6]). Moreover, the average days of hospitalization decreased substantially (43.3–7.1/person-years) after switching to PP1M. These results were consistent with those of nationwide studies from Finland [21] and Sweden [22] or similar mirror-image studies [23],[24] in reduction in hospitalization for SCH. As most of the treatment costs of SCH in Taiwan arise from hospitalization [4], reduction in hospitalization days may contribute to a reduced medical costs; however, further pharmacoeconomic studies are warranted in Taiwan to prove this.

Study limitations

The readers are warned not to overinterpret our study results because our study has four limitations:

  • The open-label, single-arm study design may have increased the risk of observational bias by investigators and/or made it difficult to distinguish disease improvement due to PP1M treatment from disease resolution over time [14].
  • The rigor and structure of a clinical trial may have improved medication adherence, making comparison with a real-world scenario difficult.
  • Patients were treated with a variety of medications before enrollment, a factor that was not considered when making inferences.
  • Although the number of patients enrolled in the original trial was large (n = 521), the subpopulation of patients from Taiwan included in this analysis was relatively small (n = 61).


Summary

Switching from oral antipsychotics to PP1M was well tolerated, improved treatment outcome and satisfaction, and reduced healthcare service use during the 18-month treatment period in patients from Taiwan with recent-onset SCH.


  Financial Support and Sponsorship Top


This study was sponsored by Janssen Pharmaceuticals of Johnson and Johnson, Taipei, Taiwan, the maker of paliperidone.


  Conflicts of Interest Top


The authors declare no conflicts of interest in writing this report. CLC, a co-author, is an employee of Janssen Pharmaceuticals of Johnson and Johnson, Taipei, Taiwan.



 
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