Table 1.

Clinical studies about PP3M

Study	Aims	Design, data sources and duration	Sample features	Main results
Ravenstijn et al59	To assess PP3M: • PK • Safety • Tolerability	Design: OCT • Phase I study • Multicenter • Randomized • Open-label • Parallel-group Duration: from 12.2 to 18.2 months	328 patients aged 18–65 years With: • Schizophrenia or schizoaffective disorder (DSM-IV) • PANSS total score of ≤70 Without: • Substance dependence nor history of suicide attempt within 12 months • History of NMS or TD	Safety and tolerability: similar to those of PP1M PK: results support a once every 3 months dosing interval
Berwaerts et al60	To assess PP3M: • Efficacy • Safety	Design: RCT PP3M vs placebo: • Phase III study • Multicenter • Randomized • Open-ended DB final phase Duration of DB phase (median time): • 5.6 months in the PP3M arm • 4.9 months in the placebo arm	506 enrolled patients from 8 Western and Asian countries, aged 18–70 years, with: • Schizophrenia (DSM-IV-TR) for at least 1 year before screening • PANSS total score of ≤120 at screening Without: • Significant risk of suicidal behavior • History of substance dependence within 6 months • History of NMS or TD 305 patients randomized in the DB phase	Efficacy: compared with placebo PP3M significantly delayed time to relapse Safety: profile consistent with other marketed paliperidone formulations
Savitz et al61	To test the non-inferiority of PP3M to PP1M	Design: RCT PP3M vs PP1M: • Phase III study • Multicenter • DB final phase • Parallel-group • Non-inferiority design Duration of the DB phase: 11.2 months	1,429 enrolled patients from 26 Western and Asian countries, aged 18–70 years, Women: postmenopausal, surgically sterile, or adequate contraception Men: adequate contraception With: • Schizophrenia (DSM-IV) • PANSS total score between 70 and 120 Without: • Any unstable or significant medical or neurological illness • Morbid obesity (BMI >40 kg/m2) • Mental retardation • Risk factors for prolonged QT interval, torsade de pointes, or sudden death • History of intolerability, hypersensitivity, or lack of response to risperidone or paliperidone 1,016 patients entered the DB phase 842 patients completed the DB phase	PP3M was non-inferior to PP1M in: • Relapse rates • Changes in PANSS scores, CGI-S score and PSP score
Savitz et al62	To assess symptomatic and functional remission achieved following PP3M vs PP1M treatment	Design: RCT PP3M vs PP1M non-inferiority design Data sources: Savitz et al study61 Duration: during DB phase, 11.2 months	The same as Savitz 2016 study61	• PP3M was non-inferior to PP1M in • Symptomatic remission (Andreansen’s criteria) • Functional remission (PSP) During last 6 months of the DB phase
Katz et al63	To quantify Berwaerts et al60 or Savitz et al61 RCT participants’ and investigators’ judgments about paliperidone formulations and adherence	Design: two discrete-choice experiment surveys: • One for patients • One for psychiatrists Duration: cross-sectional study	438 English-speaking physicians who participate as investigators in Berwaerts et al60 and/or Savitz et al61 studies 214 English-speaking patients enrolled in Australia, Canada and the USA among the participants of Berwaerts et al60 and Savitz et al61 trials	Patients and physicians preferred LAIs over oral antipsychotics Physicians showed a greater preference for 3-month over 1-month LAI antipsychotic
Chirila et al64	To compare occupational status and health care resource use between treatment groups (PP3M vs placebo and PP3M vs PP1M) in Berwaerts et al60 or Savitz et al61 trials	Design: longitudinal survey Data sources: Berwaerts et al60 and Savitz et al61 studies. Data deriving from these two RCTs were analyzed separately according to the design of the two original studies Duration: the same of Berwaerts et al60 and Savitz et al61 studies	305 patients who were randomized in the DB phase in Berwaerts et al study60 842 patients who completed the DB phase in Savitz et al study61	Work: no difference observed (only a small number of patients changed their occupational status during the studies) Hospitalization: higher rate in the placebo group, no difference between PP3M and PP1M
Gopal et al65	To evaluate caregiver burden in Berwaerts et al60 and Savitz et al61 RCTs	Design: longitudinal survey, with a mirror image analysis from a post-hoc analysis of pooled data Data sources: data derived from Berwaerts et al60 and Savitz et al61 studies Duration: the same of Berwaerts et al60 and Savitz et al61 studies	1,496 caregivers of the patients who participate to Berwaerts et al60 and Savitz et al61 studies Caregivers who had at least 1-hour contact with the patient per week	Both PP1M and PP3M may alleviate the caregiver burden The mirror image analysis showed that switching from an oral antipsychotic to either PP1M or PP3M can significantly reduce caregiver burden
Weiden et al66	To evaluate the effect of OP, PP1M and PP3M on times to relapse following medication discontinuation	Design and data sources: • Data drawn from Kramer et al,67 Hough et al,68 and Berwaerts et al60 DB RCTs comparing three paliperidone formulations (OP, PP1M and PP3M) with placebo • Post-hoc analysis of pooled data • Survival analysis of schizophrenia relapse in each placebo arm Duration: the same of Kramer et al,67 Hough et al,68 and Berwaerts et al60 studies	101 patients who were randomized in the placebo arm during the DB phase of Kramer et al study67 203 patients who were randomized in the placebo arm during the DB phase of Hough et al study68 145 patients who were randomized in the placebo arm during the DB phase of Berwaerts et al study60	50% of patients who withdrew treatment from OP, PP1M or PP3M remained relapse free for ~2, 6, and 13 months, respectively The relapse risk, in terms of hazard ratio, was 2.08-fold higher for patients discontinuing PP1M then for those discontinuing PP3M
Joshi et al69	To describe baseline characteristics and treatment patterns of patients with schizophrenia initiated on PP3M in a real-world setting	Design: • Observational retrospective longitudinal study • Cohort study • Index date: the date of the first approved claim for PP3M Data sources: pharmacy and medical PP3M claims from May 2014 to September 2016 in the Symphony Health Solutions database Duration: 12 months of continuous clinical activity prior to the index date	7,160 adult patients (100%) with at least one approved PP3M claim 5,362 patients (74.9%) had continuous clinical activity for at least 12 months prior to the index date 1,545 patients (21.6%) also had at least one schizophrenia diagnosis anytime during the study period and were included in the study (over all PP3M cohort) 1,063 patients (14.8%) had the dose transition done as labeled (per label PP3M cohort)	Patients initiated on PP3M demonstrated decreased health care resource utilization and increased adherence in quarters closer to PP3M initiation These patients were persistent on their PP3M treatment

Abbreviations: BMI, body mass index; CGI-S, Clinical Global Impression-Severity; DB, double blind; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-IV; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision; LAI, long-acting injectable; NMS, neuroleptic malignant syndrome; OCT, open-label clinical trial; OP, oral paliperidone; PANSS, Positive and Negative Syndrome Scale; PK, pharmacokinetics; PP1M, paliperidone palmitate 1-month; PP3M, paliperidone palmitate 3-month; PSP, Personal and Social Performance; RCT, randomized controlled trial; TD, tardive dyskinesia.