Summary

• The efficacy of INVEGA SUSTENNA was established in an international, long-term, double-blind, placebo-controlled, randomized-withdrawal study in patients with schizoaffective disorder.^1–3
  • There were significant improvements in mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression of Severity-Schizoaffective Disorder (CGI-S-SCA) overall score, Young Mania Rating Scale (YMRS) total score and Hamilton Depression Rating Scale (HAM-D-21) total score from week 1 to week 25/open-label endpoint (P<0.001 for all time points from baseline [week 0]).^1,2
  • Time to relapse in the double-blind phase was significantly longer for INVEGA SUSTENNA versus placebo (P<0.001).³
    • Relapse rates were significantly lower for the INVEGA SUSTENNA versus placebo groups (15.2% [n=25] versus 33.5% [n=57], respectively).
    • Risk of relapse was 2.49-fold higher for placebo versus INVEGA SUSTENNA (95% CI: 1.55, 3.99; P<0.001).
• In the long-term schizoaffective disorder study, patients received a dose of INVEGA SUSTENNA 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. Following the second initiation dose, monthly maintenance doses were administered in either the deltoid or gluteal muscle. The maintenance dose range was 78-234 mg. The 39 mg strength was not studied in the long-term schizoaffective disorder study. Dose was adjusted based on tolerability and/or efficacy using available strengths within the range of 78-234 mg.¹
• Please refer to the local labeling for country specific indication(s).

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents (mg eq) of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths available in the United States. The conversion factor from mg eq to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

CLINICAL STUDIES

Randomized, Controlled Study

Fu et al^1,3 conducted an international, long-term, double-blind, placebo-controlled, randomized-withdrawal study of INVEGA SUSTENNA in patients with schizoaffective disorder.

Study Design/Methods

• Study phases:
  • 1-7 day screening period, during which patients received oral tolerability testing if necessary
  • 13-week, open-label, lead-in period, during which patients received INVEGA SUSTENNA (234 mg on day 1 and 156 mg on day 8 in the deltoid muscle, followed by flexible doses of 117-234 mg on day 36 and 78-234 mg on days 64 and 92), as monotherapy or as an adjunct to, stable doses of their adjunctive mood stabilizer (MS) or antidepressant (AD) medications
  • 12-week, open-label, fixed-dose phase, during which patients who met predefined stabilization criteria (PANSS total scores ≤70; YMRS and HAM-D-21 scores ≤12) received INVEGA SUSTENNA once every 4 weeks, at the final dose received during the lead-in period
  • 15-month, double-blind phase, during which patients who maintained stability based on predefined criteria were randomized to placebo or a fixed dose of INVEGA SUSTENNA
• Included patients with a lifetime and current diagnosis of schizoaffective disorder as assessed by the Structured Clinical Interview for DSM-IV; an acute exacerbation of psychotic symptoms ≥4 days and ≤4 weeks in duration before screening; scores ≥4 on ≥3 specified PANSS items (delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, tension, uncooperativeness, poor impulse control); and prominent mood symptoms (scores ≥16 on YMRS and/or HAM-D-21).
• Primary efficacy endpoint: Time to relapse, defined as the first occurrence of any one of the following:
  • Psychiatric hospitalization due to worsening of symptoms
  • Any intervention to avert imminent hospitalization due to worsening of symptoms, clinically significant self-injury, suicidal or homicidal ideation, or violent behaviors
  • Worsening of ≥1 of the following PANSS items to a score ≥6 after randomization if the score was ≤4 at randomization: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness or poor impulse control
  • Worsening in any of the following measures at 2 consecutive visits within 7 days: ≥25% increase in PANSS total score from randomization if the score was >45 at randomization, ≥10-point increase in PANSS total score from randomization if the score was ≤45 at randomization, worsening of ≥1 of the following PANSS items to a score ≥5 after randomization if the score was ≤3 at randomization: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness or poor impulse control
  • Increase in CGI-S-SCA ≥2 points if the score at randomization was 1 (not ill) to 3 (mildly ill) OR increase ≥1 point if the score at randomization was ≥4 (moderately ill or worse)

Open-Label Phase Results

Patient Characteristics³

• 667 patients were enrolled in the open-label phase.
• INVEGA SUSTENNA was used as monotherapy in 320 patients, and as adjunctive therapy with a mood stabilizer or antidepressant in 347 patients.
• Demographic data: mean age: 39.5 years; 53.5% male; 53.1% white
• Disease characteristics at baseline:
  • Mean PANSS total score: 85.8
  • Mean Clinical Global Impression of Severity for Schizoaffective Disorder (CGI-S-SCA) overall score: 4.4
  • Mean YMRS total score: 18.6
  • Mean HAM-D-21 total score: 20.4
  • Mean Personal and Social Performance (PSP) scale total score: 51.4
  • Mean number of prior psychiatric hospitalizations: 4.8
  • Percentage of patients with history of suicide attempt: 24.3%
  • Mean age at schizoaffective diagnosis: 31.5 years
  • Schizoaffective subtype: depressive, 35.5%; bipolar, 64.5%
• The last dose of INVEGA SUSTENNA at the end of the open-label phase was 78 mg in 2.7% of patients, 117 mg in 7.3% of patients, 156 mg in 52.8% of patients, and 234 mg in 37.2% of patients.

Results

Efficacy¹

• An increasing proportion of patients experienced clinically meaningful symptom improvements (≥10-point decrease in PANSS scores, ≥4-point decrease in HAM-D-21 scores and ≥6-point decrease in YMRS scores) from week 1 to each time point during the 13-week acute treatment phase.
• There were significant improvements in mean change from baseline in PANSS total score, CGI-S-SCA overall score, YMRS total score and HDRS-21 total score from week 1 to week 25/open-label endpoint (P<0.001 for all time points from baseline [week 0]).
  • Mean baseline to open-label endpoint CGI-SCA overall change score: -1.3²
• The proportion of patients who completed the 25-week open-label treatment period and met remission criteria (PANSS total score ≤60, HAM-D-21 score ≤7 and YMRS score ≤7) was: overall, 49.1% (171/348); combination therapy, 49.1% (93/194); monotherapy, 50.6% (78/154).
• There was a significant improvement in mean PSP scores from week 5 to week 25/open-label endpoint (P<0.001 for all time points from baseline [week 0]).
  • Mean PSP score improvement from baseline to 25-week/open-label endpoint: 13.7²
  • Manifest to very severe impairment on PSP domains decreased from baseline to endpoint for the overall population²:
    • Socially useful activities: 92.2% to 58.3%
    • Personal and social relations: 89.1% to 45.8%
    • Self-care: 28.9% to 11.8%
    • Disturbing/aggressive behaviors: 36.7% to 9.9%
• Improvements in efficacy were similar between subjects receiving monotherapy or combination therapy.
• 333 patients discontinued due to reasons including withdrawal of consent (14.7%), failure to meet stabilization criteria (12.3%), adverse events (7.5%), lost to follow-up (6.3%) and lack of Efficacy (4.6%).

Safety¹

• Treatment-emergent adverse events (TEAEs) occurred in 62.5% of patients during the 25-week open-label phase. TEAEs occurring in ≥5% of patients included akathisia (11.1%), injection site pain (10.6%), insomnia (10.0%), increased weight (8.5%), parkinsonism (6.4%), and headache (5.4%).
• 23.2% of patients experienced an extrapyramidal symptom-related TEAE, 10% of females and 9% of males experienced a potentially prolactin-related TEAE and 0.9% experienced a glucose-related TEAE.

Double-Blind Phase Results

Patient Characteristics³

• 334 patients were randomized to INVEGA SUSTENNA (n=164) or placebo (n=170) in the double-blind phase.
• 151 patients received monotherapy while 183 patients received adjunctive therapy (MS: 105; AD: 78)
• Demographic data (n=334): mean age: 38.6 years; 50.6% male; 54.8% white
  • Mean number of prior psychiatric hospitalizations: 3.9
  • Mean age at first schizoaffective diagnosis: 30.9 years
  • Schizoaffective subtype: depressive, 30.2%; bipolar, 69.8%
• Completion rates for the double-blind phase were 61.0% and 38.2% for the INVEGA SUSTENNA and placebo groups, respectively.
• Median duration of exposure was 446 days for INVEGA SUSTENNA and 268.5 days for placebo.
• INVEGA SUSTENNA dose distribution: 78 mg (4.9%), 117 mg (9.8%), 156 mg (47%) or 234 mg (38.4%) doses.

Results

Efficacy³

• Time to relapse was significantly longer for INVEGA SUSTENNA versus placebo (P<0.001).
• Relapse rates were significantly lower for the INVEGA SUSTENNA versus placebo groups (15.2% [n=25] versus 33.5% [n=57], respectively).
  • Risk of relapse was 2.49-fold higher for placebo versus INVEGA SUSTENNA (95% CI: 1.55, 3.99; P<0.001), corresponding to a 60% decrease in relapse risk with INVEGA SUSTENNA treatment.
• Relapse risk was also higher for placebo versus INVEGA SUSTENNA for the subgroups listed in the Table: Risk of Relapse.
  • Risk ratio of relapse in favor of INVEGA SUSTENNA did not differ across different types of mood episodes.

• Reasons for relapse, which were not mutually exclusive, are found in the Table: Summary of Reasons for Relapse.

• All-cause discontinuation rates were 39% and 61.8% for the INVEGA SUSTENNA and placebo groups, respectively.
  • INVEGA SUSTENNA patients experienced a significantly longer time to all-cause discontinuation versus placebo patients (P<0.001).
• From double-blind baseline to 15-month endpoint, a significant least squares mean treatment difference in PSP total scores favored INVEGA SUSTENNA over placebo (P=0.014).
  • Good functioning (PSP total score >70) was maintained in the INVEGA SUSTENNA group from double-blind baseline (57.9%) to 15-month endpoint (59%) whereas, the proportion of placebo patients with good functioning at double-blind baseline (50.6%) decreased at the 15-month endpoint (41.1%) (between-group difference, P=0.002).
• At endpoint, the least squares-mean between-group differences for change in HDRS-21, YMRS, PANSS and CGI-S-SCA total scores favored INVEGA SUSTENNA over placebo (P<0.001).
• The proportion of patients with CGI-S-SCA scores of “not ill” to “mildly ill” decreased from double-blind baseline to endpoint (between-group differences, P<0.001).
  • INVEGA SUSTENNA: 97.6% (74/164) to 83.9% (46/161), respectively
  • Placebo: 95.9% (88/170) to 64.9% (45/168), respectively

Safety³

• Most common TEAEs (≥5%) for either INVEGA SUSTENNA or placebo, respectively were: schizoaffective disorder (3.0%; 5.9%), weight gain (8.5%; 4.7%), nasopharyngitis (5.5%; 3.5%), headache (5.5%; 3.5%), and insomnia (4.9%; 7.1%)
  • Serious AEs were reported in 5.5% of INVEGA SUSTENNA versus 9.4% of placebo patients.
• Discontinuation due to TEAEs occurred in 7.3% and 1.8% of INVEGA SUSTENNA and placebo patients, respectively.
• Additional AEs of interest are reported in the Table: Additional AEs of Interest.

Subanalyses of the Fu et al trial have been referenced for your convenience.^4–7

retrospective analyses

A retrospective, mirror-image study evaluating the long-term efficacy of initiating INVEGA SUSTENNA in reducing the number and length of hospitalizations and number of psychiatric emergency room visits in patients with schizophrenia or schizoaffective disorder, has been referenced for your review.⁸

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 17 September 2024.