Summary

• The ACLAIMS (A Comparison of Long-acting Injectable Medications for Schizophrenia) study, a double-blind, randomized, multisite, parallel-group, US clinical trial, compared the effectiveness of INVEGA SUSTENNA vs haloperidol (HAL) decanoate for the maintenance treatment of schizophrenia or schizoaffective disorder.¹
  • The primary outcome, efficacy failure, was not significantly different between treatment groups (adjusted hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.65-1.47), although the authors concluded that a meaningful clinical difference between the treatments could not be ruled out.
  • Compared to INVEGA SUSTENNA, HAL decanoate was associated with significantly more akathisia and significantly greater use of medications to treat parkinsonism and akathisia. INVEGA SUSTENNA was associated with more weight gain and significantly greater increases in prolactin levels compared to HAL decanoate.
• In a sub-group analysis of a 15-month, prospective, randomized, open-label, event monitoring board (EMB)-blinded, multicenter US study designed to reflect real-world schizophrenia patients, patients receiving conventional oral antipsychotics (n=35; HAL and perphenazine), compared to INVEGA SUSTENNA (n=136), had a 34% higher risk of treatment failure (HR: 1.34, 95% CI: 0.80-2.25; P=0.261) with a potentially lower rate of some adverse events.²
• An analysis of results from eight clinical studies indirectly compared conventional long-acting injectables with INVEGA SUSTENNA by determining estimates of benefits expressed as number needed to treat (NNT) and number needed to harm (NNH).³
  • This analysis found that the use of INVEGA SUSTENNA rather than placebo was associated with benefits, as measured with NNT for relapse prevention and clinical response, that outweighed the risks, as measured with NNH for selected safety endpoints. The NNT for relapse prevention was similar among studies of INVEGA SUSTENNA (NNT range, 2 to 3), HAL decanoate (NNT, 2), and fluphenazine decanoate (NNT range, 2 to 5).
  • An additional analysis of the likelihood of being helped or harmed (LHH), as calculated with the ratio of NNH/NNT, showed that INVEGA SUSTENNA was more favorable than fluphenazine decanoate due to its lower measures of harm.
• An analysis of published and unpublished data was used to compare steady-state peak-to-trough fluctuations for long-acting injectable antipsychotics and their oral equivalents.  The steady-state ratio for paliperidone palmitate 1-month (PP1M) was 1.56. The steady-state ratios for long-acting injectable conventional antipsychotics were 2.60 for HAL decanoate and 3.16 for zuclopenthixol decanoate. A lower ratio indicates less fluctuation.⁴

CLINICAL STUDIES

Double-Blind Trial

McEvoy et al (2014)¹ conducted the ACLAIMS study, a double-blind, randomized, multisite, parallel-group US clinical trial comparing the effectiveness of INVEGA SUSTENNA vs HAL decanoate for the maintenance treatment of schizophrenia or schizoaffective disorder.

Study Design/Methods

• Patients aged 18-65 years, with a DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder, likely to benefit from a long-acting injectable due to risk of efficacy failure (noncompliance and/or significant substance abuse), were eligible for the trial.
• Exclusions (not limited to):
  • Clinically stable and tolerating current antipsychotic regimens
  • Experiencing moderate or severe tardive dyskinesia (TD)
  • Unlikely to benefit from study medications, due to past experience with risperidone, HAL or paliperidone (adverse events [AEs]; inadequate clinical response following ≥6 weeks of treatment)
• Eligible patients (N=311) were randomized on a 1:1 basis to INVEGA SUSTENNA or HAL decanoate via the following dosing guidelines:
  • Blinded oral tolerability trial (4-7 days):
    • INVEGA SUSTENNA patients (n=157) received risperidone 2 mg on days 1 and 2 and 4 mg thereafter
    • HAL decanoate patients (n=154) received HAL 2 mg on days 1 and 2 and 4 mg thereafter
  • Long-acting injectable treatment (≤24 months):
    • INVEGA SUSTENNA (n=147): Initiation doses, IM deltoid (234 mg on day 1; 156 mg on day 8); Maintenance doses, IM deltoid or gluteal (117 mg monthly)
    • HAL decanoate (n=147): Initiation doses, IM deltoid (50 mg on day 1; 50 mg on day 8); Maintenance doses, IM deltoid or gluteal (75 mg on days 28 and 56, then 50 mg monthly)
    • Injection schedules were adjusted based on clinical judgment.
    • Concomitant use of oral antipsychotics was permitted in the first 8 weeks of treatment.
  • As determined by the clinician and safety officer, patients experiencing new-onset diabetes, weight gain ≥15 lbs, increase in low-density lipoprotein (LDL) ≥20 mg/dL, worsening TD, hospitalization, clinical worsening (Clinical Global Impressions [CGI] scale) and/or serious AEs were permitted to continue study treatment if benefit outweighed risk.
• Primary outcome of efficacy failure was defined by one of the following criteria, determined by a majority vote from an adjudication committee of three psychiatrists blinded to treatment assignment.
  • Psychiatric hospitalization
  • Need for crisis stabilization
  • Clinically meaningful increase in frequency of outpatient visits
  • Clinician’s decision that oral antipsychotic medication could not be discontinued within 8 weeks following long-acting injectable initiation
  • Clinician’s decision to discontinue long-acting injectables due to inadequate therapeutic benefit
  • Ongoing or repeated need for adjunctive oral antipsychotics following successful transition to study drug within 8 weeks
• Secondary outcomes included weight changes, highest recorded prolactin levels, measures of involuntary movements, and “worst” changes in metabolic parameters (interventions to treat abnormalities were permitted).

Results

Patient Characteristics

• Baseline demographics were similar for both treatment groups.
• Patients were followed for a median of 488 days.
• Mean monthly doses of INVEGA SUSTENNA and HAL decanoate ranged from 129-169 mg and 67-83 mg, respectively.

Efficacy Failure

• Based upon a modified intent-to-treat (mITT) population, no statistically significant difference in the rate of efficacy failure (adjusted HR: 0.98; 95% CI: 0.65-1.47) was observed for INVEGA SUSTENNA (33.8%; n=49/145) vs HAL decanoate (32.4%; n=47/145).
  • mITT: All patients who received ≥1 injection and had ≥1 postbaseline assessment
• The most common reasons for efficacy failure were: Psychiatric hospitalizations (89.8% INVEGA SUSTENNA; 72.3% HAL decanoate) and clinician discontinuation of study medication due to inadequate therapeutic effect (69.4% INVEGA SUSTENNA; 59.6% HAL decanoate).

Secondary Outcomes

• Significant treatment group differences were observed with regard to weight gain (P<0.0001). At month 6, the least-squares mean weight change increased for the INVEGA SUSTENNA group (2.17 kg; 95% CI: 1.25-3.09) and decreased for the HAL decanoate group (-0.96; 95% CI: -1.88 to -0.04).
  • Discontinuation due to weight gain: INVEGA SUSTENNA (4.8%); HAL decanoate (1.4%)
• There were no statistically significant differences between treatment groups with regard to mean changes in PANSS total scores, highest recorded levels of glycated hemoglobin, glucose, total cholesterol, LDL cholesterol or triglycerides, or lowest recorded levels of HDL cholesterol.
• With regard to movement disorders, patients receiving HAL decanoate experienced greater increases in Barnes Akathisia Scale (BAS) global scores compared to INVEGA SUSTENNA (0.73 vs 0.45; P=0.006).
  • Significantly fewer INVEGA SUSTENNA vs HAL decanoate patients started a medication to treat parkinsonism (15.8% vs 29.3%, respectively; P=0.007) and akathisia (3.6% vs 11.0%, respectively; P=0.03).
  • Incidence of TD: INVEGA SUSTENNA (10.6%); HAL decanoate (15.4%); P=0.24
• Highest mean prolactin levels (SI unit conversion factor, multiplied by 43.478 for pmol/L) were significantly higher for INVEGA SUSTENNA vs HAL decanoate patients:
  • Men: INVEGA SUSTENNA (34.56 μg/L); HAL decanoate (15.41 μg/L); P<0.001
  • Women: INVEGA SUSTENNA (75.19 μg/L); HAL decanoate (26.84 μg/L); P<0.001

Limitations

• Narrow study endpoint: efficacy failure vs relapse
• Modest dosing of HAL decanoate may have contributed to better comparative tolerability.
• Reduced sample size and early termination of the study's follow-up period may have decreased the statistical power leading to less reliable estimates with regard to weight change at later time points.
• Subjective measures of medication satisfaction and global well-being not evaluated.
• Current cost differences for payers not applied.

A post hoc analysis of the McEvoy et al (2014) study assessed the heterogeneity of treatment effects in different subgroup responses.⁵

Rater-Blinded

Kim et al (2016)² evaluated the effects of INVEGA SUSTENNA (n=135) vs 3 oral antipsychotics (oAP) subgroups on treatment failure during an exploratory subgroup analysis of a 15-month, prospective, randomized, open-label, event EMB-blinded, multicenter US study designed to reflect real-world schizophrenia patients, treatments, and outcomes⁶.

Study Design/Methods

• The clinician and patient reviewed the list of available oAPs (aripiprazole, HAL, olanzapine, paliperidone, perphenazine, quetiapine, and risperidone) before randomization and could deselect up to 6 from the list based on prior experience. Limiting the selection to suitable oAPs prior to randomization introduced a bias against INVEGA SUSTENNA in terms of Safety.
• Patients were stratified on the basis of their selection of oAP treatments and randomly assigned to flexibly dosed INVEGA SUSTENNA (78-234 mg) or flexibly dosed oAP therapy.
• The primary endpoint was the time to first treatment failure, defined as arrest or incarceration; Psychiatric hospitalization; suicide; treatment discontinuation due to inadequate efficacy, safety, or tolerability; treatment supplementation due to inadequate efficacy; or increase in level of psychiatric services to prevent imminent Psychiatric hospitalization.
• An independent EMB, blinded to patient treatment assignment, certified the occurrence and time of first treatment failure for each patient.
• Efficacy and safety analyses included the intent-to-treat (ITT) population, defined as all randomly assigned patients who received ≥1 dose of study medication.

Results for Conventional oAP Subgroup

Treatment Failure

• Compared to INVEGA SUSTENNA (n=136), conventional oAPs (n=35; HAL and perphenazine) had a 34% higher risk of treatment failure (HR: 1.34, 95% CI: 0.80-2.25; P=0.262).

Safety

• The most frequently reported TEAEs (≥10% of patients in either group) for INVEGA SUSTENNA vs conventional oAPs, respectively were: injection site pain (16.9%; 0%); insomnia (18.4%; 5.7%), akathisia (12.5%; 17.1%), anxiety (10.3%; 8.6%), nasopharyngitis (6.6%; 11.4%), schizophrenia (5.9%; 11.4%), somnolence (4.4%; 11.4%), and dizziness (0.7%; 11.4%).
• EPS-related TEAEs occurred in 25% of INVEGA SUSTENNA patients and 45.7% of conventional oAP patients.
• Prolactin-related TEAEs occurred in 25% and 5.7% of INVEGA SUSTENNA and conventional oAP patients, respectively.
• A 7% increase in weight was observed in 32.8% of INVEGA SUSTENNA patients and 11.4% of conventional oAP patients.

Literature Review

Gopal et al (2011)³ evaluated the efficacy and safety of long-acting injectable antipsychotics through the evaluation of seven randomized controlled studies and a placebo-controlled study for the acute and maintenance treatment of schizophrenia.

Study Design/Methods

• Literature search of MEDLINE and an internal company database to identify published abstracts, posters, and manuscripts that reported placebo-controlled clinical trials.
• Primary objective was to compare benefits and risks between conventional long-acting injectable antipsychotics and INVEGA SUSTENNA through determination of NNT, NNH, and LHH.
• Seven randomized controlled survival studies^7-13 that included time to relapse or relapse rate as clinical endpoints and one placebo-controlled study¹⁴ that assessed response as a reduction of ≥30% in Positive and Negative Syndrome Scale (PANSS) score were included.
  • These studies evaluated INVEGA SUSTENNA,^10,14 HAL decanoate,⁸ bromperidol decanoate,¹³ and fluphenazine decanoate.^7,9,11,12
• Each of the studies included a double-blind phase, with durations of 13 weeks to 48 months; the duration of the relapse-prevention study for INVEGA SUSTENNA ¹⁰ was variable.
• Safety endpoints considered in the NNH analysis included the incidence of reported akathisia, tremor, TD, weight gain, the proportion of patients who used anticholinergic medications, and the emergence of positive Abnormal Involuntary Movement Scale (AIMS) scores.
  • Studies that did not include a selected safety endpoint in the primary publication were not included in the NNH analysis for that harm measure.
• The LHH was calculated as a ratio of NNH to NNT for each long-acting injectable.
• The two drugs included in the LHH analysis were INVEGA SUSTENNA and fluphenazine decanoate because these were the only two drugs for which data needed for the LHH calculation were available.
• In comparison with placebo, the long-acting injectable was more beneficial when the LHH value was larger.

Results

• In all but one study, the analysis for NNT to prevent one relapse showed a statistically significant difference from placebo for INVEGA SUSTENNA, HAL decanoate, and fluphenazine decanoate.
• The NNTs showing significance ranged from 2 to 3; however, one of the fluphenazine decanoate studies⁷ was associated with an NNT of 5 when compared with placebo; this did not demonstrate statistical significance.
• The study that evaluated bromperidol decanoate did not mention the incidence of relapse in the primary manuscript and, therefore, was not included in the NNT analysis.
• The NNT for clinical response (PANSS reduction of ≥30%) significantly favored INVEGA SUSTENNA over placebo (NNT=6; 95% CI: 4-10) at 13 weeks.
• For measures of harm, the NNH favored INVEGA SUSTENNA over fluphenazine decanoate for tardive dyskinesia (infinity vs 7; infinity indicates that the denominator included an incidence of 0%), use of anticholinergic medications (30 vs 5), and emergence of a positive AIMS score (-32.2 vs 13; a negative number indicates that placebo was more likely to cause harm).
• The LHH values that could be determined and interpreted ranged from 3 for fluphenazine decanoate¹¹ (NNT, prevention of relapse; NNH, tardive dyskinesia) to 89 for INVEGA SUSTENNA¹⁴ (NNT, clinical response; NNH, emergent extrapyramidal symptoms).
• INVEGA SUSTENNA was favored over fluphenazine decanoate on all calculations of LHH when relapse prevention was evaluated as the benefit (NNT); although the measured benefit was similar between these two antipsychotics (NNT, 2 to 3), the measures of harm (use of anticholinergic medications, tardive dyskinesia, and emergent AIMS positive score) favored INVEGA SUSTENNA.

Literature Review

Sheehan et al (2012)⁴ compared steady-state, peak-to-trough changes between long-acting injectable antipsychotics and their oral equivalents through an analysis of references identified in a literature search, as well as other relevant references and unpublished data.

Study Design/Methods

• Literature search of PubMed and identification of additional published and unpublished information on peak-to-trough fluctuation for HAL decanoate, olanzapine pamoate, PP1M, risperidone long-acting injection, and zuclopenthixol decanoate.
  • Data on the oral equivalent of each agent, except zuclopenthixol decanoate, were available.
• The peak-to-trough fluctuation was calculated with the ratio of steady-state mean maximum plasma concentration (C_max) to steady-state mean minimum plasma concentration (C_min) after administration based on the recommended dosing interval for each product.

Results

• The steady-state ratios for long-acting injectable antipsychotics ranged from 1.56 for PP1M given once every 4 weeks to 4 for olanzapine pamoate given once every 4 weeks.
• The steady-state ratios and selected pharmacokinetic parameters are presented in the Table: Steady-State Peak-to-Trough Fluctuation in Plasma Concentration and Selected Pharmacokinetic Parameters.

• When dosing intervals are similar, a longer t_1/2 and/or longer T_max may generate smaller peak-to-trough fluctuation.
• For PP1M, gluteal administration and/or doses higher than 117 mg may lead to less steady-state peak-to-trough fluctuation.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 April 2024.