Risk of Breakthrough Symptoms With Long-Acting Injectable Medications

NCT ID: NCT05473741

Last Updated: 2023-09-15

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 180 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-01-09
• Study Completion Date: 2025-12-31

Brief Summary

This prospective longitudinal cohort study will follow patients with schizophrenia who are treated with second generation long-acting injectable antipsychotic medications (LAIs) for 48 weeks to determine the risk of psychotic symptom relapse when treatment adherence is established. The study is designed to minimize the other factors that have contributed to breakthrough psychotic symptoms in patients treated with LAIs including poor adherence, substance use, concurrent mood disorders, poor treatment response, failed cross-titration, and insufficient dosing. Eligible subjects will undergo a screening visit to document that inclusion criteria are met and those meeting exclusion criteria are excluded. Participants will be assessed every 12 weeks to determine whether they remain in remission or meet criteria for a relapse. More comprehensive assessment will be completed at the beginning of the study (baseline visit), at the 24-week study midpoint and the 48-week study endpoint. Plasma antipsychotic levels will be measured at these three study time points to investigate associations between plasma levels and remission/relapse status as well as side effects. Plasma prolactin will also be measured to assess the association with sexual side effects. Hemoglobin A1c and measures of total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol will be obtained to assess the effects of SGA LAIs on these measures.

Detailed Description

Rationale and Study Objectives In this study, we aim to determine the likelihood that relapse of psychosis will occur when patients with schizophrenia who have experienced a remission of their psychotic symptoms are adherent to treatment with a second generation antipsychotic (SGA) LAI on which they have been stable at a therapeutic dose for at least three months.

Primary objective:

1. To estimate the rate of psychotic relapse in patients with schizophrenia whose psychotic symptoms have remitted and who are adherent with second generation LAIs for maintenance treatment.

Secondary objectives:

1. To determine whether the risk of psychotic relapse is associated with antipsychotic plasma levels in patients treated with second generation LAIs.

Study design:

This prospective longitudinal cohort study will follow patients with schizophrenia who are treated with the second generation LAIs (paliperidone palmitate, risperidone or aripiprazole) for 48 weeks to determine the risk of psychotic symptom relapse when treatment adherence is established. The study is designed to minimize the other factors that have contributed to breakthrough psychotic symptoms in patients treated with LAIs including poor adherence, concurrent mood disorders, poor treatment response, failed cross-titration, and insufficient dosing.

Laboratory tests:

The following laboratory tests will be carried out at the baseline visit, 24-week visit and 48-week visit:

1. Urine drug screen - to document use of cannabis and other common recreational drugs. This will allow us to determine whether substance use is associated with the risk of relapse in remitted patients with established adherence to LAIs.

2. Plasma antipsychotic levels - to determine whether trough (pre-injection) plasma levels are associated with risk of relapse and medication side effects

3. Plasma prolactin - to determine whether the incidence and severity of sexual dysfunction is associated with antipsychotic plasma levels

The following laboratory tests will be carried out at the baseline visit and 48-week visit:

4. Hemoglobin A1c - to determine the effects of LAIs on blood sugar levels

5. Lipid panel - to determine the effects of LAIs on total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol

The target population is individuals diagnosed with schizophrenia whose psychotic symptoms have remitted and are receiving outpatient care at the Centre for Addiction and Mental Health (CAMH) in Toronto, Ontario, Canada. Patients who have been stabilized on long-acting injectable forms of either paliperidone palmitate, risperidone or aripiprazole with be invited to participate in this study.

Participants will be recruited from CAMH outpatient treatment teams in Toronto, Ontario, Canada, that provide follow-up to individuals diagnosed with schizophrenia including:

1. Downtown Central Flexible Assertive Community Treatment (DC-FACT)

2. Downtown West Flexible Assertive Community Treatment (DW-FACT)

3. Downtown East Flexible Assertive Community Treatment (DE-FACT)

4. Slaight Centre Early Intervention Service (SCEIS)

5. Forensic Outpatient Program for Schizophrenia (FOPS)

6. Psychosis Coordinated Care Service (PCCS)

7. General Psychosis Service (GPS)

All outpatients of the above clinics who are receiving treatment with LAI paliperidone, risperidone, or aripiprazole will be invited to participate in this study if they are considered to meet inclusion criteria and do not meet any of the exclusion criteria listed below. A screening visit will be scheduled for potential participants who express interest in the study. The study and procedures involved with be explained to eligible participants and informed consent will be obtained for study participation by the study research coordinator or research assistant. A baseline visit will then be scheduled.

Study Duration:

The study duration will be 48 weeks rather than 52 weeks as participants treated with LAIs are most commonly administered medication at intervals of two, three, four or twelve weeks. Each of these intervals would fit with major assessments as 24 weeks (study mid-point) and 48 weeks (study end-point).

Study Visit:

At the screening visit, the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) will be administered to determine if the subject meets criteria for schizophrenia and that they do not meet diagnoses that would exclude them from study participation. Screening for other exclusion criteria including medical disorders, concomitant medications, and suicide attempts or hospitalizations in the past 3 months, will be completed at this visit. Subjects who do not meet inclusion criteria or who meet exclusion criteria will be informed and will not participate in further assessments.

Following the Screening visit, all subjects will be assessed at the following time points: Baseline, 12-week, 24-week, 36-week and 48-week visits, with more comprehensive assessments carried out at baseline, 24 weeks and 48 weeks. The following laboratory tests will be carried out at the baseline visit, 24-week visit and 48-week visit: urine drug screen, plasma antipsychotic levels, plasma prolactin. Height will be collected at baseline and weight and waist circumference will be collected at these time points. Hemoglobin A1c and a lipid panel will be obtained at baseline and 48 weeks.

Conditions

Schizophrenia; Schizophrenia Relapse

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

SGA-LAI

Outpatients with schizophrenia treated with second generation long-acting injectable antipsychotics whose psychotic symptoms have remitted.

Second Generation Long-Acting Injectable Antipsychotic Medications

Intervention Type: DRUG

Patients who have been stabilized on long-acting injectable formulations of paliperidone palmitate, risperidone and aripiprazole will be followed for 48 weeks to determine the rate of relapse when adherence is established. Blood samples to measure plasma antipsychotic levels and prolactin levels, and urine samples for drug screen will be collected at baseline and at the 24-week and 48-week time points.

Interventions

Second Generation Long-Acting Injectable Antipsychotic Medications

Patients who have been stabilized on long-acting injectable formulations of paliperidone palmitate, risperidone and aripiprazole will be followed for 48 weeks to determine the rate of relapse when adherence is established. Blood samples to measure plasma antipsychotic levels and prolactin levels, and urine samples for drug screen will be collected at baseline and at the 24-week and 48-week time points.

Intervention Type: DRUG

Other Intervention Names

paliperidone palmitate, risperidone, aripiprazole

Eligibility Criteria

Inclusion Criteria

• DSM-5 Schizophrenia
• Age 18-65 years
• On SGA LAI: paliperidone palmitate (4-week or 12-week formulations), risperidone or aripiprazole
• Receiving LAI injections through clinical services based at CAMH
• History of improvement in psychotic symptoms with antipsychotic medication as evidenced by a rating of mild or less on the Clinical Global Impression - Severity (CGI-S) for Positive symptoms
• Demonstrated adherence to LAIs defined as not having received any injections more that 7 days past its due date in the past 3 months
• On stable dose of LAI for 3 months or longer
• Capable of providing informed consent for participation in this study

Exclusion Criteria

• Current DSM-5 major depressive episode or manic episode
• Receiving any oral antipsychotic medication in the past 3 months
• History of organic brain disease (e.g. cerebrovascular accident, Huntington's Disease, Parkinson's Disease, epilepsy, etc.)
• History of untreated or unstable medical illness (e.g. thyroid disease, cancer)
• History of electroconvulsive therapy (ECT) in the past year
• History of suicide attempt in the past 3 months
• History of psychiatric hospitalization in the past 3 months
• Inability to read and communicate in English

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Inc.

INDUSTRY

Sponsor Role: collaborator

Centre for Addiction and Mental Health

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert B Zipursky, MD

Role: PRINCIPAL_INVESTIGATOR

Centre for Addiction and Mental Health

Locations

Centre for Addiction and Mental Health

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Robert B Zipursky, MD

Role: CONTACT

robert.zipursky@camh.ca

416-535-8501 ext. 33471

Ofer Agid, MD

Role: CONTACT

ofer.agid@camh.ca

416-535-8501 ext. 34862

Facility Contacts

Robert B Zipursky, MD

Role: primary

robert.zipursky@camh.ca

4165358501 ext. 33471

Ofer Agid, MD

Role: backup

ofer.agid@camh.ca

4165358501 ext. 34862

References

Alphs L, Nasrallah HA, Bossie CA, Fu DJ, Gopal S, Hough D, Turkoz I. Factors associated with relapse in schizophrenia despite adherence to long-acting injectable antipsychotic therapy. Int Clin Psychopharmacol. 2016 Jul;31(4):202-9. doi: 10.1097/YIC.0000000000000125.

Reference Type: BACKGROUND

PMID: 26974214 (View on PubMed)

Gaebel W, Schreiner A, Bergmans P, de Arce R, Rouillon F, Cordes J, Eriksson L, Smeraldi E. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology. 2010 Nov;35(12):2367-77. doi: 10.1038/npp.2010.111. Epub 2010 Aug 4.

Reference Type: BACKGROUND

PMID: 20686456 (View on PubMed)

Gaebel W, Riesbeck M, Wolwer W, Klimke A, Eickhoff M, von Wilmsdorff M, Lemke M, Heuser I, Maier W, Huff W, Schmitt A, Sauer H, Riedel M, Klingberg S, Kopcke W, Ohmann C, Moller HJ; German Study Group on First-Episode Schizophrenia. Relapse prevention in first-episode schizophrenia--maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry. 2011 Feb;72(2):205-18. doi: 10.4088/JCP.09m05459yel. Epub 2010 Jun 29.

Reference Type: BACKGROUND

PMID: 20673559 (View on PubMed)

Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A, Rodriguez MJ, Rele R, Orta J, Kharbeng A, Araya S, Gervin M, Alonso J, Mavreas V, Lavrentzou E, Liontos N, Gregor K, Jones PB; SOHO Study Group. The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl. 2003;(416):16-23. doi: 10.1034/j.1600-0447.107.s416.5.x.

Reference Type: BACKGROUND

PMID: 12755850 (View on PubMed)

Ikai S, Remington G, Suzuki T, Takeuchi H, Tsuboi T, Den R, Hirano J, Tsunoda K, Nishimoto M, Watanabe K, Mimura M, Mamo D, Uchida H. A cross-sectional study of plasma risperidone levels with risperidone long-acting injectable: implications for dopamine D2 receptor occupancy during maintenance treatment in schizophrenia. J Clin Psychiatry. 2012 Aug;73(8):1147-52. doi: 10.4088/JCP.12m07638.

Reference Type: BACKGROUND

PMID: 22967779 (View on PubMed)

Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000 Apr;157(4):514-20. doi: 10.1176/appi.ajp.157.4.514.

Reference Type: BACKGROUND

PMID: 10739409 (View on PubMed)

Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry. 1999 Feb;156(2):286-93. doi: 10.1176/ajp.156.2.286.

Reference Type: BACKGROUND

PMID: 9989565 (View on PubMed)

Kirson NY, Weiden PJ, Yermakov S, Huang W, Samuelson T, Offord SJ, Greenberg PE, Wong BJ. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry. 2013 Jun;74(6):568-75. doi: 10.4088/JCP.12r08167. Epub 2013 Apr 19.

Reference Type: BACKGROUND

PMID: 23842008 (View on PubMed)

Kishimoto T, Hagi K, Nitta M, Leucht S, Olfson M, Kane JM, Correll CU. Effectiveness of Long-Acting Injectable vs Oral Antipsychotics in Patients With Schizophrenia: A Meta-analysis of Prospective and Retrospective Cohort Studies. Schizophr Bull. 2018 Apr 6;44(3):603-619. doi: 10.1093/schbul/sbx090.

Reference Type: BACKGROUND

PMID: 29868849 (View on PubMed)

Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry. 2013 Oct;74(10):957-65. doi: 10.4088/JCP.13r08440.

Reference Type: BACKGROUND

PMID: 24229745 (View on PubMed)

Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, Borenstein M, Kane JM, Correll CU. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 2014 Jan;40(1):192-213. doi: 10.1093/schbul/sbs150. Epub 2012 Dec 17.

Reference Type: BACKGROUND

PMID: 23256986 (View on PubMed)

Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012 Jun 2;379(9831):2063-71. doi: 10.1016/S0140-6736(12)60239-6. Epub 2012 May 3.

Reference Type: BACKGROUND

PMID: 22560607 (View on PubMed)

Olivares JM, Sermon J, Hemels M, Schreiner A. Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry. 2013 Oct 23;12(1):32. doi: 10.1186/1744-859X-12-32.

Reference Type: BACKGROUND

PMID: 24148707 (View on PubMed)

Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, Marder S, Nuechterlein KH. Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry. 2015 Aug;72(8):822-9. doi: 10.1001/jamapsychiatry.2015.0270.

Reference Type: BACKGROUND

PMID: 26107752 (View on PubMed)

Other Identifiers

176/2020

Identifier Type: -

Identifier Source: org_study_id