Clinical trial NCT01435928: PEARL Schizophrenia Maintenance
Official title: A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study Of Lurasidone For The Maintenance Treatment Of Subjects With Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Schizophrenia
Keywords: Schizophrenia
Lurasidone
Latuda
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2011-09-19
Enrollment: 676
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Lurasidone HCI is a compound that is FDA-approved for the treatment of schizophrenia. This clinical study is designed to test the hypothesis that Lurasidone is effective in the long term maintenance treatment of schizophrenia.


Eligibility criteria: Inclusion Criteria:

Open Label:

Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the Investigator.

Subject is ≥ 18 and ≤ 75 years of age, on the day of signing the informed consent.

Subject meets DSM-IV-TR criteria for a primary diagnosis of schizophrenia \[including disorganized (295.10), paranoid (295.30), undifferentiated (295.90) subtypes as established by clinical interview (using the DSM-IV-TR as a reference and confirmed using the SCID-CT)\]. The duration of the subject's illness whether treated or untreated must be ≥ 1 year.

Subject has had at least one prior episode of psychotic exacerbation as judged by the Investigator in the two years preceding screening.

Subject has a PANSS Total score ≥ 80 with a score ≥ 4 on 1 or more of any PANSS Positive subscale items at screening and open-label baseline (Visit 2).

Subject has a CGI-S score of ≥ 4 at screening and open-label baseline (Visit 2).

Subject is not pregnant (must have a negative serum pregnancy test at screening) or nursing (must not be lactating) and is not planning pregnancy within the projected duration of the study.

Female subject of reproductive potential agrees to remain abstinent or use adequate and reliable contraception throughout the study and for at least 30 days after the last dose of lurasidone has been taken. In the Investigator's judgment, the subject will adhere to this requirement.

Adequate contraception is defined as continuous use of either two barrier methods (e.g., condom and spermicide or diaphragm with spermicide) or a hormonal contraceptive. Acceptable hormonal contraceptives include the following: a) contraceptive implant (such as Norplant®) implanted at least 90 days prior to screening; b) injectable contraception (such as medroxyprogesterone acetate injection) given at least 14 days prior to screening; or c) oral contraception taken as directed for at least 30 days prior to screening.

Subjects who are of non-reproductive potential, i.e., subject who is surgically sterile, has undergone tubal ligation, or is postmenopausal (defined as at least 12 months of spontaneous amenorrhea or between 6 and 12 months of spontaneous amenorrhea with follicle stimulating hormone (FSH) concentrations within postmenopausal range as determined by laboratory analysis) are not required to remain abstinent or use adequate contraception.

Subject is able and agrees to remain off prior antipsychotic medication for the duration of the study.

Subject has had a stable living arrangement at the time of screening and agrees to return to a similar living arrangement after discharge, if hospitalized. This criterion is not meant to exclude subjects who have temporarily left a stable living arrangement (e.g., due to psychosis). Such subjects remain eligible to participate in this protocol. Chronically homeless subjects should not be enrolled.

Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.

Subject who requires concomitant medication treatment with the following agents may be included if they have been on stable doses (i.e., minor adjustments only) for the specified times: 1) antidepressant agents (except fluvoxamine) and/or mood stabilizers (except carbamazepine or oxcarbazepine) must be stable for at least 30 days prior to open-label baseline, 2) oral hypoglycemics must be stable for at least 30 days prior to screening, 3) antihypertensive agents must be stable for at least 30 days prior to screening, and 4) thyroid hormone replacement must be stable for at least 90 days prior to screening. (Note: CYP3A4 inducers and inhibitors will not be allowed).

Subject is willing and able to comply with the protocol assessments and visits, in the opinion of the study nurse/coordinator and the Investigator.

Double-blind -

Subject must achieve and maintain clinical stability for a total of at least 12 weeks in the open label phase, defined as:

1. a PANSS Total score ≤ 70, a CGI-S score \< 4 and a PANSS item score of ≤ 4 (moderate or less) on all PANSS Positive subscale items over at least 12 weeks with the allowance of two excursions (except during the last 4 weeks of the open-label phase) assessed at weekly study visits:

   • An excursion is defined as a PANSS total score up to a maximum of 80 and/or a CGI-S score up to a maximum of 4 and/or a PANSS Positive subscale item score up to a maximum of 5.
2. a PANSS item score of ≤ 4 (moderate or less) on item G8 (uncooperativeness)
3. taking a stable dose of lurasidone for the last 4 weeks of the open-label phase.

Exclusion Criteria:

Open Label - Subject has a DSM-IV Axis I or Axis II diagnosis other than schizophrenia that has been the primary focus of treatment within 3 months of screening.

Subject answers "yes" to "Suicidal Ideation" item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS assessment at screening (in the past month) or baseline.

Subject has attempted suicide within 3 months prior to the screening phase. Subject currently has a clinically significant medical condition including the following: neurological, metabolic (including Type 1 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder such as unstable angina, congestive heart failure (uncontrolled), or central nervous system (CNS) infection that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study. Subjects with human immunodeficiency virus (HIV) seropositivity (or history of seropositivity) will be excluded.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Monitor should be consulted. Any subject with a known cardiovascular disease or condition (even if controlled) must be discussed with the Medical Monitor before being screened.

Subject has evidence of any chronic organic disease of the CNS such as tumors, inflammation, and active seizure disorder, vascular disorder, Parkinson's disease, Alzheimer's disease or other forms of dementia, myasthenia gravis, or other degenerative processes. In addition, subject must not have a history of mental retardation or persistent neurological symptoms attributable to serious head injury. Note: Past history of febrile seizures, drug-induced seizures, or alcohol withdrawal seizures is not exclusionary.

Note: Past history of febrile seizures, drug-induced seizures, or alcohol withdrawal seizures is not exclusionary.

Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation.

Note: Subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 3 times the upper limit of the reference ranges provided by the central laboratory require retesting. If on retesting, the laboratory value remains ≥ 3 times the upper limit, such subjects will be discussed with the Medical Monitor for enrollment consideration.

Subject has a history of stomach or intestinal surgery or any other condition that could interfere with or is judged by the Investigator to interfere with absorption, distribution, metabolism, or excretion of study drug.

Subject with Type 1 or Type 2 insulin-dependent diabetes.

Subject with newly diagnosed Type 2 diabetes during screening. Subject with Type 2 diabetes is eligible for study inclusion if the following condition is met at screening:

if a subject is currently being treated with oral anti-diabetic medication(s), the dose must have been stable for at least 4 weeks prior to screening. Such medication may be adjusted or discontinued during the study, as clinically indicated.

Subject has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the Investigator. Subjects with a fasting blood glucose at screening ≥ 126 mg/dL (7.0 mmol/L) or HbA1c ≥ 7.0% will be excluded.

Note: Subjects with random (non-fasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) must be retested in a fasted state.

Subject has a prolactin concentration \> 100 ng/mL at screening or has a history of pituitary adenoma.

Subject has a history of malignancy \< 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary tumors of any duration are excluded.

Subject is judged to be resistant to antipsychotic treatment defined as any one of the following:

1. failure to respond to \> 2 marketed antipsychotic agents, given at an adequate dose and for an adequate duration (within the past 2 years)
2. history of treatment with clozapine for refractory psychosis Subject is unlikely to achieve a stable condition for ≥ 12 weeks during the open-label lurasidone phase based on the totality of evidence from the psychiatric history and/or the current presentation.

Subject is receiving an antipsychotic medication above the maximum recommended (country-specific) dose at or prior to screening and, in the judgment of the Investigator, is unlikely to respond to standard doses of lurasidone.

Subject has received depot antipsychotics unless the last injection was at least one treatment cycle or at least 30 days (whichever is longer) prior to the screening phase.

Subject has received treatment with MAO inhibitors within 14 days prior to the screening phase.

Subject requires treatment with any potent CYP3A4 inhibitors or inducers during the study (see Appendix 3).

Subject has received electroconvulsive therapy treatment within the 3 months prior to screening or is expected to require electroconvulsive therapy (ECT) during the study.

Subject has a history of neuroleptic malignant syndrome. Subject exhibits evidence of severe tardive dyskinesia, severe dystonia, or any other severe movement disorder. Severity will be determined by the Investigator.

Subject has a history of alcohol or substance abuse (DSM-IV-TR criteria) within 3 months prior to screening or alcohol or substance dependence (DSM-IV-TR criteria) within 12 months prior to screening. The only exceptions include caffeine or nicotine abuse/dependence.

Subject tests positive for drugs of abuse at screening. In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), the Investigator will evaluate the subject's ability to abstain from using this drug during the study. This information will be discussed with the Medical Monitor prior to study enrollment.

Subject had a history or presence of an abnormal electrocardiogram (ECG), which in the Investigator's opinion is clinically significant (Medical Monitor may be consulted to determine clinical significance).

Subject has poor peripheral venous access that will limit the ability to draw blood as judged by the Investigator.

Subject has a history of hypersensitivity to more than 2 distinct chemical classes of drug (e.g., sulfas and penicillins).

Subject was screened or washed out previously more than three times for this study.

Subject is currently participating, or has participated in, a study with an investigational or marketed compound or device within 3 months prior to signing the informed consent, or has participated in 2 or more studies within 12 months prior to signing the informed consent.

Subject is homeless or did not have a stable residence for the 3 months prior to the screening phase.

Subject is unable to cooperate with any study procedures, unlikely to adhere to the study procedures and keep appointments, in the opinion of the Investigator, or was planning to relocate during the study.

Subject requires guardianship under the laws of his/her country.

Double-blind - Subjects who in the Investigator's judgment have not been compliant with study medication during the open-label stabilization phase.

Primary outcomes:
measure: Time to First Relapse Event During Double-blind Phase
timeFrame: Double-blind phase - 28 Weeks
Secondary outcomes:
measure: Time to All-cause Discontinuation
timeFrame: Double-blind phase - 28 weeks
measure: Change From Double-blind Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score
timeFrame: Double-Blind phase - 28 Weeks
measure: Change From Double-blind Baseline in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score
timeFrame: Double-blind phase - 28 Weeks
measure: Change From Double-blind Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
timeFrame: Double-blind phase - 28 Weeks
measure: Change From Double-blind Baseline in Short Form-12v2 Health Survey (SF-12v2) Physical Component Score
timeFrame: Double-blind phase - 28 Weeks
measure: Change From Double-blind Baseline in Modified Specific Levels of Functioning (SLOF) Total Score
timeFrame: Double-blind phase - 28 Weeks
measure: Brief Adherence Rating Scale
timeFrame: Double-blind phase - 28 Weeks
measure: Smoking Questionnaire (Average Number of Cigarettes Per Day) at Week 28 (LOCF)
timeFrame: 28 Weeks - Double Blind Phase
measure: Intent to Attend (ITA) Assessment at Open-label Baseline
timeFrame: Open Label Baseline
Other outcomes:
measure: EuroQol (EQ-5D): EQ-VAS Score
timeFrame: Double-blind phase - 28 Weeks
Locations:
city: Springdale
country: United States
facility: Woodland Research Northwest
state: Arizona
city: Little Rock
country: United States
facility: K&S Professional Research
state: Arkansas
city: Little Rock
country: United States
facility: Woodland International Research Group
state: Arkansas
city: Cerritos
country: United States
facility: Comprehensive Clinical Development Inc.
state: California
city: Downey
country: United States
facility: Diligent Clinical Trials
state: California
city: Escondido
country: United States
facility: Synergy Escondido
state: California
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Network, Inc.
state: California
city: Los Angeles
country: United States
facility: Axis Clinical Trials
state: California
city: National City
country: United States
facility: Synergy Clinical Research Center
state: California
city: Oceanside
country: United States
facility: Excell Clinical Trials
state: California
city: Pico Rivera
country: United States
facility: CNRI - Los Angeles LLC,8309 Telegraph Road
state: California
city: San Diego
country: United States
facility: California Neuropsychopharmacology Clinical Research Instit
state: California
city: Santa Ana
country: United States
facility: Neuropsychiatric Research Center of Orange County
state: California
city: Torrance
country: United States
facility: Collaborative Neuroscience Network Inc.
state: California
city: Bradenton
country: United States
facility: Florida Clinical Research Center, LLC
state: Florida
city: Kissimme
country: United States
facility: Accurate Clinical Trials
state: Florida
city: Maitland
country: United States
facility: Florida Clinical Research Center, LLC
state: Florida
city: Miami Springs
country: United States
facility: Galiz Research
state: Florida
city: Orange City
country: United States
facility: Medical Research Group of Central Florida
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Atlanta
country: United States
facility: Comprehensive NeuroScience, Inc.
state: Georgia
city: Lake Charles
country: United States
facility: Lake Charles Clinical Trials
state: Louisiana
city: Shreveport
country: United States
facility: Lousiana Clinical Research, LLC
state: Louisiana
city: Rockville
country: United States
facility: CBH Health LLC
state: Maryland
city: O'Fallon
country: United States
facility: Psychiatric Care and Research Center
state: Missouri
city: St. Louis
country: United States
facility: Psych Care Consultants Research
state: Missouri
city: Las Vegas
country: United States
facility: Horne Research
state: Nevada
city: Las Vegas
country: United States
facility: Center for Psychiatry and Behavioral Medicine, Inc.
state: Nevada
city: Willingboro
country: United States
facility: CRI Worldwide LLC
state: New Jersey
city: Buffalo
country: United States
facility: University of New York, Dept. of Psychiatry
state: New York
city: Cedarhurst
country: United States
facility: Neurobehavioral Research, Inc.
state: New York
city: Fresh Meadows
country: United States
facility: Comprehensive Clinical Development, Inc
state: New York
city: Rochester
country: United States
facility: Finger Lakes Clinical Research
state: New York
city: Staten Island
country: United States
facility: Behavioral Medical Research of Staten Island
state: New York
city: Oklahoma City
country: United States
facility: Cutting Edge Research Group
state: Oklahoma
city: Oklahoma City
country: United States
facility: Oklahoma Clinical Research
state: Oklahoma
city: Philadelphia
country: United States
facility: CRI Worldwide LLC at Kirkbride
state: Pennsylvania
city: Lincoln
country: United States
facility: Lincoln Research
state: Rhode Island
city: Austin
country: United States
facility: Community Clinical Research, Inc.
state: Texas
city: Austin
country: United States
facility: FutureSearch Clinical Trials LP
state: Texas
city: Dallas
country: United States
facility: FutureSearch Clinical Trials, LP
state: Texas
city: Dallas
country: United States
facility: Pillar Clinical Research LLC
state: Texas
city: The Woodlands
country: United States
facility: Family Psychiatry of the Woodlands
state: Texas
city: Salt Lake City
country: United States
facility: Department of Psychiatry, University of Utah Health Sciences Center
state: Utah
city: Spokane
country: United States
facility: Frontier Institute
state: Washington
city: Clermont-Ferrand Cedex 1
country: France
facility: CHU Clermont-Ferrand - CMP B
city: Dole
country: France
facility: Centre Hospitalier Specialise du Jura - Centre Medico Psychiatric
city: Rennes Cedex
country: France
facility: Centre Hospitalier Guillaume Regnier
city: Toulon
country: France
facility: Hopital Chalucet, Centre hospitalier intercommunal de toulon la Seyne sur mer (CHITS)
city: Toulouse
country: France
facility: Cabinet Medical
city: La Spezia
country: Italy
facility: SC SPDC-Edificio n. 7, Ospedale S. Andrea
city: Massa
country: Italy
facility: Dipartimento Salute Mentale ASL 1
city: Pisa
country: Italy
facility: A.O.U. Santa Chiara, U.O di Psichiatria 1 building n.4
city: Lipetsk
country: Russian Federation
facility: Regional Government Institution Kipetsk Regional Psychoneurology Hospital
city: Rostov-on-Don
country: Russian Federation
facility: Limited Liability Company (LLC) Research Center for Treatment and rehabilitation "Phoenix"
city: St-Petersburg
country: Russian Federation
facility: City Psychoneurological Dispensary #7 (with Hospital)
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Budgetary Healthcare Institution City Psychoneurology Dispensary #7 (with in-patient dept.) (SPb SBHI CPNDD-7), at daycare facility #1
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Healthcare Institution (SPbSH) "City Psychiatric Hospital #6"
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Government Healthcare Institution City Psychiatric Hospital #4 (St. Petersburg Insane Asylum Distributor)
city: Belgrade
country: Serbia
facility: Institute of Mental Health
city: Belgrade
country: Serbia
facility: Military Medical Academy, Clinic for Psychiatry
city: Kragujevac
country: Serbia
facility: Clinical Centre Kragujevac, Clinic for Psychiatry
city: Nis
country: Serbia
facility: Clinical Centre Nis, Clinic for mental health protection
city: Novi Knezevac
country: Serbia
facility: Specialized Hospital for psychiatric diseases "Sveti Vracevi"
city: Novi Sad
country: Serbia
facility: Clinical Centre Vojvodina, Clinic for Psychiatry
city: Bojnice
country: Slovakia
facility: Nemonnica s poliklinikou v Prievidzi so sidlom v Bojniciach, Psychiatricke oddelenie
city: Bratislava
country: Slovakia
facility: Psychiatricka ambulancia Mentum, s.r.o.
city: Michalovce
country: Slovakia
facility: Psychiatricka nemocnica Michalovce
city: Rimavska Sobota
country: Slovakia
facility: PsychoLine s.r.o. Psychiatricka ambulancia
city: Rimavska Sobota
country: Slovakia
facility: Psychiaticke oddelenie Vseobecna nemocnica Riimavska Sobota, NaP n.o.
city: Roznava
country: Slovakia
facility: Psychiatricke oddelenie, Nemocnica s poliklinikou sv. Barbory Roznava, a.s.
city: Svidnik
country: Slovakia
facility: Centrum zdravia R. B.K. s.r.o. Psychiatricka ambulancia
city: Bloemfontein
country: South Africa
facility: Research Unit, Department of Psychiatry Free State Psychiatric Complex
city: Cape Town, W. Cape
country: South Africa
facility: Cape Trial Centre
city: Pretoria
country: South Africa
facility: Denmar Hospital Consulting Rooms
Study officials:
affiliation: Sumitomo Pharma America, Inc.
name: Medical Director, MD
role: STUDY_DIRECTOR
References: