Trial record 1 of 1 for:    NCT01874756
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The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) for Negative Symptoms and Cognitive Impairment Associated With Schizophrenia

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Indiana University
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Nikki Mehdiyoun, Indiana University
ClinicalTrials.gov Identifier:
NCT01874756
First received: May 20, 2013
Last updated: September 24, 2014
Last verified: September 2014
  Purpose

The primary objectives of this application are to determine if the selective ERβ agonist LY500307, when added to antipsychotic medications, improves negative and/or cognitive symptoms in patients with schizophrenia. The specific hypotheses to be tested are to determine if LY500307 is safe and well tolerated in this population and whether it elicits a sufficient efficacy signal to be advanced for further testing in schizophrenia. A two-stage Phase 1b/Phase 2a adaptive ("drop the inferior dose") experimental design is ongoing that combines three studies (clinical dose optimization, cortical target engagement confirmation and efficacy and safety assessment) into a single clinical trial.

Stage 1 was conducted in year 1 and Stage 2 will be conducted in years 2 and 3. The goal of Stage 1 was to identify and advance the highest dose that did not demonstrate a safety signal and had target selectivity as determined by lack of TT suppression. This criteria was fulfilled at both doses, the larger of the two (75 mg/day dose) was advanced to Stage 2. Furthermore, there was no suggestion of ERα receptor activation (i.e., no pattern of TT decreases or feminization AEs) at either dose (25 mg/day and 75 mg/day). A third arm of 150 mg/day was added to Stage 2 for evaluation. Stage 2 results in the following three arms: placebo, 75 mg/day and 150 mg/day. The goals of Stage 2 are to further assess LY500307 doses for safety and target selectivity, confirm cortical target engagement and assess efficacy.

Primary Aim 1: To determine if LY500307 demonstrates cortical target engagement as assessed by fMRI/N-back in frontal-parietal regions. Secondary measures of target engagement are fMRI episodic memory, Pseudo-Continuous Arterial Spin Labeling, Mismatch Negativity/evoked response potentials, Auditory Steady State Response, Auditory P300 and Quantitative EEG (QEEG).

Primary Aim 2: To determine if LY500307 is superior to placebo for one or more of the primary efficacy endpoints: negative symptoms (Negative Symptom Assessment Scale - 16-item total score), working memory (the composite score for the Letter Number Sequencing and Spatial Span tests) and verbal memory (Hopkins Verbal Learning Test).

Primary Aim 3: To determine if LY500307 reduces total testosterone (TT) plasma concentrations, which is indicative of loss of selectivity for ERβ and engagement of ERα, using the following criteria: Decrease in TT plasma concentrations of 50% from baseline in 50% of subjects per arm treated for two consecutive post-randomization values with LY500307 in Stage 1 and Stage 2 of the trial.

Primary Aim 4: To assess the safety of LY500307 by determining if there are SAEs, AEs "probably related to study drug," QTc prolongation, TT suppression (50% reduction from baseline) and to evaluate for other safety signals.

Secondary aims are to assess LY500307 effects on regional brain activation and connectivity during working (2-Back visual-verbal working memory task) and episodic (scene encoding and recognition)and memory tasks, and to evaluate electrophysiological indices of auditory sensory processing and working memory (auditory steady state responses, mismatch negativity (MMN) and auditory P300). It is predicted that LY500307 will produce greater increases than placebo in brain activity in prefrontal cortex and hippocampus during the working memory and episodic memory tasks, respectively, connectivity during resting fMRI, as well as increases in power of the auditory steady state response, MMN amplitude and P300 amplitude. The fMRI and electrophysiological measures will provide evidence of target engagement of LY500307 in schizophrenia and will be assessed as potential biomarkers for future clinical trials. Additional secondary aims will include assessing the effects of LY500307 on safety, positive symptoms, depression, social functioning and quality of life.


Condition Intervention Phase
Schizophrenia
Drug: LY500307 150mg
Drug: LY500307 75mg
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) for Negative Symptoms and Cognitive Impairment Associated With Schizophrenia

Resource links provided by NLM:


Further study details as provided by Indiana University:

Primary Outcome Measures:
  • Negative symptoms [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    To determine if one dose of LY500307 is superior to placebo for negative symptoms (Negative Symptom Assessment Scale - 16-item total score)

  • Working memory [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    LY500307, when added to antipsychotic medications, improves cognitive symptoms in patients with schizophrenia (as measured by working memory (the composite score for the Letter Number Sequencing and Spatial Span tests)

  • Verbal memory [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    To determine if one dose of LY500307 is superior to placebo for verbal memory (Hopkins Verbal Learning Test)

  • total testosterone suppression [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    To determine if either LY500307 dose reduces total testosterone plasma concentrations, which is indicative of loss of selectivity for ERβ and engagement of ERα, using the following criteria: Decrease in total testosterone plasma concentrations of 50% from baseline.


Secondary Outcome Measures:
  • Working memory [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assess LY500307 effects on regional brain activation and connectivity during working (2-Back visual-verbal working memory task)

  • Episodic Memory [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assess LY500307 effects on regional brain activation and connectivity during episodic (scene encoding and recognition) memory tasks

  • auditory sensory processing [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assess LY500307 effects on regional brain activation and connectivity and to evaluate electrophysiological indices of auditory sensory processing

  • Working memory [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assess LY500307 effects on regional brain activation and connectivity and working memory (auditory steady state responses, mismatch negativity (MMN) and auditory P300).

  • Positive symptoms [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assessing the effects of LY500307 on positive symptoms of schizophrenia (including but not limited to delusions, hallucinations, bizarre behavior) on PANSS Marder positive symptom subscale score)

  • Depression [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assessing the effects of LY500307 on depression

  • Social functioning [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assessing the effects of LY500307 on social functioning as measured by a change in PSP score from baseline

  • Quality of life [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assessing the effects of LY500307 on quality of life.


Estimated Enrollment: 100
Study Start Date: June 2013
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LY500307 150mg
LY500307 150mg
Drug: LY500307 150mg
LY500307 150mg daily dose (6 capsules of 25mg) for 8 weeks
Placebo Comparator: placebo
placebo 6 pills of inactive drug
Drug: Placebo
6 placebo capsules daily for 8 weeks
Experimental: LY500307 75mg
LY500307 75mg
Drug: LY500307 75mg
LY500307 75mg daily dose (3 capsules of 25mg and 3 capsules of placebo) for 8 weeks

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 to 60 years of age at study entry
  • Male
  • DSM IV-TR diagnosis of schizophrenia as confirmed by Structured Clinical Interview for DSM-IV-TR (SCID)
  • Outpatient or inpatient status
  • Mild to moderate overall disease severity as defined by a CGI-S score of less than or equal to 4 (moderately ill) at randomization
  • Moderate levels of negative symptoms as defined by a PANSS negative symptom sub-score greater than or equal to 11.
  • Clinical stability as defined by:

    1. No exacerbation of illness leading to an intensification of treatment in the opinion of the investigator within four weeks prior to randomization, and
    2. No change in antipsychotic medication for at least four weeks prior to randomization

Exclusion Criteria:

  • Subjects with current acute, serious, or unstable medical conditions, including, but not limited to: inadequately controlled diabetes, asthma, COPD, severe hypertriglyceridemia, recent cerebrovascular accidents, acute systemic infection or immunologic disease, unstable cardiovascular disorders, malnutrition, or hepatic, renal gastroenterologic, respiratory, endocrinologic, neurologic, hematologic, or infectious diseases
  • Known or suspected history of prostate cancer, breast cancer, or other clinically significant neoplastic disease (other than squamous cell or basal cell carcinoma of skin)
  • Known or suspected history of deep venous thrombosis, stroke, venous thromboembolism, pulmonary embolism, paresis or paralysis that may be thrombogenic in origin
  • Subjects currently receiving testosterone replacement therapy or drugs that influence the hypothalamus-pituitary-gonadal axis.
  • A morning (between 6am-12pm) total testosterone (TT) concentration of <300 ng/dL. Repeat evaluation may be conducted at the discretion of the Principal Investigator.
  • Subjects who have clinically significant extrapyramidal signs (EPS) as defined by a score of >20 on the Simpson-Angus Scale (SAS)
  • Subjects with high anticholinergic medication burden, as defined by a score of >5 on the Anticholinergic Cognitive Burden Scale (ABS). Allow the following: one score of 3, one score of 3 AND one score of 2, two scores of 2's, and one score of 2. Do not count ABS 1 Category. (50)
  • Clinically significant electrocardiogram (ECG) abnormality, including, but not limited to, a corrected QT interval (Bazett's; QTcB) >450 msec. Repeat ECGs may be conducted at the discretion of the principal investigator.
  • Subjects with known medical history of Human Immunodeficiency Virus positive (HIV+) status
  • Subjects with an active seizure disorder
  • Subjects with implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS unit, ventriculoperitoneal shunt, or other contraindication to undergoing an MRI scan
  • Known IQ less than 70 based on medical history
  • Current DSM IV-TR diagnosis of substance dependence (excluding caffeine and nicotine)
  • Subjects who test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody
  • Subjects with moderate to severe renal impairment as defined by creatinine clearance (CrCl) < 60 ml/min (measured by the Cockcroft-Gault equation) at screening. Repeat evaluation may be conducted at the discretion of the Principal Investigator.
  • Subjects with hepatic impairment as defined by liver transaminases or total bilirubin > 3 × upper limit of normal (ULN). Repeat evaluation may be conducted at the discretion of the Principal Investigator.
  • Subjects considered a high risk for suicidal acts - active suicidal ideation as determined by clinical interview OR any suicide attempt in 30 days prior to screening
  • Subjects who have participated in a clinical trial with any pharmacological treatment intervention for which they received study-related medication in the four weeks prior to randomization OR subjects currently receiving treatment (within 1 dosing interval plus four weeks) with an investigational depot formulation of an antipsychotic medication
  • Subjects who demonstrate overtly aggressive behavior or who are deemed to pose a substantial risk of danger in the Investigator's opinion
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01874756

Locations
United States, Indiana
Indiana University Center for NeuroImaging Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Andrew Saykin, PsyD    317-963-7229    E-mailmarihelm@iupui.edu   
Sub-Investigator: Andrew Saykin, PsyD         
Sub-Investigator: Brenna McDonald, PsyD         
Sub-Investigator: Thomas Hummer, PhD         
Sub-Investigator: John West, MS         
Sub-Investigator: Yang Wang, MD         
Sub-Investigator: Leah Moravec, BS         
Larue D Carter Memorial Hospital Recruiting
Indianapolis, Indiana, United States, 46222
Contact: Nikki Mehdiyoun, MA    317-941-4287    iupdp@iupui.edu   
Contact: Amanda Roebel, MS    3179414287    iupdp@iupui.edu   
Principal Investigator: Alan Breier, MD         
Sub-Investigator: Emily Liffick, MD         
Sub-Investigator: Alexander Radnovich, MD, PhD         
Sub-Investigator: Michael Francis, MD         
Sub-Investigator: Nicole Mehdiyoun, MA         
Sub-Investigator: Frederick Malloy, MS         
Sub-Investigator: Jenifer Vohs, PhD         
Sub-Investigator: Amanda Roebel, MS         
Sub-Investigator: Richard Kovacs, MD         
Sub-Investigator: Ronald Matsouri, MD         
Sub-Investigator: William Hetrick, PhD         
Sub-Investigator: Brian O'Donnell, PhD         
Sub-Investigator: Amy Visco, BS         
Sub-Investigator: Josselyn Howell, BS         
Sub-Investigator: Steven Lindgren, BA         
Sub-Investigator: Megan Gaunnac, MBA         
Sub-Investigator: Dominique White, MS         
Sub-Investigator: Emily Good, MS         
Sub-Investigator: Matthew Yung, BA         
Sub-Investigator: Lindsay Joy, BA         
Prevention and Recovery Center for Early Psychosis Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Nikki Mehdiyoun, MA    317-630-6046      
Sub-Investigator: Teresa Kulig, MS         
Sub-Investigator: Carol Ott, PharmD         
Sub-Investigator: David Spradley, RN         
Sub-Investigator: Joan Showalter, MA         
Sub-Investigator: Emmalee Metzler, BA         
Sponsors and Collaborators
Indiana University
Eli Lilly and Company
  More Information

Additional Information:
No publications provided

Responsible Party: Nikki Mehdiyoun, Clinical Research Manager, Indiana University
ClinicalTrials.gov Identifier: NCT01874756     History of Changes
Other Study ID Numbers: 1303010802
Study First Received: May 20, 2013
Last Updated: September 24, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Indiana University:
schizophrenia
Estrogen receptor agonist
cognitive impairment
negative symptoms

Additional relevant MeSH terms:
Cognition Disorders
Schizophrenia
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Schizophrenia and Disorders with Psychotic Features
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 30, 2014