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HDAC Inhibitor Augmentation to Clozapine

This study is not yet open for participant recruitment.
Verified September 2017 by Virginia Commonwealth University
Sponsor:
ClinicalTrials.gov Identifier:
NCT03263533
First Posted: August 28, 2017
Last Update Posted: September 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Virginia Commonwealth University
  Purpose
The main goal of this pilot study is to test the extent to which adjunctive treatment with the histone deacetylase (HDAC) inhibitor vorinostat improves brain plasticity and cognition in a pilot placebo-controlled trial in patients with schizophrenia who are on clozapine.

Condition Intervention Phase
Schizophrenia Drug: Vorinostat Oral Capsule Group 1 Drug: Vorinostat Oral Capsule Group 2 Early Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: HDAC Inhibitor Augmentation to Clozapine

Resource links provided by NLM:


Further study details as provided by Virginia Commonwealth University:

Primary Outcome Measures:
  • Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 10 weeks ]
    Safety of vorinostat measured by number of adverse events

  • Change in clinical cognitive symptoms during adjunctive vorinostat therapy in schizophrenia patients treated with clozapine [ Time Frame: Baseline, Visit 4 (end of first intervention group/week 4), Visit 7 (end of study/10 weeks) ]
    Participants will be given a cognitive test to assess executive function and speed.


Estimated Enrollment: 6
Anticipated Study Start Date: January 1, 2018
Estimated Study Completion Date: July 31, 2019
Estimated Primary Completion Date: December 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vorinostat Group 1 (P-V-P-P)

This group will receive this sequence after the 1 initial week washout:

vorinstat (4 weeks) placebo (1 week) placebo (4 weeks)

Drug: Vorinostat Oral Capsule Group 1
Following the initial washout and first 4-week period of the trial, all patients will enter a second 1-week washout. After the washout, all patients will then enter a second 4 week alternate treatment (vorinostat or placebo). During the vorinostat sequence, doses will be increased over the first 2 weeks in each phase of the crossover study, starting by 100 mg per day, and increasing to 200 mg by week 2 and 300 mg per day at the start of week 3 until the end of week 4.
Experimental: Vorinostat Group 2 (P-P-P-V)

This group will receive this sequence after the 1 initial week washout:

placebo (4 weeks) placebo (1 week) vorinostat (4 weeks)

Drug: Vorinostat Oral Capsule Group 2
Following the initial washout and first 4-week period of the trial, all patients will enter a second 1-week washout. After the washout, all patients will then enter a second 4 week alternate treatment (vorinostat or placebo). During the vorinostat sequence, doses will be increased over the first 2 weeks in each phase of the crossover study, starting by 100 mg per day, and increasing to 200 mg by week 2 and 300 mg per day at the start of week 3 until the end of week 4.

Detailed Description:

The goal of this study is to perform a pilot clinical study with a small sample of subjects to evaluate the safety and tolerability of vorinostat when combined with clozapine treatment in patients with schizophrenia. The investigators will also evaluate the potential translation of our preclinical data into a clinical use of vorinostat for cognitive impairment in clozapine-treated schizophrenic patients.

Potential participants will be receiving stables doses of clozapine for a minimum period of 6 months before entry into the study. Clozapine was selected because i) the majority of our studies in mouse models were performed after chronic treatment with this atypical antipsychotic, and ii) the investigators' data in postmortem human brain samples of subjects with antemortem diagnosis of schizophrenia suggest up-regulation of HDAC2 in frontal cortex of schizophrenic subjects treated with atypical, but not typical, antipsychotic drugs.

The HDAC inhibitor vorinostat was selected because preliminary data suggest that chronic treatment with vorinostat improves HDAC2-dependent cognitive function in rodent models. Additionally, vorinostat is the first HDAC inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma. Dose(s) of vorinostat have been selected based on previous clinical studies in such patients with brain metastasis.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosed with DSM-5 Schizophrenia
  • Receiving stable dose pf clozapine (≥ 300 mg per day) for at least 6 months before entering the study

Exclusion Criteria:

  • Taking specific psychotropic medications (lamotrigine and valproic acid)
  • Current or recent (12-months) substance use or induced disorder
  • History of significant neurological or medical disorders
  • Intellectual disability
  • Known contraindications to the administration of vorinostat per product labeling
  • Women currently pregnant, planning to become pregnant, or receiving hormone therapy and refusing any form of birth control
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03263533


Contacts
Contact: Javier Gonzalez-Maeso, PhD 804-628-4520 javier.maeso@vcuhealth.org
Contact: Ananda Pandurangi, MD (804) 828-4570 ananda.pandurangi@vcuhealth.org

Locations
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Virginia Commonwealth University
Investigators
Principal Investigator: Javier Gonzalez-Maeso, PhD Virginia Commonwealth University
  More Information

Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT03263533     History of Changes
Other Study ID Numbers: HM20007977
First Submitted: August 14, 2017
First Posted: August 28, 2017
Last Update Posted: September 8, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Virginia Commonwealth University:
schizophrenia
clozapine
vorinostat
HDAC
histone deacetylase inhibitor

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Vorinostat
Histone Deacetylase Inhibitors
Clozapine
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
GABA Antagonists
GABA Agents