HDAC Inhibitor Augmentation to Clozapine

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.

Study Overview

• Status: Withdrawn
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Vorinostat Oral Capsule Group 1; Drug: Vorinostat Oral Capsule Group 2

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.

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Safety of vorinostat measured by number of adverse events	10 weeks
Change in clinical cognitive symptoms during adjunctive vorinostat therapy in schizophrenia patients treated with clozapine	Participants will be given a cognitive test to assess executive function and speed.	Baseline, Visit 4 (end of first intervention group/week 4), Visit 7 (end of study/10 weeks)

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Investigators: Principal Investigator: Javier Gonzalez-Maeso, PhD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): April 1, 2017
• Primary Completion (ANTICIPATED): February 1, 2019
• Study Completion (ANTICIPATED): February 1, 2019

Study Registration Dates

• First Submitted: August 14, 2017
• First Submitted That Met QC Criteria: August 21, 2017
• First Posted (ACTUAL): August 28, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 22, 2019
• Last Update Submitted That Met QC Criteria: February 20, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: schizophrenia; histone deacetylase inhibitor; clozapine; HDAC; vorinostat
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: HM20007977

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No