Clinical trial NCT03263533: HDAC Inhibitor Augmentation to Clozapine
Official title: HDAC Inhibitor Augmentation to Clozapine
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: EARLY_PHASE1
Conditions: Schizophrenia
Keywords: schizophrenia
clozapine
vorinostat
HDAC
histone deacetylase inhibitor
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
First posted: 2017-08-28
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
timeFrame: 10 weeks
measure: Change in clinical cognitive symptoms during adjunctive vorinostat therapy in schizophrenia patients treated with clozapine
timeFrame: Baseline, Visit 4 (end of first intervention group/week 4), Visit 7 (end of study/10 weeks)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Virginia Commonwealth University
name: Javier Gonzalez-Maeso, PhD
role: PRINCIPAL_INVESTIGATOR
References: