Pilot Study of ORG 25935 Modulation of Ketamine-Induced Behavioral and Cognitive Effects in Healthy Male Subjects - Full Text View

Sponsors and Collaborators:	Yale University Organon
Information provided by:	Yale University
ClinicalTrials.gov Identifier:	NCT00700076

Purpose

There is growing evidence in support of the hypothesis that abnormal glutamatergic neurotransmission plays an important role in the pathophysiology of schizophrenia. The involvement of decreased glutamatergic neurotransmission in schizophrenia is suggested by the ability of N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine to mimic many of the symptoms of schizophrenia.

Org 25935 is a new putative antipsychotic agent developed by N.V. Organon. It specifically acts as a glycine uptake inhibitor to enhance NMDA receptor function mediated through increased brain levels of glycine.

This study is to investigate the effect of Org 25935 on ketamine-induced impairments in immediate recall. Also, to investigate the effect of Org 25935 on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, subjective "high", and deficits in attention, working memory and planning. The exploratory objective of this study is to investigate the interaction of polymorphisms of candidate genes with the effects of Org 25935 on ketamine induced psychotomimetic and amnestic effects.

The hypothesis behind this study is that Org 25935 decreases the ketamine-induced schizophrenia like symptoms by increasing the levels of glycine and thereby restoring the glutamatergic neurotransmission.

This study may lead to the possible development of novel treatment for schizophrenia, an illness that afflicts significant fraction of the population.

Condition	Intervention	Phase
Healthy	Drug: Ketamine and Org 25935 Drug: Placebo and Ketamine	Phase I

MedlinePlus related topics: Schizophrenia

Drug Information available for: Ketamine Ketamine hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Basic Science, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment
Official Title:	Pilot Study of ORG 25935 Modulation of Ketamine-Induced Behavioral and Cognitive Effects in Healthy Male Subjects

Further study details as provided by Yale University:

Primary Outcome Measures:

Attenuation of ketamine-induced cognitive deficits by Org 25935 [ Time Frame: +20 to +100 minutes ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Attenuation of ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, subjective high and deficits in attention and working memory by Org 25935. [ Time Frame: 0 to +100 minutes ] [ Designated as safety issue: No ]
Investigation of interaction of polymorphisms of candidate genes e.g., BDNF, COMT with the effect of Org 25935 on ketamine induced psychotomimetic and amnestic deficits. [ Time Frame: 0 to +100 minutes ] [ Designated as safety issue: No ]

Estimated Enrollment:	18
Study Start Date:	December 2006
Estimated Study Completion Date:	January 2009
Estimated Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator	Drug: Ketamine and Org 25935 Oral administration of Org 25935 16 mg and intravenous administration of ketamine (0.23 mg/kg bolus over 1 minute, followed by 0.58 mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 69 minutes)
2: Placebo Comparator	Drug: Placebo and Ketamine Oral administration of placebo and intravenous administration of ketamine (0.23 mg/kg bolus over 1 minute, followed by 0.58 mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 69 minutes)

Detailed Description:

This study is based on the concept of involvement of reduced glutamatergic neurotransmission in schizophrenia and is suggested by the ability of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist to mimic many of the symptoms of schizophrenia. Org 25935 developed by N.V. Organon is believed specifically to act as a glycine uptake inhibitor to enhance NMDA receptor function mediated through increased brain levels of glycine.

The primary objective of this study is to investigate the effect of Org 25935 on ketamine-induced impairments in immediate recall. The secondary objective is to investigate the effect of Org 25935 on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, subjective "high", and deficits in attention, working memory and planning. The exploratory objective is to investigate the interaction of polymorphisms of candidate genes e.g., Brain Derived Neurotrophic Factor (BDNF) and Catechol-O-methyl transferase (COMT) with the effects of Org 25935 on ketamine induced psychotomimetic and amnestic effects.

Research Design: Twenty healthy male subjects will receive a single oral dose of 16mg Org 25935 (2x tablets of 8 mg as one single a.m. dose) and placebo in a randomized, counter-balanced, cross-over design. There will be a wash-out of at least 7 days between successive dosing occasions. Ketamine will be administered as a bolus followed by a constant infusion (0.23 mg/kg bolus over 1 minute, followed by 0.58 mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 69 minutes).

Additionally the pre-pilot phase of the study includes six healthy male subjects and is an open-label, non-placebo controlled phase. This is to establish the dose-escalation of Org 25935. Of these six subjects, the first two will receive 4mg of Org 25935, the next two will receive 8mg and the last two will receive 16mg of Org 25935.

Methodology: The study will follow a double-blind, placebo-controlled, cross-over design. Each subject will receive 16 mg Org 25935 and placebo in a randomized, counter-balanced order, spread over two periods (period 1 and period 2). Two and a half hours after administration of Org 25935 or placebo, subjects will receive a ketamine bolus followed by a constant infusion. Behavioral, cognitive, and blood level data will be obtained on each test day. The subjects will be in fasting condition until the end of the ketamine infusion.

The pre-pilot study is for a single day, and is open-labeled and non-placebo controlled as aforementioned. Methodologically, all the assessments and data collection procedures will remain unchanged except for the escalating dose of Org 25935 from 4mg to 16mg for every two subjects.

Significance: The study may lead to the possible development of novel treatment for schizophrenia, an illness that afflicts significant fraction of the population.

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Male and between 18 and 55 years (extremes included) on the day of the first dosing.
A body weight resulting in a body mass index (BMI) between 18.0 and 29.9 kg/m2, extremes included.
Able and willing to sign the Informed Consent Form prior to screening evaluations.
(History of) good physical and mental health as determined by history taking, the Structured Clinical Interview for DSM-NP (SCID-NP) and collateral information, Perceptual Aberration-Magical Ideation Scale, physical and laboratory examinations, ECG and vital signs recordings as judged by the investigator.
Able to refrain from all use of (methyl)xanthines (e.g. coffee, tea, cola, chocolate) and alcohol from 7 days prior to the first dose until the last pharmacodynamic assessment.
Able to refrain from all use of grapefruit containing products from 7 days prior to the first dose until the last pharmacodynamic assessment.
Does not smoke more than 5 cigarettes or equivalent per day

Exclusion Criteria:

History of sensitivity/idiosyncrasy to the drugs used in the study or chemically related compounds or excipients which may be employed in the study or to any other unknown drug used in the past.
Use of any drug or substance that is known to induce or inhibit drug-metabolizing enzymes within one month prior to the first dose.
Use of any drug or substance within one week prior to the first dosing, (including NSAIDs), except for paracetamol or some topical medication (i.e. creams, ointments, gels or lotions to induce a local effect without systemic exposure).
Lifetime history of treatment with any psychotropic medications for > 1 month duration suggestive of psychiatric illness.
Lifetime diagnosis of DSM-IV substance dependence (except caffeine and nicotine).
Substance abuse, as per clinical judgment, in the past 1 year
Positive drug or alcohol screen.
Use of any illicit substances in the 4 weeks prior to study participation.
Use of glycine supplements within one month prior to first dosing.
A history of significant medical/neurological disease potentially interfering with this trial, such as cardiac, thyroid, renal, hepatic or neurological disorder.
Current DSM-IV Axis-I diagnosis, and/or Axis I diagnosis in first-degree relatives.
Clinically relevant abnormal laboratory, ECG, vital signs or physical findings at screening (and just prior to dosing).
Clinically relevant ophthalmologic abnormalities, such as cataract, color blindness, macula degeneration, glaucoma or retinal disease.
A hearing deficit greater than one band in an ear detected using a Welch-Allyn audioscope (500, 1000, 2000 and 4000 Hz threshold will be evaluated).
Major current or recent (<6 weeks) stressors.
History of counseling, except if counseling was for a life circumstance disorder (e.g., bereavement, divorce) or in the opinion of the investigator, is not clinically significant.
Any history indicating learning disability, mental retardation, or attention deficit disorder.
History of head injury with loss of consciousness greater than fifteen minutes.
Any other condition which in the opinion of the investigator would preclude participation in the study.
Without at least a 12th grade education level or equivalent.
Non-English speaking.
Participation in an investigational drug study within 30 days prior to the first dose.
Donation of blood for transfusion (450 ml) within 90 days prior to the first dose.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00700076

Contacts

Contact: Nagendra M Singh, MBBS

203-932-5711 ext 4495

nagendra.madansingh@yale.edu

Locations

United States, Connecticut
Biological Studies Unit at the VA Connecticut Healthcare System, Yale School of Medicine	Recruiting
West Haven, Connecticut, United States, 06516
Contact: Schizophrenia Research Clinic 203-932-5711 ext 4525
Principal Investigator: Deepak C D'Souza, MD

Sponsors and Collaborators

Yale University

Organon

Investigators

Principal Investigator:

Deepak C D'Souza, M.D.

Yale University, School of Medicine, Department of Psychiatry

More Information

Responsible Party:	Yale University School of Medicine, Department of Psychiatry ( Deepak Cyril D'Souza, MD )
Study ID Numbers:	0701002174
Study First Received:	June 13, 2008
Last Updated:	June 17, 2008
ClinicalTrials.gov Identifier:	NCT00700076
Health Authority:	United States: Food and Drug Administration

Keywords provided by Yale University:

ORG 25935
Ketamine
healthy subjects

Study placed in the following topic categories:

Excitatory Amino Acids
Ketamine
Healthy

Additional relevant MeSH terms:

Anesthetics, Intravenous
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Agents
Anesthetics, Dissociative

Pharmacologic Actions
Sensory System Agents
Anesthetics, General
Therapeutic Uses
Peripheral Nervous System Agents
Analgesics
Central Nervous System Agents
Excitatory Amino Acid Antagonists

ClinicalTrials.gov processed this record on January 16, 2009