Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus

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.
ClinicalTrials.gov Identifier: NCT03336398
Recruitment Status : Not yet recruiting
First Posted : November 8, 2017
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Diana Martinez, New York State Psychiatric Institute

Brief Summary:

PLEASE NOTE: This study recruits patients who are being seen at the ENT service of Columbia University Medical Center.

Tinnitus, or ringing in the ears, is a very common problem that often accompanies hearing loss. It affects up to 1 in 10 adults, and about 30% of people who experience chronic tinnitus find it very distressing. In these patients, symptoms of depression and anxiety often accompany tinnitus and there are no approved treatments. Clinical trials are ongoing to test a glutamate NMDA receptor antagonist (called esketamine), which is injected into the inner ear. However, the preliminary results with this medication show that it only works for tinnitus that results from acute injury. It does not treat tinnitus resulting from progressive hearing loss.

Research in humans and animals suggest that the neurotransmitters glutamate and GABA are important in the development and maintenance of tinnitus. This data shows that over-activation of the NMDA receptor and a decrease in GABA signaling in the brain play a crucial role. Previous studies show that ketamine, which an antagonist at the NMDA receptor, increases GABA levels in the brain in participants with depression. Thus, in this experiment, this study will test the effect of ketamine on tinnitus, since it blocks the NMDA glutamate receptor and increase GABA levels.

Two groups of participants will be included in this study: those who experience distress (symptoms of anxiety or depression) with tinnitus and those who have tinnitus but do not experience distress. Each participant will receive both ketamine and placebo on different days. Magnetic Resonance Spectroscopy (MRS) scans will be


Condition or disease Intervention/treatment Phase
Tinnitus Drug: Ketamine Hydrochloride in saline Drug: Saline Phase 2

Detailed Description:

Tinnitus has a prevalence of approximately 1 in 10 adults in the United States. Among those with tinnitus, 36% had nearly constant symptoms and almost 30% of those report that their tinnitus as a big or a very big problem. Currently there are few effective treatments for tinnitus, and no approved medications. Cognitive behavioral and retraining therapy provide some relief, but many patients fail to respond.

Animal research and human studies indicate that maladaptive plasticity plays a role in tinnitus, which involves glutamatergic signaling largely at the NMDA and AMPA receptors. Additionally, GABA signaling has been shown to be impaired in tinnitus. Rodent models show a diminished sensitivity to GABA signaling and human magnetic resonance spectroscopy (MRS) studies show decreased GABA levels in the auditory cortex.

Ketamine is a non-competitive NMDA receptor antagonist that has also been shown to activate AMPA receptors, and modulates ongoing plasticity. Additionally, ketamine activates a subpopulation of cortical GABAergic interneurons and projection neurons and increases GABA levels in the human brain, measured with MRS. Ketamine is FDA approved as an anesthetic, and recent work has demonstrated its efficacy in treating refractory depression and chronic pain. Importantly, these demonstrate that low dose ketamine, at doses lower than those required for anesthesia, are effective in lifting depressed mood and improving the sensation of chronic pain.

For many, tinnitus has an important affective component to it, with distress and co-morbid symptoms of depression and anxiety. The onset and severity of tinnitus can correlate with stressful events, and it has been posited that stress lowers the threshold of perception, and unmasks tinnitus. Tinnitus then triggers more anxiety and depressed mood, which in turn reinforces the symptoms. An advantage of ketamine may be its effect on depression and anxiety, in addition to tinnitus, to interrupt this cycle.

The goal of this study is to perform a proof-of-concept preliminary study of ketamine in tinnitus associated with sensori-neural hearing loss. This will be studied both in participants who report depressed mood and anxiety and those who do not. MRS imaging will be used to assess ketamine-induced changes in GABA in the auditory cortex.


Layout table for study information
Study Type : Interventional
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tinnitus

Arm Intervention/treatment
Experimental: Tinnitus Distressed Patients
Tinnitus distressed patients are patients who experience symptoms of anxiety or depression with tinnitus. This group will receive both 0.5 mg/kg ketamine hydrochloride in saline and placebo, saline, with Magnetic Resonance Spectroscopy scans and audiometry testing and scales.
Drug: Ketamine Hydrochloride in saline
0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan
Other Name: Ketamine HCI

Drug: Saline
Saline will be administered with the other MRS scan
Other Name: Saline solution

Experimental: Tinnitus Patients
Tinnitus patients are patients who do not experience symptoms of anxiety or depression with tinnitus. This group will receive both 0.5 mg/kg ketamine hydrochloride in saline and placebo, saline, with Magnetic Resonance Spectroscopy scans and audiometry testing and scales.
Drug: Ketamine Hydrochloride in saline
0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan
Other Name: Ketamine HCI

Drug: Saline
Saline will be administered with the other MRS scan
Other Name: Saline solution




Primary Outcome Measures :
  1. Change in GABA and Glutamate (Glx) levels in the auditory cortex derived from 3T Magnetic Resonance Spectroscopy [ Time Frame: during ketamine and placebo MRS scans ]
    The GABA and Glx peaks will be quantified as ratios


Secondary Outcome Measures :
  1. Change in The Brief Psychiatric Rating Scale (BPRS) [ Time Frame: Baseline, at the end of MRS scan, 110 minutes after ketamine or placebo infusion ]
    The Brief Psychiatric Rating Scale (BPRS) is a rating scale used by a clinician to measure psychiatric symptoms. The scores range from a minimum 16 to maximum of 112. Higher scores indicate a more severe disorder.

  2. Change in Clinician Administered Dissociative Symptom Scale (CADSS) [ Time Frame: Baseline, at the end of MRS scan, 110 minutes after ketamine or placebo infusion ]
    The Clinician Administered Dissociative Symptom Scale is a clinician-administered scale used to measure present-state dissociative symptoms. Scores range from a minimum of 0 to a maximum of 96 points. Higher scores are indicative of present state dissociative symptoms.

  3. Change in Tinnitus Pitch Match (TPM) [ Time Frame: screening, 1 day after each scan ]
    The TPM is obtained to identify the frequency or frequency range that most closely matches the pitch of the participants' tinnitus.

  4. Change in Tinnitus Loudness Match (TLM) [ Time Frame: Screening, 1 day after each scan ]
    A1 kHz tone will be presented at 15 dB above hearing threshold, and participants will be asked to indicate whether their tinnitus is louder or softer than the tone. The loudness is then adjusted upward or downward in 1-dB steps until the tinnitus loudness is matched.

  5. Change in Minimum Masking Level (MML) [ Time Frame: Screening, 1 day after each scan ]
    This measures the loudness at which an external narrowband noise can mask the participant's perception of tinnitus. The external stimulus will be adjusted in small steps (1-2 dB) until the participants report that they can no longer hear their tinnitus

  6. Change in the Tinnitus Functional Index (TFI) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
    The TFI is a widely used and reliable self-administered test to determine the degree of functional impairment in tinnitus participants. Scores range from 0 to 100. Higher scores are indicative of greater functional impairment from tinnitus.

  7. Change in The Tinnitus Handicap Inventory (THI) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
    The Tinnitus Handicap Inventory is a self-administered test to determine the degree of distress in tinnitus patients. Scores range from 0 to 100 with higher scores indicating a greater degree of distress from tinnitus.

  8. Change in Visual Analogue Scale (VAS) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]

    Visual Analogue Scale (VAS) is a scale that consists of a straight line with gradients from 0 (no tinnitus) to 10 (severe tinnitus).

    (maximal experience of tinnitus)


  9. Change in Hamilton Depression Rating Scale (HDRS) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
    The Hamilton Depression Rating Scale (HDRS) is a 24 item questionnaire that measures symptoms of depression. Scores range from 0 to 50. Higher scores indicate depression severity.

  10. Change in the Beck Depression Inventory (BDI) Depression Inventory (BDI) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
    The Beck Depression Inventory (BDI) is a 21 question multiple choice inventory used to asses depressed mood. Scores range from 0 (no depression) to 63 (severe depression)

  11. Change in Profile of Mood States (POMS) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
    The Profile of Mood States (POMS) is a questionnaire used to assess mood states.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant aged 21-60 referred by physician in the ENT service at the Columbia University Medical Center.
  • Tinnitus associated with at least mild sensori-neural hearing loss of at least 6 months duration
  • Score at least 32 on the Tinnitus Handicap Inventory and a score of 5dB or greater on the minimum masking level
  • Tinnitus not due to medical disease (other than sensorineural hearing loss)
  • Score of at least 14 on the Hamilton Depression Rating Scales with a score of at least 2 on the Hamilton Anxiety Rating Scale (in the distressed group).

Exclusion Criteria:

  • DSM-V psychiatric disorders other than mild-moderate depression and anxiety, including substance use disorder.
  • History of recreational ketamine use, recreational PCP use,exposure to ketamine as an anesthetic, or an adverse reaction to ketamine
  • Currently taking psychotropic medication (e.g.antipsychotics, antidepressants, benzodiazepines)
  • Presence or positive history of significant medical or neurological illness, including high blood pressure (SBP >140, DBP > 90), cardiac illness, abnormality on EKG, head injury.
  • Pregnancy, abortion, or lack of effective birth control during 15 days before the scan
  • Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the
  • Medicinal patch that cannot be removed for the scans.

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): NCT03336398


Contacts
Layout table for location contacts
Contact: Diana Martinez, MD 646-774-6160 dm437@cumc.columbia.edu

Locations
Layout table for location information
United States, New York
1051 Riverside Drive
New York, New York, United States, 10032
Sponsors and Collaborators
New York State Psychiatric Institute
Investigators
Layout table for investigator information
Principal Investigator: Diana Martinez NYSPI/Columbia University

Layout table for additonal information
Responsible Party: Diana Martinez, Medical Doctor, New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT03336398     History of Changes
Other Study ID Numbers: 7432
First Posted: November 8, 2017    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Tinnitus
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Ketamine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action