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Nitrous Oxide for the Treatment of Major Depressive Disorder

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ClinicalTrials.gov Identifier: NCT03869736
Recruitment Status : Recruiting
First Posted : March 11, 2019
Last Update Posted : March 11, 2019
Sponsor:
Information provided by (Responsible Party):
Bayside Health

Brief Summary:

The investigators are conducting a randomized controlled trial to evaluate the antidepressant effects of nitrous oxide in people with Major Depressive Disorder (MDD). MDD is a global medical condition that causes significant health and economic burden. Recent studies have shown that a single dose of ketamine, an NMDA-antagonist, has fast and long lasting anti-depressant effect. Nitrous oxide, another NMDA-antagonist, is widely used for anesthesia and analgesia, safer to administer and has fewer side effects than ketamine.

A randomized controlled crossover feasibility study showed significant reduction in depressive symptoms at 2 and 24 hours after a single 1-hour treatment session of inhaled nitrous oxide compared with placebo. Nitrous oxide is inexpensive and can be safely administered by any trained clinician. If found to be efficacious, it could be used to provide rapid anti-depressant effect whilst the benefit of traditional anti-depressants has its delayed effect. Another potential application could be in acutely suicidal patients.

This investigated-initiated phase 2b trial will enable confirmation and extension of the findings from the feasibility study, and identify the optimal dose and regimen in a broader population of those with MDD. Participants will be randomized to receive a weekly 1-hour inhalational sessions of either nitrous oxide or placebo (oxygen-air mixture) for 4 weeks, and the nitrous group will be further randomly assigned to a dose of 50% nitrous oxide or 25% nitrous oxide. Depression severity will be assessed by a blinded observer pre-treatment and at weekly intervals during and for 4 weeks after treatment using the Hamilton Depression Rating Scale.


Condition or disease Intervention/treatment Phase
Depression Major Depressive Disorder Drug: Nitrous Oxide Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 172 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluation of the Antidepressant Effects of Nitrous Oxide in People With Major Depressive Disorder
Actual Study Start Date : January 22, 2019
Estimated Primary Completion Date : October 10, 2020
Estimated Study Completion Date : December 10, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nitrous Oxide 50% or 25%
Nitrous oxide at an inhaled concentration of 50% or 25%
Drug: Nitrous Oxide
1-hour sessions of inhaled nitrous oxide at concentrations of 25% or 50% (randomly assigned) to be administered weekly for 4 weeks.

Sham Comparator: Placebo
Oxygen-air mixture
Drug: Placebo
1-hour sessions of inhaled oxygen-air mixture (inspired oxygen concentration ~23-30%) to be administered weekly for 4 weeks.




Primary Outcome Measures :
  1. Change in HDRS-21 score [ Time Frame: over 4 weeks from baseline ]

    21-point Hamilton Depression Rating Scale

    Interview-based questionnaire used to measure the severity of depression. Consists of 21 items with a score calculated from the first 17 answers. Higher scores are associated with more severe depression:

    0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52



Secondary Outcome Measures :
  1. Treatment response and remission [ Time Frame: at 24 hours ]
    Treatment response (≥50% reduction on HDRS-21) and remission (HDRS-21 ≤7 points), nitrous oxide vs. placebo

  2. Pattern of treatment response [ Time Frame: daily over the first week after first treatment session ]

    Assessed using daily Profile of Mood States (POMS) scale, nitrous oxide vs. placebo

    The Profile of Mood States (POMS) questionnaire is a validated psychological test containing 65 emotions/ mood states. Participants are asked to rank their current mood states using the scale 'not at all', 'a little', 'moderately', 'quite a lot' or 'extremely'. Total Mood Disturbance (TMD) score and an analysis of tension, depression, anger, vigour, fatigue and confusion is performed based on the participants mood states. Total Mood Disturbance (TMD) can be calculated by adding the scores for Tension, Depression, Anger, Fatigue and Confusion and then subtracting the score for Vigour.

    • TMD = (Tension + Depression + Anger + Fatigue + Confusion) - Vigour


  3. Sustainability of treatment response - change in HDRS-21 scores [ Time Frame: over 7 weeks ]

    Change in the HDRS-21 score, nitrous oxide vs placebo

    HDRS-21 is an interview-based questionnaire used to measure the severity of depression. Consists of 21 items with a score calculated from the first 17 answers. Higher scores are associated with more severe depression:

    0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression > 23 = Very Severe Depression Max score = 52


  4. Sustainability of treatment response - response and remission rates [ Time Frame: over 7 weeks ]
    Response and remission rates (%), nitrous oxide vs placebo

  5. Treatment compliance rate [ Time Frame: over 4 weeks ]
    Refusal or inability to attend further treatments, nitrous oxide vs placebo

  6. Dose effect of nitrous oxide using treatment-by-dose interaction term in a logistic regression model [ Time Frame: over 7 weeks ]
    Dose effect of nitrous oxide at 25% and 50% using a treatment-by-dose (group) interaction term in a logistic regression model to assess for statistical significance.

  7. Computerized Adaptive Test-Depression Inventory (CAT-DI) [ Time Frame: over 7 weeks ]
    Adaptive testing questionnaire that assesses severity, likelihood and percentile of depression based on an average of 12 items administered from a question bank of 400 items. Questions are adapted to the participants answers and targeted to their level of impairment. Results generate include: severity of depression (normal, mild, moderate, severe), likelihood of depression (out of probability of 1), percentile of severity.

  8. Computerized Adaptive Test-Suicide Scale (CAT-SS) [ Time Frame: over 7 weeks ]
    Adaptive testing questionnaire that assesses risk and severity of suicide based on items administered from a question bank. Questions are adapted to the participants answers and targeted to their level of impairment. Results generate include: risk of suicide (low, intermediate, high) and a percentile of risk.


Other Outcome Measures:
  1. Adverse events [ Time Frame: over 7 weeks ]
    Psychiatric AEs, such as new suicidal ideation and psychotic symptoms Other AEs, such as cardiorespiratory AEs or nausea and vomiting



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult (≥18 years, both sexes), with DSM-IV-TR criteria for MDD without psychosis, as determined using a structured clinical interview [Mini International Neuropsychiatric Interview]
  2. MDD, as defined by a pretreatment score >18 on the HDRS-21 scale

Exclusion Criteria:

  1. A history of bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses; active suicidal intention, as determined by clinical interview
  2. Active or recent (<12 months) substance abuse or dependence; excluding nicotine
  3. Administration of NMDA-antagonists (e.g., ketamine) in previous 3 months
  4. Ongoing treatment with ECT
  5. Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
  6. Pregnancy or breastfeeding
  7. Any contraindications to the use of nitrous oxide (e.g., pneumothorax, middle ear occlusion, elevated intracranial pressure, chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).

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): NCT03869736


Contacts
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Contact: Carolyn Deng, MBChB +61399030760 c.deng@alfred.org.au
Contact: Sophie Wallace, MPH +61 3 90762651 s.wallace@alfred.org.au

Locations
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United States, Illinois
University of Chicago Medicine Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Peter Nagele, MD, MSc       pnagele@dacc.uchicago.edu   
Australia, Victoria
Alfred Hospital Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Carolyn Deng, MBChB    +61399030760    c.deng@alfred.org.au   
Contact: Sophie Wallace, MPH    +61 3 90762651    s.wallace@alfred.org.au   
Sponsors and Collaborators
Bayside Health
Investigators
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Principal Investigator: Paul Myles, MD The Alfred

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Responsible Party: Bayside Health
ClinicalTrials.gov Identifier: NCT03869736     History of Changes
Other Study ID Numbers: 438/19
First Posted: March 11, 2019    Key Record Dates
Last Update Posted: March 11, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by Bayside Health:
Depression
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Nitrous Oxide
Anesthetics, Inhalational
Anesthetics
Anesthetics, General
Physiologic Effects of Drugs
Analgesics, Non-Narcotic
Analgesics

Additional relevant MeSH terms:
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Disease
Depression
Depressive Disorder
Depressive Disorder, Major
Pathologic Processes
Behavioral Symptoms
Mood Disorders
Mental Disorders
Anesthetics
Nitrous Oxide
Analgesics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Inhalation
Anesthetics, General
Analgesics, Non-Narcotic