Treatment Resistant DepressionPhase 4SMILENCT04957368
Sustained Mood Improvement With Laughing Gas Exposure: A Randomized Controlled Pilot Trial
A Phase 4 study testing Nitrous Oxide 99 % and Oxygen + Midazolam in people with Treatment Resistant Depression and Major Depressive Disorder, run by Unity Health Toronto at 1 site in Canada.
Trial summary
The purpose of the study is to investigate a short-term treatment option for major depressive disorders by administering nitrous oxide gas. At this time, the main purpose is to complete a feasibility study with 40 participants suffering from treatment-resistant depression. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Treatment Resistant Depression, Major Depressive Disorder
- What is being tested?
- Nitrous Oxide 99 % and Oxygen + Midazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteCanada
- Study dates
- 3 Nov 2021to 27 Feb 2024
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 to 65 years of age
- Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)
- Current major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) for DSM-5
- Experiencing moderate to severe depressive episode, as defined by the Hamilton Depression Rating Scale (HAMD)>17
- Failure of two trials of antidepressant therapy of adequate dose and duration, during the current depressive episode
- For women of childbearing potential, use of highly effective or double-barrier methods of contraception. Abstinence is acceptable if it is the preferred and usual lifestyle of the female participant
- Capacity to provide informed consent.
Who cannot join
- Acute suicidality defined as score ≥3 on HAMD item 3
- Major Depressive Episode in people with Bipolar Disorder
- Current substance abuse or dependence and/or history of alcohol abuse or dependence within the past year
- Dementia
- Current or lifetime history of schizophrenia or schizoaffective disorder
- Current history of dissociative disorders
Show all 15Show fewer
- Known history of hypersensitivity or allergy to Nitrous Oxide, Midazolam or any ingredients in the study formulations
- Contraindication to receiving nitrous oxide
- Chronic cobalamin or folate deficiency
- Contraindication to receiving the placebo midazolam
- Use of centrally acting medicinal products, such as opioid agonists, morphine derivatives, benzodiazepines and/or other central nervous system depressants such as barbiturates and alcohol
- Pregnancy or breastfeeding in female participants
- Electroconvulsive therapy within the current depressive episode
- Receiving ketamine treatment within the current depressive episode
- Unwilling to maintain current antidepressant regimen.
Trial locations and contacts
1 site in 1 country.
About this study
The purpose of the study is to investigate a short-term treatment option for major depressive disorders by administering nitrous oxide gas. At this time, the main purpose is to complete a feasibility study with 40 participants suffering from treatment-resistant depression. Participants will be randomized to (1) Study group: Nitrous oxide (inhaled) + solution of saline (injected) and the (2) Control group: Oxygen (inhaled) + Midazolam (injected) as an Active Placebo.
- Being tested
- Nitrous Oxide 99 %, Oxygen + Midazolam
- Keywords
- Feasibility trial, Nitrous Oxide
- Medical subject headings
- Depressive Disorder, Treatment-Resistant, Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitrous Oxide 99 %Drug
Nitrous oxide will be administered at an inspiratory concentration of 50% with concurrent intravenous saline (100ml) for one hour.
Oxygen + MidazolamDrug
Oxygen will be administered at 50% with intravenous midazolam (0.02mg/kg in 100ml) for one hour
| Study group | Role | What they receive |
|---|---|---|
| Nitrous Oxide + saline solution | Experimental | Not described Receives: Drug: Nitrous Oxide 99 % |
| Oxygen + Midazolam | Active comparator | Not described Receives: Drug: Oxygen + Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recruitment rate
Recruitment rate
Measured: 2 Years
Withdrawal rate
Measured: 2 Years
Adherence rate
Feasibility
Measured: 2 Years
Frequency of adverse events
Safety and tolerability
Measured: 2 Years
Secondary outcomes (2)
Montgomery-Åsberg Depression Rating Scale (MADRAS) Score 0-60 (Higher scores represent higher depression). Measure changes in symptoms of depression
Frequencies on numbers of 1.- Remissions (defined as MADRS score < 10), 2.- Responses (defined as ≥ 50% reduction in MADRS score from baseline) 3.- No Responses
Measured: 6 weeks
Toronto Side Effects Scale (TSES) - 32 items (each item has a score 1-25; higher score means higher intensity). Measure adverse side effects from antidepressant treatment
Frequencies of safety and tolerability
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2021
- Study start3 Nov 2021
- Primary completion27 Feb 2024
- Study completion27 Feb 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Treatment Resistant DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Unity Health Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04957368
- Sponsor's protocol ID
- 21-096
- Acronym
- SMILE
- Status last verified
- May 2024
- First submitted
- 26 Apr 2021
- Last updated
- 8 May 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No individual participant data has been planned to be shared with other researchers at this point since this is a feasibility study with only 40 participants
Publications
Ladha KS, Lee J, Mattina GF, Pazmino-Canizares J, Wijeysundera DN, Gholamali Nezhad F, Philip K, Tassone VK, Adamsahib F, Bhat V; SMILE Study Investigators. Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression. PLoS One. 2024 Jan 19;19(1):e0297330. doi: 10.1371/journal.pone.0297330. eCollection 2024.
PubMed 38241247
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sustained Mood Improvement With Laughing Gas Exposure: A Randomized Controlled Pilot Trial
- ClinicalTrials.gov ID
- NCT04957368
- Acronym / sponsor ID
- SMILE / 21-096
- Keywords
- Feasibility trial, Nitrous Oxide
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Unity Health TorontoUniversity, hospital or other
- Study start
- 3 Nov 2021 (actual)
- Primary completion
- 27 Feb 2024 (actual)
- Study completion
- 27 Feb 2024 (actual)
- First posted
- 12 Jul 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of the study is to investigate a short-term treatment option for major depressive disorders by administering nitrous oxide gas. At this time, the main purpose is to complete a feasibility study with 40 participants suffering from treatment-resistant depression. Participants will be randomized to (1) Study group: Nitrous oxide (inhaled) + solution of saline (injected) and the (2) Control group: Oxygen (inhaled) + Midazolam (injected) as an Active Placebo.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitrous Oxide + saline solution | Experimental | Drug: Nitrous Oxide 99 % |
| Oxygen + Midazolam | Active comparator | Drug: Oxygen + Midazolam |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 18 to 65 years of age
- Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)
- Current major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) for DSM-5
- Experiencing moderate to severe depressive episode, as defined by the Hamilton Depression Rating Scale (HAMD)>17
- Failure of two trials of antidepressant therapy of adequate dose and duration, during the current depressive episode
Key exclusion criteria (15 listed)
- Acute suicidality defined as score ≥3 on HAMD item 3
- Major Depressive Episode in people with Bipolar Disorder
- Current substance abuse or dependence and/or history of alcohol abuse or dependence within the past year
- Dementia
- Current or lifetime history of schizophrenia or schizoaffective disorder
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitrous Oxide 99 %Nitrous oxide will be administered at an inspiratory concentration of 50% with concurrent intravenous saline (100ml) for one hour. | Drug | Nitrous Oxide + saline solution |
| Oxygen + MidazolamOxygen will be administered at 50% with intravenous midazolam (0.02mg/kg in 100ml) for one hour | Drug | Oxygen + Midazolam |
Primary outcome
Recruitment rate
Time frame: 2 Years
Recruitment rate
Withdrawal rate
Time frame: 2 Years
Adherence rate
Time frame: 2 Years
Feasibility
Frequency of adverse events
Time frame: 2 Years
Safety and tolerability
2 secondary outcomes
Montgomery-Åsberg Depression Rating Scale (MADRAS) Score 0-60 (Higher scores represent higher depression). Measure changes in symptoms of depression
Time frame: 6 weeks
Toronto Side Effects Scale (TSES) - 32 items (each item has a score 1-25; higher score means higher intensity). Measure adverse side effects from antidepressant treatment
Time frame: 6 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2024.
- Derived from this study: PubMed 38241247Ladha KS, Lee J, Mattina GF, Pazmino-Canizares J, Wijeysundera DN, Gholamali Nezhad F, Philip K, Tassone VK, Adamsahib F, Bhat V; SMILE Study Investigators. Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression. PLoS One. 2024 Jan 19;19(1):e0297330. doi: 10.1371/journal.pone.0297330. eCollection 2024.
- Individual participant dataSharing planned: No. No individual participant data has been planned to be shared with other researchers at this point since this is a feasibility study with only 40 participants
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Nitrous Oxide 99 % and Oxygen + Midazolam in people with Treatment Resistant Depression and Major Depressive Disorder, run by Unity Health Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recruitment rate (time frame: 2 Years). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04957368, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2024.