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Trial registered on ANZCTR

Registration number

ACTRN12616001568404

Ethics application status

Approved

Date submitted

1/11/2016

Date registered

14/11/2016

Date last updated

12/01/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Nitrous Oxide (N2O) treatment of adolescents with depression (NOTAD)

Scientific title

Nitrous Oxide (N2O) treatment of adolescents with depression (NOTAD) - A randomised single-blind placebo controlled pilot study

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

NOTAD

Linked study record

N/A

Health condition

Health condition(s) or problem(s) studied:

Depression

Condition category

Condition code

Mental Health

Depression

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This intervention will consist of a single inhaled dose of nitrous oxide.

The study design will be a randomised single-blind placebo controlled trial, and the study will consist of two phases, Phase A and Phase B. During Phase A, participants will receive a dose of either nitrous oxide (N2O), or placebo (blinded to participants). Phase B will last for 12 weeks, and will consist of weekly psychiatric follow ups conducted by Consultant Psychiatrists.

Prior to Phase A, all participants and their caregivers will be provided with an information sheet and consent form prior to the commencement of the study. The information sheet that will be provided will outline the rationale of the study, the tasks that the participants will be asked to complete.

The procedure of Phase A is as follows: Participants will arrive at Princess Margaret Hospital, and will be assessed by a Consultant Psychiatrist. They will then be randomly allocated to either a group receiving nitrous oxide (50% N2O / 50% O2) or a second group receiving a placebo (50% nitrogen / 50% oxygen). For both groups, the flow rate will be 6L per minute for 60 minutes. Group assignment will be performed using a random number generator. Apart from the inhalational mixture, the sessions for administration of N2O and placebo will be indistinguishable as regards to their setting, setup, and monitoring. Standardized mood assessment will take place at baseline as well as 2 and 24 hours after N2O / placebo administration, and at weekly intervals into fluoxetine administration.

Phase B will begin 24 hours after Phase A. All participants that were enrolled will be prescribed with fluoxetine (an intention to start treatment with fluoxetine is an inclusion criteria). Participants will be prescribed and administered fluoxetine in a fixed-dose approach, which will employ a fixed dose of fluoxetine of 20mg per day (after an introduction period of 7 days with 10 mg). The total duration of administration will be the duration of the study period (i.e., 12 weeks), and will be administered via oral tablets. Adherence to fluoxetine will be monitored by empty drug packet return. With regard to fluoxetine treatment, the participant would have been consented for this off-label medicine in minors, and a baseline ECG and thyroid function test would have been completed. Fluoxetine will be continued with weekly monitoring of clinical symptoms and mood.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

This study will consist of a randomised single-blind placebo controlled design. We aim to recruit 30 participants to the trial. 15 participants will be randomly allocated to the intervention group (N2O), and 15 participants will be randomly allocated to the placebo group (50% nitrogen and 50% oxygen).

Control group

Placebo

Outcomes

Primary outcome [1]

Mood, assessed by the Child Depression Rating Scale - Revised (CDRS), the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS).

Timepoint [1]

2 hours post administration of nitrous oxide or placebo

Secondary outcome [1]

Mood, assessed by the Child Depression Rating Scale - Revised (CDRS), the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS).

Timepoint [1]

24 hours after administration of nitrous oxide

Secondary outcome [2]

Mood, assessed by the Child Depression Rating Scale - Revised (CDRS), the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS).

Timepoint [2]

Mood will be measured on a weekly basis after the initiation of Phase B (i.e., commencement of fluoxetine treatment) for the 12 weeks of fluoxetine administration.

Secondary outcome [3]

Mood and behaviour, assessed by the Child Behaviour Checklist (CBCL)

Timepoint [3]

Measures will be conducted during Week 6 and Week 12 of follow up (Phase B).

Eligibility

Key inclusion criteria

1. Participants with a confirmed diagnosis of moderate to severe Major Depressive Disorder (according to ICD-10 or DSM-V)
2. Participants aged between 12 and 17 years
3. Intention to start fluoxetine as treatment in Phase B

Minimum age

12 Years

Maximum age

17 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Active suicidal ideation or plans
2. Currently taking other psychiatric medications at study entry
3. Intellectual disability
4. Active or past diagnosis of an eating disorder
5. Current or recent abuse of alcohol
and current or recent abuse of illicit substances or dependence (recent = within the past 12
months).
6.Pregnancy in female participants
7. Chronic medical or neurological disorder
8. History of bipolar disorder, schizophrenia, schizoaffective disorder, obsessive compulsive disorder, or other Axis II diagnosis
9. Presence of acute medical illness that
could interfere with study participation, including (but not limited to) significant pulmonary
disease.
10. Active psychotic symptoms
11. Previous administration of NMDA receptor
antagonists (e.g., N2O or ketamine) during the preceding 3 months.
12. Ongoing or past treatment with electroconvulsive therapy
13. Contraindications against the use of N2O (e.g.
pneumothorax)
14. Contraindications against the use of fluoxetine

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation to group will be concealed, as participants will be allocated through the use of a random number generator, i.e., central randomisation by a computer.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a random number generator will be used.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Type of endpoint/s

Statistical methods / analysis

The primary outcome measure (mood) will be statistically analysed using a between-subjects mixed effects linear model. These analyses will also be repeated for the BDI and CBCL scales.

In addition, correlational analyses (Pearson / Spearman’s Rho, depending on data distribution) between fluoxetine levels and relevant symptom changes will be
calculated. We will use the SPSS and GraphPad Prism software packages for these particular analyses.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

14/11/2016

Actual

20/10/2017

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Princess Margaret Hospital Foundation (PMHF)

Address [1]

1/68 Hay Street
Subiaco 6008
Western Australia

Country [1]

Australia

Primary sponsor type

University

Name

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, The University of Western Australia

Address

35 Stirling Highway (M561)
Crawley, 6009
Western Australia
Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

None

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Princess Margaret Hospital Human Research Ethics Committee

Ethics committee address [1]

Roberts Road
Subiaco, 6008
Western Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

02/09/2016

Ethics approval number [1]

Summary

Brief summary

Major depression affects one in 16 young Australians. The first line of pharmacological treatment for severe depressive disorders in young people is selective serotonin reuptake inhibitors (SSRI). However, beneficial clinical effects are rarely observed before 4-8 weeks, whilst negative side effects (e.g., increased activity leading to increased suicide risk) are present. Consequently, a major question is whether there is a treatment strategy that could alleviate depressive symptoms in the initial 4-8 weeks? Recent data showed that a single dose of nitrous oxide (N2O) in adults with severe depression had significant antidepressant effects, and maximum effects were observed 24 hours after administration. However, no studies using N2O in minors have been conducted. The proposed research aims to investigate whether N2O has the same antidepressant effects in minors by using a between-group single-blind design. Participants will be randomly allocated to treatment (N2O) or placebo, and monitored weekly up to 12 weeks after treatment initiation. We expect that an average improvement in mood will be observed for the group allocated to the nitrous oxide condition.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Florian Zepf

Address

The University of Western Australia
35 Stirling Highway M561
Crawley, 6009
Western Australia
Australia

Country

Australia

Phone

+6189340 8606

Fax

florian.zepf@uwa.edu.au

Contact person for public queries

Name

Janice Wong

Address

Child and Mental Health Services (CAMHS)
70 Hay Street
Subiaco, 6008
Western Australia
Australia

Country

Australia

Phone

+61863895835

Fax

janice.wong@research.uwa.edu.au

Contact person for scientific queries

Name

Richard Stewart

Address

Bentley Child Health Service
35 Mills Street
Bentley 6102
Western Australia,
Australia

Country

Australia

Phone

+6189416 3800

Fax

richard.stewart@health.wa.gov.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Nitrous oxide (N2O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): Study protocol for a randomised controlled trial.	2017	https://dx.doi.org/10.1186/s13063-017-2342-4

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added automatically