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Trial registered on ANZCTR


Registration number
ACTRN12621000310864
Ethics application status
Approved
Date submitted
11/01/2021
Date registered
19/03/2021
Date last updated
3/05/2023
Date data sharing statement initially provided
19/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Microdose Antagonist Combination for Depression (MAC-D) Trial: combination of low dose naltrexone and flumazenil for treatment of major depressive disorder
Scientific title
Microdose Antagonist Combination for Depression (MAC-D) Trial; An open label proof of concept clinical trial, using a series of subcutaneous infusions combining low dose naltrexone and flumazenil, for the treatment of major depressive disorder.
Secondary ID [1] 300489 0
Nil known
Universal Trial Number (UTN)
U1111-1247-9776
Trial acronym
MAC-D
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 316166 0
Condition category
Condition code
Mental Health 314461 314461 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The proposed intervention is an open label, proof of concept trial with participants receiving subcutaneous infusions of a microdose combination of naltrexone / flumazenil. The investigational agents will be combined into an infusion, and each infusion will have a total volume of 30mls. Each patient will receive 4 infusions in total over the course of the trial. 22 days of treatment (4 x 96 hour subcutaneous infusions of combination naltrexone / flumazenil with a 6 day intermission) will occur.

Participants will be patients presenting to Currumbin Clinic as inpatients or outpatients primarily for treatment of major depressive disorder. Patients will be screened for eligibility and offered to participate in the study during an appointment with the chief investigator.

The infusion apparatus will be a Springfusor device, 30ml, with flow rate limited tubing. A sterile 25 gauge butterfly needle will be inserted into the subcutaneous tissue of the abdomen for each infusion, using a clean technique.

Fixomull with or without crepe bandages will be required to secure the infusion to the abdomen. No formal monitoring of adherence is possible due to the prolonged and continuous nature of the treatments, but disturbance of the infusion apparatus would be noticed when the investigator is changing or removing the infusion.
Intervention code [1] 316798 0
Treatment: Drugs
Comparator / control treatment
The proposed intervention is an open label, proof of concept trial without a control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322813 0
To assess if combined and repeated subcutaneous microdoses of naltrexone and flumazenil are effective and safe in the management of treatment resistant major depressive disorder as measured by the Montgomery-Asberg Depression Rating Scale.
Timepoint [1] 322813 0
The baseline primary outcome will be assessed prior to commencement of treatment.

During treatment, the primary outcome will assessed at days 4, 8, 14, 18, 22.

The primary outcome will then be re-assessed 6 weeks and 12 weeks following completion of treatment.
Primary outcome [2] 326845 0
To assess if combined and repeated subcutaneous microdoses of naltrexone and flumazenil are effective and safe in the management of treatment resistant major depressive disorder as measured by the Snaith Hamilton Pleasure Scale.
Timepoint [2] 326845 0
The baseline primary outcome will be assessed prior to commencement of treatment.

The primary outcome will then be re-assessed 6 weeks and 12 weeks following completion of treatment.
Primary outcome [3] 326846 0
To assess if combined and repeated subcutaneous microdoses of naltrexone and flumazenil are effective and safe in the management of treatment resistant major depressive disorder as measured by the Beck Depression Inventory.
Timepoint [3] 326846 0
The baseline primary outcome will be assessed prior to commencement of treatment.

The primary outcome will then be re-assessed 6 weeks and 12 weeks following completion of treatment.
Secondary outcome [1] 379879 0
To assess whether improvements in functioning are associated with this treatment as assessed by the Social and Occupational Functioning Assessment Scale.
Timepoint [1] 379879 0
The baseline secondary outcome will be assessed prior to commencement of treatment.

During treatment, the secondary outcome will assessed at days 4, 8, 14, 18, 22.

The secondary outcome will then be re-assessed 6 weeks and 12 weeks following completion of treatment.
Secondary outcome [2] 392879 0
To assess whether improvements in comorbidities are associated with this treatment as assessed by the Beck Anxiety Inventory.
Timepoint [2] 392879 0
The baseline secondary outcome will be assessed prior to commencement of treatment.

The secondary outcome will then be re-assessed 6 weeks and 12 weeks following completion of treatment.

Eligibility
Key inclusion criteria
Major Depressive Disorder, with any current symptoms according to DSM criteria. There will be no inclusion criteria based on symptom range or severity.

Treatment resistance defined as 3 (three) or more failed trials of antidepressant treatments of adequate dose and duration, which can include neurostimulation and/or completed structured psychotherapy.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they suffer hepatitis or hepatic failure, severe immunosuppression, multiple sclerosis, epilepsy or have a history of seizures, organ transplantation, are pregnant or are breastfeeding, take >5mg daily dose equivalent of Diazepam, are under 18 years of age or are unable or unwilling to provide informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable to open label trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable to open label trial.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data will be analysed using SPSS. Paired t-tests with bonferonni corrections will be used to compare psychometric test results within samples.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
7/04/2021
Actual
22/04/2021
Date of last participant enrolment
Anticipated
1/08/2022
Actual
22/08/2022
Date of last data collection
Anticipated
30/11/2022
Actual
23/11/2022
Sample size
Target
10
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 15817 0
Currumbin Clinic - Currumbin
Recruitment postcode(s) [1] 29253 0
4223 - Currumbin

Funding & Sponsors
Funding source category [1] 304907 0
Commercial sector/Industry
Name [1] 304907 0
Trexapharm Pty Ltd
Country [1] 304907 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Trexapharm Pty Ltd
Address
9A/204 Alice St, Brisbane QLD Australia 4000
Country
Australia
Secondary sponsor category [1] 305250 0
None
Name [1] 305250 0
Address [1] 305250 0
Country [1] 305250 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305316 0
GRIFFITH UNIVERSITY HUMAN RESEARCH ETHICS COMMITTEE
Ethics committee address [1] 305316 0
Office for Research
Griffith University
Level O, Bray Centre
170 Kessels Road
Nathan
QLD
4111
Australia
Ethics committee country [1] 305316 0
Australia
Date submitted for ethics approval [1] 305316 0
18/12/2020
Approval date [1] 305316 0
11/01/2021
Ethics approval number [1] 305316 0
GU Ref No: 2020/772

Summary
Brief summary
Major Depressive Disorder is a leading cause of death and disability worldwide. Although the uptake of treatment varies between nations and amongst socio-demographic groups, overall there is a considerable unmet need for treatment. Many reasons exist for this, including lack of education, social stigma, limited treatment options and unaffordability.

There is increasing interest in repurposing and repositioning of extant compounds in the management of mental illnesses, partly due to the retreat of pharmaceutical companies in neurosciences potentially as a result of lengthy approval processes for new discoveries, poor or delayed returns on investment relative to the investment risks, and logistical barriers.

The investigational agents, Naltrexone and Flumazenil, both have existing uses in medicine and psychiatry around the world, but both may offer unique mechanisms of action in the treatment of depression contingent upon the doses utilised. Both have short elimination half-lives in the human body and have either a low oral bioavailability and/or short duration of action.

Subcutaneous infusions allow for pulsatile, sustained and predictable delivery of the investigational agents in an ambulatory setting.

The investigational agents will be combined into a 4 day infusion, and each infusion will have a total volume of 30mls. In total, each participant will receive 4 infusions with a break between the 2nd and 3rd infusions. There is no proposal for ongoing treatment.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 99970 0
Dr Tim MacDonald
Address 99970 0
Currumbin Clinic
37 Bilinga St
Currumbin
QLD
4223
Australia
Country 99970 0
Australia
Phone 99970 0
+61 755259683
Fax 99970 0
+61 755259686
Email 99970 0
[email protected]
Contact person for public queries
Name 99971 0
Tim MacDonald
Address 99971 0
Currumbin Clinic
37 Bilinga St
Currumbin
QLD
4223
Australia
Country 99971 0
Australia
Phone 99971 0
+61 755259683
Fax 99971 0
+61 755259686
Email 99971 0
[email protected]
Contact person for scientific queries
Name 99972 0
Tim MacDonald
Address 99972 0
Currumbin Clinic
37 Bilinga St
Currumbin
QLD
4223
Australia
Country 99972 0
Australia
Phone 99972 0
+61 755259683
Fax 99972 0
+61 755259686
Email 99972 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.