Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000881730
Ethics application status
Approved
Date submitted
13/05/2022
Date registered
21/06/2022
Date last updated
3/04/2024
Date data sharing statement initially provided
21/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Low-dose naltrexone as an adjunctive treatment in major depressive disorder.
Scientific title
A randomised, double-blind, placebo-controlled, hybrid parallel arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder
Secondary ID [1] 306661 0
Nil known
Universal Trial Number (UTN)
U1111-1279-1773
Trial acronym
NALDEP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major depressive disorder (MDD) 325690 0
Condition category
Condition code
Mental Health 323039 323039 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention, low-dose naltrexone (LDN), consists of 1.5 mg of naltrexone hydrochloride with microcrystalline cellulose (MCC) within a gelatine capsule shell. Participants in the durability arm will take 1 capsule orally once daily at night for 1 week, then 2 capsules at night for 1 week, then 3 capsules (4.5 mg) orally once daily at night for 10 weeks. This dosing schedule will be repeated again at 12 weeks, the beginning of the 12 week open-label extension, to maintain blinding. If participants experience adverse effects, the dose may be titrated down to either 2 capsules daily or 1 capsule twice daily.

An unblinded pharmacist independent of the study team will dispense the interventions to participants once a month. At the end of each month participants will return their capsule bottles, and the number of capsules left in the bottle will be used to calculate intervention compliance. Participants will be contacted by the study team after the day of medication delivery at 1 day, 3 days, 1 week, 2 weeks , 4 weeks, 8 weeks, 12 weeks, 13 weeks, 14 weeks, 16 weeks and 20 weeks to remind participants to adhere to study protocols and to check for adverse effects.
Intervention code [1] 323160 0
Treatment: Drugs
Comparator / control treatment
The placebo is microcrystalline cellulose (MCC) within a gelatine capsule shell, taken orally once daily at night. Participants in the placebo arm will take 1 placebo capsule orally once daily at night for 1 week, then two capsules at night for 1 week, then 3 capsules at night for 10 weeks. Then, participants will receive intervention capsules in an open-label extension, starting at one intervention capsule orally once daily at night for 1 week, then two intervention capsules at night for 1 week, then three intervention capsules at night for 10 weeks. There is no wash-out period between these treatments

Healthy controls (n=24) will be recruited to undergo baseline measures only.
Control group
Placebo

Outcomes
Primary outcome [1] 330799 0
Depression assessed by Montgomery- Åsberg depression rating scale (MADRS) score
Timepoint [1] 330799 0
MADRS will be assessed at weeks 0 (baseline), 2, 4, 8, and 12 after starting treatment. The primary endpoint being the fifth assessment in week 12.
Secondary outcome [1] 407601 0
Depression assessed by MADRS score
Timepoint [1] 407601 0
MADRS will continue to be assessed on weeks 14, 16, 20, and 24, after starting treatment. The secondary endpoint being the final assessment in week 24.
Secondary outcome [2] 407699 0
Measurement of serum concentrations of peripheral inflammatory markers including high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1ß IL-2, IL-6, IL-8, IL-10, IL-12p70, tumour necrosis factor alpha (TNF-a), interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), erythrocyte sedimentation rate (ESR), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) and glycoprotein nonmetastatic melanoma protein B (GPNMB).
Timepoint [2] 407699 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [3] 407700 0
Changes in brain tissue composition indicated by magnetisation transfer exchange measured from magnetisation-weighted magnetic resonance imaging (MRI) scan
Timepoint [3] 407700 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [4] 407701 0
Changes in brain temperature measured by echo-planar spectroscopic imaging MRI scan
Timepoint [4] 407701 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [5] 407702 0
Changes in brain tissue composition measured by diffusion-weighted measures obtained from diffusion weighted MRI scans
Timepoint [5] 407702 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [6] 407704 0
Attention indicated by electroencephalography (EEG) - Attention network task
Timepoint [6] 407704 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [7] 407705 0
Brain response to violations of a rule indicated by EEG - mismatch negativity
Timepoint [7] 407705 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [8] 407707 0
Memory indicated by EEG - Long term potentiation
Timepoint [8] 407707 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [9] 407710 0
Intrinsic brain activity indicated by EEG - Resting state tasks
Timepoint [9] 407710 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [10] 407711 0
Reward responsiveness indicated by EEG - Doors task
Timepoint [10] 407711 0
Measurements will. be taken at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third measurements at 12 and 24 weeks.
Secondary outcome [11] 407715 0
Profile of Mood States (POMS)
Timepoint [11] 407715 0
POMS will. be assessed at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessments at 12 and 24 weeks.
Secondary outcome [12] 407717 0
Beck Depression Inventory (BDI)-II score
Timepoint [12] 407717 0
BDI-II will. be assessed at baseline, 2, 4, 8, 12, 14, 16, 20 and 24 weeks after starting treatment, with the endpoint being the assessment at 12 and 24 weeks.
Secondary outcome [13] 407718 0
Behavioural Activation for Depression Scale (BADS) score
Timepoint [13] 407718 0
BADS will. be assessed at baseline, 2, 4, 8, 12, 14, 16, 20 and 24 weeks after starting treatment, with the endpoint being the assessment at 12 and 24 weeks.
Secondary outcome [14] 407719 0
Quality of Life assessed by Short Form (SF) 36 score
Timepoint [14] 407719 0
SF 36 will be assessed at baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [15] 407720 0
General Assessment of Side Effects (GASE)
Timepoint [15] 407720 0
GASE will. be assessed at baseline, 1, 2, 4, 8, 12, 13, 14, 16, 20 and 24 weeks after starting treatment.
Secondary outcome [16] 407783 0
Expectancy assessed using the Stanford Expectations of Treatment Scale (SETS)
Timepoint [16] 407783 0
Baseline and 12 weeks after starting treatment
Secondary outcome [17] 410047 0
Attention and executive function indicated by Flanker Inhibitory Control and Attention test (NIH Cognition Battery)
Timepoint [17] 410047 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [18] 410154 0
Executive function indicated by Dimensional Change Card Sort Test (NIH cognition battery)
Timepoint [18] 410154 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [19] 410155 0
Episodic memory indicated by Picture Sequence Memory Test (NIH cognition battery)
Timepoint [19] 410155 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [20] 410156 0
Working memory indicated by List Sorting Working Memory Test (NIH cognition battery)
Timepoint [20] 410156 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [21] 410157 0
Processing speed indicated by Pattern Comparison Processing Speed Test (NIH cognition battery)
Timepoint [21] 410157 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [22] 410158 0
Immediate recall indicated by Auditory Verbal Learning Test (NIH cognition battery)
Timepoint [22] 410158 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [23] 410596 0
Feelings of sickness indicated by Sickness Questionnaire (SicknessQ)
Timepoint [23] 410596 0
Baseline, 12 weeks and 24 weeks after starting treatment, with the endpoint being the second and third assessment at 12 and 24 weeks.
Secondary outcome [24] 412892 0
Depression assessed by MADRS score in the high inflammation group
Timepoint [24] 412892 0
MADRS will be assessed at weeks 0 (baseline), 2, 4, 8 and 12 after starting treatment. The secondary timepoint being the fifth assessment in week 12
Secondary outcome [25] 412893 0
Depression assessed by MADRS score in the low inflammation group
Timepoint [25] 412893 0
MADRS will be assessed at weeks 0 (baseline), 2, 4, 8 and 12 after starting treatment. The secondary timepoint being the fifth assessment in week 12

Eligibility
Key inclusion criteria
Inclusion criteria for participants with depression:
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Male or female, aged 18 to 55 years.
- Diagnosis of MDD as per the Diagnostic and Statistical Manual 5 criteria for MDD
- Experiencing significant depressive symptoms, as indicated by a score greater than or equal to 18 on the MADRS
- Receiving treatment with an antidepressant agent (not greater than Stage II antidepressant resistance as defined by the Thase and Rush treatment-resistant depression staging method)
- Clinically stable for at least four weeks
- hsCRP levels either greater than or equal to 3 mg/L, or less than or equal to 1 mg/L
- Ability to take oral medication and be willing to adhere to the dosing regimen
- Agreement to adhere to Lifestyle Considerations throughout study duration (participants will be asked to abstain from alcohol and drugs for 24 hours before the start of each MRI and EEG session, and have a plan with their doctor to stay on the same antidepressant for at least 12 weeks).

Inclusion criteria for healthy controls:
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Male or female aged 18 to 55 years
-hsCRP levels less than or equal to 1 mg/L
- Agreement to adhere to Lifestyle Considerations throughout study duration (healthy participants will be asked to abstain from alcohol and drugs for 24 hours before the start of each MRI and EEG session)
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for participants with depression:
- Current use of prescription opioid analgesics, psychostimulants, dopamine agonists
- Current use of any opioid-based drugs recreationally
- Any current or past bipolar or psychiatric disorder or psychotic features (other psychiatric conditions such as anxiety will be allowed for individuals with MDD, provided they are not the primary source of the participant’s depressive symptomatology)
- Acute risk of suicide
- Any known neurological disorders or neurodegenerative condition
- Acute infectious pathology, or chronic or acute inflammatory diseases that, in the judgement of the investigators, interferes with study measures or procedures
- Any clinically significant medical conditions, e.g., renal, hepatic, or cardiovascular conditions, uncontrolled thyroid dysfunction, metabolic disorders, cancer, seizure disorders
- Uncontrolled autoimmune diseases or severe chronic pain
- Or any other condition that, in the judgement of the investigators, interferes with study measures or procedures
- Long-term, frequent, anti-inflammatory or immunosuppressive therapy
- Contraindications to MRI or blood tests, including those who refuse to be informed of an incidental finding
- Women who are pregnant or breastfeeding, or women of child-bearing age who are not on a medically acceptable form of contraception
- Substance use disorders within the previous 12 months
- Any allergy or intolerance to naltrexone

Exclusion criteria for healthy controls:
- Current use of any medication other than contraception
- Current use of any opioid-based drugs recreationally
- Any current or past psychiatric conditions
- Any known neurological disorders or neurodegenerative condition
- Acute infectious pathology, or chronic or acute inflammatory diseases
- Any clinically significant medical conditions, e.g., renal, hepatic, or cardiovascular conditions, uncontrolled thyroid dysfunction, metabolic disorders, history of cancer, seizure disorders
- Autoimmune diseases or chronic pain
- Long-term anti-inflammatory or immunosuppressive therapy
- Contra-indications to MRI or blood tests, including those who refuse to be informed of an incidental finding.
- Women who are on hormone suppressants.
- Women who are pregnant or breastfeeding

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 involved contacting the holder of the allocation schedule who was "off-site" and sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
This study will use a randomised, double-blind, placebo controlled, hybrid parallel study design consisting of four arms, two for the high inflammation group (hsCRP greater than or equal to 3mg/ml, n =24), and two for the low inflammation group (hsCRP less than or equal to 1mg/ml, n=24). One arm from each group will receive low dose naltrexone (LDN) for the first 12 weeks (n=12), and the other will receive placebo for the first 12 weeks (n=12). After the initial 12 weeks, there will be a further open-label 12 weeks where all participants receive LDN. Healthy controls (n=24) will be recruited to undergo baseline measures only.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/10/2022
Actual
3/10/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
72
Accrual to date
45
Final
Recruitment outside Australia
Country [1] 24674 0
New Zealand
State/province [1] 24674 0
Auckland

Funding & Sponsors
Funding source category [1] 310989 0
Government body
Name [1] 310989 0
Health Research Council of New Zealand
Country [1] 310989 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 312374 0
None
Name [1] 312374 0
Address [1] 312374 0
Country [1] 312374 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310542 0
Southern Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 310542 0
Ethics committee country [1] 310542 0
New Zealand
Date submitted for ethics approval [1] 310542 0
02/06/2022
Approval date [1] 310542 0
14/06/2022
Ethics approval number [1] 310542 0
12781

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118022 0
Dr Joanne Lin
Address 118022 0
School of Pharmacy
The University of Auckland
Private Bag 92019
Auckland 1142
Country 118022 0
New Zealand
Phone 118022 0
+64 9 923 2255
Fax 118022 0
Email 118022 0
[email protected]
Contact person for public queries
Name 118023 0
Joanne Lin
Address 118023 0
School of Pharmacy
The University of Auckland
Private Bag 92019
Auckland 1142
Country 118023 0
New Zealand
Phone 118023 0
+64 9 923 2255
Fax 118023 0
Email 118023 0
[email protected]
Contact person for scientific queries
Name 118024 0
Joanne Lin
Address 118024 0
School of Pharmacy
The University of Auckland
Private Bag 92019
Auckland 1142
Country 118024 0
New Zealand
Phone 118024 0
+64 9 923 2255
Fax 118024 0
Email 118024 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlies the results reported in any article, after de-identification.
When will data be available (start and end dates)?
Immediately following publication, no end date.
Available to whom?
Researchers who provide a methodologically sound proposal
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approvals by Principal Investigator ([email protected]).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16336Study protocol  [email protected]
16337Informed consent form  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder.2022https://dx.doi.org/10.1186/s13063-022-06738-3
N.B. These documents automatically identified may not have been verified by the study sponsor.