Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000777796
Ethics application status
Approved
Date submitted
13/05/2022
Date registered
31/05/2022
Date last updated
1/03/2024
Date data sharing statement initially provided
31/05/2022
Date results information initially provided
1/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised placebo-controlled trial examining the efficacy and safety of an adjunct herbal medicine formulation in patients with major depressive disorder and poor response to anti-depressant therapy
Scientific title
A randomised placebo-controlled trial examining the efficacy and safety of an adjunct herbal medicine formulation in patients with major depressive disorder and poor response to anti-depressant therapy
Secondary ID [1] 307119 0
Nil known
Universal Trial Number (UTN)
U1111-1278-2504
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 326284 0
Anxiety 326285 0
Condition category
Condition code
Mental Health 323598 323598 0 0
Depression
Mental Health 323599 323599 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants enrolled in the trial will receive either Active tablets or Placebo tablets as an adjunct prescription to their existing anti-depressant medication. Participants will be directed to take two tablets, orally, twice daily, two in the morning and two in the evening (total of 4 tablets per day).
All participants will be randomised to either Active or Placebo study medication for eight weeks.
- Active Tablets contain four concentrated herbal extracts (dry herb equivalent): Curcuma longa rhizome (6.4 g), Boswellia serrata resin (1.5 g), Bupleurum falcatum root (750 mg), and Centella asiatica leaf (1.5 g). Compliance will be assessed through count of return tablets.
Intervention code [1] 323577 0
Treatment: Other
Comparator / control treatment
- Placebo Tablets contain microcrystalline cellulose and excipients for colour matching.
Control group
Placebo

Outcomes
Primary outcome [1] 331370 0
Adequate response to treatment – Yes or No (binary outcome)
Adequate response to treatment defined as an improvement of >50% or more on the Montgomery-Asberg Depression Rating Scale (MADRS)
Timepoint [1] 331370 0
Randomisation and eight weeks after intervention commencement
Secondary outcome [1] 409617 0
Mean Montgomery–Åsberg Depression Rating Scale (MADRS) score
Timepoint [1] 409617 0
Randomisation and eight weeks after intervention commencement
Secondary outcome [2] 409618 0
Mean Beck Depression Inventory II (BDI-II) score
Timepoint [2] 409618 0
Randomisation, four weeks and eight weeks after intervention commencement
Secondary outcome [3] 409619 0
Mean Zung’s self-rating anxiety scale (SAS) score
Timepoint [3] 409619 0
Randomisation, four weeks and eight weeks after intervention commencementent
Secondary outcome [4] 409620 0
Patient Global Impression of Change (PGI-C) - participant self-report of change in mood/ emotional distress
Timepoint [4] 409620 0
Assessed at week four, week eight and at 12 weeks after intervention commencement
Secondary outcome [5] 409621 0
Changes in sleep quality as assessed by PROMIS—Sleep Disturbance—Short Form
Timepoint [5] 409621 0
Randomisation, four weeks and eight weeks after intervention commencement
Secondary outcome [6] 409623 0
Serum level of high sensitivity C-reactive protein (Hs-CRP)
Timepoint [6] 409623 0
Randomisation and eight weeks after intervention commencement

Eligibility
Key inclusion criteria
- Adults (18-65 years) with previously diagnosed depression
- Presents with moderate to severe depression BDI-II score >20 at time of study entry
- Currently taking one of the following anti-depressant types: SSRI, SNRI, alpha-2 agonists (mirtazapine), or bupropion.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Concomitant diagnosis of other DSM-IV mental disorder including but not limited to: personality disorder, substance-related or addictive disorders, bipolar disorder, schizophrenia; or any other neuro-cognitive disorders
- Diagnosed with any of the following medical conditions: cancer (if active within last 10 years), liver or gallbladder disease, kidney disease, neurological disease, advanced type-2 diabetic neuropathy, currently unwell with acute infection or fever
- Abnormal laboratory values (clinically significant abnormal values will result in exclusion)
- In poor general health
- Taking any of the following medications: MAOIs (reversible or non-reversible) or tricyclic anti-depressants; any type of neuro-active medications, i.e. mood stabilisers, stimulants, anti-psychotics; warfarin, anti-platelet or anti-coagulant medications; talinolol
- Current use of specified complementary medicines including, but not limited to; St John’s wort, SAMe, 5-HTP, folic acid >500 mcg/d, omega-3 containing >180 mg EPA/d, zinc >15 mg/d (in such cases a four week washout can be employed before re-screening and potential inclusion)
- Change in anti-depressant medication or dose within the previous four weeks
- Patients with suicidal ideation (4 or higher on MADRS suicidal thoughts domain) at time of study entry
- Three or more failed trials of pharmacotherapy or somatic therapy for the current major depressive episode
- More than ten years of medicated major depressive disorder in current episode
- Recently commenced psychotherapy (>4 weeks of stable treatment acceptable)
- Pregnancy or breastfeeding or planned pregnancy
- Allergy/sensitivity to study drugs or their formulations.

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)
Consecutively numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be conducted using a random numbers table.
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A sample size of 50 patients per treatment group provides 80% power and 0.05 significance to detect a 27% between-treatment group difference in proportions of patients achieving >50% improvement on the MADRAS scale. Finally, 60 patients per treatment group will be enrolled to account for a 20% drop out rate, thus creating a total enrolment of 120 patients.
Descriptive statistics, (means, range, minimum and maximum) will be calculated for all outcomes. A modified intent to treat (ITT) approach will be used for data analysis, where all participants who are randomized, completed baseline and commenced the treatment will be included in the analysis. Comparison of demographics (age, weight, height, BMI and blood pressure) will be assessed at baseline by Chi square. It is anticipated that the primary outcome, the MADRS, measured at baseline and week 8, will be assessed using student T-tests. The secondary outcomes, (questionnaires BDI-II, SAS and PROMIS Sleep Disturbance SF) which are administered at 3 timepoints in the study (baseline, week 4 and week 8) and the PGI-C (week 4, week 8 and week 12) will be analyzed using t-tests and also repeated measures ANOVA with post hoc between group multiple comparisons. The laboratory markers will be assessed by student tests. All tests of treatment effects will be conducted using a two-sided alpha level of 0.05 and 95% confidence intervals.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
14/10/2022
Actual
16/11/2022
Date of last participant enrolment
Anticipated
27/10/2023
Actual
8/09/2023
Date of last data collection
Anticipated
22/12/2023
Actual
10/11/2023
Sample size
Target
120
Accrual to date
Final
96
Recruitment in Australia
Recruitment state(s)
NSW,QLD

Funding & Sponsors
Funding source category [1] 311427 0
Commercial sector/Industry
Name [1] 311427 0
Integria Healthcare (Australia) Pty. Ltd.
Country [1] 311427 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Integria Healthcare (Australia) Pty. Ltd.
Address
Building 5, 2728 Logan Road, Freeway Office Park, Eight Mile Plains, QLD 4113
Country
Australia
Secondary sponsor category [1] 312822 0
None
Name [1] 312822 0
Address [1] 312822 0
Country [1] 312822 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310904 0
National Institute of Integrative Medicine
Ethics committee address [1] 310904 0
11-23 Burwood Rd, Hawthorn, Melbourne Victoria 3122
Ethics committee country [1] 310904 0
Australia
Date submitted for ethics approval [1] 310904 0
04/11/2021
Approval date [1] 310904 0
20/01/2022
Ethics approval number [1] 310904 0
0094E_2021

Summary
Brief summary
Anti-depressants are a commonly used medication in Australia, with over 15 million prescriptions dispensed in 2018-2019 (Australian Institute of Health and Welfare 2019). However, the response to anti-depressants is varied, and some patients experience flatline emotion, ongoing depression, decreased cognition, changes in sexual function/desire, insomnia, and other symptoms. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed first-line treatment for major depression, however, the rate of treatment response from baseline symptoms following first-line treatment with SSRIs is moderate, varying from 40-60% and lower in subsequent treatment attempts.
There is evidence that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals (Felger and Lotrich 2013), and research supporting anti-inflammatory approaches to depression management has been shown to increase effectiveness of some anti-depressants in clinical trials (Muller, Schwarz et al. 2006, Akhondzadeh, Jafari et al. 2009, Hang, Zhang et al. 2021).
Given the large proportion of patients who do not respond adequately to first-line therapy, or experience negative side-effects, incorporating adjunct treatments may need to be considered. Certain herbal medicines may be able to assist treatment response by decreasing inflammation and reducing side effects.
It is hypothesised that specific anti-inflammatory and anti-depressant herbs may effect a clinically meaningful improvement when added as an adjunct to existing anti-depressants in patients with poor response to anti-depressant therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119294 0
Dr Elizabeth Steels
Address 119294 0
Evidence Sciences, Unit 2, 884 Brunswick street, New Farm, Qld, 4005
Country 119294 0
Australia
Phone 119294 0
+61 431 003 929
Fax 119294 0
Email 119294 0
drbeth@evidencesciences.com.au
Contact person for public queries
Name 119295 0
Dr Elizabeth Steels
Address 119295 0
Evidence Sciences, Unit 2, 884 Brunswick street, New Farm, Qld, 4005
Country 119295 0
Australia
Phone 119295 0
+61 431 003 929
Fax 119295 0
Email 119295 0
drbeth@evidencesciences.com.au
Contact person for scientific queries
Name 119296 0
Dr Elizabeth Steels
Address 119296 0
Evidence Sciences, Unit 2, 884 Brunswick street, New Farm, Qld, 4005
Country 119296 0
Australia
Phone 119296 0
+61 431 003 929
Fax 119296 0
Email 119296 0
drbeth@evidencesciences.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data for published outcomes
When will data be available (start and end dates)?
Up to a period of 2 years after publication
Available to whom?
Researchers with a methodologically sound proposal or on a case-by-case basis at the discretion of the Sponsor
Available for what types of analyses?
meta-analysis
How or where can data be obtained?
Access subject to approval by Principal Investigator. An email requesting permission may be sent to the Principal Investigator at drbeth@evidencesciences.com.au


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.