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Trial registered on ANZCTR


Registration number
ACTRN12616000759493
Ethics application status
Approved
Date submitted
5/06/2016
Date registered
9/06/2016
Date last updated
6/05/2019
Date data sharing statement initially provided
6/05/2019
Date results information initially provided
6/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
L-Theanine in the Adjunctive Treatment of Generalised Anxiety Disorder:
A Double-Blind Randomised Placebo-Controlled Trial
Scientific title
L-Theanine in the Adjunctive Treatment of Generalised Anxiety Disorder:
A Double-Blind Randomised Placebo-Controlled Trial
Secondary ID [1] 289371 0
Nil
Universal Trial Number (UTN)
Trial acronym
TAGS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Generalized Anxiety Disorder 299002 0
Condition category
Condition code
Mental Health 299063 299063 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
L-theanine capsules (each capsule contains 225mg of L-theanine and 25mg excipients).

One capsule will be taken orally twice per day (totaling 450mg L-theanine OR placebo) for the first four weeks of the the trial. In cases of non-response (determined by reduction in SIGH-A score <35% from baseline), the dose will be doubled (2 capsules twice per day; equating to 900mg L-theanine OR placebo) from week-4 onwards.

All participants will receive placebo capsules (microcellulose) in a single blinded manner for the final 2-weeks of the trial (placebo run-out from week-8 to week-10).

Participants will be required to take the capsules as instructed during the 10 weeks of the study. At each follow-up visit, the participants will be asked to return their current treatment container with any remaining capsules inside. These will be counted and recorded to determine participant compliance to the treatment regime.
Intervention code [1] 294958 0
Treatment: Drugs
Comparator / control treatment
Placebo (microcellulose) capsules taken in the same dosage regime as listed above (1 capsule bid from week-0 to week-4, Increased to 2 bid in cases of non-response from week-4 onwards). All participants will receive placebo from week-8 to week-10 in a single blinded manner (placebo run out).
Control group
Placebo

Outcomes
Primary outcome [1] 298537 0
Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A)
Timepoint [1] 298537 0
The SIGH-A will be administrated at baseline (week-0), week-2, week-4, week-6, week-8 and week-10.
Secondary outcome [1] 324510 0
Structured guide for the Montgomery–Asberg Depression Rating Scale (SIMGA)
Timepoint [1] 324510 0
The SIGMA will be administrated at will be administrated at baseline (week-0), week-2, week-4, week-6, week-8 and week-10.
Secondary outcome [2] 324511 0
Penn State Worry Questionnaire (PSWQ)
Timepoint [2] 324511 0
The PSWQ will be given to participants to complete at baseline (week-0), week-2, week-4, week-6 and week-8. Note, the PSWQ will not be used at week-10 (after the 2-week placebo run-out).
Secondary outcome [3] 324512 0
WHO Quality of Life – BREF (WHOQOL-BREF)
Timepoint [3] 324512 0
(WHOQOL-BREF) will be given to participants to complete at baseline (week-0) and week-8 only.
Secondary outcome [4] 324513 0
Insomnia Severity Index (ISI)
Timepoint [4] 324513 0
The ISI will be given to participants to complete at baseline (week-0), week-2, week-4, week-6 and week-8. Note, the ISI will not be used at week-10 (after the 2-week placebo run-out).
Secondary outcome [5] 324514 0
The Emotional Stroop Task
Timepoint [5] 324514 0
The Emotional Stroop task will be administrated at Week-0 and Week-8 to assess for potential effects of the investigational product (IP) on cognitive function, particularly attentional biases
Secondary outcome [6] 324541 0
Beck Anxiety Inventory (BAI)
Timepoint [6] 324541 0
The BAI will be given to participants to complete at baseline (week-0), week-2, week-4, week-6 and week-8. Note, the BAI will not be used at week-10 (after the placebo run-out).
Secondary outcome [7] 324543 0
Side-effects assessment scale (SAFTEE).

A key animal model study evaluated the safety of L-theanine administered as a dietary admixture to male and female rats at concentrations providing doses of 0, 1500, 3000 or 4000 mg/kg per day for 13 weeks (Borzelleca, Peters et al. 2006). Results revealed there were no consistent, statistically significant treatment-related adverse effects on behaviour, morbidity, mortality, body weight, clinical chemistry, hematology, or urinalysis. There were no consistent treatment-related adverse effects in gross pathology, organ weights or ratios or histopathology. Studies in humans highlight no clinically significant side effects observable in vital signs, electrocardiograms or clinical laboratory markers when L-theanine was used adjunctively to anti-psychotic medication (Ritsner et al., 2011). Other research has found that the compound has neuroprotective properties (Kim, Lee et al. 2009); immune modulating activity (Bukowski and Percival 2008); and hepatoprotective effects (Li, Ye et al. 2012).
Timepoint [7] 324543 0
The SAFTEE will be given to participants to complete at week-2, week-4, week-6, week-8 and week-10
Secondary outcome [8] 324544 0
Trail Making B
Timepoint [8] 324544 0
The Trail Making B task will be administrated at baseline (week-0) and week-8 to assess for any change in participant's processing speed, mental flexibility and executive functions.

Eligibility
Key inclusion criteria
1. Aged between 18-70 years
2. Meets the DSM-IV and DSM-5 diagnostic criteria for generalised anxiety disorder (GAD) based on structured interview (Mini International Neuropsychiatric Interview- 6.0 [MINI 6.0]. Note that while the MINI 6.0 uses the DSM-IV criteria, the same criteria are used in the DSM-5)
3. Currently taking an antidepressant for anxiety
4. Presents with anxiety (SIGH-A score equal to or greater than 16) at the time of study entry
5. Fluent in spoken and written English
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Primary diagnosis other than GAD
2. Presentation of moderate to severe depressive symptoms (SIGMA score equal to or greater than 16) at time of study entry
3. Presentation of suicidal ideation (score of 3 or greater on SIGMA suicidal thoughts domain) at time of study entry
4. Current diagnosis of a psychotic disorder (bipolar disorder I, schizophrenia) or Major Depressive Disorder (current episode) on structured interview (MINI 6.0)
5. Current substance/alcohol use disorder on structured interview (MINI 6.0)
6. Three or more failed trials of antidepressant pharmacotherapy for the current GAD episode. A failed trial is defined as limited improvement (equal to or less than 50% improvement) in symptoms after trialing an antidepressant for an adequate dose and duration (recommended therapeutic dose for at least 4 weeks).
7. Drinking more than 3 cups of tea (in any form e.g. black or green) per day
8. Recently commenced psychotherapy (within four weeks of study entry)
9. Known or suspected clinically unstable systemic medical disorder (e.g. cancer, organ failure) or at the discretion of the medical investigators.
10. Pregnancy or breastfeeding, or trying to conceive
11. Not using a medically approved form of contraception (including abstinence) if female and of childbearing age
12. Unable to participate in all scheduled visits, treatment plan, tests and other trial procedures according to the protocol

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each set of treatments for Weeks 0 to 8 will be coded with a treatment number which has been randomly allocated to a treatment arm using permuted block randomisation. An independent researcher will develop a computer-generated randomisation plan utilising a predetermined design for two treatment arms and will label bottles with their treatment numbers accordingly. Trial clinicians will then allocate treatment numbers sequentially to enrolled participants.
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
From Week-8 to Week-10, all participants will receive placebo capsules (placebo run out and remain blinded). However, researchers will be unblinded for this period of the study.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We will recruit a sample size of 78 participants (39/39 participants in each arm). The study is powered to detect a small to moderate difference between L-theanine and placebo on the efficacy outcome (using data with at least one post-baseline measurement in intention-to-treat analysis). As a small to moderate effect size F of 0.25 is expected with L-theanine over placebo on the SIGH-A, for a two tailed analysis with alpha=0.05 and the study powered at 80% (Z beta=0.80) with a correlation among repeated measures (ANOVA model) over five time-points of 0.5, 78 participants are required (critical F2,77 of 3.97).

Analysis of data will be conducted with blinding to group allocations. The primary efficacy analysis will assess average treatment group differences for the primary outcome measure (SIGH-A) over the entire study period and use a likelihood based mixed-effects model, repeated measures approach (MMRM). Results from the analysis of dichotomous data (e.g. demographics and genetic data) will be presented as proportions (e.g. Relative Risks), with 95% confidence interval, and Fisher’s Exact p-value where appropriate. Non-parametric statistics will be used when assumptions for parametric methods are violated. Cohen’s d effect sizes will be calculated. All tests of treatment effects will be conducted using a two-sided alpha level of 0.05 and 95% confidence intervals. Data will be analysed using SPSS 23.0.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
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)
NSW,QLD,VIC
Recruitment hospital [1] 5911 0
The Melbourne Clinic - Richmond
Recruitment hospital [2] 5912 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 13357 0
3121 - Richmond
Recruitment postcode(s) [2] 13359 0
4006 - Herston
Recruitment postcode(s) [3] 16402 0
2560 - Campbelltown

Funding & Sponsors
Funding source category [1] 293750 0
University
Name [1] 293750 0
University of Melbourne
Address [1] 293750 0
Parkville, Melbourne, VIC, 3052
Country [1] 293750 0
Australia
Primary sponsor type
Individual
Name
Dr. Jerome Sarris
Address
The University of Melbourne, Department of Psychiatry
2 Salisbury St, Richmond, VIC, 3121
Country
Australia
Secondary sponsor category [1] 292579 0
None
Name [1] 292579 0
Address [1] 292579 0
Country [1] 292579 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295187 0
The Melbourne Clinic Research Ethics Committee (TMCREC)
Ethics committee address [1] 295187 0
2 Salisbury St, Richmond, VIC 3121
Ethics committee country [1] 295187 0
Australia
Date submitted for ethics approval [1] 295187 0
24/11/2015
Approval date [1] 295187 0
16/12/2015
Ethics approval number [1] 295187 0
Ethics committee name [2] 297930 0
Western Sydney University Human Research Ethics Committee
Ethics committee address [2] 297930 0
Penrith Campus
Great Western Highway
Werrington
NSW 2747
Ethics committee country [2] 297930 0
Australia
Date submitted for ethics approval [2] 297930 0
22/05/2017
Approval date [2] 297930 0
05/06/2017
Ethics approval number [2] 297930 0
EC00380
Ethics committee name [3] 297931 0
UQ Medical Research Ethics Committee (MREC)
Ethics committee address [3] 297931 0
University of Queensland (UQ)
Level 3, Brian Wilson Chancellery
The University of Queensland
St Lucia QLD 4072, Australia
Ethics committee country [3] 297931 0
Australia
Date submitted for ethics approval [3] 297931 0
18/05/2016
Approval date [3] 297931 0
10/06/2016
Ethics approval number [3] 297931 0
2016000774

Summary
Brief summary
The objective of this trial is to assess the effectiveness and safety of L-theanine (an amino acid constituent of green tea [Camellia sinensis]) as an adjunctive therapy to treat GAD by conducting a phase II double-blind randomised controlled trial. It is hypothesised that L-theanine will be superior to placebo in reducing anxiety in participants with GAD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66442 0
Dr Jerome Sarris
Address 66442 0
University of Melbourne, Department of Psychiatry
2 Salisbury St, Richmond, VIC, 3121
Country 66442 0
Australia
Phone 66442 0
+61394874748
Fax 66442 0
Email 66442 0
jsarris@unimelb.edu.au
Contact person for public queries
Name 66443 0
Miss Georgina Oliver
Address 66443 0
University of Melbourne, Department of Psychiatry
2 Salisbury St, Richmond, VIC, 3121
Country 66443 0
Australia
Phone 66443 0
+61394874748
Fax 66443 0
Email 66443 0
georgina.oliver@unimelb.edu.au
Contact person for scientific queries
Name 66444 0
Miss Georgina Oliver
Address 66444 0
University of Melbourne, Department of Psychiatry
2 Salisbury St, Richmond, VIC, 3121
Country 66444 0
Australia
Phone 66444 0
+61394874748
Fax 66444 0
Email 66444 0
georgina.oliver@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participants in the trial did not consent to this
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 2003 0
Sarris, J., Byrne, G. J., Cribb, L., Oliver, G., Murphy, J., Macdonald, P., ... & Ee, C. (2019). L-theanine in the adjunctive treatment of generalized anxiety disorder: A double-blind, randomised, placebo-controlled trial. Journal of psychiatric research, 110, 31-37.
Attachments [1] 2003 0
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
Partial or non-response to antidepressants in Generalized Anxiety Disorder (GAD) is common in clinical settings, and adjunctive biological interventions may be required. Adjunctive herbal and nutraceutical treatments are a novel and promising treatment option. L-theanine is a non-protein amino acid derived most-commonly from tea (Camellia sinensis) leaves, which may be beneficial in the treatment of anxiety and sleep disturbance as suggested by preliminary evidence. We conducted a 10-week study (consisting of an 8-week double-blind placebo-controlled controlled period, and 1-week pre-study and 2-week post-study single-blinded observational periods) involving 46 participants with a DSM-5 diagnosis of GAD. Participants received adjunctive L-theanine (450-900mg) or matching placebo with their current stable antidepressant treatment, and were assessed on anxiety, sleep quality, and cognition outcomes. Results revealed that adjunctive L-theanine did not outperform placebo for anxiety reduction on the HAMA (p = 0.73) nor insomnia severity on the Insomnia Severity Index (ISI; p = 0.35). However, LT treated participants reported greater self-reported sleep satisfaction than placebo (ISI item 4; p = 0.015). Further, a separation in favour of L-theanine was noted on the ISI in those with non-clinical levels of insomnia symptoms (ISI = 14; p = 0.007). No significant cognitive effects (trail making time and the modified emotional Stroop) were revealed.