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Trial registered on ANZCTR


Registration number
ACTRN12619000067178
Ethics application status
Approved
Date submitted
26/11/2018
Date registered
17/01/2019
Date last updated
8/02/2023
Date data sharing statement initially provided
17/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of zinc and B6 on individuals with anxiety: A double blind, randomised, placebo controlled trial.
Scientific title
Effect of zinc and vitamin B6 in the treatment of adults with symptoms of generalized anxiety: a double blind, randomised placebo-controlled trial
Secondary ID [1] 296453 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Generalized Anxiety 310237 0
Social Anxiety 310238 0
Condition category
Condition code
Mental Health 308962 308962 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dose of intervention is 100 mg of zinc and 100 mg of vitamin B6 as pyrodoxine and 50 mg of vitamin B6 as P5P.
Duration of intervention is 6 weeks.
Mode of administration is an oral tablet.
Participants will be required to return any unused supplements as a measure of adherence.

The same participants (both placebo and treatment) will then be offered treatment for a further 6 weeks in an open label phase of the study. The duration between phases will be 7 days.

During open label participants will be offered dose of is 100 mg of zinc and 100 mg of vitamin B6 as pyrodoxine and 50 mg of vitamin B6 as P5P.
Duration of open label is 6 weeks.
Mode of administration is an oral tablet.
Participants will be required to return any unused supplements as a measure of adherence.
Intervention code [1] 312778 0
Treatment: Other
Comparator / control treatment
Microcellulose placebo tablet. The control group will have the opportunity to participate in the open-label phase of the study.
Control group
Placebo

Outcomes
Primary outcome [1] 307930 0
Generalized Anxiety Disorder 7-item (GAD-7) scale
(Spitzer, Kroenke, Williams, & Löwe, 2006)
Timepoint [1] 307930 0
The GAD-7 will be assessed during screening, baseline and through RCT (0-42 days), 14 days, 28 days and 42 days. With baseline and 42 days being primary time points. At completion of open label (day 84) and 3, 6 and 12 months following completion of the open label phase.
Primary outcome [2] 307931 0
Modified Clinical Global Impressions (CGI-I) (Spearing, Post, Leverich, Brandt, & Nolen, 1997)
Timepoint [2] 307931 0
End of RCT (day 42) and day 42 of open label
Secondary outcome [1] 353372 0
Modified Antidepressant Side-Effect Checklist (ASEC) (Uher et al., 2009)
Timepoint [1] 353372 0
Baseline, Day 14, 28 and 42 of the RCT and day 14, 28 and 42 of the open label phase.
Secondary outcome [2] 353373 0
Social Phobia and Anxiety Scale – 18 (SPAI-18) (de Vente, Majdandžic, Voncken, Beidel, & Bögels, 2014)
Timepoint [2] 353373 0
Baseline, day 42 of the RCT, day 42 of the open label (OL) phase and at month 3, 6 and 12 of the naturalistic follow up.
Secondary outcome [3] 353374 0
Profile of Mood States – Short Form (POMS-SF) (Curran, Andrykowski, & Studts, 1995)
Timepoint [3] 353374 0
Baseline, on day 42 of the RCT, day 42 of the OL and at month 3, 6 and 12 of the naturalistic follow up.
Secondary outcome [4] 354108 0
Urine hydroxyhemoppyrrole-2-one (HPL)
Timepoint [4] 354108 0
Baseline and on day 42 of the RCT.
Secondary outcome [5] 354110 0
Depression, Anxiety and Stress Scale (DASS)- 21 (Lovibond & Lovibond, 1995)
Timepoint [5] 354110 0
Baseline, on day 42 of RCT, day 42 of the OL phase and at month 3, 6 and 12 of the naturalistic follow up.
Secondary outcome [6] 354111 0
General Health Questionnaire 60 (GHQ-60) (Goldberg & Hillier, 1979)
Timepoint [6] 354111 0
Baseline, on day 42 of the RCT, day 42 of the OL phase and at month 3, 6 and 12 into the naturalistic follow up
Secondary outcome [7] 354112 0
Quality of Life Scale (QOLS) (Burckhardt & Anderson, 2003)
Timepoint [7] 354112 0
Baseline, on day 21 and day 42 of the RCT, on day 42 of the OL phase and at month 3, 6 and 12 into the naturalistic follow up.
Secondary outcome [8] 354115 0
Walsh/Jaa Pyroluria Questionnaire (WJPQ) (Walsh & Jaa, 2017)
Timepoint [8] 354115 0
Baseline and on day 42 of the RCT
Secondary outcome [9] 354116 0
Practitioner Pyrroles Screening Questionnaire (PPSQ) (Larson, 2011)
Timepoint [9] 354116 0
Baseline and on day 42 of the RCT
Secondary outcome [10] 354117 0
Eysenck Personality Questionnaire (EPQ-R) (Eysenck, Eysenck, & Barrett, 1985)
Timepoint [10] 354117 0
Baseline - used as a predictor
Secondary outcome [11] 354118 0
Treatment Satisfaction Questionnaire for Medication – 14 (TSQM-14) (Atkinson et al., 2004)
Timepoint [11] 354118 0
Day 42 of the RCT and on day 42 of the OL phase and month three, six and 12 of the naturalistic follow up
Secondary outcome [12] 354119 0
Eating Behaviours Questionnaire (Baker, Little, & Brownell, 2003)
Timepoint [12] 354119 0
Baseline, on day 42 of the RCT and on day 42 of the OL phase

Eligibility
Key inclusion criteria
Eligible participants will be: 1) Aged 18 years and older; 2) not be on any medications for the treatment of anxiety; 3) score above 10 on the GAD-7; 4) considered reliable and compliant with the protocol.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they: 1) have a history of a chronic health issue with acute attacks (e.g. advanced ulcerative colitis); 2) are known to be intolerant to nutritional supplements; 3) are known to be allergic to the ingredients of the intervention; 4) are unable to give written informed consent; 5) are pregnant; 6) are currently taking antibiotics, altretamine (antineoplastic agent) or amiodarone (antiarrhythmic medication), (Yetley, 2007), 7) any psychiatric medications such as antidepressants, anxiolytics, antipsychotics, and 8) any major psychiatric condition or serious medical condition likely to require hospitalization (e.g. Psychotic Disorders; Bipolar Disorders).

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)
The study pharmacist will utilise a randomisation sequence to allow the correct packaging of the active and placebo treatments. The study pharmacist will then use a sealed opaque envelope to record this information for each participant
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be computer-generated by an independent researcher using the website: http://www.randomization.com and will be arranged in a 1:1 ratio using blocks of 4.
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
Other
Other design features
RCT phase followed by an open label phase
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Effect sizes for mental health interventions, specifically anxiety associated conditions range from 0.33 to 0.36 for placebo (Acarturk, Cuijpers, Van Straten, & De Graaf, 2009; Power et al., 1990; Zhang et al., 2013; Zhang, Connor, & Davidson, 2005), 0.95 for self-help (Andersson et al., 2005), 0.71 to 1.81 for Cognitive Behavior Therapy (CBT) (Acarturk et al., 2009; Bandelow et al., 2015; Power et al., 1990) and 1.42 to 2.86 for medications (Bandelow et al., 2015; Zhang et al., 2005). In micronutrient interventions on mood and behaviour, Kaplan et al. (2001) reported Cohen’s d higher than 0.80 for three treatment outcomes. When examining stress and anxiety reductions associated with micronutrient supplementation, Rucklidge, Blampied, Gorman, Gordon, and Sole (2014) found effect sizes of 0.69 to 1.31; similarly, Kaplan, Rucklidge, Romijn, and Dolph (2015) found effect sizes of 0.76 to 1.08 of micronutrients compared to a single vitamin (D) nutrient. When comparing against placebo, Power et al. (1990) found treatment compared to waitlist had an effect size of 0.86, compared to psychological placebo (d = 0.34), and pill placebo (d = 0.36). Solati et al. (2015) found zinc significantly decreased depression in 46 participants with an effect size of d=0.82. Based on this study and within the background context of effect sizes looking at broad spectrum micronutrients and mental health, it is reasonable to assume a large effect size (> d=0.80) on the treatment group if the research hypothesis is to be accepted. For the calculation of the sample size a medium effect size will be used, d=0.60. Significance will be set at 0.05. Attrition rates for micronutrient studies of similar length average 16% (16 week trial) (Sarris et al., 2012). Andersson et al. (2005) also had attrition rates of 16% on an eight-week internet based self-help experimental design. Based on these attrition rates, a 20% attrition rate will be built into the design of this study.
At d=0.60 and an attrition rate of 20% 108 subjects will be required, therefore for ease of randomization, the target n will be 120, 60 in each group. This n is also supported by the research of Carroll et al. (2000) who found a multivitamin combination including zinc improved psychological well-being in 28 days with a total n of 80.
With 3,500,000 New Zealanders over 18 and rates of Anxiety estimated to be between 4.2% and 7.8% (Baxter et al., 2013; Crome et al., 2014), there is a pool of at least 147,000 participants within New Zealand for this study.
For the primary outcome GAD-7 scores will be analysed using the repeated measures of the outcome variables will be modeled using generalized linear mixed effects regression models (F – Test). A moderate score and potential GAD diagnosis is above 10 and a 2-3 point movement reflects a meaningful difference (Parkerson, Thibodeau, Brandt, Zvolensky, & Asmundson, 2015).
This modelling procedure allows us to fit individual-specific slopes and intercept terms, which helps to account for individual variability in treatment response. In the case of the GAD-7 baseline scores will be used as a covariate factor, as well as demographic characteristics, current dietary habits, blood biomarkers, and other subjective questionnaires with HPL as a predictor of treatment outcome.
Confidence intervals generated from generalized linear mixed effects regression models will be set at 95%. Cohen’s d will be used to reflect effect sizes with 0.2=small effect; 0.5=medium effect; 0.8=large effect (Cohen, 1988). The mean difference in scores across all repeated measures will be used to calculate d.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2019
Actual
15/07/2019
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
120
Accrual to date
95
Final
Recruitment outside Australia
Country [1] 20982 0
New Zealand
State/province [1] 20982 0
New Zealand wide

Funding & Sponsors
Funding source category [1] 301048 0
Charities/Societies/Foundations
Name [1] 301048 0
Vic Davis Trust
Country [1] 301048 0
New Zealand
Funding source category [2] 301049 0
Charities/Societies/Foundations
Name [2] 301049 0
UC Foundation
Country [2] 301049 0
New Zealand
Primary sponsor type
Individual
Name
Dr. Julia Rucklidge
Address
Mental Health and Nutrition Research Group
Mental Health and Nutrition Laboratory; Room 465
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
New Zealand
Country
New Zealand
Secondary sponsor category [1] 300724 0
None
Name [1] 300724 0
Address [1] 300724 0
Country [1] 300724 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301803 0
Health and disability ethics committee
Ethics committee address [1] 301803 0
Ministry of Health 133 Molesworth Street PO Box 5013 Wellington 6011
Ethics committee country [1] 301803 0
New Zealand
Date submitted for ethics approval [1] 301803 0
05/11/2017
Approval date [1] 301803 0
18/12/2017
Ethics approval number [1] 301803 0
17/STH/241

Summary
Brief summary
Anxiety related disorders are found in 7.3% of the population worldwide. Anxiety is the body’s natural response to stress and can include feelings of excessive nervousness, fear, apprehension, and worry. Traditional treatments for anxiety include psychological therapies and pharmacological drugs, both of which have shown good efficacy. However, these treatments have limitations including side effects and access. One approach which is gaining international attention is treating psychiatric symptoms with nutrients. Two nutrients in particular, zinc and vitamin B6, may have potential as a treatment for anxiety but have yet to be adequately tested. This clinical trial aims to test the efficacy of these nutrients using a randomized controlled trial (RCT). The RCT will compare micronutrient supplementation of zinc and vitamin B6 versus a placebo supplementation in the treatment of anxiety. One hundred and twenty participants with high anxiety will take part in this 6 week RCT followed by a 6 week open label extension. A urine biomarker, known as hydroxyhemoppyrrole-2-one (HPL), and believed to be associated with depletions in zinc and B6, will be measured before and after exposure to the micronutrients/placebo to determine whether higher levels predict response to the intervention. Elevated HPL (commonly referred to as pyroluria) has been observed in individuals with mental health disorders and it has been suggested that the molecule binds and combines with zinc and vitamin B6.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88162 0
Prof Julia Rucklidge
Address 88162 0
Mental Health and Nutrition Research Group
Mental Health and Nutrition Laboratory; Room 465
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
New Zealand
Country 88162 0
New Zealand
Phone 88162 0
+64 33694398
Fax 88162 0
Email 88162 0
[email protected]
Contact person for public queries
Name 88163 0
Angela Sherwin
Address 88163 0
Mental Health and Nutrition Research Group
Mental Health and Nutrition Laboratory; Room 465
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 88163 0
New Zealand
Phone 88163 0
+64 27 284 9087
Fax 88163 0
Email 88163 0
[email protected]
Contact person for scientific queries
Name 88164 0
Angela Sherwin
Address 88164 0
Mental Health and Nutrition Research Group
Mental Health and Nutrition Laboratory; Room 465
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 88164 0
New Zealand
Phone 88164 0
+64 27 284 9087
Fax 88164 0
Email 88164 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
Ethics did not extend to IPD


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
38Statistical analysis plan    376276-(Uploaded-29-10-2018-13-41-46)-Study-related document.docx
39Informed consent form    376276-(Uploaded-29-10-2018-13-45-08)-Study-related document.docx
40Ethical approval    376276-(Uploaded-29-10-2018-13-45-54)-Study-related document.pdf



Results publications and other study-related documents

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