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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.
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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
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Secondary ID [1]
296453
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None
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Generalized Anxiety
310237
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Social Anxiety
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Condition category
Condition code
Mental Health
308962
308962
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0
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Anxiety
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
312778
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Treatment: Other
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Comparator / control treatment
Microcellulose placebo tablet. The control group will have the opportunity to participate in the open-label phase of the study.
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Generalized Anxiety Disorder 7-item (GAD-7) scale
(Spitzer, Kroenke, Williams, & Löwe, 2006)
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Assessment method [1]
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Timepoint [1]
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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.
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Primary outcome [2]
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Modified Clinical Global Impressions (CGI-I) (Spearing, Post, Leverich, Brandt, & Nolen, 1997)
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Assessment method [2]
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Timepoint [2]
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End of RCT (day 42) and day 42 of open label
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Secondary outcome [1]
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Modified Antidepressant Side-Effect Checklist (ASEC) (Uher et al., 2009)
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Assessment method [1]
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Timepoint [1]
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Baseline, Day 14, 28 and 42 of the RCT and day 14, 28 and 42 of the open label phase.
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Secondary outcome [2]
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Social Phobia and Anxiety Scale – 18 (SPAI-18) (de Vente, Majdandžic, Voncken, Beidel, & Bögels, 2014)
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Assessment method [2]
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Timepoint [2]
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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.
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Secondary outcome [3]
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Profile of Mood States – Short Form (POMS-SF) (Curran, Andrykowski, & Studts, 1995)
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Assessment method [3]
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Timepoint [3]
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Baseline, on day 42 of the RCT, day 42 of the OL and at month 3, 6 and 12 of the naturalistic follow up.
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Secondary outcome [4]
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Urine hydroxyhemoppyrrole-2-one (HPL)
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Assessment method [4]
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Timepoint [4]
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Baseline and on day 42 of the RCT.
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Secondary outcome [5]
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Depression, Anxiety and Stress Scale (DASS)- 21 (Lovibond & Lovibond, 1995)
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Assessment method [5]
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Timepoint [5]
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Baseline, on day 42 of RCT, day 42 of the OL phase and at month 3, 6 and 12 of the naturalistic follow up.
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Secondary outcome [6]
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General Health Questionnaire 60 (GHQ-60) (Goldberg & Hillier, 1979)
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Assessment method [6]
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Timepoint [6]
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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
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Secondary outcome [7]
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Quality of Life Scale (QOLS) (Burckhardt & Anderson, 2003)
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Assessment method [7]
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Timepoint [7]
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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.
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Secondary outcome [8]
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Walsh/Jaa Pyroluria Questionnaire (WJPQ) (Walsh & Jaa, 2017)
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Assessment method [8]
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Timepoint [8]
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Baseline and on day 42 of the RCT
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Secondary outcome [9]
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Practitioner Pyrroles Screening Questionnaire (PPSQ) (Larson, 2011)
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Assessment method [9]
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Timepoint [9]
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Baseline and on day 42 of the RCT
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Secondary outcome [10]
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Eysenck Personality Questionnaire (EPQ-R) (Eysenck, Eysenck, & Barrett, 1985)
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Assessment method [10]
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Timepoint [10]
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Baseline - used as a predictor
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Secondary outcome [11]
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Treatment Satisfaction Questionnaire for Medication – 14 (TSQM-14) (Atkinson et al., 2004)
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Assessment method [11]
354118
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Timepoint [11]
354118
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Day 42 of the RCT and on day 42 of the OL phase and month three, six and 12 of the naturalistic follow up
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Secondary outcome [12]
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Eating Behaviours Questionnaire (Baker, Little, & Brownell, 2003)
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Assessment method [12]
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Timepoint [12]
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Baseline, on day 42 of the RCT and on day 42 of the OL phase
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Females
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Can healthy volunteers participate?
No
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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).
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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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
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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.
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Other
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Other design features
RCT phase followed by an open label phase
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Phase
Not Applicable
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Type of endpoint/s
Safety/efficacy
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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.
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Recruitment
Recruitment status
Recruiting
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Date of first participant enrolment
Anticipated
1/03/2019
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Actual
15/07/2019
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Date of last participant enrolment
Anticipated
31/12/2023
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Actual
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Date of last data collection
Anticipated
31/12/2024
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Actual
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Sample size
Target
120
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Accrual to date
95
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Final
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Recruitment outside Australia
Country [1]
20982
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New Zealand
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State/province [1]
20982
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New Zealand wide
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Funding & Sponsors
Funding source category [1]
301048
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Charities/Societies/Foundations
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Name [1]
301048
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Vic Davis Trust
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Address [1]
301048
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The Vic Davis Memorial Trust
PO Box 793
Whakatane 3158
NEW ZEALAND
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Country [1]
301048
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New Zealand
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Funding source category [2]
301049
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Charities/Societies/Foundations
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Name [2]
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UC Foundation
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Address [2]
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The University of Canterbury Foundation,
Private Bag 4800, Christchurch, 8140, New Zealand
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Country [2]
301049
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New Zealand
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Primary sponsor type
Individual
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Name
Dr. Julia Rucklidge
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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
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Country
New Zealand
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Secondary sponsor category [1]
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None
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Name [1]
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Address [1]
300724
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Country [1]
300724
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
301803
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Health and disability ethics committee
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Ethics committee address [1]
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Ministry of Health 133 Molesworth Street PO Box 5013 Wellington 6011
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Ethics committee country [1]
301803
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New Zealand
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Date submitted for ethics approval [1]
301803
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05/11/2017
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Approval date [1]
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18/12/2017
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Ethics approval number [1]
301803
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17/STH/241
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Julia Rucklidge
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Address
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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
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Country
88162
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New Zealand
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Phone
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+64 33694398
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Fax
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Email
88162
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[email protected]
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Contact person for public queries
Name
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Ms Angela Sherwin
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Address
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Mental Health and Nutrition Research Group
Mental Health and Nutrition Laboratory; Room 465
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
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Country
88163
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New Zealand
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Phone
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+64 27 284 9087
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Name
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Ms Angela Sherwin
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Address
88164
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Mental Health and Nutrition Research Group
Mental Health and Nutrition Laboratory; Room 465
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
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Country
88164
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New Zealand
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Phone
88164
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+64 27 284 9087
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Fax
88164
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Email
88164
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Ethics did not extend to IPD
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What supporting documents are/will be available?
No Supporting Document Provided
Doc. No.
Type
Citation
Link
Email
Other Details
Attachment
38
Statistical analysis plan
376276-(Uploaded-29-10-2018-13-41-46)-Study-related document.docx
39
Informed consent form
376276-(Uploaded-29-10-2018-13-45-08)-Study-related document.docx
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Ethical approval
376276-(Uploaded-29-10-2018-13-45-54)-Study-related document.pdf
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.
Download to PDF