Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000354381
Ethics application status
Approved
Date submitted
14/02/2017
Date registered
8/03/2017
Date last updated
7/04/2024
Date data sharing statement initially provided
4/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A multi-nutrient intervention for pregnant women experiencing symptoms of depression and anxiety.
Scientific title
An investigation examining the efficacy and safety of a multi-nutrient intervention on symptoms of antenatal depression and anxiety in pregnant women who are symptomatic: A double blind, randomized, controlled trial
Secondary ID [1] 291145 0
Nil
Universal Trial Number (UTN)
U1111-1189-4070
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 301993 0
Anxiety 301994 0
Condition category
Condition code
Mental Health 301634 301634 0 0
Depression
Reproductive Health and Childbirth 301635 301635 0 0
Normal pregnancy
Mental Health 301636 301636 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Multi-nutrient formula
Participants will be randomly assigned to receive either a multi-nutrient formula or an active control for twelve weeks. After twelve weeks, all participants will enter into an open-label phase where they can choose to take the multi-nutrient formula until the birth of their child. Both the multi-nutrient formula and the active control are in capsule form and are to be taken orally at a dose of 12 capsules per day; four capsules taken three times per day with food and water. The multi-nutrient formula and active control adhere to the New Zealand Ministry of Health recommendation for the daily intake of iodine for pregnant and lactating women. The multi-nutrient intervention is a blend of vitamins, minerals, antioxidants and amino acids. The formula, Daily Essential Nutrients, is being manufactured and donated by Hardy Nutritionals (Registered Trademark), Canada and consists of the following ingredients. The following doses are for 12 capsules (full dose per day): Vitamin A (as retinyl palmitate), 5,760 IU; Vitamin C (as ascorbic acid), 600 mg; Vitamin D (as cholecalciferol), 3,000 IU; Vitamin E (as d-alpha tocopheryl succinate), 360 IU; Vitamin K (75% as phylloquinone; 25% as menaquinone-7), 120 mcg; Thiamin (as thiamin mononitrate), 60 mg; Riboflavin, 18 mg; Niacin (as niacinamide), 90 mg; Vitamin B6 (as pyridoxine hydrochloride), 69.9 mg; Folate (as L-methylfolate calcium), 801 mcg; Vitamin B12 (as methylcobalamin), 900 mcg; Biotin, 1080 mcg; Pantothenic acid (as d-calcium pantothenate), 30 mg; Calcium (as chelate), 1,320 mg; Iron (as chelate), 13.8 mg; Phosphorus (as chelate), 840 mg; Iodine (as chelate), 204 mcg; Magnesium (as chelate), 600 mg; Zinc (as chelate), 48 mg; Selenium (as chelate), 204 mcg; Copper (as chelate), 7.2 mg; Manganese (as chelate), 9.6 mg; Chromium (as chelate), 624 mcg; Molybdenum (as chelate), 144 mcg; Potassium (as chelate), 240 mg. Proprietary blend: Choline bitartrate, Alpha-lipoic acid, Mineral wax, Inositol, Acetyl-L-carnitine, Grape seed extract, Ginkgo biloba leaf extract, L-methionine, N-acetyl-L-cysteine, Boron, Vanadium, Lithium orotate, Nickel. Other ingredients: Vegetarian capsule (hypromellose), microcrystalline cellulose, magnesium stearate, silicon dioxide, titanium dioxide.
Adherence to the intervention will be assessed fortnightly throughout the study period. Participants are required to report the number of capsules missed over a two week period and return any unused capsules to the study investigators every fourth week.
Intervention code [1] 297126 0
Treatment: Other
Comparator / control treatment
Active placebo formula
The active placebo formula is manufactured and donated by Hardy Nutritionals (Registered Trademark), Canada and consists of the following ingredients taken orally at a dose of 12 capsules per day; four capsules taken three times per day with food and water. The following doses are for 12 capsules: Riboflavin, 1.2g; Potassium iodide, 150 mcg; Silicon dioxide, 30mg; Magnesium stearate, 60mg; Microcrystalline cellulose, 6g.

Riboflavin is known to change the colour of urine and has been added to the active control so that both the intervention and active control group experience the same change in urine colour. Adding riboflavin to the active control formula will ensure the blind is maintained.

Reference group
A reference group of pregnant women will be recruited in order to further interpret the impact of the intervention. The reference group will not receive the intervention.
Control group
Active

Outcomes
Primary outcome [1] 301032 0
Edinburgh Postnatal Depression Scale (EPDS; Cox et al, 1987) assesses the presence of depression and anxiety.
Timepoint [1] 301032 0
Screening, baseline, every two weeks until birth and at 1 month, 6 months postpartum.
Primary outcome [2] 301033 0
The Clinical Global Impressions Improvement Scale (Guy, 1976) produces a score based on how much the clinician (CGI-I) thinks the participant has improved since baseline ranging from 1 (very much improved) to 7 (very much worse).
Timepoint [2] 301033 0
For the CGI-I every four weeks until birth and at 1 month, 6 months postpartum.
Secondary outcome [1] 331520 0
The Montgomery and Asberg Depresion Rating Scale (MADRS; Montgomery & Asberg, 1979) will replace the HAM-D to assess the frequency, severity and duration of depressive symptoms.
Timepoint [1] 331520 0
Baseline, every four weeks until birth and at 1 month, 6 months postpartum.
Secondary outcome [2] 331521 0
Depression, Anxiety, Stress Scale - 21 - assesses the severity of depression, anxiety and stress.
Timepoint [2] 331521 0
Baseline, every two weeks until birth and at 1 month, 6 months postpartum.
Secondary outcome [3] 331522 0
Nutrient levels: vitamin C, vitamin B12, vitamin D, copper, zinc, iron and homocysteine - assessed in plasma from blood samples taken at baseline and at 12 weeks RCT.
Timepoint [3] 331522 0
Baseline and at 12 weeks (end of the randomized controlled trial phase)
Secondary outcome [4] 331523 0
Inflammatory biomarkers: interleukin – 6 (IL-6), tumor necrosis factor alpha (TNF-a), interleukin-4 (IL-4) and interleukin-10 (IL-10), C-reactive protein (CRP) assessed in plasma from blood samples taken at baseline and at 12 weeks RCT. A complete blood count from the blood samples will also be assessed to assist in the interpretation of the biomarkers.
Timepoint [4] 331523 0
Baseline and at 12 weeks (end of the randomized controlled trial phase).
Secondary outcome [5] 331525 0
Microbiome assessed from stool samples taken at baseline and at week 12 RCT.
Timepoint [5] 331525 0
Baseline and at 12 weeks (end of the randomized controlled trial phase).
Secondary outcome [6] 331537 0
The Pittsburgh Sleep Quality Index (PSQI; Buysse, Reynolds, Monk, Verman & Kupfer, 1989) assesses sleep quality, latency, duration, disturbance, efficiency and daytime dysfunction.
Timepoint [6] 331537 0
Baseline, every four weeks until birth and at 1 month, 6 months postpartum.
Secondary outcome [7] 331538 0
Short Form Health Survey - 12 (SF-12; Ware, Kosinski & Keller, 1996) assesses quality of life.
Timepoint [7] 331538 0
Baseline, every four weeks until birth and at 1 month, 6 months postpartum.
Secondary outcome [8] 331540 0
Difficulties in Emotion Regulation Scale - Short Form (DERS-SF; Kaufman et al, 2015) assesses emotion disregulation.
Timepoint [8] 331540 0
Baseline, every four weeks until birth and at 1 month, 6 months postpartum.
Secondary outcome [9] 331597 0
Electroencephalography (EEG) will be measured at rest and in response to simple audio/visual cues will be used to index anxiety-related endophenotypes, neurophysiological markers of anxiety and related psychophysiological processes.
Timepoint [9] 331597 0
Baseline and end of 12 weeks RCT
Secondary outcome [10] 331764 0
The Antidepressant Side-Effect Checklist (ASEC; Uher et al, 2009) and a review of medical records will assess side effects, safety & adverse events of the intervention. The ASEC has been adapted for the purposes of this study.
Timepoint [10] 331764 0
ASEC will be administered every two weeks until birth; medical records reviewed 3 months after birth.
Secondary outcome [11] 347053 0
Generalized Anxiety Disorder – 7 item (GAD-7; Spitzer, Kroenke, Williams and Lowe, 2006) a self report questionnaire measuring the severity of anxiety.
Timepoint [11] 347053 0
Baseline, every two weeks until birth and at 1 month and 6 months postpartum.
Secondary outcome [12] 433699 0
Participant rating of clinical global impression improvement over the trial (modified clinical global impression improvement - M-CGI-I) from 1 (very much improved) to 7 (very much worse)
Timepoint [12] 433699 0
Secondary outcome [13] 433700 0
Participant rating of clinical global impression improvement over the trial (modified clinical global impression improvement - M-CGI-I) from 1 (very much improved) to 7 (very much worse)
Timepoint [13] 433700 0
End of RCT

Eligibility
Key inclusion criteria
1) women aged 16 years and over; 2) 12-24 weeks gestation; 3) low risk singleton pregnancy; 4) free from psychiatric medication for four weeks; 5) score of 13 or more on the Edinburgh Postnatal Depression Scale (EPDS); 6) deemed reliable and compliant with the protocol.

Reference group inclusion criteria:
1) pregnant women aged 16 years and over; 2) low risk singleton pregnancy
Minimum age
16 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1) regular vomiting; 2) high risk pregnancy; 3) significant pregnancy complications; 4) known foetal abnormalities; 5) serious current or historical medical condition; 6) known allergy to the ingredients of the intervention; 7) known metabolic condition such as Wilson’s disease, hemochromatosis.; 8) untreated or unstable thyroid disease; 9) known neurological disorder; 10) desire to continue taking prenatal supplements that either exceed the upper limit or are not required for medical purposes (decisions discussed and made on a case-by-case basis)

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)
Sealed opaque envelopes.
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.
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
Safety/efficacy
Statistical methods / analysis
In 2014, there were 57,242 live births in New Zealand, 6,575 of which were in Christchurch (Statistics New Zealand, 2015). Assuming at least 12% meet criteria for PND and accounting for twin births of 1 in every 100 pregnancies, approximately 781 women per year would be eligible for the proposed study in Christchurch alone.

Based on previous research, to detect a medium effect (Cohens d = 0.6) on the EPDS between groups at a two tailed significance level of 0.05 and power of 0.8 the minimum sample size would be 90 (45 in each group). Assuming a 30% attrition rate (based on the mean attrition rate from previous nutrient RCTs using perinatal women) the adjusted number per treatment condition would be approximately 60. Therefore, the total target sample size for this study is 120 (60 in the micronutrient group and 60 in the placebo group). In order to further interpret the impact of the intervention, we will be following a non-randomized control group of pregnant women who are either not eligible to participate in the intervention trial or choose not to participate. The total sample size of this group is unknown.

All statistical analyses will be carried out using the Statistical Package for Social Science (SPSS). Demographic characteristics will be compared across the treatment groups using independent samples t-tests in order to test for potential failures of randomization. All data will be analyzed on an intention-to-treat basis using the last observation carried forward method.

For the primary outcomes (EPDS and CGI-I scores), the repeated measures of the outcome variables will be modelled using generalized linear mixed effects regression models. These models will permit the testing of differences between the micronutrient group and the placebo group over the course of the trial. In the case of the EPDS, baseline scores will be used as a covariate factor, as well as measures of demographic characteristics, behaviour and social support, and measures of inflammatory biomarkers.

For secondary outcomes (MADRS. DASS, biomarkers), linear mixed effects models will also be used, and again will be supplemented by as measures of demographic characteristics, behaviour and social support, and measures of inflammatory biomarkers.

The pooled mean scores (and standard deviations) over the course of the trial on each of the primary outcomes will be used to compute estimates of effect size (Cohen’s d).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
13/03/2017
Actual
12/04/2017
Date of last participant enrolment
Anticipated
31/12/2020
Actual
5/10/2020
Date of last data collection
Anticipated
30/10/2021
Actual
10/01/2021
Sample size
Target
120
Accrual to date
Final
88
Recruitment outside Australia
Country [1] 8649 0
New Zealand
State/province [1] 8649 0
New Zealand

Funding & Sponsors
Funding source category [1] 295582 0
University
Name [1] 295582 0
University of Canterbury, Dept of Psychology Research Funds
Country [1] 295582 0
New Zealand
Funding source category [2] 295593 0
Charities/Societies/Foundations
Name [2] 295593 0
Univeristy of Canterbury Foundation - donations given to the principal investigator
Country [2] 295593 0
New Zealand
Funding source category [3] 295594 0
Charities/Societies/Foundations
Name [3] 295594 0
Canterbury Medical Research Foundation
Country [3] 295594 0
New Zealand
Funding source category [4] 295642 0
Commercial sector/Industry
Name [4] 295642 0
Hardy Nutritionals (Registered Trademark)
Country [4] 295642 0
Canada
Funding source category [5] 299511 0
Charities/Societies/Foundations
Name [5] 299511 0
Foundation for Excellence in Mental Health Care
Country [5] 299511 0
United States of America
Funding source category [6] 301363 0
Charities/Societies/Foundations
Name [6] 301363 0
The Nurture Foundation for Reproductive Research
Country [6] 301363 0
New Zealand
Funding source category [7] 301364 0
Hospital
Name [7] 301364 0
St George's Hospital
Country [7] 301364 0
New Zealand
Funding source category [8] 301365 0
Charities/Societies/Foundations
Name [8] 301365 0
The Waterloo Foundation
Country [8] 301365 0
United Kingdom
Primary sponsor type
Individual
Name
Professor Julia Rucklidge
Address
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 294413 0
Individual
Name [1] 294413 0
Professor Roger Mulder
Address [1] 294413 0
Department of Psychological Medicine
University of Otago
PO Box 4345
Christchurch 8140
Country [1] 294413 0
New Zealand
Other collaborator category [1] 279428 0
Individual
Name [1] 279428 0
Dr Jackeline Henderson
Address [1] 279428 0
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [1] 279428 0
New Zealand
Other collaborator category [2] 279429 0
Individual
Name [2] 279429 0
Professor Martin Kennedy
Address [2] 279429 0
Department of Pathology
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country [2] 279429 0
New Zealand
Other collaborator category [3] 279430 0
Individual
Name [3] 279430 0
Dr Kyle Nash
Address [3] 279430 0
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [3] 279430 0
New Zealand
Other collaborator category [4] 279431 0
Individual
Name [4] 279431 0
Dr Lesley Dixon
Address [4] 279431 0
New Zealand College of Midwives
376 Manchester Street
Christchurch 8014
Country [4] 279431 0
New Zealand
Other collaborator category [5] 279432 0
Individual
Name [5] 279432 0
Hayley Bradley
Address [5] 279432 0
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [5] 279432 0
New Zealand
Other collaborator category [6] 280452 0
Individual
Name [6] 280452 0
Associate Professor Joseph Boden
Address [6] 280452 0
Department of Psychological Medicine University of Otago PO Box 4345 Christchurch 8140
Country [6] 280452 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296904 0
Southern Health and Disabilty Ethics Committee
Ethics committee address [1] 296904 0
Ethics committee country [1] 296904 0
New Zealand
Date submitted for ethics approval [1] 296904 0
10/11/2016
Approval date [1] 296904 0
03/02/2017
Ethics approval number [1] 296904 0
16/STH/187
Ethics committee name [2] 296966 0
Univeristy of Canterbury Human Ethics Committee
Ethics committee address [2] 296966 0
Ethics committee country [2] 296966 0
New Zealand
Date submitted for ethics approval [2] 296966 0
03/02/2017
Approval date [2] 296966 0
10/02/2017
Ethics approval number [2] 296966 0

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

Contacts
Principal investigator
Name 72386 0
Prof Julia Rucklidge
Address 72386 0
Mental Health and Nutrition Research Group
Department of Psychology
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country 72386 0
New Zealand
Phone 72386 0
+64 3369 4398
Fax 72386 0
+64 33642181
Email 72386 0
[email protected]
Contact person for public queries
Name 72387 0
Hayley Bradley
Address 72387 0
Mental Health and Nutrition Research Group
Department of Psychology
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country 72387 0
New Zealand
Phone 72387 0
+64 03 3692386
Fax 72387 0
Email 72387 0
[email protected]
Contact person for scientific queries
Name 72388 0
Julia Rucklidge
Address 72388 0
Mental Health and Nutrition Research Group
Department of Psychology
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country 72388 0
New Zealand
Phone 72388 0
+64 3369 4398
Fax 72388 0
Email 72388 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
This trial collects clinical data and thus we need to assess, after the trial has finished, whether releasing participant's data is ethical.


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
SourceTitleYear of PublicationDOI
EmbaseCan broad-spectrum multinutrients treat symptoms of antenatal depression and anxiety and improve infant development? Study protocol of a double blind, randomized, controlled trial (the 'NUTRIMUM' trial).2020https://dx.doi.org/10.1186/s12884-020-03143-z
N.B. These documents automatically identified may not have been verified by the study sponsor.