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Trial registered on ANZCTR


Registration number
ACTRN12615000131550
Ethics application status
Approved
Date submitted
26/11/2014
Date registered
12/02/2015
Date last updated
18/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A natural approach to treating premenstrual complaints: a randomized control trial comparing Vitamin B6 to a Broad Spectrum Micronutrient formula.
Scientific title
Investigation into the effect of a nutritional supplement on premenstrual symptoms in a sample of women with premenstrual syndrome (PMS): a double blind, randomised controlled trial.
Secondary ID [1] 285744 0
Nil
Universal Trial Number (UTN)
U1111-1164-2407
Trial acronym
NTP (Natural Treatment of Premenstrual syndrome)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Premenstrual syndrome (PMS)
293630 0
Women's mental health 293632 0
Condition category
Condition code
Mental Health 293926 293926 0 0
Other mental health disorders
Reproductive Health and Childbirth 293996 293996 0 0
Menstruation and menopause

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomly assigned to receive either the vitamin B6 treatment or the micronutrient formula. In both treatment groups they will be asked to take a total of eight capsules per day; four in the morning, four in the afternoon/evening with plenty of food and water. Treatment adherence will be monitored through the return of unused pills at the beginning of each month. The treatment phase will last for a total of three months.
Women assigned to the micronutrient formula will take a blend of vitamins and minerals in the supplement EMPowerplus Advanced. This formula will be provided by Truehope located in Raymond, Alberta, Canada. The dose and ingredients are as follows: Vitamin A (as retinyl palmitate), 3072 IU, Vitamin C (as ascorbic acid) 320mg, Vitamin D (as cholecalciferol), 768 IU, Vitamin E (as d-alpha tocopheryl succinate) 192 IU, Thiamin (as thiamin mononitrate) 9.6mg, Riboflavin 7.2mg, Niacin (as niacinamide) 48mg, Vitamin B6 (as pyridoxine hydrochloride) 19.2mg, Folic acid 768mcg, Vitamin B12 (as methylcobalamin) 480mcg, Biotin 576mcg, Pantothenic acid (as calcium pantothenate) 11.52mg, Calcium (as chelate) 704mg, Iron (as chelate) 7.328mg, Phosphorus (as chelate) 448mg, Iodine (from Pacific kelp) 108.8mcg, Magnesium (as chelate) 320mg, Zinc (as chelate) 25.6mg, Selenium (as chelate) 108.8mcg, Copper (as chelate) 3.84mg, Manganese (as chelate) 5.12mg, Chromium (as chelate) 332.8mcg, Molybdenum (as chelate) 76.8 mcg, Potassium (as chelate) 128mg, Choline bitartrate 288mg, DL-phenylalanine 192mg, Bioflavonoids 128mg, Inositol 96mg, L-Glutamine 96mg, L-Methionine 32mg, Grape seed extract 24mg, Gingko biloba leaf extract 19.2mg, Germanium sesquioxide 11.04mg, Boron (as chelate) 1.28mg, Vanadium (as chelate) 0.6368mg, and Nickel (as chelate) 15.68mcg. Other ingredients: capsule shell (gelatin, titanium dioxide) microcrystalline cellulose, glycine, citric acid, magnesium stearate, silicon dioxide, mineral wax. The values given are based on a consumption of eight capsules per day.
Intervention code [1] 290700 0
Treatment: Other
Comparator / control treatment
Vitamin B6
For those participants assigned to receive the vitamin B6 treatment, they will take a total of 80mg per day. The B6 treatment also contains riboflavin, a vitamin known to change the colour of urine. This ensures that the blind can be maintained as both groups will experience the same change in urine colour.
Control group
Active

Outcomes
Primary outcome [1] 293697 0
Premenstrual symptoms as measured by the Daily Record of Severity of Problems (DRSP) questionnaire.
Timepoint [1] 293697 0
Baseline, month one, two and three of treatment during the week leading up to menses (the luteal phase) and three months post-treatment.
Three months post treatment there will be a natural follow up where participants will answer questions about their premenstrual symptoms through a modified version of the Daily Record of Severity of Problems questionnaire.
Primary outcome [2] 293698 0
Number of treatment responders for each of the two treatments and a comparison between the two different rates of responses. A participant will be deemed to be a responder if they show a total PMS score improvement of 50% or more as based on baseline scores from the DRSP.
Timepoint [2] 293698 0
PMS scores from baseline will be compared to scores obtained on the final month of treatment.
Secondary outcome [1] 311616 0
The impact of PMS on the participant’s quality of life as assessed by the Women’s Quality of Life Questionnaire (Women’s QoL Questionnaire).
Timepoint [1] 311616 0
Baseline and during month one, two and three of treatment.
Secondary outcome [2] 311617 0
Levels of depression, stress and anxiety, as measured by the Depression and Anxiety Stress Scales- 42 (DASS-42).
Timepoint [2] 311617 0
Baseline and during month one, two and three of treatment.
Secondary outcome [3] 311618 0
Measure of the participant’s impression of their illness improvement with the Clinical Global Impression scale (CGI-I scale).
Timepoint [3] 311618 0
At the end of the treatment phase.
Secondary outcome [4] 312838 0
Secondary outcome 4: sleep quality improvement as measured by the Pittsburgh Sleep Quality Index (PSQI).
Timepoint [4] 312838 0
Timepoint: baseline and during month one, two and three of treatment.
Secondary outcome [5] 312839 0
Secondary outcome 5: stress sensitivity reduction as measured by the Perceived Stress Scale (PSS).
Timepoint [5] 312839 0
Timepoint: baseline and during month one, two and three of treatment.
Secondary outcome [6] 312840 0
Secondary outcome 6: sexual satisfaction as measured by the New Sexual satisfaction Scale- Short form (NSSS-S).
Timepoint [6] 312840 0
Timepoint: baseline and during month one, two and three of treatment.
Secondary outcome [7] 312841 0
Secondary outcome 7: Premenstrual symptom improvement as measured by a third party observer using a modified version of the daily record severity of problems questionnaire.
Timepoint [7] 312841 0
Timepoint: Baseline and at the end of treatment phase.

Eligibility
Key inclusion criteria
For inclusion participants must be regularly menstruating females over the age of 18 (cycle length must last between 21-35 days) who have premenstrual syndrome (PMS) as determined by information given on the Daily Record of Severity of Problems questionnaire.
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Cannot be pregnant or planning to become pregnant, no accompanying major mood disorder, cannot currently be taking medication for premenstrual syndrome (PMS). Participants with any of the following will be excluded: 1) neurological disorder involving brain or other central nervous system function (e.g., epilepsy), 2) pregnant or breastfeeding, 3) evidence of untreated or unstable thyroid disease, 4) any known abnormality of mineral metabolism (e.g., Wilson’s disease, haemochromatosis), 5) judged clinically to be at serious risk of suicide or violence, or 6) currently taking any other medication with primarily central nervous system activity.

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)
Potential participants will be directed to an online website (bit.ly/UCnutritionresearch) to complete a screening questionnaire. Those who meet inclusion criteria will meet with the researcher in person to undertake a structured clinical mood interview (SCID-I). Those who are deemed free of any current mood disorder will be randomly assigned to one of two treatment groups; vitamin B6 or micronutrient formula. Researchers will also remain blind to the random allocation process.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised using a randomisation table created by computer software (www.randomization.com). A total of four lists will be generated whereby the pharmacy will choose one list for the randomization.
Provided that an individual meets the inclusion criteria and does not meet exclusion criteria, the person is allocated the next available number on the list. All pills (ie active ingredient or placebo) have been pre-packaged by the pharmacy who holds the randomization code. A sealed envelope is contained within each pill package only to be opened in an emergency (ie patient deteriorates significantly).
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
Determining the sample size is a challenge based on the diversity of studies that have thus far been conducted. We are aiming to recruit 40 participants per group, making a total of 80 participants. The final sample size was calculated via a sample size calculation where the best estimate of the effect size (ES) of vitamin B6 on psychiatric symptoms was 0.36, while EMP+ produced (in a conservative estimate) an ES of 0.64 on mood symptoms. Yet in open label trials the reported effect size is above 1. To detect a medium ES of 0.6 in this study, a total of 72 participants are needed. This number has been increased to 80, 40 per-group, to allow for attrition. We have chosen to detect a medium effect as we believe this will be clinically relevant for those women choosing to use natural supplements in treating PMS. Based on the available data is it reasonable to expect to see a medium ES difference between the two treatments; currently estimates for mood in blinded micronutrient trials appears to be medium to large.
The changes from baseline to the end of treatment will be compared between randomized groups using repeated-measures ANCOVA, with the baseline level as the covariate. Change measures assessed at the end of treatment with no baseline will be compared using one-way ANOVA. The differences between treatment groups in these measures will be summarized as the mean differences and 95% confidence intervals generated from the ANCOVA/ANOVA models. Categorical outcomes will be compared between groups using Chi-square tests and will be described using odds ratios and 95% confidence intervals. All analyses will be undertaken on an intention-to-treat (ITT) basis that includes all randomized participants analyzed according to the group to which they were randomized. For those participants not completing the full treatment, data from their final assessment will be used to evaluate the change scores. Secondary analyses will be undertaken on all outcomes using the per-protocol (completers) analysis set. All tests will be two tailed and any p values less than 0.05 will be considered statistically significant.

The results of each case will also be looked at using Brinley plots to examine each participant’s baseline measures and then response as the treatment is introduced.

Categorical outcomes (individual symptoms) will be compared between groups using chi-square tests with odds ratios and 95% confidence intervals.

Effect size (ES) measures (Cohen’s D) will be calculated for each of the treatment conditions in comparison to baseline scores. A difference score between the two effects will then be calculated to see if one treatment is significantly better at the 0.05 level.

Mediation analysis will be used to explore whether the change in PMS symptoms is mediated by change in stress sensitivity. Hierarchical linear regression will be employed to investigate base-line stress sensitivity and mood measures as possible moderators.

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 outside Australia
Country [1] 6495 0
New Zealand
State/province [1] 6495 0
Canterbury

Funding & Sponsors
Funding source category [1] 290317 0
University
Name [1] 290317 0
University of Canterbury- The cost of the study are coming from research grants allocated for a PhD project through the university. Each student completing a masters project at the University of Canterbury is given a standard sum to cover the costs of their study.
Address [1] 290317 0
University of Canterbury, Private Bag 4800, Christchurch 8140
Country [1] 290317 0
New Zealand
Primary sponsor type
University
Name
University of Canterbury
Address
University of Canterbury, Private Bag 4800, Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 289033 0
None
Name [1] 289033 0
Address [1] 289033 0
Country [1] 289033 0
Other collaborator category [1] 278252 0
Individual
Name [1] 278252 0
Professor Julia Rucklidge
Address [1] 278252 0
Department of Psychology
University of Canterbury
Private Bag 4800
Ilam 8140
Christchurch
New Zealand
Country [1] 278252 0
New Zealand
Other collaborator category [2] 278253 0
Individual
Name [2] 278253 0
Professor Neville Blampied
Address [2] 278253 0
Department of Psychology
University of Canterbury
Private Bag 4800
Ilam 8140
Christchurch
New Zealand
Country [2] 278253 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292023 0
University of Canterbury Human Ethics Committee
Ethics committee address [1] 292023 0
University of Canterbury, Te Whare Wananga o Waitaha, Private Bag 4800, Christchurch 8140
Ethics committee country [1] 292023 0
New Zealand
Date submitted for ethics approval [1] 292023 0
Approval date [1] 292023 0
13/11/2014
Ethics approval number [1] 292023 0
HEC 2014/129

Summary
Brief summary
This study aims to look at the effect that a micronutrient formula (vitamins and minerals) has on premenstrual symptoms. The efficacy of this formula is to be compared to an already validated premenstrual syndrome (PMS) treatment, vitamin B6. Previous research has shown that combinations of nutrients, like those found in the micronutrient formula, can lower symptoms of stress, mood, and anxiety. Since these symptoms are often reported in PMS, it is hypothesised that the micronutrient formula will decrease overall symptoms, producing a greater measurable effect than by using vitamin B6 alone.
Trial website
Bit.ly/UCnutritionresearch
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53090 0
Miss Hannah Retallick-Brown
Address 53090 0
Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
Country 53090 0
New Zealand
Phone 53090 0
+64 0274521015
Fax 53090 0
Email 53090 0
hahna.retallick-brown@pg.canterbury.ac.nz
Contact person for public queries
Name 53091 0
Miss Hannah Retallick-Brown
Address 53091 0
Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
Country 53091 0
New Zealand
Phone 53091 0
+64 0274521015
Fax 53091 0
Email 53091 0
hahna.retallick-brown@pg.canterbury.ac.nz
Contact person for scientific queries
Name 53092 0
Miss Hannah Retallick-Brown
Address 53092 0
Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
Country 53092 0
New Zealand
Phone 53092 0
+64 0274521015
Fax 53092 0
Email 53092 0
hahna.retallick-brown@pg.canterbury.ac.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary