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Trial registered on ANZCTR


Registration number
ACTRN12618000704291p
Ethics application status
Submitted, not yet approved
Date submitted
20/04/2018
Date registered
30/04/2018
Date last updated
30/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The “NATURE” Trial: Nutritional Adjunctive Treatment Used for Recovery in Early psychosis
Scientific title
A 12-week, randomized, placebo-controlled, pilot trial of a novel nutritional formula developed as an adjunctive treatment for negative symptoms in first-episode psychosis
Secondary ID [1] 294643 0
None
Universal Trial Number (UTN)
U1111-1212-5159
Trial acronym
NATURE (Nutritional Adjunctive Treatment Used for Recovery in Early psychosis)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
first-episode psychosis 307510 0
Condition category
Condition code
Mental Health 306593 306593 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Novel nutritional formula containing a combination of vitamins, minerals and amino-acids; administered as 10g of effervescent fruit-flavoured drink mix, once per day for 12 weeks

Adherence to the intervention will be measured through both self-report and observational measures.

Self Report: a reminder application will be installed on each participant’s mobile phone. This will be set to present a reminder message once per day for 12 weeks, along with a single-touch tick box for participants to record their adherence. Adherence logs will be saved only to the participants phone, for collection upon 12-week in person visit. However, all participants will be free to decline using the smartphone app without it affecting their participation.

Observational: Adherence (as total number of doses) will be corroborated by asking participant to bring their tubs of the nutritional formula to the 6-week and 12-week assessment visits; these will be weighed by the researcher. Participants will be informed that their compliance to the protocol is measured for research purposes only and will have no bearing on their payment or continued participation in the study.

Intervention code [1] 300960 0
Treatment: Other
Comparator / control treatment
Control group:: Placebo formula (containing no nutrients) administered as 10g of effervescent fruit-flavoured drink mix, once per day for 12 weeks.

Adherence to this will also be measured in the same ways as the active condition.
Control group
Placebo

Outcomes
Primary outcome [1] 305589 0
Negative Symptoms subscale of the PANSS (Positive and Negative Syndrome Scale)
Timepoint [1] 305589 0
12 weeks after randomization
Secondary outcome [1] 345847 0
Waist circumference (tape measure)
Timepoint [1] 345847 0
6 and 12 weeks after randomization
Secondary outcome [2] 346060 0
Handgrip strength (handgrip dynamometer)
Timepoint [2] 346060 0
6 and 12 weeks after randomization
Secondary outcome [3] 346061 0
Depression (Beck Depression Inventory)
Timepoint [3] 346061 0
6 and 12 weeks after randomization
Secondary outcome [4] 346062 0
Body Mass Index (electronic scales for bodyweight, tape measure for height)
Timepoint [4] 346062 0
6 and 12 weeks after randomization
Secondary outcome [5] 346063 0
Systolic and Diastolic blood pressure (Blood Pressure Monitor using Upper-Arm Cuff)
Timepoint [5] 346063 0
6 and 12 weeks after randomization
Secondary outcome [6] 346064 0
Cognitive Functioning (COGSTATE software)
Timepoint [6] 346064 0
6 and 12 weeks after randomization
Secondary outcome [7] 346065 0
Psychosocial Functioning (Self-Reported Graphic version of the Personal and Social Performance)
Timepoint [7] 346065 0
6 and 12 weeks after randomization
Secondary outcome [8] 346066 0
Anxiety (Social Interaction Anxiety Scale)
Timepoint [8] 346066 0
6 and 12 weeks after randomization
Secondary outcome [9] 346067 0
Self-reported Negative Symptoms (The Motivation and Pleasure Scale – Self-Report)
Timepoint [9] 346067 0
2, 4, 6, 8, 10 and 12 weeks after randomization
Secondary outcome [10] 346068 0
Dietary food intake (University of Newcastle ‘Healthy Eating Quiz’)
Timepoint [10] 346068 0
2, 4, 6, 8, 10 and 12 weeks after randomization

Eligibility
Key inclusion criteria
• Currently engaged in Early Intervention in Psychosis mental health services
• Aged 18 to 35 years
• Sufficient level of spoken English to complete the baseline assessments
• Has the capacity to consent to the study and follow its procedures
• Within the first 3 years of receiving antipsychotic medication for a psychotic disorder, currently prescribed at a stable dose (as determined by referring clinician)
• Report ongoing negative symptoms; defined as scoring at least 3/5 for severity on at least 4 items of the ‘Motivation and Pleasure Scale – Self-Report’
Minimum age
18 Years
Maximum age
35 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Changes in antipsychotic medication dose or type within the last 4 weeks
• Non-compliance with current antipsychotic medication regime
• Current use of specified nutraceuticals above stated thresholds
• Taking warfarin or phenytoin
• Known or suspected clinically unstable systemic medical disorder (including cancer, organ failure, or serious cardio/cerebrovascular disease)
• Pregnancy or breastfeeding
• Previous known allergic reactions to any ingredients featured in the formulated product
• Currently suicidal (as defined by a score of >1 on item 9 of the BDI-II)
• Co-morbid alcohol/substance-use disorder or dependency (as determined by referring clinician)

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)
To minimise bias this study will employ both randomisation and double blinding.
Allocation to a treatment arm (identified to researchers only by product number) will be assigned at random. The computer-generated randomisation plan will be developed by an independent third-party. Research assistants will allocate packs sequentially, concealing treatment allocation and blinding.

The code which links pack numbers to treatment arms will be helped by the independent third party.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to a treatment arm (identified to researchers only by product number) will be assigned at random using permutated block randomisation. The computer-generated randomisation plan will be developed by an independent third-party
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
Efficacy
Statistical methods / analysis
Analysis of all data will be conducted with blinding to group allocations. The primary analysis will determine effect of adjunctive nutrient supplementation on negative symptoms in FEP on an intention-to-treat basis. For this pilot study, our analyses were powered from results of a recent trial of folate supplementation for patients with long-term schizophrenia. This study observed statistically significant reductions in PANSS negative symptoms in a sample of 55 participants (29 folate vs. 26 placebo) with an effect size of 0.68. Power calculations were performed using this as the estimated effect size (0.68), against a one-tailed hypothesis for the pilot study with alpha set at p=0.05 and beta=0.80, determined at total of 56 participants would be required to detect a significant effect on negative symptoms. We consider this to be a conservative estimate given that (i) participants in this study are in early stages on illness, and thus perhaps more sensitivity to treatment, and (ii) the ingredients in our nutraceutical combine folate with multiple other beneficial nutrients to theoretically increase the magnitude of effect.

The primary efficacy analysis will compare baseline to 12-week changes in negative symptoms between active vs. placebo conditions using a Mixed-Effect Model Repeated Measure (MMRM) approach toward imputing missing data. Secondary analyses will be conducted using ANOVA to assess changes in all physical and mental health outcomes (listed above) across all time-points measured (0, 6, 12 weeks) by treatment group. Non-parametric statistics will be used when assumptions for parametric methods are violated. Effect sizes will be calculated using Cohen’s d. All tests of treatment effects will be conducted using a two-tailed alpha level of 0.05 and 95% confidence intervals. Data will be analysed via SPSS 22.0.

Supplementary analyses will also be used to determine the feasibility of nutraceutical supplementation in FEP. Recruitment rate will be calculated as ‘number of people with consented’ divided by ‘number of people with FEP approached’. Retention will be calculated as the percentage of enrolled participants who complete both the 12-week intervention and the assessments at follow-up. Compliance will be assessed among those completing the trial (i.e. the 12-week intervention and 12-week assessments). This will firstly be assessed from mobile device self-recorded adherence data, in order to calculate:
(i) Mean % of days (across all completers) on which participants were ‘fully adherent’ (i.e. taking both doses) and ‘partially adherent’ (i.e. taking 1 dose)
(ii) Proportion of ‘partially compliant’ participants: defined as % of completing participants who were at least partially adherent on 80% of days
(iii) Proportion of ‘fully compliant’ participants: defined as % of completing participants who were fully adherent on 80% of days
Compliance will also be assessed by weighing the remaining product at follow-up. Total weight consumed (in grams) will be divided by 6 (gram amount per serving) to calculate the average number of doses consumed per participant over the intervention period.
Additionally, regression analyses will be performed to assess the correlation between objective (i.e. weighing) and self-report (i.e. smartphone app) measures of adherence.

Safety will be assessed by comparing the numbers of 'adverse events' and 'serious adverse events' which occur over the 12-week trial in the active intervention vs. the placebo control conditions. Specific types of 'adverse events' will also be recorded, and reported descriptively in the final paper.

Intention-to-treat analyses will include of all participant data even if only completing baseline, using a Mixed-Effect Model Repeated Measure (MMRM) approach for handling missing data. Any participants with data that satisfy statistical criteria for outliers will be excluded from analyses as that variable will not meet the assumptions of non-parametric statistical testing. Finally, per-protocol analyses will be conducted for participants identified as at least ‘partially compliant’ and completing both the intervention and 12-week assessments.
Where appropriate, missing values will be marked and explained in individual data tables. When one or more outliers are defined, scientific evidence or explanations will be provided to justify the exclusion of the subject's data from the statistical analysis. In case of outliers, the corresponding statistical analysis will be provided with and without these values.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/06/2018
Actual
Date of last participant enrolment
Anticipated
31/12/2019
Actual
Date of last data collection
Anticipated
31/03/2020
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 22500 0
2770 - Mount Druitt
Recruitment postcode(s) [2] 22501 0
2150 - Parramatta
Recruitment postcode(s) [3] 22502 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 299260 0
University
Name [1] 299260 0
NICM Health Research Institute, Western Sydney University
Country [1] 299260 0
Australia
Funding source category [2] 299283 0
Commercial sector/Industry
Name [2] 299283 0
Blackmores Institute
Country [2] 299283 0
Australia
Primary sponsor type
University
Name
Western Sydney University
Address
Western Sydney University, Sydney, NSW, Australia
Postal address: Locked Bag 1797 PENRITH NSW 2751
Country
Australia
Secondary sponsor category [1] 298551 0
None
Name [1] 298551 0
Address [1] 298551 0
Country [1] 298551 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 300177 0
Western Sydney University Human Research Ethics Committee
Ethics committee address [1] 300177 0
Ethics committee country [1] 300177 0
Australia
Date submitted for ethics approval [1] 300177 0
22/03/2018
Approval date [1] 300177 0
Ethics approval number [1] 300177 0

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

Contacts
Principal investigator
Name 82802 0
Dr Joseph Firth
Address 82802 0
Joseph Firth
NICM Health Research Institute
University of Western Sydney
Locked Bag 1797
PENRITH
NSW 2751
Country 82802 0
Australia
Phone 82802 0
+ 61 457 231 851
Fax 82802 0
Email 82802 0
[email protected]
Contact person for public queries
Name 82803 0
Joseph Firth
Address 82803 0
Joseph Firth
NICM Health Research Institute
University of Western Sydney
Locked Bag 1797
PENRITH
NSW 2751
Country 82803 0
Australia
Phone 82803 0
+ 61 457 231 851
Fax 82803 0
Email 82803 0
[email protected]
Contact person for scientific queries
Name 82804 0
Joseph Firth
Address 82804 0
Joseph Firth
NICM Health Research Institute
University of Western Sydney
Locked Bag 1797
PENRITH
NSW 2751
Country 82804 0
Australia
Phone 82804 0
+ 61 457 231 851
Fax 82804 0
Email 82804 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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