Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613001188729
Ethics application status
Approved
Date submitted
3/09/2013
Date registered
29/10/2013
Date last updated
18/05/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Nutritional supplements and withdrawal symptoms in smoking cessation.
Scientific title
Investigation into the effect of a nutritional supplement combined with standard Quitline New Zealand care on withdrawal symptoms during smoking cessation: a double blind randomized placebo controlled trial with a multiple baseline.
Secondary ID [1] 283021 0
none
Universal Trial Number (UTN)
U1111-1146-7925
Trial acronym
SCAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tobacco addiction 289853 0
Condition category
Condition code
Alternative and Complementary Medicine 290211 290211 0 0
Other alternative and complementary medicine
Mental Health 290636 290636 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Double blind randomized controlled trial (RCT) comparing a mineral and vitamin supplement Daily Essential Nutrients (DEN) with a placebo. The intervention consists of a micronutrient formula (DEN) containing 41 ingredients: The doses of each ingredient of one capsule are:
Vitamin A (as retinyl palmitate) 384 IU
Vitamin C (as ascorbic acid) 40 mg
Vitamin D (as cholecalciferol) 200 IU
Vitamin E (as d-alpha tocopheryl succinate) 24 IU
Vitamin K (as phylloquinone) 6 mcg
Vitamin K (as menaquinone-7) 2 mcg
Thiamin (as thiamin mononitrate) 4 mg
Riboflavin 1.2 mg
Niacin (as niacinamide) 6 mg
Vitamin B6 (as pyridoxine hydrochloride) 4.6667 mg
Folate (as folic acid) 50 mcg
Folate (as L-methylfolate calcium) 50 mcg
Vitamin B12 (as methylcobalamin) 60 mcg
Biotin 72 mcg
Pantothenic acid (as d-calcium pantothenate) 2 mg
Calcium (as chelate) 88 mg
Iron (as chelate) 0.916 mg
Phosphorus (as chelate) 56 mg
Iodine (as chelate) 13.6 mcg
Magnesium (as chelate) 40 mg
Zinc (as chelate) 3.2 mg
Selenium (as chelate) 13.6 mcg
Copper (as chelate) 0.48 mg
Manganese (as chelate) 0.64 mg
Chromium (as chelate) 41.6 mcg
Molybdenum (as chelate) 9.6 mcg
Potassium (as chelate) 16 mg

Choline bitartrate 36 mg
Alpha-lipoic acid 33.333 mg
Shilajit 12.5 mg
Inositol 12 mg
Acetylcarnitine (as acetyl-L-carnitine hydrochloride) 4 mg
Grape seed extract 3 mg
Ginkgo biloba leaf extract 2.4 mg
Methionine (as L-methionine hydrochloride) 2 mg
Cysteine (as N-acetyl-L-cysteine) 2 mg
Germanium sesquioxide (as chelate) 1.38 mg
Boron (as chelate) 0.16 mg
Vanadium (as chelate) 0.0796 mg
Lithium orotate (as chelate) 0.0667 mg
Nickel (as chelate) 0.002 mg

Other ingredients:
Cellulose 49.122 mg
Glycine 45 mg
Citric acid 26.814 mg
Magnesium stearate 24 mg
Silicon dioxide 20 mg

Baseline phase:
Participants complete a baseline phase of 1,2, or 3 weeks. During the baseline phase cigarette consumption, mood and withdrawal symptoms are monitored daily.

Capsule intervention phase:
Participants swallow up to a target dose of 12 capsules of DEN or placebo a day divided into three doses of 4 pills each dose for a total of 16 weeks. Participants will begin by taking one capsule, 3 times each day, increasing the dose by three capsules every two days up to a target dose of 12 capsules per day: 4 taken at 3 different intervals. Compliance will be monitored with diaries and pill counts. Cigarette consumption, mood and withdrawal will be monitored during week 1 and 4 of this phase.

Smoking Cessation phase:
After 4 weeks of taking the capsules participants begin a smoking cessation intervention following Quitline New Zealand's five step program (with the exclusion of step 4 nicotine patches and gum). Standard Quitline care coincides with the continuing consumption of the capsules. Participants monitor mood and withdrawal symptoms for the first month after quit date, then for the last week of the consecutive 2 months using a diary that they carry with them. Every 2 weeks participants complete withdrawal, dependence, depression, anxiety sensitivity and a side effects questionnaire. Participants come in to the laboratory every 4 weeks for 3 months to receive more capsules, complete questionnaires and talk about smoking cessation. Participants take the capsules for 3 months during the smoking cessation phase. Adherence to protocol during the smoking cessation phase is monitored with self report diaries, and pill counts. All participants will then be followed up 3 months after the trial.
Intervention code [1] 287739 0
Treatment: Other
Intervention code [2] 287740 0
Behaviour
Comparator / control treatment
The placebo consists of riboflavin, fiber acacia gum, Maltodextrin, and cocoa powder. Patients swallow 12 capsules a day divided into three doses of 4 pills each dose for a total of 16 weeks. Participants randomized to the placebo condition follow the same protocol as the DEN group. Participants take the placebo capsules throughout the 4 week capsule intervention phase and for the three month smoking cessation phase.
Control group
Placebo

Outcomes
Primary outcome [1] 290268 0
Minnesota Nicotine Withdrawal Scale - Short 8 item and long 18 item version
Timepoint [1] 290268 0
Baseline, short version daily during week 1 and 4 of nutrient intervention and long version on day 14 of this phase, short scale daily for first month of smoking cessation and last week of consecutive three months, long version fortnightly during smoking cessation, long version 3 months post trial.
Secondary outcome [1] 304225 0
Depression Anxiety Sensitivity Index-21,
Timepoint [1] 304225 0
Baseline, 2 weeks in to nutrient intervention, and 2, 4, 6, 8, 12, weeks in to smoking cessation. At a 3 month follow up.
Secondary outcome [2] 304316 0
Fagerstrom Test for Nicotine Dependence
Timepoint [2] 304316 0
Baseline, 2 weeks in to nutrient intervention, and 2, 4, 6, 8, 12, weeks in to smoking cessation. At a 3 month follow up.
Secondary outcome [3] 304317 0
Anxiety Sensitivity Index.
Timepoint [3] 304317 0
Baseline, 2 weeks in to nutrient intervention, and 2, 4, 6, 8, 12, weeks in to smoking cessation. At a 3 month follow up.
Secondary outcome [4] 304320 0
Mood and Physical symptoms scale.
Timepoint [4] 304320 0
Daily during baseline phase, first and last week of nutrient intervention, daily for first month of smoking cessation and daily for last week of consecutive 2 months during smoking cessation.
Secondary outcome [5] 304321 0
Quit Rate assessed with self-report diaries that ask about cigarette consumption.
Timepoint [5] 304321 0
During smoking cessation phase at week 1,2,3,4,7, and 11. Participants are also instructed to email researcher if any smoking occurs.
Secondary outcome [6] 304322 0
Relapse rate assessed with self report diaries.
Timepoint [6] 304322 0
During smoking cessation phase at week 1,2,3,4,7, and 11. Participants are also instructed to email researcher if any smoking occurs.
Secondary outcome [7] 304403 0
Quitline use assessed with self report diaries.
Timepoint [7] 304403 0
During smoking cessation phase at week 1,2,3,4,7, and 11.
Secondary outcome [8] 304404 0
Cigarette consumption assessed with self report diaries.
Timepoint [8] 304404 0
Daily during baseline phase and nutrient phase. During the smoking cessation participants are instructed to tell the researcher if any smoking occurs with self reported diaries and an email.
Secondary outcome [9] 304405 0
Capsule compliance assessed by counting any left over capsules and self report diaries.
Timepoint [9] 304405 0
Daily throughout capsule intervention phase and smoking cessation phase.

Eligibility
Key inclusion criteria
1) 18 years old or over 2) Meet a 'current smoking' criteria of smoking at least 2 cigarettes a day for the past year. 3) No serious medical conditions requiring treatment during the trial period. 4) Are not on psychoactive medication. Participants must be medication free for at least 4 weeks prior to beginning the trial.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Under 18 years old. 2) On any psychoactive medication. 3) Any serious medical condition.

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)
Provided that an individual meets the inclusion criteria and does not meet exclusion criteria, the person is allocated the next available participant number. Baseline length has been predetermined by a research assistant outside the laboratory. Baseline length is revealed by opening an envelope when the consent form is signed. Ramdomization to active ingredient or placebo was done by a research assistant outside of the laboratory and given to a pharmacist. All capsules (ie active ingredient or placebo) have been pre-packaged by a pharmacist 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).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization for pill allocation and baseline length was completed by a research assistant. The research assistant used block randomization. A pharmacist received a list of placebo or active ingredients with participant number. The research assistant kept a list of the multiple baseline length but gave the researcher the envelopes with a participant number on the front and baseline number inside.
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
Multiple baseline design of 1,2, or 3 weeks is blind until participant consents then it is revealed for participant and researcher.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Demographic Information
Descriptive statistics will be calculated for demographic measures of the participants.

Withdrawal Measures
Time series graphs will be constructed to show intensity and trajectory of change in withdrawal patterns during smoking cessation overtime. Single case research design visual analysis will compare the DEN group and placebo. Computer generated trend and level lines will be used to further analyse data.

Individual Differences
Hierarchical multiple regression will be used to evaluate how individual differences in anxiety sensitivity, nicotine dependence, depression, cigarette consumption, physcial symptoms and mood effect withdrawal symptoms during the smoking cessation. It is understood that the small sample size will limit the number of predictor variables that can be entered in the analysis.

Effect Size
Effect size measures will be calculated from one of the nine non-overlap effect size estimators of single case research design e.g., percent of all non-overlapping data (PAND) or Percent Exceeding the Median (PEM).

Sample Size
In the single-case research design tradition participants are not regarded as samples from some putative population and the aim of the research is not to draw inferences from sample statistics to population parameters. Issues of power, in the statistical sense of the adequacy of the sample size to support statistical inferences (in particular, to avoid Type II error), do not therefore arise. Single-case research supports inferences about the effects of the intervention via a process of Replication, where the question is the degree to which the pattern of results observed in one participant (or one condition, in the case of some designs) is replicated across other participants, given that each participant has been exposed to the same intervention under comparable circumstances. The more successful replications achieved the stronger the support for the inference that the treatment caused the observed changes. How many replications are needed. THe Institute of Education Science commissioned an expert group to formulate standards for single-case research design (Kratochwill, et al., 2010). They provide the following advice in the case of the multiple-baseline design:

“The multiple baseline design involves an effect replication option across participants, settings, or behaviors. Multiple AB data series are compared and introduction of the intervention is staggered across time. In this design, more valid causal inferences are possible by staggering the intervention across one of the aforementioned units (i.e., sequential introduction of the intervention across time). The minimum number of phase repetitions needed to meet the standard advanced by Horner et al. (2005) is three, but four or more is recognized as more desirable… . Adding phase repetitions increases the power [of the design], similar to adding participants in a traditional group design. … Among the characteristics of this design, effect replication across series is regarded as the characteristic with the greatest potential for enhancing internal and statistical-conclusion validity.” (p7, emphasis added)

The current trial is aiming for 12 replications per condition (active vs placebo treatment), which is considerably more than the four recommended by the Institute of Education Science Technical Documentation cited above.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
24/06/2013
Actual
18/07/2013
Date of last participant enrolment
Anticipated
Actual
31/01/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment outside Australia
Country [1] 5298 0
New Zealand
State/province [1] 5298 0

Funding & Sponsors
Funding source category [1] 287789 0
University
Name [1] 287789 0
University of Canterbury
Country [1] 287789 0
New Zealand
Funding source category [2] 287824 0
Government body
Name [2] 287824 0
The Health Promotion Agency
Country [2] 287824 0
New Zealand
Primary sponsor type
University
Name
University of Canterbury
Address
Private Bag 4800
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 286519 0
Government body
Name [1] 286519 0
The Health Promotion Agency
Address [1] 286519 0
PO Box 2142
Wellington
6140
Country [1] 286519 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289738 0
University of Canterbury Human Ethics Committee
Ethics committee address [1] 289738 0
University of Canterbury Private Bag 4800, Christchurch 8140
Ethics committee country [1] 289738 0
New Zealand
Date submitted for ethics approval [1] 289738 0
Approval date [1] 289738 0
10/06/2013
Ethics approval number [1] 289738 0
HEC 2013/55

Summary
Brief summary
Approximately 20% of the New Zealand adult population are current tobacco smoking. Tobacco smoking has many adverse consequences. An individual continues to smoke as tobacco contains the addictive substance called nicotine. Complementary alternative medicine (CAM) has been used in previous studies to help with the symptoms of withdrawal from drugs, however there is very little research on nicotine withdrawal and CAM. The aim of the current study is to assess the effect that the consumption of a micronutrient formula has on withdrawal symptoms when incorporated in a tobacco smoking cessation intervention (Quitline New Zealand's five step program). This study will use one micronutrient formula called Daily Essential Nutrients (DEN), a revision of EMPowerplus(EMP+) which is sold in NZ, has received international attention as a treatment for several psychiatric disorders including bipolar disorder, depression and ADHD. Our research team has published results using a variety of designs including open label, case studies and RCTs, showing that EMP+ has significant positive effects on mood, anxiety, hyperactivity, impulsivity and emotional lability. Given the encouraging results to date, this study seeks to conduct a randomized controlled trial using this revised formula, DEN, for current smokers 18 years and over. The primary outcome assessed is the change of withdrawal symptoms during initial smoking cessation and withdrawal symptoms of the placebo group compared to the nutrient group.
Trial website
www.mentalhealthandnutrition.co.nz
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 42162 0
Miss Phillipa Newton
Address 42162 0
Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand
Country 42162 0
New Zealand
Phone 42162 0
+64 (0)3 364 2987 ext. 7705
Fax 42162 0
Email 42162 0
phillipa.newton@pg.canterbury.ac.nz
Contact person for public queries
Name 42163 0
Miss Phillipa Newton
Address 42163 0
Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand
Country 42163 0
New Zealand
Phone 42163 0
+64 (0)3 364 2987 ext. 7705
Fax 42163 0
Email 42163 0
phillipa.newton@pg.canterbury.ac.nz
Contact person for scientific queries
Name 42164 0
Miss Phillipa Newton
Address 42164 0
Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand
Country 42164 0
New Zealand
Phone 42164 0
+64 (0)3 364 2987 ext. 7705
Fax 42164 0
Email 42164 0
phillipa.newton@pg.canterbury.ac.nz

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