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Trial registered on ANZCTR

Registration number

ACTRN12615000201572

Ethics application status

Approved

Date submitted

12/02/2015

Date registered

2/03/2015

Date last updated

26/03/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Using Micronutrients in Smoking Cessation Treatment: A Double-Blind Randomized Placebo-controlled trial.

Scientific title

Investigation in to the effect of a micronutrient supplement combined with standard Quitline New Zealand care on quit success, withdrawal symptoms and associated psychological measures during smoking cessation': a double-blind randomized placebo-controlled trial.

Secondary ID [1]

none

Universal Trial Number (UTN)

Trial acronym

SCAN

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Nicotine addiction

Condition category

Condition code

Alternative and Complementary Medicine

Other alternative and complementary medicine

Mental Health

Addiction

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Double blind randomized controlled trial (RCT) comparing a micronutrient (vitamins and minerals) supplement Daily Essential Nutrients (DEN) with a placebo during a smoking cessation intervention followed by an open-label phase. The intervention consists of standard Quitline New Zealand care combined with a micronutrient formula (DEN) containing 41 ingredients: The doses of each ingredient in 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 mgCysteine (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 will be recruited via advertising to complete an online questionnaire that will assess their eligibility for the study and collect their demographic information. Eligible participants will be invited to the laboratory for their first consultation. At this consultation information will be given to the participant about the study and if they agree to take part they will sign a consent form. Participants will then complete baseline questionnaires; Smoking history, FTND, mCEQ, AUTOS, TCQ-12, AUDIT-C, Self-efficacy, MNWS, WSWS, DASS-21, ASI, DEMF and side effects. Participant’s weight and blood pressure will also be measured at this consultation. During the two week baseline participants will complete a daily diary of MPSS withdrawal symptoms and the number of cigarettes consumed. After the two weeks (end of baseline) the participants will come back in to the laboratory and complete the questionnaires again, excluding the smoking history questionnaire.

Pre-quitting (second baseline) phase (4 weeks): Once baseline phase is completed participants will come in to the laboratory for a second time and receive a four weeks supply of capsules (randomized to placebo (n=40) or micronutrients (n=40)) in plain containers. On days 1-2 participants will take 1 capsule 3 times daily, day 3-4 2 capsules 3 times daily, 5-6 3 capsules 3 times daily. On day 7 they will have titrated up to their full dose of 12 capsules/day and will continue to take three doses of four capsules with food and plenty of water each day for the remainder of the trial. For the first and the last weeks of the pre-quitting phase participants will complete a daily diary of recordings identical to baseline. Participants will complete the same questionnaires as baseline at two and four weeks of this phase. This phase permits the assessment of micronutrient consumption on smoking and related symptoms and on psychological health and wellbeing prior to any quit attempt being made.

Smoking cessation phase (12 weeks): After four weeks of taking the capsules participants will begin a smoking cessation intervention following Quitline New Zealand's five-step program (with the exclusion of step 4 that involves Nicotine Replacement Therapy) and continue to consume the capsules for 12 weeks. This smoking cessation phase will begin on an agreed quit date. Participants will monitor withdrawal symptoms (MPSS) for the first month after their quit date, then again in weeks eight and 12 using the daily diary. Every two weeks participants will also receive an email to complete questionnaires. Every 4 weeks participants will come in to the laboratory to complete questionnaires, receive more capsules and measure breath carbon monoxide to confirm smoking abstinence. Smoking relapse will be monitored, and participants are instructed to contact the researcher if they inhale a cigarette and to record it in the diary. Any participant that recorded smoking for 3 days in a row is counted as having a relapse. Participants that relapse continue to consume capsules and the researcher will help them to set a new quit date. If a participant is not smoke free at week 8 of this phase they will be asked to start the open-label phase (4-weeks earlier).

Open-label phase (4 weeks): At the end of smoking cessation phase participants will come in to the laboratory. All participants (smoking/non-smoking) will be offered a four-week open label phase where they will all be placed on the micronutrient capsules (12/day). During this phase they will complete a daily diary. Participants who are still smoking will be contacted prior to this visit to make the start of this phase a new quit date for them to re-attempt to quit smoking. Two-weeks in to this phase participants will receive an email to complete questionnaires. At the end of this phase participants will come back in to the laboratory for the last time, complete questionnaires and discuss any smoking cessation techniques Quitline suggests for long-term abstinence. Participants will be followed up 2 months after this phase by completing online questionnaires and report any smoking.

Intervention code [1]

Treatment: Other

Intervention code [2]

Behaviour

Comparator / control treatment

Placebo: Consists of riboflavin, fiber acacia gum, maltodextrin, and cocoa powder.
Patients swallow 12 capsules a day divided in to three doses of four pills each dose for a total of 16 weeks (4-week capsule alone phase and 12-week smoking cessation phase) (if participants do not quit smoking open-label phase will begin after 12 weeks of taking capsules). Participants randomized to the placebo condition follow the same protocol as the DEN group.

Control group

Placebo

Outcomes

Primary outcome [1]

Continuous abstinence from cigarette smoking at 12-weeks measured by self report and carbon monoxide (CO) test. Continuous abstinence is defined as: 12 weeks abstinence with no relapses (a relapse is defined as returning to a normal pattern of smoking for 3 days in a row).

Timepoint [1]

End of smoking cessation phase (12-weeks)

Secondary outcome [1]

Continuous abstinence from two weeks (two-week grace period) in smoking cessation phase to end of treatment at 12-weeks. Assessed using self-report and carbon monoxide (CO) test.

Timepoint [1]

End of smoking cessation phase (12-weeks)

Secondary outcome [2]

Continuous abstinence from the start of the smoking cessation phase to four and eight weeks of the phase. Assessed using self-report and carbon monoxide (CO) test.

Timepoint [2]

Four and eight weeks of the smoking cessation phase.

Secondary outcome [3]

Seven-day point prevalence at four, eight, and 12 weeks of smoking cessation phase and four-weeks of open-label phase. Assessed using self-report and carbon monoxide (CO) test.

Timepoint [3]

Four, eight, and 12 weeks of smoking cessation phase and four-weeks of open-label phase.

Secondary outcome [4]

Minnesota Nicotine withdrawal scale

Timepoint [4]

Baseline, before and after pre-quitting, 2,4,6,8,10, and 12-weeks of the smoking cessation phase. Two and four weeks of open label phase. Six-month follow-up.

Secondary outcome [5]

Depression Anxiety Sensitivity Scale-21

Timepoint [5]

Baseline, before and after pre-quitting phase, 2,4,6,8,10, and 12-weeks of the smoking cessation phase. Two and four weeks of open label phase. Six-month follow-up.

Secondary outcome [6]

Weight

Timepoint [6]

Baseline, before and after pre-quitting phase, 4,8, and 12-weeks of the smoking cessation phase. Four weeks after the open-label phase. Measured using digital scales.

Secondary outcome [7]

Fagerstrom Test for Nicotine Dependence

Timepoint [7]

Baseline, before and after pre-quitting phase at the start of smoking cessation and after a relapse during smoking cessation phase and at 6-month follow up. Relapse is when a participant has normal smoking pattern for 3 continuous days.

Secondary outcome [8]

Mood and Physical Symptoms Scale

Timepoint [8]

Daily during baseline phase, first and last week of pre-quitting phase, weeks 1-4, week-8 and week-12 of smoking cessation phase. First and last week of open label phase.

Secondary outcome [9]

AUDIT-C

Timepoint [9]

Baseline, before and after pre-quitting phase, 2,4,6,8,10, and 12-weeks of the smoking cessation phase. Two and four weeks of open label phase. Six-month follow-up.

Secondary outcome [10]

Smoking Self-Efficacy Questionnaire

Timepoint [10]

Secondary outcome [11]

Wisconsin Smoking Withdrawal Scale

Timepoint [11]

Baseline, before and after pre-quitting phase, 2,4,6,8,10, and 12-weeks of the smoking cessation phase. Two and four weeks of open label phase. Six-month follow-up.

Secondary outcome [12]

Diener and Emmons Mood Form

Timepoint [12]

Baseline, before and after pre-quitting phase, 2,4,6,8,10, and 12-weeks of the smoking cessation phase. Two and four weeks of open label phase. Six-month follow-up.

Secondary outcome [13]

Number of cigarettes smoked per day

Timepoint [13]

Daily during baseline phase, first and last week of pre-quitting phase, weeks 1-4, week-8 and week-12 of smoking cessation phase. First and last week of the open-label phase. Assessed using self report in the daily diary.

Secondary outcome [14]

Breath Carbon Monoxide

Timepoint [14]

Baseline, before and after pre-quitting phase, week 4,8, and 12 of smoking cessation phase. Week four of open-label phase.

Secondary outcome [15]

Side effects: Participants complete a questionnaire that asks if they have had a range of 19 symptoms, e.g. urinary retention, blurred vision, constipation, weight gain, if they have experienced any other symptoms, and what they did to remedy any symptoms they had experienced.
This side effect questionnaire is used by researchers in the Mental Health and Nutrition Research Group at the University of Canterbury to monitor side effects when participants consume capsules.

Timepoint [15]

Baseline, before and after pre-quitting phase, weeks 4,8, and 12 of smoking cessation phase. Week two and four of open-label phase. Assessed using a self-report questionnaire

Secondary outcome [16]

Capsule compliance. Counting any left over capsules.

Timepoint [16]

Daily throughout pre-quitting phase, smoking cessation phase and open-label phase.

Secondary outcome [17]

Continious abstinence throughout four week open-label phase. Assessed using self report and CO readings.

Timepoint [17]

End of four week open-label phase.

Secondary outcome [18]

Continious abstinence from two (grace period) to four weeks of open-label phase. Assessed using self report diary and CO reading with Bedfont Smokerlyzer.

Timepoint [18]

End of four week open-label phase.

Secondary outcome [19]

Abstinence at six month follow-up. Assessed using self report.

Timepoint [19]

Six month follow-up

Secondary outcome [20]

Blood Pressure (mm Hg). Measured using an automatic sphygmomanometer.

Timepoint [20]

Baseline, before and after pre-quitting phase, 4,8, and 12-weeks of the smoking cessation phase. Four weeks after the open-label phase.

Secondary outcome [21]

Abstinence and smoking habits (cigarettes per day) at 12-month follow-up.
Assessed with email and/or telephone call.

Timepoint [21]

12 months after quit day.

Eligibility

Key inclusion criteria

1) 18 years old or over 2) meet a 'current smoking' criteria of smoking at least three cigarettes a day for the past year 3) no serious medical conditions that require treatment during trial period 4) are not on psychoactive medication. Participants must be medication free for at least four weeks prior to beginning the trial.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1) under 18 years old 2) not a 'current smoker' of three or more cigarettes a day for the past year 3) on any psychoactive medication 4) 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 when they consent to take part in the study. Randomization to active or placebo will be done by a research assistant outside of the laboratory and the randomization list is given to the 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), this means only the blind for that participant would be broken.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomization for pill allocation will be done by a research assistant using randomization.com. Randomization.com uses block randomization. A pharmacist will receive a list of participant numbers and whether they are allocated to active or a placebo condition.

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

The RCT aims to recruit 80 participants (40 in DEN group, 40 in the placebo group). Participant number are based on initial pilot results, using power = 0.8 to detect a large effect size (0.8), with two tailed a=0.05.

Descriptive statistics will be calculated for demographic measures of the participants. Time series graphs will be constructed to show intensity and trajectory of change in MPSS withdrawal patterns during smoking cessation overtime. Computer generated trend and level lines will be used to further analyse data. Visual analysis (Modified Brinley Plots) will compare the DEN group and placebo. Patterns of individual change in monthly questionnaire ratings over study phases within groups will be examined using modified Brinley plots. Cohen’s d(between)(within) effect size will be used in the current study. Categorical outcome (quit/not-quit) will be compared using Chi-squared tests with odds ratio (ORs) and 95% confidence intervals and logistic regression. Hierarchical multiple regression will be used to evaluate how individual differences in psychological measures effect withdrawal symptoms and smoking abstinence rates throughout the study.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

9/03/2015

Actual

9/03/2015

Date of last participant enrolment

Anticipated

Actual

21/07/2015

Date of last data collection

Anticipated

Actual

21/07/2016

Sample size

Target

Accrual to date

Final

107

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Canterbury

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Canterbury

Address [1]

Private bag 4800
Christchurch 8140

Country [1]

New Zealand

Primary sponsor type

University

Name

University of Canterbury

Address

Private bag 4800
Christchurch 8140

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of Canterbury Human Ethics Committee

Ethics committee address [1]

University of Canterbury
Private Bag 4800
Christchurch 8140

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

22/01/2015

Approval date [1]

11/02/2015

Ethics approval number [1]

2015/11

Summary

Brief summary

Nicotine addiction is a chronic condition caused by continued tobacco smoking to prevent unpleasant nicotine withdrawal symptoms that occur after smoking cessation. Smoking cessation has immediate as well as long-term health benefits. The two main components in the process of quitting are (i) making a quit attempt, and (ii) maintaining abstinence after that attempt. Smoking cessation interventions typically involve some counselling and pharmacotherapy. A national quit line service is provided by 53 countries giving information and counselling to smokers who want to quit. Quitline New Zealand reports a quit rate of 43% at four weeks, a rate comparable to that of other high-income countries, maintaining this abstinence long-term is crucial for the prevalence of smoking to decrease. A few (<10%) of the quit line services offer discounted Nicotine Replacement Therapy (NRT), the most common pharmacotherapy used for smoking cessation which includes nicotine gum, patches, and lozenges. Bupropion hydrochloride [Zyban Registered Trademark] doubles a person’s chance of quitting compared to placebo with quit rates similar to NRT reporting a four week quit rate of 30- 60%. Varenicline [Chantix/Champix Registered Trademark] is reported to have quit rates between 30-50%. Pharmacological therapies improve the chances of abstinent rates but they can be relatively complex to deliver, require prescription and supervision, and side effects can be problematic. Alternative treatments that are safe, effective, and readily available are needed. Nutritional interventions are one such alternative. Over the last decade, interest in the impact that nutrition on both health and psychological wellbeing in the treatment of mental illness has grown and micronutrients (vitamins and minerals) are being studied for the treatment of psychiatric conditions (Rucklidge & Kaplan, 2013). In the treatment of addictions, Blum and colleagues developed formulas called “neuronutrients” or “nueroadaptagens” that mainly consist of amino acids, minerals and vitamins (Blum, Allison, Trachtenberg, Williams, & Loeblich, 1988), nutrients to reduce relapse rates, drug hunger and withdrawal, and improve psychological functioning. One case study, using a single case reversal (off-on-off-on-off) design, showed on-off control of psychiatric symptoms as the micronutrients were consumed or withdrawn, but also simultaneous on-off use of cannabis and tobacco smoking (Harrison, Rucklidge, & Blampied, 2013). I have also conducted a pilot study examining the use of a micronutrient formula, Daily Essential Nutrients (DEN) in conjunction with standard Quitline New Zealand care, by individuals attempting to quit smoking (Newton, Blampied, Rucklidge, 2014 in preparation). The micronutrient intervention resulted in a significantly increased chance of being successful at a quit attempt and an increased rate of quitting at four, eight and 12-weeks compared to placebo, providing evidence that micronutrients improve quit success. My PhD will attempt to further support the role of micronutrients in addiction by conducting a randomised controlled trial study with a larger sample size and improved assessments. Participants will take micronutrients or placebo while trying to quit smoking

Trial website

www.bit.ly/nutritionresearch

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Miss Phillipa Kate Newton

Address

Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8041

Country

New Zealand

Phone

+64 (0)3 364 2987 ext. 7705

Fax

[email protected]

Contact person for public queries

Name

Miss Phillipa Newton

Address

Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8041

Country

New Zealand

Phone

+64 (0)3 364 2987 ext. 7705

Fax

[email protected]

Contact person for scientific queries

Name

Miss Phillipa Newton

Address

Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8041

Country

New Zealand

Phone

+64 (0)3 364 2987 ext. 7705

Fax

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

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Doc. No.	Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
4495	Study results article	Yes		Reihana, P. K., Blampied, N. M., & Rucklidge, J. J... [More Details]

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Source	Title	Year of Publication	DOI
Embase	Novel Mineral-Vitamin Treatment for Reduction in Cigarette Smoking: A Fully Blinded Randomized Placebo-Controlled Trial.	2019	https://dx.doi.org/10.1093/ntr/nty168

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