Heated Tobacco Products vs Electronic Cigarettes

• Sponsor: University of Catania (Other)
• Overall Status: Completed
• CT.gov ID: NCT03569748
• Collaborator: Philip Morris Products S.A. (Industry)
• Enrollment: 220
• Location: 1
• Arms: 2
• Actual Duration (Months): 12
• Patients Per Site Per Month: 18.3

Study Details

Study Description

Brief Summary

This is a 12-weeks, open label, non-inferiority trial comparing HTPs vs ECs in terms of efficacy, adoption rate and acceptability, tolerability, and tobacco harm reduction in 220 healthy smokers, not motivated to quit, randomized (1:1) to switch to one of these products. The duration of the study, from the enrollment to the study close out for all the patients at week 24 (follow-up), will be approximately 12 months. Enrollment period will last about 6 months with the support of a multi-channel advertising method. This will include location-based advertising on social networks, advertising in local media, information days organized within the city.

Condition or Disease	Intervention/Treatment	Phase
Smoking, Cigarette	Device: IQOS; Device: E-CIG	N/A

Detailed Description

Before the baseline visit, a face to face screening (V0) for pre-eligibility checks will be conducted. Subjects will be asked to practice with the step test for 10-15 minand will be instructed how to collect and store their morning urine before bringing it to the hospital on their Baseline visit (V1). This study will consist of a baseline visit (V1) and 6 follow-up study visits (V2-V7). At baseline (V1), participants will be randomized in two separate study groups. The randomization sequence will be computer generated by using blocks size of 5, with an allocation ratio of 1:1 for each of the study products (IQOS, JustFog-EC). Subjects will use and familiarize with their allocated product, as per randomization. They will be trained and counseled on the use of their allocated study product; oral explanation and practical demonstration will be followed by product trial during which participants will also have the option to try and choose their preferred flavour (either from a selection of 3 e-liquids or 3 tobacco sticks, depending on the allocated arm). Participants randomized in the IQOS arm will receive one iQOS kit and a full 1 week supply of tobacco sticks of their choice (they will receive a number of tobacco sticks/day corresponding to the number of cigarettes smoked at baseline); those randomized in the JustFog-EC arm of the study will receive one JustFog Starter Kit and a full 1 week supply of e-liquids of their choice (they will receive 4, 10 mls refill containers).Free products will be supplied at each subsequent visit throughout the study. No supply of tobacco stick or e-liquid will be given at week-12, but users will be offered to keep using their products to minimize the risk of relapsing back to cigarette smoking. A prospective evaluation of cigarette consumption, adoption rates, acceptability and tolerability will be recorded throughout the study.

Visit 2 (V2):This will be scheduled 1 week after V1 (with a tolerance of +/- 3 days). Cigarette/day, eCO, AEs, BP, HR will be measured and product use recorded. Full 1 week supply of the chosen product will be provided.

Visit 3 (V3):This will be scheduled 2 weeks after V1 (with a tolerance of +/- 3 days). Cigarette/day, eCO, AEs, BP, HR will be measured and product use recorded. Participants will be instructed on how to collect and store their second urine sample before bringing it to the hospital at V4. Full 2 weeks supply of the chosen product will be provided.

Visit 4 (V4):This will be scheduled 4 weeks after V1 (with a tolerance of +/- 3 days). Cigarette/day, eCO, AEs, BP, HR will be measured, questionnaires completed and product use recorded. Step test will be carried out. Second urine sample will be collected, aliquotted and stored. Full 4 weeks supply of the chosen product will be provided.

Visit 5 (V5):This will be scheduled 8 weeks after V1 (with a tolerance of +/- 7 days). Cigarette/day, eCO, AEs, BP, HR will be measured, questionnaires completed and product use recorded. Full 4 weeks supply of the chosen product will be provided.

Visit 6 (V6):This will be scheduled 12 weeks after V1 (with a tolerance of +/- 7 days). Cigarette/day, eCO, AEs, BP, HR, weight, height will be measured, questionnaires completed and product use recorded. Step test will be carried out. No more products will be dispensed.

Follow-up Visit (V7):This final visit will be scheduled 24 weeks after V1 (with a tolerance of +/- 7 days)to review product usage and smoking behavior under naturalistic condition of use. Cigarette/day, eCO, AEs, BP, HR, weight, height will be measured, questionnaires completed and product use recorded. Step test will be carried out.

Data will be recorded from every subject on an electronic CRF, provided by a CRO, GCP compliant, 21 CFR Part 11 FDA compliant, listed in AIFA list of operating CRO. Urine samples will be collected at baseline and wk 4, and sent to an external laboratory for analytical assessment of selected Biomarkers of Exposure (BoE).

The study will be conducted at the University of Catania, Catania, Italy.

Participants Healthy smokers, not motivated to quit, will be randomized in two intervention groups in a 1:1 ratio to compare HTPs vs ECs in terms of reductions in cigarette consumption, adoption rate and acceptability, tolerability, and tobacco harm reduction. Sample size determination (better detailed below, in the relevant section) for no-inferiority testing is based on the assumptions that 1) expected quit rates based on most recent EC literature is about 20-25% and 2) that differences in quit rates between products under investigation should not exceed 10-15% (as per non-inferiority definition). According to these hypotheses the required number of participants per study arm is 104. Hence investigators intend to include 220 participants, 110 per group.

Study Products Tested

• Heated Tobacco Product (HTP):Investigators will use a HTP that does not involve combustion, generating a nicotine-containing aerosol. At the time of writing, IQOS is the only HTP available on the Italian market. IQOS is composed by: 1) a tobacco stick - a novel patent-pending tobacco product with unique processed tobacco made from tobacco powder; 2) an electronic holder into which the tobacco stick is inserted and which heats the tobacco by means of an electronically controlled heating blade; 3) a charger that is used to recharge the holder after each use.

• Investigators will use the three types of tobacco sticks specifically designed for IQOS(named HEETS) that are currently for sale in the Italian market: Heets Amber, Heets Yellow, and Heets Turquoise. These products are compliant to the EU Tobacco Product Directive.

• Electronic Cigarette (EC):JustFog Q16 Starter Kit and three types of e-liquid flavours, Puff Riserva Country 16 mg, Puff Riserva Toscana 16 mg, and Puff Artic 16 mg (2 tobacco-flavours and one menthol flavour), were chosen for the study.

• Products were selected by an Italian expert panel of 3 e-liquid producers and 3 vaping product distributors, moderated by the editor of a popular e-cigarette blog. Experts convened in Verona (Italy) during a major vaping expo event. Through consensus, the expert panel provided specific recommendation on the device(JustFog Q16 Starter Kit is one of the most popular e-cigarette device in Italy due to its good performance and quality, affordable price, and user friendliness especially for beginners) and the choice of e-liquids that could best match the sensorial experience of the iQOS tobacco sticks to be used in a switching study and minimize the local irritant effects of excessive PG/VG ratio. These products are compliant to the EU Tobacco Product Directive.

Study Design

• Study Type: Interventional
• Actual Enrollment: 220 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Non-Inferiority Trial ComparingCigarette Consumption, Adoption Rates, Acceptability, Tolerability, and Tobacco Harm Reduction Potential in Smokers Switching to Heated Tobacco Products or Electronic Cigarettes: Study Protocol
• Actual Study Start Date: May 25, 2019
• Actual Primary Completion Date: May 25, 2020
• Actual Study Completion Date: May 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IQOS HEAT NOT BURN REDUCED RISK PRODUCT	Device: IQOS; IQOS USE FOR 12 WEEKS
Active Comparator: E-CIG ELECTRONIC CIGARETTE REDUCED RISK PRODUCT	Device: E-CIG; ELECTRONIC CIGARETTE FOR 12 WEEKS

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Smoking Cessation [12 WEEK]

   to compare the efficacy of HTP and EC, in terms of quit rates at week 12, by self-reporting abstinence from classic cigarette [validated by an Exhaled breath Carbon monoxide (eCO) measurement ≤10ppm)]

Secondary Outcome Measures

1. Number of Participants Smoking Reduction [Week 12]

   To compare the smoking reduction derived from the use of HTP and EC, intended as a 50% reduction in the number of conventional cigarette/day at week 12, defined through self-reporting;

2. Adoption Rate [Week 12]

   To compare the adoption rate to product use [by collecting (empty) refill bottles and used heathsticks on a daily basis, verified by a study diary filled daily by the subject];

3. Acceptability [Week 12]

   To compare the acceptability derived from the use of HTP and EC by the modified Cigarette Evaluation Questionnaire (mCEQ). It is a self-administered questionnaire that contains 12 items covering both reinforcing and aversive effects of smoking. The items are rated on a 7-point scale from 1 not at all to 7 extremely The total mCEQ score range from min 12 to max 84. Higher scores for the total mCEQ reflect a better outcome. There are also the following 5 subscales: Smoking Satisfaction (items 1, 2, 12) range of scores min 3 max 21;higher scores mean a better outcome. Psychological Reward (items 4-8), range of scores min 5 max 35; higher scores mean a better outcome. Aversion (items 9 and 10), range of scores min 2 max 14;higher scores mean a worse outcome. Single item score Enjoyment Respiratory Tract Sensations (item 3) range scores min 1 max 7;higher scores mean a better outcome. Single item score Craving Reduction (item 11), higher scores mean a better outcome

4. Number of Participants With Product-related Adverse Events [Week 12]

   To compare number of participants with adverse events derived from the use of HTP and EC as assessed by CTCAE v4.0

5. Changes in Biomarkers of Biological Effects (BoBE) [Week 12]

   changes in Biomarkers of Biological Effects (BoBE) such as: eCO in the exhaled breath (i.e. eCO), step test values

6. Reliability [Baseline visit, Week 12]

   To compare the reliability of HTP and EC, in terms of incidence and kind of malfunctioning events, through self-reporting.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the study:

1. Able to comply with the study procedures

2. Male or female healthy smokers aged ≥19

3. Smoking at least 10 cigarettes a day

4. Smoking for at least one year

5. Not currently attempting to quit smoking or wishing to do so in the next 30 days (this will be verified at screening by the answer ''NO'' to both questions ''Do you intend to quit in the next 30 days?'' and ''Are you interested in taking part in one of our smoking cessation programs?'')

6. Female smokers not planning to become pregnant are using an acceptable form of contraception.

Exclusion Criteria:

The presence of any of the following will exclude a subject from study enrolment:

1. Use of smokeless tobacco, or any other tobacco products (including e-cigarettes, cigars, chewing tobacco, snus, etc.) within the last 3 months, at baseline and during the whole study.

2. Use of nicotine replacement therapy or other smoking cessation therapies within the last 3 months and at baseline.

3. Self-reported pregnancy, planned pregnancy or breastfeeding.

4. Tobacco industry employees and 1st degree relatives will be excluded in order to safeguard independence of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Catania, Italy	Catania		Italy

Sponsors and Collaborators

• University of Catania
• Philip Morris Products S.A.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 26, 2017
• Statistical Analysis Plan - Jul 8, 2020

More Information

Publications

None provided.

• Responsible Party: Enrico Gian Maria Mondati, Researcher of Internal Medicine, University of Catania
• ClinicalTrials.gov Identifier: NCT03569748
• Other Study ID Numbers: 215/2017/PO
• First Posted: Jun 26, 2018
• Last Update Posted: Jun 25, 2021
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Enrico Gian Maria Mondati, Researcher of Internal Medicine, University of Catania: smoking; harm reduction; electronic cigarette; heated tobacco product

Study Results

Participant Flow

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	HEAT NOT BURN REDUCED RISK PRODUCT IQOS: IQOS USE FOR 12 WEEKS	ELECTRONIC CIGARETTE REDUCED RISK PRODUCT E-CIG: ELECTRONIC CIGARETTE FOR 12 WEEKS
Period Title: Overall Study
STARTED	110	110
COMPLETED	110	101
NOT COMPLETED	0	9

Baseline Characteristics

Arm/Group Title	IQOS	E-CIG	Total
Arm/Group Description	HEAT NOT BURN REDUCED RISK PRODUCT IQOS: IQOS USE FOR 12 WEEKS	ELECTRONIC CIGARETTE REDUCED RISK PRODUCT E-CIG: ELECTRONIC CIGARETTE FOR 12 WEEKS	Total of all reporting groups
Overall Participants	110	110	220
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.3 (16.1)	41.3 (16.9)	41.3 (16.5)
Sex: Female, Male (Count of Participants)
Female	54 49.1%	40 36.4%	94 42.7%
Male	56 50.9%	70 63.6%	126 57.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	110 100%	110 100%	220 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Smoking Cessation
Description	to compare the efficacy of HTP and EC, in terms of quit rates at week 12, by self-reporting abstinence from classic cigarette [validated by an Exhaled breath Carbon monoxide (eCO) measurement ≤10ppm)]
Time Frame	12 WEEK

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	HEAT NOT BURN REDUCED RISK PRODUCT IQOS: IQOS USE FOR 12 WEEKS	ELECTRONIC CIGARETTE REDUCED RISK PRODUCT E-CIG: ELECTRONIC CIGARETTE FOR 12 WEEKS
Measure Participants	110	107
Count of Participants [Participants]	60 54.5%	44 40%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IQOS, E-CIG
	Comments	H0: P1-P2 ≤ -Margin
	Type of Statistical Test	Non-Inferiority
	Comments	Margin=0.04
Statistical Test of Hypothesis	p-Value	0.0051
	Comments
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Proportion Difference
	Estimated Value	0.1342
	Confidence Interval	(2-Sided) 95%; 0.0014 to 0.2671
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Smoking Reduction
Description	To compare the smoking reduction derived from the use of HTP and EC, intended as a 50% reduction in the number of conventional cigarette/day at week 12, defined through self-reporting;
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	HEAT NOT BURN REDUCED RISK PRODUCT IQOS: IQOS USE FOR 12 WEEKS	ELECTRONIC CIGARETTE REDUCED RISK PRODUCT E-CIG: ELECTRONIC CIGARETTE FOR 12 WEEKS
Measure Participants	110	107
Count of Participants [Participants]	100 90.9%	77 70%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IQOS, E-CIG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Adoption Rate
Description	To compare the adoption rate to product use [by collecting (empty) refill bottles and used heathsticks on a daily basis, verified by a study diary filled daily by the subject];
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	4 PARTICIPANTS WITHOUT ADHERENCE IN IQOS GROUP	19 PARTICIPANTS WITHOUT ADHERENCE IN E-CIG GROUP
Measure Participants	110	107
Count of Participants [Participants]	102 92.7%	84 76.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IQOS, E-CIG
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	14.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Acceptability
Description	To compare the acceptability derived from the use of HTP and EC by the modified Cigarette Evaluation Questionnaire (mCEQ). It is a self-administered questionnaire that contains 12 items covering both reinforcing and aversive effects of smoking. The items are rated on a 7-point scale from 1 not at all to 7 extremely The total mCEQ score range from min 12 to max 84. Higher scores for the total mCEQ reflect a better outcome. There are also the following 5 subscales: Smoking Satisfaction (items 1, 2, 12) range of scores min 3 max 21;higher scores mean a better outcome. Psychological Reward (items 4-8), range of scores min 5 max 35; higher scores mean a better outcome. Aversion (items 9 and 10), range of scores min 2 max 14;higher scores mean a worse outcome. Single item score Enjoyment Respiratory Tract Sensations (item 3) range scores min 1 max 7;higher scores mean a better outcome. Single item score Craving Reduction (item 11), higher scores mean a better outcome
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	MEAN CHANGES AT FINAL VISIT (WEEK 12) FROM BASELINE IN MCEQ SCORES: O.73	MEAN CHANGES AT FINAL VISIT (WEEK 12) FROM BASELINE IN MCEQ SCORES: -O.17
Measure Participants	110	107
Mean (95% Confidence Interval) [score on a scale]	0.73	-0.17

5. Secondary Outcome

Title	Number of Participants With Product-related Adverse Events
Description	To compare number of participants with adverse events derived from the use of HTP and EC as assessed by CTCAE v4.0
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	HEAT NOT BURN REDUCED RISK PRODUCT IQOS: IQOS USE FOR 12 WEEKS	ELECTRONIC CIGARETTE REDUCED RISK PRODUCT E-CIG: ELECTRONIC CIGARETTE FOR 12 WEEKS
Measure Participants	110	110
Count of Participants [Participants]	20 18.2%	24 21.8%

6. Secondary Outcome

Title	Changes in Biomarkers of Biological Effects (BoBE)
Description	changes in Biomarkers of Biological Effects (BoBE) such as: eCO in the exhaled breath (i.e. eCO), step test values
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IQOS	E-CIG
Arm/Group Description	at v6 (week 12) mean(sd) eCO: 8.2 (8.0) at v6 (week 12) mean(sd) Step Test VoMax: 44.7 (28.7)	at v6 (week 12) mean(sd) eCO: 10.1 (11.3) at v6 (week 12) mean(sd) Step Test VoMax: 50.9 (31.9)
Measure Participants	110	107
Mean (Standard Deviation) [ppm]	8.2 (8.0)	10.1 (11.3)

7. Secondary Outcome

Title	Reliability
Description	To compare the reliability of HTP and EC, in terms of incidence and kind of malfunctioning events, through self-reporting.
Time Frame	Baseline visit, Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Any participants showed/reported signs and symptoms considered serious by the medical investigators with absence of all-cause of mortality
Arm/Group Title	IQOS		E-CIG
Arm/Group Description	HEAT NOT BURN REDUCED RISK PRODUCT IQOS: IQOS USE FOR 12 WEEKS		ELECTRONIC CIGARETTE REDUCED RISK PRODUCT E-CIG: ELECTRONIC CIGARETTE FOR 12 WEEKS
All Cause Mortality
	IQOS		E-CIG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/110 (0%)		0/110 (0%)
Serious Adverse Events
	IQOS		E-CIG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/110 (0%)		0/110 (0%)
Other (Not Including Serious) Adverse Events
	IQOS		E-CIG
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/110 (59.1%)		56/110 (50.9%)
General disorders
Fatigue	21/110 (19.1%)	21	12/110 (10.9%)	12
Respiratory, thoracic and mediastinal disorders
Cough	27/110 (24.5%)	27	24/110 (21.8%)	24
Dyspnoea	8/110 (7.3%)	8	15/110 (13.6%)	15
Oropharyngeal pain	4/110 (3.6%)	4	7/110 (6.4%)	7
Palpitations	4/110 (3.6%)	4	4/110 (3.6%)	4
Catarrh	3/110 (2.7%)	3	5/110 (4.5%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.