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EE--CIGARETTES:CIGARETTES:A Large Scale Randomized Clinical TrialA Large Scale Randomized Clinical TrialA Large Scale Randomized Clinical TrialA Large Scale Randomized Clinical Trial

Prof Riccardo PolosaProf Riccardo PolosaProf. Riccardo PolosaProf. Riccardo PolosaInstitute of Internal Medicine and Clinical ImmunologyInstitute of Internal Medicine and Clinical Immunology

University Centre for the Prevention and Cure of TabagismUniversity Centre for the Prevention and Cure of TabagismUniversity of CataniaUniversity of CataniaUniversity of CataniaUniversity of Catania

[email protected]@unict.it

97th ANNUAL MEETING & INDUSTRY CONFERENCE

Ki ill R t d S Willi b VAKingsmill Resort and Spa Williamsburg, VA

Monday, May 21st, 2012

Conflict of interestConflict of interest –– Prof. R. PolosaProf. R. PolosaConflict of interest Conflict of interest Prof. R. PolosaProf. R. Polosa

PfizerPfizer GlaxoSmithKlineGlaxoSmithKline Global Health Alliance for the treatment of tobaccoGlobal Health Alliance for the treatment of tobacco Global Health Alliance for the treatment of tobacco Global Health Alliance for the treatment of tobacco dependencedependence LIAF (Lega Italiana AntiFumo)LIAF (Lega Italiana AntiFumo) LIAF (Lega Italiana AntiFumo)LIAF (Lega Italiana AntiFumo)……several Eseveral E--cigs and Ecigs and E--juice retailers/companiesjuice retailers/companies

OutlineOutline

•• EE--cigs cigs -- Clinical evidenceClinical evidence•• ECLAT study design and protocolECLAT study design and protocol•• ECLAT major findingsECLAT major findings•• Next stepsNext steps

3

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188999966466

• Design: Single blind randomised repeated measures cross-over trial

• Participants: 40 adult dependent smokers

• Interventions: Participants were randomised to use e-cig (16 mg nicotine or 0 mg),

Nicorette nicotine inhalator or their usual cigarette on 4 separate study daysNicorette nicotine inhalator or their usual cigarette on 4 separate study days

• Primary outcome measure: change in desire to smoke, measured by VAS

• Secondary outcomes: withdrawal symptoms, acceptability and adverse events

• In nine participants, serum nicotine levels were also measured.

Reduction in desire to smoke from baseline

Bullen C, et al. Tob Control. 2010;19(2):98Bullen C, et al. Tob Control. 2010;19(2):98--103.103.

Reduction in desire to smoke from baseline

2.1 ng/ml2.1 ng/ml

SerumNicotineLevels


Comparisons of change in desire to smokeand other withdrawal symptoms from baseline

between 0 and 16 mg nicotine e-cigsbetween 0 and 16 mg nicotine e-cigs

NS


Product preferences


Adverse events reported by participantsafter 9 h of product use


• Design: Single blind randomised repeated measures cross-over trial

• Participants: 32 adult dependent smokers

• Interventions: Participants were randomised to use nicotinized e-cig (NPRO EC;

18-mg; and Hydro EC; 16-mg), their usual cigarette or sham smoking (an unlit18 mg; and Hydro EC; 16 mg), their usual cigarette or sham smoking (an unlit

cigarette of the participant's preferred brand) on 4 separate study days

• Outcome measures: Plasma nicotine and carbon monoxide (CO) concentration,

heart rate, and subjective effects.

Acute effects of e-Cig:QSU and craving ratings

Vansickel AR, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1945Vansickel AR, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1945--5353

Acute effects of e-Cig:Plasma nicotineand heart rate

Vansickel AR, et al.Vansickel AR, et al.Cancer Epidemiol Biomarkers Prev. 2010;19:1945Cancer Epidemiol Biomarkers Prev. 2010;19:1945--5353

Acute effects of e-Cig:Exhaled Carbon Monoxide

Vansickel AR, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1945Vansickel AR, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1945--5353

Following 4 weeks use:1. Significant reduction in daily cigarette consumption2. No changes in BP, haematological data, blood chemistryo c a ges , ae ato og ca data, b ood c e st y3. No severe adverse events4. Trace amounts of acrolein detected in the vapour of one cartridge (but much

less of that normally found in sidestream smoke)

• Design: Prospective 6-month proof-of-concept open study (five study visits)

• Participants: 40 (26M) adult smokers (cig/day ≥15;FTND ≥6) unwilling to quit

• Interventions: Partecipanti used Categoria e-cig (nicotine 7.4mg) for 6-monthsInterventions: Partecipanti used Categoria e cig (nicotine 7.4mg) for 6 months

• Outcome measures:1) sustained 50% reduction in cig/day from baseline (reducers);

2) sustained 80% reduction in cig/day from baseline (heavy reducers);

3) sustained smoking abstinence (quitters);

4) eCO levels;) ;

5) adverse events;

6) product preferences.

Effect of an Electronic Nicotine Delivery Device (eEffect of an Electronic Nicotine Delivery Device (e--Cigarette) on Smoking Cigarette) on Smoking Reduction and Cessation: A Prospective 6Reduction and Cessation: A Prospective 6--Month Pilot Study.Month Pilot Study.

R Polosa, et al.R Polosa, et al. BMC Public Health 2011BMC Public Health 2011

>50% reductionChanges in cigarette use for each study subgroups

,,

>80% reduction Quitters

Failures

Changes in cigarette use for each study subgroups

30

40

igar

ette

s/da

y

20

Mea

n C

10

-5

0

Week 4 Week 8 Week 12 Week 24Week 0

Effect of an Electronic Nicotine Delivery Device (eEffect of an Electronic Nicotine Delivery Device (e--Cigarette) on Smoking Cigarette) on Smoking Reduction and Cessation: A Prospective 6Reduction and Cessation: A Prospective 6--Month Pilot Study.Month Pilot Study.

R Polosa, et al.R Polosa, et al. BMC Public Health 2011BMC Public Health 2011,,

>50% reduction

>80% reduction Quitters

Changes in eCO levels for each study subgroupsxi

de 40

50 Failures

Car

bon

Mon

ox

20

30

Mea

n E

xhal

ed

0

107 ppm

M 0

Week 4 Week 8 Week 12 Week 24Week 0

Outcome measures at 24-week

EFFICACYEFFICACY50%

60%

40% 32.5%

20%

30%

12.5%

22.5%

10%

0%50% reduction

in cigarette smoking

80% reductionin cigarette

smoking

Sustained abstinence

Smoking failures

Outcome measures at 24-week

EFFICACYEFFICACY50%

60% 55.0%

40% 32.5%

20%

30%

12.5%

22.5%

10%

0%50% reduction

in cigarette smoking

80% reductionin cigarette

smoking

Sustained abstinence

Reduction (≥50%) + Abstinence

Smoking failures

AdverseEvents

35%

Events

25%

30%

20% Throat irritation

M h I i i

15%

Mouth Irritation

Sore Throat

Dry cough

h

5%

10% Dry mouth

Mouth ulcers

Dizziness

d h

4‐week 8‐week 12‐week 24‐week0%

Headache

Nausea

e-Cig toxicity? Comparative Evidence

749 f ld 658 f ld 1065 fold 145 fold749-foldlower

658-foldlower

1065-fold lower

145-foldlower

EffiCacy and safety of an eLectronic cigAreTte


Hypotheses

• 7,2 mg E-cigs are more effective than 0 mg E-cigs at helping smokers to refrain from tobacco smoking, at suppressing desire to smoke and relieving withdrawal symptoms• Nicotine tapering with E-cigs is an effective mean to wean smokers and/or vapers from nicotine use• E-cigs are acceptable to smokers to use as a mean to avoid tobacco smoking• E-cigarettes are safe to useg


Study Participants

• 300 smokers recruited via media/TV• healthy smokers with no important co-morbidities• not wishing to quit smoking in the next 30 days• median age 45 years old• ≥ 10 cigarettes per day for at least the past 10 years≥ 10 cigarettes per day for at least the past 10 years• mean pack/yrs of 29.4• mean FTND = 6.1

CO 23 2• mean eCO = 23.2 ppm


Treatment PhaseTreatment Phase Nontreatment PhaseNontreatment PhaseTreatment PhaseTreatment Phase Nontreatment PhaseNontreatment Phase

uatio

ns,

rol g

roup

s

7,2 mg nicotine 7,2 mg nicotine

Bas

elin

e ev

alu

tmen

t or c

ontr

= 30

0

, g , g

7,2 mg nicotine 4,8 mg nicotine

ning

, Elig

ibilit

y,is

atio

n to

trea

tN

=

g g

NO i tiNO i ti NO i tiNO i ti

1212 2424 5252 WeekWeek22 44 66 88 1010

Visit Visit Visit Visit Visit Visit Visit Visit Visit

Scr

eeR

ando

mi

00

NO nicotineNO nicotine NO nicotineNO nicotine

Visit1

Visit2

Visit3

Visit4

Visit5

Visit6

Visit7

Visit8

Visit9


STUDY ASSESSMENTS Procedure BL Wk2 Wk4 Wk6 Wk8 Wk10 Wk12 Wk24 Wk52 Procedure BL

Visit Wk2 Wk4 Wk6 Wk8 Wk10 Wk12 Wk24 Wk52

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Informed consent

X

Sociodemografic factors X Medical history X

S Medical history X

Drug history X Physical examination X X X X Vital signs – HR & BP X X X X X X X X X Weight - Kg X X X X Smoking Hx X BDI and BAI X

M O K E

C H A BDI and BAI X

FTND X A R T

eCO X X X X X X X X X GN-SBQ X NO and spirometry X X X X X X Saliva collection for cotinine X X Gi S d Di X X X X X XGive Study Diary X X X X X XCollect Study Diary X X X X X X Craving/VAS X X X X X X X X X MNWS (past 2 weeks) X X X X X X X X X MNWS (past 24 hrs) X X X X X X X X X Adverse events X X X X X X X X X E-cig training and dispense of E-cig kit

X

Dispense study cartridges X X X X X X Cartridges use record X X X X X X Smokers’ preference X X X


Mean (±SE) no. of cig/die distribution for each three study groups and over time(p<0.0001 vs Baseline at each step)

22

24

26

16

18

20

/die

5.4 mg nicotine7,2 mg nicotine

10

12

14

No.

of c

ig/

NO nicotineg

4

6

8

B‐C=0.0009 B‐C=0.024

BL 2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk


Evaluation of “switch” effect after step 4 (means±SE)

12

13

14

10

11

12

f cig

aret

te/d

ie

7,2 mg nicotine

7

8

9

No.

o

NO nicotine5.4 mg nicotine

, g

6

7

6wk 8wk 10wk

p=0.006 at Step 4 between groups B and Cp=0.013 at Step 5 between groups B and Cp=0.025 at Step 6 between groups B and C


Changes in eCO levels for each study subgroups

22

24

26p=0.045 B vs C

p=0.038 A vs Cp=0.005 B vs C

p=0.049 A vs Cp=0.032 B vs C

18

20

hale

d C

O p

pm

5.4 mg nicotine7,2 mg nicotine

14

16Exh

NO nicotine

10

12

BL 2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk


Changes in cartridge use for each study subgroups

32wk 4wk 6wk 8wk 10wk 24wk 52wk12wk

2

artri

dges

7,2 mg nicotine

1No.

Of c

NO nicotine5.4 mg nicotine

0


Reducers90

70

80

90

40

50

60

%

5.4 mg nicotine

7,2 mg nicotine

20

30

40 NO nicotine

0

10

2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk


Heavy Reducers

80

90

Heavy Reducers

50

60

70

5.4 mg nicotine

7,2 mg nicotine

20

30

40

% NO nicotine

0

10

20

2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk


Quitters90

70

80

90

40

50

60

% 5.4 mg nicotine

7,2 mg nicotine

20

30

40 NO nicotine


0

10


Smoking is AddictiveSmoking is Addictivegg

•• 70% of smokers say70% of smokers say70% of smokers say 70% of smokers say they would like to quitthey would like to quit

•• 30% attempts to quit30% attempts to quit30% attempts to quit30% attempts to quit•• 3% are successful 3% are successful

each yeareach yearyy

Bridgwood Bridgwood et al,et al, General Household Survey 1998.General Household Survey 1998.WestWest,, Getting serious about stopping smokingGetting serious about stopping smoking 1997.1997.

Self mutilation by smokingSelf mutilation by smoking –– thisthis

estest,, Gett g se ous about stopp g s o gGett g se ous about stopp g s o g 9999ArnstenArnsten,, Prim PsychiatryPrim Psychiatry 1996.1996.

39

Self mutilation by smoking Self mutilation by smoking this this patient had all four limbs amputated patient had all four limbs amputated

for a Buerger’s type obliterative for a Buerger’s type obliterative vascular diseasevascular disease


Quitters90

70

80

90

40

50

60

% 5.4 mg nicotine

7,2 mg nicotine

20

30

40 NO nicotine


0

10

3%



Quitters90

70

80

90

40

50

60

%

median cotinine level was < 100 ng/mL in all samples of e-cig users

5.4 mg nicotine

7,2 mg nicotine

20

30

40 NO nicotine


0

10

3%



Product PreferencesProduct Preferences• Enables to refrain from smoking• Pleasure of inhalation and exhalation of the vapour• Cleaner and fresher breath, absence of odours in clothing and hairclothing and hair• Not easy of use• Technical defectsTechnical defects• Poor availability

Perception and acceptance of the productcould be improved by increasing p y gmanufacturing standards


Quitters90

70

80

90

• Not easy of use

40

50

60

%

• Technical defects• Poor availability

5.4 mg nicotine

7,2 mg nicotine

20

30

40 NO nicotine


0

10

3%



Quitters90

70

80

90

40

50

60

% 5.4 mg nicotine

7,2 mg nicotine

20

30

40 NO nicotine


0

10

3%


Nicotine free inhalatorsNicotine free inhalators

Pl ti d i th t i t d d t id i h i fPl ti d i th t i t d d t id i h i fPlastic devices that are intended to provide a coping mechanism for Plastic devices that are intended to provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated conditioned smoking cues by replacing some of the rituals associated

with smoking gestures (e.g. handwith smoking gestures (e.g. hand--toto--mouth action of smoking).mouth action of smoking).

90%

100%

Quit Rate at 24 wkQuit Rate at 24 wk

70%

80%

66.7%

QQAmong individual with high GNAmong individual with high GN--SBQSBQ

40%

50%

60%

20%

30%

40%

19.2%

0%

10%

PAIPO group Reference group


Safety of long term E-cig useSafety of long term E cig use

•• Adverse events (Adverse events (dry cough, mouth and throath irritationdry cough, mouth and throath irritation))•• Withdrawal symptoms (Withdrawal symptoms (depression, anxiety, insomnia, irritability, depression, anxiety, insomnia, irritability,

hunger, constipationhunger, constipation) ) Vit l (HR BP)Vit l (HR BP)•• Vitals (HR, BP)Vitals (HR, BP)

•• Weight managementWeight management•• eCOeCO•• eCOeCO•• FeNOFeNO•• SpirometrySpirometrySpirometrySpirometry

E-cigs – TAKE HOME MESSAGE

• Mimics sensation gestures or actions of smokingMimics sensation, gestures or actions of smoking• Relieves craving for tobacco• Facilitates smoking abstinence/reductiong• No serious side effects• Much less toxic than tobacco smoke• Healthier alternative to tobacco smoke• Needs improvement in its design, adequate regulation and accessability for widespread adoption

222200

1001111224922


Natural Hx of smokers switching to E-cigs:A dynamic representationA dynamic representation

E-cigUptake(100%)

cigs

/day

Toba

cco

E-cigUptake(25%) E-cig

Uptake(15%)

1212 2424 5252 WeekWeek22 44 66 88 101000

( )

* 50-60% of UCTD do not evolve/resolve

1212 2424 5252 WeekWeek22 44 66 88 101000

Replacing cigarettes with e‐cigarettes ?

Sumner W. Estimating health consequences of replacing cigarettes with nicotine inhalers. Tob Control 2003, 12: 124‐132.

„The health consequences of completelydisplacing cigarettes with a widely used,

deeply inhaled highly addictivedeeply inhaled, highly addictive, pharmaceutical grade nicotine inhaler

=reducing smoking prevalence to 12%”

Cigarette smokers switching into a high quality regulated vaping will by themselves improve public health as much

as any feasible tobacco control effortas any feasible tobacco control effort.

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