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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
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
Bullen C, et al. Tob Control. 2010;19(2):98Bullen C, et al. Tob Control. 2010;19(2):98--103.103.
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
Bullen C, et al. Tob Control. 2010;19(2):98Bullen C, et al. Tob Control. 2010;19(2):98--103.103.
Product preferences
Bullen C, et al. Tob Control. 2010;19(2):98Bullen C, et al. Tob Control. 2010;19(2):98--103.103.
Product preferences
Bullen C, et al. Tob Control. 2010;19(2):98Bullen C, et al. Tob Control. 2010;19(2):98--103.103.
Adverse events reported by participantsafter 9 h of product use
Bullen C, et al. Tob Control. 2010;19(2):98Bullen C, et al. Tob Control. 2010;19(2):98--103.103.
• 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
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
Quitters90
70
80
90
40
50
60
% 5.4 mg nicotine
7,2 mg nicotine
20
30
40 NO nicotine
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
0
10
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
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
EffiCacy and safety of an eLectronic cigAreTte
Quitters90
70
80
90
40
50
60
% 5.4 mg nicotine
7,2 mg nicotine
20
30
40 NO nicotine
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
0
10
3%
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
EffiCacy and safety of an eLectronic cigAreTte
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
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
0
10
3%
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
0
10
3%
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
EffiCacy and safety of an eLectronic cigAreTte
Quitters90
70
80
90
40
50
60
% 5.4 mg nicotine
7,2 mg nicotine
20
30
40 NO nicotine
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
0
10
3%
2wk 4wk 6wk 8wk 10wk 24wk 52wk12wk
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
EffiCacy and safety of an eLectronic cigAreTte
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
EffiCacy and safety of an eLectronic cigAreTte
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.