Prof Riccardo Polosa

Director

Institute of Internal Medicine and Clinical Immunology

University of Catania

Conflict of interest – Riccardo Polosa

• Professor of Internal Medicine supported by the University of Catania, Italy

• Scientific advisor for LIAF (Italian acronym for Italian Anti Smoking League)

• Research grant

• Pharma industry (Pfizer, GSK, Novartis)

• E-cig industry (Arbi Group Srl)

• Consultancy role

• Global Health Alliance for treatment of tobacco dependence

• Pfizer

• ECITA (Electronic Cigarette Industry Trade Association, in the UK)

Lectures fees from E-cig industry and trade associations (including FIVAPE

in France and FIESEL in Italy) were entirely donated to vaper advocacy

organizations

Clinical Studies of e-Cigarettes:

What we have learned so far

Prof. Riccardo Polosa

Institute of Internal Medicine

Centre for the Prevention and Cure of Tabagism

University of Catania - ITALY

E-Cigarette Summit | 13 Nov 2014 | London

• RCTs

– Subjective effects

– Physiological effects

• Uncontrolled studies

– Subjective effects

– Physiological effects

• Laboratory studies

– Subjective effects

– Physiological effects

OUTLINE

Bullen C, et al. Tob Control. 2010;19(2):98-103.

Reduction in tobacco withdrawal symptoms:

Desire to smoke

Bullen C, et al. Tob Control. 2010;19(2):98-103.

2.1 ng/ml

Serum

Nicotine

Levels

Reduction in tobacco withdrawal symptoms:

Desire to smoke

Comparisons of change in desire to smoke

and other withdrawal symptoms from baseline

between 0 and 16 mg nicotine e-cigs

Bullen C, et al. Tob Control. 2010;19(2):98-103.

Vansickel AR, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1945-53

Reduction in tobacco withdrawal symptoms:

QSU and craving ratings

Important factors when interpreting EC data

Findings with the product under investigation

cannot be extended to other models

Craving control – 2° generation ECs

#

*

#

Adriaens K et al. IJERPH 2014

8 weeks

Craving control – 2° generation ECs

#

*

#

Adriaens K et al. IJERPH 2014

8 weeks

Craving control – 2° generation ECs

#

*

#

Adriaens K et al. IJERPH 2014

8 weeks

Working Memory (Trigram WM Task)

* *

*

* p < 0.01 compared to nicotine

Learning Points

• EC can reduce craving and (to a lesser

extent) nicotine withdrawal symptoms

• Effect on craving more “ritual” dependent

• Effect on withdrawal symptoms more

nicotine dependent

• Nicotine EC can prevent the memory

decrement

Randomised Controlled Trials

• ‘Categoria’ 24mg nicotine EC vs. 18mg nicotine EC vs. no nicotine EC

• 300 smokers (unwilling to quit)

• 1 year abstinence rates: 13%, 9% and 4%

• good tolerability

(Caponnetto et al. Plos One 2013)

• ‘Elusion’ 16mg nicotine EC vs. nicotine patch vs. no nicotine EC

• 657 smokers (motivated to quit)

• 6 month abstinence rates: 7.3%, 5.8% and 4.1%

• good tolerability

(Bullen et al. Lancet 2013)

STUDY ASSESSMENTS

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

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

FTND X

S M O K E

C H 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

Give Study Diary X X X X X X

Collect 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

Exploring the harm reduction/reversal potential (e.g.

reduction in biomarker known to be used as proxy for

risk prediction in CVD)

No changes in resting systolic BP

(separately for each continuous phenotype)

Long effect of smoking abstinence/reduction

on BP and HR in smokers switching to ECs

Submitted for publication

2013 ESH/ESC criteria for “high normal”

Modelling new strategies for harm reversal

n = 86 in ECLAT

n = 59 in ECLAT

Cut-off level

Long effect of smoking abstinence/reduction

on BP and HR in smokers switching to ECs

SBP changes at Week 52 from baseline

Long effect of smoking abstinence/reduction

on BP and HR in smokers switching to ECs

SBP changes at Week 52 from baseline

Harm

Reversal!

BLOOD PRESSURE CONTROL IN E-CIG USERS K. Farsalinos et al. Int. J. Environ. Res. Public Health 2014

(N = 2162)

Dual users Single users

Learning Points

• Smoking abstinence by using ECs may lower elevated systolic BP

• Decreases were reported also in reducers

• ECs may be a helpful alternative to cigarettes in smokers with elevated BP

Flouris AD, et al.

Inhal Toxicol. 2013

baseline

3 min after

60 min after

Effects on user health:

spirometry

• RCTs in healthy smokers have shown that ECs are

effective and safe

• No data about EC use among vulnerable populations,

including people with asthma

• We investigated changes in subjective and objective

asthma outcomes as well as safety in smoking

asthmatics who switched to EC.

No significant differences between Pre-Baseline and Baseline Assessments

EC use in smoking asthmatics

1st F/up Visit

Assessment Timepoints

Baseline Pre-Baseline

Fo

rce

d E

xp

ira

tory

Vo

lum

e in 1

se

co

nd

(L

)

3.0

3.2

3.4

3.6

3.8

2nd F/up Visit

**

FEV1

Improvement from baseline at 12 months

p=0.005 mean increase of 100mls

Harm

Reversal!

Regular EC use

Fo

rce

d V

ita

l C

ap

acity (

L)

3.8

4.0

4.2

4.4

4.6

4.8

1st F/up Visit

Assessment Timepoints

Baseline Pre-Baseline

2nd F/up Visit

**

FVC

Improvement from baseline at 12 months

p=0.006 mean increase of 150mls

Harm

Reversal!

Regular EC use

FE

F2

5-7

5 (

L/s

ec)

2.4

2.6

2.8

3.0

3.2

3.4

1st F/up Visit

Assessment Timepoints

Baseline Pre-Baseline

2nd F/up Visit

**

***

FEF25-75

Improvement from baseline at 6 and 12 months

p=0.006 mean increase of 250mls/sec

p=0.001 mean increase of 360mls/sec

Harm

Reversal!

Regular EC use

Pre-Baseline

Me

tha

cho

line

PC

20

(m

g/m

L)

1.0

1.5

2.0

2.5

3.0

3.5

Baseline 2nd F/up Visit

1st F/up Visit

Assessment Timepoints

**

Methacholine PC20

Improvement from baseline at 12 months

p=0.003 mean increase of 1.2 DD

Harm

Reversal!

Regular EC use

AC

Q s

co

res

1.2

1.4

1.6

1.8

2.0

2.2

2.4

1st F/up Visit

Assessment Timepoints

Baseline Pre-Baseline

2nd F/up Visit

***

***

Juniper’s ACQ

Improvement from baseline at 6, 12 months

p=0.001 mean decrease of 0.43

p=0.001 mean decrease of 0.56

Harm

Reversal!

Regular EC use

Smoking habit and

asthma exacerbations

Parameter Baseline 1st follow-up visit

(6 months ± 1)

2nd follow-up visit

(12 months ± 2)

p value to

Baseline

p value to

Baseline

Cigarettes/day 21.9 (±4.5) 5.0 (±2.6) <0.001 3.9 (±1.0) <0.001

Exacerbations 1.17 (±0.9) 0.87 (±0.7) 0.296 0.78 (±0.7) 0.153

Frequent exacerbators (≥ 2 exacerbations; n=6)

halved their exacerbations at both follow-up visits

Safety and Tolerability

• No severe adverse reactions or acute

exacerbations of asthma requiring

hospitalisation/ITU admissions.

• ECs were well tolerated with dry mouth

and throat irritation occasionally reported.

(N = 1173)

(N = 1062)

Dual users Single users

RESPIRATORY SYMPTOMS IN E-CIG USERS K. Farsalinos et al. Int. J. Environ. Res. Public Health 2014

(N = 1173)

(N = 1062)

Dual users Single users

RESPIRATORY SYMPTOMS IN E-CIG USERS K. Farsalinos et al. Int. J. Environ. Res. Public Health 2014

Learning Points

• EC use improves lung function, respiratory symptoms, subjective asthma outcomes

• Improvements were reported also in dual users

• Exposure to e-vapour in this vulnerable population did not trigger acute symtoms

• ECs are a safe alternative to cigarettes in smokers with chronic airways disease

Additional learning points from

ECLAT

• Abuse potential was relatively low

• Improved sensorial quality (i.e. taste) is key to a

wider adoption

• Efficiency (i.e. switching) can be maximized with

better quality/technology (i.e. improved product

reliability)

No. O

f su

bje

cts

Reducers

0

50

100

150

200

250

300

Week-12 Week-52

Intention-to-treat

Quitters

Week-6 Week-24

Reduction and abstinence rates (%) throughout the study

22.3%

10.3%

10.7% 8.7%

26.9%

73.1%

Using e-cigs

Not using e-cigs

Abuse potential?

Caponnetto et al. Plos One 2013

Quitters

2wk 4wk 6wk 8wk 10wk 24wk 52wk 12wk

0

10

20

30

40

50

60

70

80

90

%

3%

NO nicotine

5.4 mg nicotine

7,2 mg nicotine

Inferior performance of group C compared to group A and B. Driven by what?

Week 6 Week 12

0

50

100

150

200

250

300

Cotinin

e (

ng/m

l)

Group A Group B Group C Group A Group B Group C

Saliva cotinine levels in quitters

among study groups

Group A: 24 mg/ml nicotine

Group B: 18 mg/ml nicotine

Group C: no nicotine Is it nicotine? I do not think so!

Ordinary concentration threshold

for regular smokers

Score

Q1 Q2 Q3

Group C

Group B

Group A

Week-24

Q1 Q2 Q3

Week-52

0

2

4

6

8

10

12

Q1 Q2 Q3

Week-12

”how much do you rate this EC compared to your own brand?”

Participants’ liking of the product V

AS

sco

re

VAS from 0 to 10 points (0 = being ‘completely unsatisfied’, 10 being = ‘fully satisfied’)

COMPLAINTS/CONCERNS

0

10

20

30

40

50

60

70

80

C: no nic

B: medium nic

A: high nic

CONS, W-12 N

o.

tim

es r

eport

ed

poor taste heavy bulky mulfunctions

p=0.002

…or is it taste? I do think so!

0

10

20

30

40

50

60

70

80

C: no nic

B: medium nic

A: high nic

CONS, W-12 N

o.

tim

es r

eport

ed

poor taste discomfort heavy bulky mulfunctions

p=0.002

p=0.02

COMPLAINTS/CONCERNS

Best results – an act of balance

Aroma

Nicotine levels Liquidware Hardware

Reliability

Convenience

User satisfaction/appeal

E-Cig: a product in (fast) evolution

ECLAT was planned in the 2009 when

E-cig technology was in its infancy

The future A.D. 2009

Future studies will have to focus on

improved technology and

overall customer satisfaction

A.D. 2014

Improved product reliability

Better taste

More nicotine delivery

0

10

20

30

40

50

60

70

50% reduction 80% reduction abstinence reduction+abstinence failure

cig

ali

ke

cig

ali

ke

cig

ali

ke

cig

ali

ke

cig

ali

ke

Success rates at 6 months: Cigalikes vs PVs

Combined data: Polosa, et al. BMC Public Health 2011 and Polosa, et al. BMC Public Health 2014

0

10

20

30

40

50

60

70

50% reduction 80% reduction abstinence reduction+abstinence failure

cig

ali

ke

cig

ali

ke

cig

ali

ke

cig

ali

ke

cig

ali

ke

2°

ge

ne

rati

on

PV

s

2°

gen

era

tio

n P

Vs

2°

gen

era

tio

n P

Vs

2°

gen

era

tio

n P

Vs

2°

ge

ne

rati

on

PV

s

Combined data: Polosa, et al. BMC Public Health 2011 and Polosa, et al. BMC Public Health 2014

Success rates at 6 months: Cigalikes vs PVs

0

10

20

30

40

50

60

70

50% reduction 80% reduction abstinence reduction+abstinence failure

cig

ali

ke

cig

ali

ke

cig

ali

ke

cig

ali

ke

cig

ali

ke

2°

ge

ne

rati

on

PV

s

2°

gen

era

tio

n P

Vs

2°

gen

era

tio

n P

Vs

2°

gen

era

tio

n P

Vs

2°

ge

ne

rati

on

PV

s

Combined data: Polosa, et al. BMC Public Health 2011 and Polosa, et al. BMC Public Health 2014

Success rates at 6 months: future gen models

Future generation model image

Acknowledgments