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Secondary prevention of allergic disease

Dr Adam Fox United Kingdom


Disclosures •

Lecture fees: Danone, Mead Johnson, ALK-Abello, Stallergenes, Allergy Therapeutics

Industry-sponsored grant: Danone, ALK-Abello

Consultancy: NICE, Danone, Mead Johnson, Arla, Thermofisher Scientific


St Thomas’ Hospital, London, UK


Contents of Today’s Presentation  How do we define “prevention”?  Evidence for secondary prevention of allergic disease  Grazax Asthma Prevention trial (GAP)

 Implications of a positive outcome


Prevention definitions: general Doctor’s side

absent

Illness

Patient’s side

Prevention levels

present

Disease absent

present

Primary prevention (illness absent, disease absent)

Secondary prevention (illness absent, disease present)

Tertiary prevention (illness present, disease present)


Prevention and the “allergic march� According to ARIA Level

Definition with respect to allergy

Primary prevention

Primary prevention is employed where there is no evidence of allergic sensitisation, focused on populations at high risk of becoming sensitised

Secondary prevention

Secondary prevention is employed in individuals who show evidence of sensitisation but not evidence of allergic symptoms

Tertiary prevention

Tertiary prevention are preventive strategies for the management of established allergic rhinitis or asthma

Bousquet et al. Allergy 2008;63 (Suppl 86):8-160


Secondary Prevention


Preventive effect Randomised, controlled prospective trials Subcutaneous Immunotherapy Authors/study

Population

Study design/type

Polosa et al. 2004

Adults, 20-54 yrs (n=30)

Randomised, double-blind, placebo-controlled, 3-year trial

AR (Parietaria)

Alutard SQ, ALK-Abell贸

Endpoint: preventive effects of SIT At 3 years: Asthma developed in 14% vs 47% of controls (p=0.056)

No asthma PAT Trial (Preventive Allergy Treatment)

M枚ller et al. 2002

Children, 6-14 yrs (n=205)

Randomised, open, controlled, 10-year follow-up trial

Niggeman et al. 2006

AR (grass/birch)

Alutard SQ, ALK-Abell贸

Jacobsen et al. 2007

No asthma

At 3, 5, 10 years: Significant reduction in development of asthma


Preventive Allergy Treatment (PAT) Alutard SQ •

Open, randomised, controlled trial, (Den, Swe, Fin, Nor, Ger)

205 children (6 to 14 years), with clinical history of rhinoconjunctivitis to grass pollen (60%), birch pollen (21%), or both (19%)

Despite negative histories of asthma at screening, 42 children (20%) were identified as having mild asthma in the baseline season

Subjects randomized to receive either: • Alutard SQ (Phl p and/or Bet v) 100,000 SQ • Open control group – usual therapy

Subjects received 3 years treatment and were followed for total of 10 years! Möller et al. JACI 2002;109:251-6

Jacobsen et al. Allergy 2007:62:943-8


SCIT preventive effect

Subjects developing asthma (%)

Reduced risk of developing asthma Subject developing asthma at 3, 5, and 10 years (percent of subjects; n=151)

60

*

Control Alutard SQ

*

*

40 OR=2.5

OR=2.5

OR=3.1

45%

20

**

0

00

1

2

33

Treatment Mรถller et al. JACI 2002;109:251-6

4

55

6

7

Follow-up Jacobsen et al. Allergy 2007:62:943-8

8

9

p<0.05

10 years 10


Preventive effect Randomised, controlled prospective trials Sublingual Immunotherapy Authors/study

Population

Study design/type

Preventive effects of SIT

Novembre et al. 2004

Children, 5-14 yrs (n=113)

Randomised, open, controlled, 3-year trial

At 3 year:

AR (grass)

SLIT drops, ALK-Abell贸

No asthma

Marogna et al. 2008

Children, 5-17 yrs (n=216)

Randomised, open, controlled, 3-year trial

AR (multiple species) 卤 intermittent asthma

SLIT drops, Anallergo

Asthma development: 18% vs 41% of controls (p=0.04, OR 3.8)

At 3 year: Development of mild persistent asthma: 1.5% vs 28.8% of control (p<0.001)


Novembre et al. 2004 ALK-SLIT drops •

Open, randomised, controlled trial

Italy

113 children (5 to 14 years), with clinical history of rhinoconjunctivitis to grass pollen, no asthma

Subjects randomised to receive either: • ALK-SLIT drops (biologically standardised 5-grass mixture), pre-seasonally and co-seasonally regimen • Open control group – usual therapy

Subjects received 3 years treatment Novembre E et al. JACI 2004;114:851-7


SLIT drop asthma preventive effect Percentages of children with and without asthma* after 3 years (age and centre adj. odds-ratio = 3.8)

100

Percent of subjects (%)

Asthma 80

No asthma

82% 60

59% 40

41% 20

18% 0

ALK-SLIT ALK-SLIT drops

Control group group Control

* â&#x2030;Ľ3 episodes of wheezing-breathing difficulty and/or cough, separated by â&#x2030;Ľ1 week, and requiring bronchodilator Novembre E et al. JACI 2004;114:851-7


GRAZAX Asthma Prevention Trial

GT-21 (GAP) 16


GRAZAX Summary •

Grazax demonstrated to be both efficacious and well tolerated in children with grass pollen induced rhinoconjunctivitis

Grazax proven to result in a disease-modifying effect in adults

Grazax induces similar immunological response in children as in adults; supporting hypothesis that disease-modifying effect will also occur in children

Extrapolation from adult studies is not acceptable and paediatric studies are required*

Hence there is a rationale that Grazax can “stop the allergic march” and prevent the development of asthma in children with allergic rhinoconjunctivitis The GAP trial we hope will provide a conclusive answer to this question! *Calderon et al. EAACI Position statement, 2012


GAP study principles •

Randomised, parallel group, double-blind, placebo-controlled, multicentre trial

Recruit children with proven grass pollen related rhinoconjunctivitis who do not have asthma or overlapping symptomatic allergies

Randomised to 3 years of Grazax or Placebo

Regularly screen for asthma through treatment and 2 year follow-up period

Primary outcome is time to onset of asthma


Key entry criteria

Children 5-12 years of age at time of randomisation

A clinical relevant history of grass pollen induced allergic rhinoconjunctivitis having received symptomatic treatment during GPS 2009 and GPS 2010

Positive SPT response and positive specific IgE against Phleum pratense

Without medical history of asthma and/or wheezing within last 2 years or since 5th birthday


Randomisation

Screening 2

Screening 1

GAP Trial Design

Grazax n=310 75 000 SQ-T AIT daily

Placebo AIT n=310 2010

2013

2015

6-monthly visits Screening (1st season)

Treatment period (3 years) Status

Year

Post-treatment period (2 years)


Trial Recruitment

Enrolment of 620 subjects was planned

Total of 812 children randomised, distributed ≈100 centres

37% girls, 96% Caucasian, mean age at randomisation was 9.4 years

71% of subjects had at least one first degree relative with a history of allergy and 35% had at least one first degree relative with a history of asthma

26


Sensitisation pattern at screening

27


Clinical Implications of Preventive Trials if Positive?


Clinical Implications • Significant change in health economics of SIT if disease prevention proven • Long-term view required by health providers • Enhanced importance of early recognition of allergic disease • Requirement for capacity to desensitise significantly larger numbers of children


Summary  SIT offers potential to halt the allergic march  Current studies underway should provide robust answers about

disease prevention  Disease preventative effects may significantly alter the place of SIT

in clinical practice


Acknowledgements  GAP team – St Thomas’ Hospital

Prof Gideon Lack (joint site PI) Dr George DuToit Dr Kate Swan Roisin Fitzsimons Victoria Timms Graham Roberts (CI) Sue Driver (ALK)

Adam Fox  
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