recommendations for appropriate slit trials giovanni passalacqua

RECOMMENDATIONSFOR APPROPRIATE

SLIT TRIALS

Giovanni Passalacqua

Allergy & Respiratory DiseasesAllergy & Respiratory DiseasesDept.Internal Medicine-Dept.Internal Medicine-IRCCS S.Martino – IST -IRCCS S.Martino – IST -

University of Genoa ITALYUniversity of Genoa ITALY

CHICAGO-WAO-2013CHICAGO-WAO-2013

NOON

1928 1960

EMPIRICAL USE

1986 2012

Randomized trials

ISHIZAKA

IgE

1986 2012

SLITPeptides Recombinants Liposomes

Adjuvants

DNA-ITSAllergoids

Th1/Th2

1990

Mechanisms

DURHAM

ROMAGNANI

1998

WHOPos Pap

ILITEPIT

UK CSM

Where does IT preferentially works?

INFLAMMATIONIgE REACTION

HymenopteraAllergy

FoodAllergy

Seasonalrhinitis

Perennialrhinitis

AsthmaAtopicdermatitis

Factors to be evaluate in SIT prescription

1 IgE mediated disease2 Clear identification of the responsible allergen3 Severity and duration of symptoms4 Efficacy of pharmacological treatment5 Compliance6 Availability of standardized products7 demonstration of the efficacy

Standards for practical allergen-specific immunotherapy.

Allergy 2006

Allergen immunotherapy: A practice parameter second updateJACI 2011

WHO Pos Pap. Therapeutical vaccines for allergic diseasesAllergy 1998

Randomized

Trials

Case Report, Ideas

Editorials, Expert Opinion

Cohort Studies

Case series

Meta-analysis andSystematic reviews

EBM Hierarchy

D

ADBPC trials

E.B.M.E.B.M.Evidence Based MedicineEvidence Based Medicine

CERTAINTIES - EVIDENCE

GREY AREAS

UNMET NEEDS

UNKNOWN

Tabella meta analisi

JACI 2013

JAMA, 2013

WAO POS PAP 2013

JACI 2011

SymptomScoreRhintis

JACI 2010

CERTAINTIES - EVIDENCE

DOUBTFUL

UNMET NEEDS

UNKNOWN

GRADE: Grading ofRecommendation Assessment, Developing and Evaluation

Quesito clinico(es. efficacia trattamento)

ESAME LETTERATURA

Valutazione della qualitàdella prova sperimentale

SicurezzaPreferenzaCosto

RACCOMANDAZIONEFORTE

RACCOMANDAZIONEDEBOLE

Should subcutaneous specific immunotherapy be used for treatment of AR in adults without concomitant ASTHMA?

RecommendationWe suggest subcutaneous allergen specific immunotherapy in adults with seasonal AR (conditional recommendation | moderate-quality evidence) and persistent AR caused by mites (conditional recommendation | low-quality evidence).

Should subcutaneous specific immunotherapy be used for treatment of in children without concomitant ASTHMA?

RecommendationIn children with , we suggest subcutaneous specific immunotherapy (conditional recommendation | low-quality evidence).

Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision

Should sublingual allergen-specific immunotherapy be used in patients with AR and concomitant asthma ?

RecommendationIn patients with AR and asthma, we suggest sublingual specific immunotherapy for treatment of asthma (conditional recommendation | low-quality evidence).

Should subcutaneous allergen-specific immunotherapy be used in patients with AR and concomitant asthma?

RecommendationIn patients with AR and asthma , we suggest subcutaneous specific immunotherapy for treatment of asthma (conditional recommendation | moderate-quality evidence).

Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision

JACI 2013

Curr Opin Allergy Clin Immunol 2012

Pham Ti, PAI 2007

March 2009

PROBLEMS:

The majority of the trials were not designed and sized for asthma as primary outcome

Heterogeneity of study designs, duration, dose and evaluation parameters.

Few studies had functional parameters evaluated

Implications for clinical trials:

If asthma is investigated, the trial should consider asthma as primary outcome

Functional parameters (FEV1, VEMS, oscillometry) should be evaluated

Patients should be symptomatic, or therapeutic control should be evaluated.

EIFAN

Implications for clinical trials:

The optimal study design to compare SLIT and SCIT is the DB DD RPC fashion

This is not currently feasible, due to economic limitations.

AUTHORAnticoDunskyEifanBlazowskiRodriguezDe GrootDe GrootBuyukozurkBuyukozurkRodriguezRodriguez

SEXMFFFMMFMMMF

AGE363111161113272835277

ALLERGLatexMixMixMiteMite

GrassGrassLatexLatexMiteMite

EPINEPH?NNYNYYYYYY

ANAPHYLAXES DUE TO SLIT

JACI 2013

Implications for clinical trials:

Adverse events should be described, graded and classified in a standardized fashion

Adverse events should be notified promptly, to monitoring authorities or manufacuturers

CERTAINTIES - EVIDENCE

DOUBTFUL

UNMET NEEDS

UNKNOWN

UNSOLVED QUESTIONS

Optimal maintenance regimen (continuous VS pre-coseasonal)

Dose and extract standardization?

Better drugs or SIT?

Polysensitized?

Optimal maintenance SLIT dose for other allergens

METHODOLOGICAL ISSUES

- HETEROGENEITY OF TRIALS

- DOSES

-PATIENTS’ SELECTION

- PRIMARY OUTCOME/ANALYSIS

- SAMPLE SIZE CALCULATION

- ADHERENCE

- REPORTING

Patients with symptomsout of the season

VS PLACEBOSymptoms-28% (-39%)Medications- 24% (-48%)

Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis

Wahn 2009

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis.Dahl et al, JACI 2006

VERSUS PLACEBO:

SYMPTOM REDUCTION

- 30%MEDICATION REDUCTION

- 38%

634 PATIENTS !!!

Sastre,Clin Exp Allergy 2010

GRASSPhl p 1Phl p 5Phl p 6

Phl p 7 (profilin)Phl p 12 (CBP)

BIRCHBet v 1

Bet v 2 (profilin)Bet v 3 (CBP)

PARIETARIAPar j 1Par j 2

Par j 3 (profilin)

Senna GE, Lomabrdi C, Passalacqua G. JACI 2010

SCIT: 46 trials

CONSORT: 1 trialFlowchart: 16 trialsDropouts: 12 trialsRandomization: 16 trials

SLIT: 48 trials

CONSORT: 3 trialFlowchart: 20 trialsDropouts: 16 trialsRandomization: 12 trials

CERTAINTIES - EVIDENCE

DOUBTFUL

UNMET NEEDS

UNKNOWN

BIOMARKERS

FOR RESPONDER (NON RESPONDER) ?

JACI, Oct 09

THANK YOU !Contact us at

canonica@unige.itpassalacqua@unige.it

WAO, Chicago, Dec 2013