Topic has BIG Potential for Influencing Practice and/or Policy in U.S. – *Important Context* • Subcutaneous immunotherapy is used worldwide … • Sublingual immunotherapy used broadly in Europe, Latin America and Asia, but 3 tablets only recently approved in US! • Meanwhile, increasing number of US docs use sublingual immunotherapy “off-label” • Increasing interest in sublingual immunotherapy as alternative and patient-centered approach to subcutaneous – Does not require injections – Can be administered by patients at home
Our Goal for Today • Identify and refine clinical comparative effectiveness research question(s) on immunotherapy options (i.e., subcutaneous and sublingual) for the treatment of allergic asthma.
The Plan • Step 1: Perspectives and insight from around the table » Each workgroup participant will have a few minutes to share perspective on this research topic • Step 2: Discuss key considerations for trial » Discuss trial design and implementation: methods, intervention, population(s) and recruitment, cost and feasibility » Discuss patient, system, and community factors (e.g., clinical settings, community involvement) » Achieve consensus on most important evidence gaps • Step 3: Identify and refine research question(s) » Identify specific populations, setting, outcomes, etc. (PICOTS framework) » Consideration of PCORI criteria for research topics 32
How PCORI Manages the Potential for Conflict of Interest • Participants in this workgroup will be eligible to apply for funding if PCORI decides to produce a funding announcement. • The Chair(s) of the workgroup will be eligible to apply for funding should they not participate in any subsequent discussions with PCORI following the workgroup. Input received during the workgroup deliberations are broadcast via • webinar, and the webinar is then archived and available to other researchers, patients, or stakeholders on the website. • PCORI does not have subsequent discussions with the participants after this workgroup. • Participants are expected to address a set of questions we’ve asked – not to tell us about their research. • There should be no “influence advantage” to being a workgroup member, or any knowledge advantage by participating in the workgroup. 33
Immunotherapy for the Treatment of Allergic Asthma: Setting the Stage Sandra Y. Lin, MD Johns Hopkins School of Medicine Department of Otolaryngology – Head and Neck Surgery
Definitions • Allergic rhinitis is an inflammatory, IgE-mediated, disease characterized by nasal congestion, rhinorrhea (nasal drainage), sneezing, and/or nasal itching. • Asthma is a chronic lung disease that inflames/narrows the airways. Symptoms can include wheezing, chest tightness, shortness of breath, and coughing. • Allergic asthma is asthma that can have an allergic trigger. 35
Healthcare Burden: Allergic Asthma • 9% of Americans suffer from asthma, 230 million worldwide • Asthma is the leading chronic disease in children and reason for missed school days • Cause for 2 million ER visits annually • 62% of asthmatics show evidence of allergy (1 or more positive allergy tests) 36
Treatment Options for AR and Allergic Asthma Immunotherapy Only true hope of “cure” Disease Modulation Pharmacotherapy Avoidance
KAS 11: Immunotherapy AAO-HNS Allergy Rhinitis CPG: Candidates for Immunotherapy • Diagnosis is confirmed with specific IgE testing (skin testing or blood testing). • Inadequate response to environmental controls/pharmacotherapy • Patient preference • Adherence to therapy • Medication requirements/adverse effects • Allergic asthma • Prevention of asthma/new sensitivities Otolaryngology -- Head and Neck Surgery February 2015 152: S1-S43, doi:10.1177/0194599814561600
Allergen Immunotherapy • Allergen specific immunotherapy (IT) – recognized as effective since early 1900’s – subcutaneous route most common in U.S. – immune system “modulation” to develop “tolerance” to environmental allergens
KAS 11: Immunotherapy Immunotherapy in the US Subcutaneous Immunotherapy Sublingual Immunotherapy -Aqueous - injections -Tablet -Ragweed -Timothy -Grass Mix
Subcutaneous Immunotherapy (SCIT) • Dosed in physicians office – Once/week first year • Typical duration: 3-5 years of treatment • Continued benefit after discontinuation of therapy • How effective is SCIT?
Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review Lin SY, Erekosima N, Suarez-Cuervo C, Ramanathan M, Kim JM, Ward D, Chelladuria Y, Segal JB. AHRQ Grant HHSA 290 2007 10061 AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2013.http://effectivehealthcare.ahrq.gov/ehc/products/270/1427/allergy-asthma-immunotherapy- 130802.pdf
Disclaimer: This report was based on research conducted by the Johns Hopkins University Evidence- based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10061-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. 7/28/2015 43
Systematic Review: SCIT Effectiveness • Objective: Systematically review the effectiveness and safety of SCIT for allergic rhinitis and asthma • Methods: RCTs comparing SCIT to placebo, medication, or other SCIT – English language – Adults and Children – Similar formulation must be available in the U.S. – Must contain direct clinical outcomes 44
Literature Search Medline, Embase, Lilacs, Cochrane abstracts Full article Final included Search 7,746 1804 74 RCTs from database 4,350 inception to Dec participants 2012 45
Grading the Evidence Category Definitions Consistency Overall consistency of the direction of change Directness Does this measure a direct clinical outcome (symptoms, medication use)? Magnitude of Effect Percent difference pre/post to comparator: -weak <15% -moderate 15-40% -strong >40% Risk of Bias -Random Allocation -Allocation Concealment -Inadequate Blinding -Incomplete Data Reporting -Sponsor Participation in Study Design *from GRADE Working Group Guide for CER
Evidence Grade Definition Criteria Grading the Evidence High High confidence that evidence -At least 2 low ROB, one with reflects true effect; further strong MOE research unlikely to change -Overall evidence consistent confidence Moderate Moderate confidence that -1 low ROB with Strong MOE, evidence reflects true effect; or further research may change -2 or more medium ROB with estimate strong MOE, or -1 low ROB with mod MOE plus 1 medium ROB plus strong MOE Low Low confidence that evidence -Does not meet the above reflects true effect; further research likely to change estimate Insufficient Evidence unavailable 47
Results • Age Range: 3-72 years • Children only studies: • Risk of Bias Moderate (52%) • Comparator groups – Placebo 73% – Meds 9% 48
SCIT Results Outcome No. Studies No. Participants Strength of Evidence Asthma symptoms 16 1,178 High Asthma symptoms 6 550 Moderate (children only) 49
SCIT SR Conclusion • Strong to moderate evidence supports the effectiveness of SCIT for AR and allergic asthma 50
SR: SCIT Safety • Safety data reported in 45/74 studies • No consistent reporting system for adverse events— cannot pool • Local reactions: 5-58% patients/0.6-54% injections – mild • Systemic reactions: in 15% of injections – Most commonly respiratory – Most mild • Anaphylaxis: 13 reactions • Deaths: none 51
Sublingual Immunotherapy in the United States • Dosed at home • Aqueous “Drops” FDA off label • Tablets: FDA Approval April 2014
Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and Asthma: A Systematic Review Lin SY, Erekosima N, Kim JM, Ramanathan M, Suarez-Cuervo C, Chelladurai Y, Ward D, Segal JB. JAMA.2013;309(12):1278-88. AHRQ Grant HHSA 290 2007 10061
SLIT Aqueous SR Results • Objective: Systematically review the effectiveness and safety of aqueous SLIT for allergic rhinitis and asthma • Methods: RCTs comparing SLIT to placebo, medication, or other SLIT – English language – Adult and Children – Similar formulation must be available in the U.S. – Must contain direct clinical outcomes 54
Literature Search Medline, Embase, Lilacs, Cochrane abstracts Full article Final included Search 8,156 1827 63 RCTs from database 5131 inception participants to Dec 2012 55
SLIT Results • Age range 4-74 • Children only 20 studies (n=1814) • Risk of Bias Moderate (68%) • Comparator groups – Placebo 73% – Other SLIT 14% – Meds 13% 56
SLIT Results Outcome No. Studies No. Participants Strength of Evidence Asthma 13 625 High Symptoms Asthma 9 471 High Symptoms* *Kim JM, Lin SY, Suarez-Cuervo C, Chelladurai Y, Ramanathan M, Segal JB, Erekosima N. Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review.Pediatrics. 2013 Jun;131(6):1155-67 57
Systematic Review Conclusions • “The overall evidence provides a moderate grade level of evidence to support effectiveness of SLIT for AR and asthma, but high-quality studies are still needed to answer questions regarding optimal dosing strategies. There were limitations in the standardization of adverse events reporting, but no life-threatening adverse events were noted in this review.” 58
SR: Safety Aqueous SLIT • 45 (75%) reported safety data • Lack of standardized reporting • Local reactions: – SLIT 0.2-97% – Comparator 3-38.5% • Systemic reactions rare • No anaphylaxis or deaths Lin SY, Erekosima N, Kim JM, Ramanathan M, Suarez-Cuervo C, Chelladurai Y, Ward D, Segal JB. JAMA.2013;309(12):1278-88. 59
SLIT Tablet Efficacy: United States Studies 60
SLIT Tablets: US Ragweed RCTs Study N Age Dose Duration Outcome Amb 1-U Asthma Creticos P 784 Adults 12 1 year 27% 2013 Asthma Sx Score, Entire Season (p=.022) Nolte HS 565 Adults 12 1 year Not reported 2013 61
SLIT Tablets: US Timothy RCTs Study N Age Dose Duration Outcome: Micrograms Asthma Phl p 5 Blaiss M 345 Children 15 Pre/co- No significant 2011 5-17 seasonal improvement well 23 weeks controlled and allowed asthma meds Nelson HS 439 Adults 15 Pre/co- 24% 2011 seasonal TASS (p=.004) 23 weeks 62
SLIT Tablets: US Grass Mix RCTs Study N Age Dose Duration Outcome: Asthma Wahn U 278 Children 300IR Pre/co-seasonal Not reported 2009 5-17 Didier A 633 Adults 300IR 4 mo pre/co- Not reported 2011 seasonal Cox LS 473 Adults 300IR 4 mo pre/co- Not reported 2012 seasonal Didier A 628 Adults 300IR 4 mo pre/co- Not reported 2007 seasonal
Which is more effective: SLIT vs SCIT? Effectiveness of Subcutaneous Versus Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and Asthma: A Systematic Review Yohalakshmi Chelladurai, MBBS, MPH, Catalina Suarez-Cuervo, MD, Nkiruka Erekosima, MD, MPH, Julia M. Kim, MD, MPH, Murugappan Ramanathan, MD, Jodi B. Segal, MD, MPH, and Sandra Y. Lin, MD J Allergy Clin Immunol Pract. 2013 Jul-Aug;1(4):361-9.
SCIT vs SLIT SR • Systematic review of studies with head to head comparison of SCIT and SLIT • English language RCTs • Results: – 8 studies – 4 studies: allergic asthma outcomes – 6 studies: allergic rhinitis outcomes 65
SLIT vs SCIT Results Outcome No. No. Strength of Evidence Studies Participants Low favoring Asthma 4 171 subcutaneous Moderate favoring Rhinoconjunctivitis 6 412 subcutaneous Low Medication Use 5 219 minimal difference Low favoring Combined 2 65 Med Sx subcutaneous QOL 1 48 Insufficient 66
Studies– Challenges for Systematic Review • Heterogeneous symptom scoring – Sx-med scores primary outcome • Lack of standardization for adverse event reporting – WHO standards • Lack of consistent statistical reporting • Dosing units varied—how to translate? • Comparison of US and European allergens 67
What are the knowledge gaps and challenges in SLIT facing US practitioners? 68
Effectiveness of SLIT tablets for allergic asthma? • Need for U.S. studies 69
What dose should we give in the US for Aqueous SLIT? • Majority of SLIT efficacy studies done in Europe – JAMA 7/63 studies N. America – Units not standardized around world • Lack of Ag standardization: US vs. Europe – Definitions & units vary – Translation to US dosing difficult • Lack of large scale US studies Calderon MA, Simons FER, Malling HJ et al. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67:302-311.
What dose should we give in the US for Aqueous SLIT? • JAMA 2013: – Dust mite – Conversion to micrograms/month – Highest dose 50x greater than lowest effective dose 71
How long to treat? • Aqueous SLIT (Marogna 2010) – DM 3, 4, 5 year – All lasting effects after d/c, up to 8 years – 4 years recommended as equivalent to 5 • Timothy SLIT Tab (Durham 2012) – 3 yrs – 2 yr f/u continued effect • Pre/coseasonal vs Year Round – Need further follow up on pre/coseasonal 72
To treat with single or multi-allergen SLIT? • Europe-Single • US-Multiple • Most studies monotherapy • Yet unanswered question as inconsistent results 73
Is safety/effectiveness of immunotherapy different in distinct subpopulations? • Elderly • Pregnant women • Minorities • Inner-city and rural residents • Patients with severe asthma 74
Other Concerns • SLIT aqueous – No CPT dosing – Limited publications on U.S. dosing • SLIT tablets – Limited number of allergens available 75
SCIT SLIT KAS 11: Immunotherapy Effectiveness for allergic rhinitis Supported by systematic reviews of Supported by systematic reviews of randomized, controlled trials randomized, controlled trials Deaths: 1 per 2.5 million injections Safety No reported deaths Rate of systemic reactions 0.06%-0.9% 0.056% Administered in physician’s office Administered at home Dosing SLIT aqueous dosing not standardized First dose of SLIT tablet should be administered in physician’s office, epi autoinjector SLIT aqueous FDA “off-label” use FDA status FDA approved SLIT tablets approved by FDA in April 2014; limited number of allergens available for treatment Socioeconomic CPT code exists for SCIT vial preparation No CPT code exists for SLIT aqueous and injections preparation. SLIT aqueous not covered by most insurance plans. SLIT tablet insurance coverage to be Covered by most insurance plans determined by individual insurance carriers.
Conclusions • Moderate to high grade evidence supports use of both SCIT and SLIT for allergic rhinitis and asthma. • Low grade evidence supports SCIT more effective for allergic asthma • Clinical choice of therapy dependant on patient- physician decision making 77
Questions
Immunotherapy for the Treatment of Allergic Asthma: NIAID Research Programs Alkis Togias, MD Branch Chief Allergy, Asthma, and Airway Biology Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases National Institutes of Health
Allergen Immunotherapy: Reasons for NIAID’s Interest • Long-term effects after therapy is discontinued • Potential for asthma prevention • Conduit to understand immune tolerance – Fundamental immune alterations of “allergy” – Insights into other immune-mediated diseases (autoimmunity)
Allergen Immunotherapy for Allergic Rhinitis and Asthma: Needs (A) • Efficacy well-demonstrated However, • Magnitude and duration of the clinical effect require improvement • Risks must be reduced • Duration of treatment must be reduced • Mechanism of action must be elucidated
Goals and New Directions in Allergen Immunotherapy • Increase immunogenicity • Decrease allergenicity • Promote particular types of immune responses Alternative routes of Alternative forms of administration allergen Allergen Allergen Immunodominan Sublingual Epicutaneous Intranodal Oral modification “plus” t peptides Chemical Molecular Adjuvants Immunomodulators
Allergen Immunotherapy for Allergic Rhinitis and Asthma: Needs (B) • Questions raised by the AHRQ review – SCIT vs SLIT – Mono vs multi-allergen therapy – Effects on disease progression (rhinitis to asthma) – Optimization of the dosing and duration of currently available forms of therapy
Allergen Immunotherapy for Allergic Rhinitis and Asthma: Needs (C) • Biomarker development • Development of immunotherapy for allergens important to populations with increased morbidity
NIAID Programs on Allergen Immunotherapy for Allergic Rhinitis and Asthma • Cockroach allergen immunotherapy program (Inner City Asthma Consortium) • Development of new forms of allergen immunotherapy and investigations of the mechanisms of immune tolerance by allergen immunotherapy (Immune Tolerance Network) • Individual grant support
The Importance of Cockroach Allergy in Inner-City Asthma NCICAS 1991-1995 Observational Study Cockroach allergy: ICAS Major risk factor for 1996-2001 asthma morbidity Environmental Intervention Study Stronger benefits in ICAC I cockroach allergic and 2002-2008 exposed anti-IgE trial Stronger benefits in cockroach allergic ICAC II and exposed 2009-2014 Asthma phenotyping
The Importance of Cockroach Allergy in Inner- City Asthma “Difficult-to-control” Probability of Allergen levels in house dust (µg/g)
Cockroach Allergen Immunotherapy Program • Development of a successful german cockroach immunotherapy regimen for the treatment (and prevention) of asthma and rhinitis in inner city populations – Stepwise approach • Step 1 : extract evaluation • Step 2 : SLIT safety • Step 3 : SLIT and SCIT immunologic activity (3 studies)
Cockroach Allergen Immunotherapy Program N=10 N=99 N=54 Wood et al J Allergy Clin Immunol 2014;133:846
Cockroach Allergen Immunotherapy Program (ICAC 2015-2021) • Step 4: Efficacy evaluation of cockroach SCIT – Study 1: Development of a nasal cockroach challenge model (10 adults followed by 25 children) – Study 2: Utilization of the nasal cockroach challenge as the primary outcome in a Phase IIa trial (children) • 2 maintenance doses vs placebo • 1 year duration • Include secondary clinical outcomes of asthma and rhinitis • Assess confounders (allergen exposure)
Mouse Allergen Immunotherapy • Development of a successful mouse immunotherapy regimen for the treatment (and prevention) of asthma and rhinitis in inner city populations – Study 1: SCIT safety and immunologic activity
Immune Tolerance Network (ITN) • The ITN is focused on the development of therapeutic approaches for asthma and allergy, autoimmune diseases, type 1 diabetes and solid organ transplantation that lead to immune tolerance
Allergen Immunotherapy for Allergic Rhinitis and Asthma: ITN • Pioneering the concept of “allergen plus” where allergen immunotherapy is delivered in combination with immunomodulators – Anti-cytokine agents – T-cell depletion – Immune deviation – T-reg induction • Modified allergens • Alternative routes of allergen administration
Allergen Immunotherapy for Allergic Rhinitis and Asthma: ITN G auging the R esponse in A llergic rhinitis to S ublingual and S ubcutaneous immunotherapy
GRASS Design Subcutaneous immunotherapy Sublingual immunotherapy Placebo (double dummy) Mar-Sept Oct 2011-Feb 2012 Jan 2013 Jan 2015 Dec 2013 Start Rx 2011 Tolerance? End Rx Recruit/ screen Baseline Year 1 Year 2 Random Year 3 assessment allocation assessment assessment assessment
GRASS Design Subcutaneous immunotherapy Sublingual immunotherapy Placebo (double dummy) Oct 2011-Feb 2012 Jan 2013 Mar-Sept Dec 2013 Jan 2015 Start Rx 2011 End Rx Tolerance? Recruit/ screen Baseline Random Year 1 Year 2 Year 3 assessment allocation assessment assessment assessment
GRASS Design Subcutaneous immunotherapy Sublingual immunotherapy Placebo (double dummy) Oct 2011-Feb 2012 Jan 2013 Mar-Sept Dec 2013 Jan 2015 Start Rx 2011 End Rx Tolerance? Recruit/ screen Baseline Random Year 1 Year 2 Year 3 assessment allocation assessment assessment assessment 106 randomized, 92 completed the study
GRASS Design Nasal challenge device 2 sprays 100mcL each nostril 10-10,000 BU/ml Phleum Pratense
GRASS Design Nasal challenge device 2 sprays 100mcL each nostril 10-10,000 BU/ml Phleum Pratense Peak nasal inspiratory Symptom score (TNSS) flow Sneezing 0-3 Nose running 0-3 Blockage 0-3 Itch 0-3 TOTAL 0-12 Modified from Bousquet et al 1987 and Lent et al 2006
GRASS Results - Symptoms On On Off Treatment Treatment Treatment
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