EDUCATION

“Recommendations for the Standardisation of Clinical Outcomes used in Allergen Immunotherapy (AIT) Trials for Allergic Rhinoconjunctivitis: an EAACI Position Paper” Pfaar O, Demoly P, Gerth van Wijk R, Bonini S, Bousquet J, Canonica GW, Durham S, Jacobsen L, Malling HJ, Moesges R, Papadopoulos NG, Rak S, Rodriguez del Rio P, Valovirta E, Wahn U, Calderon MA

Allergen immunotherapy (AIT) has been in clinical use for more than a century. Yet it is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. Many modifications of this ‘causal’ treatment including e.g., alternative routes of allergen application (sublingual AIT), innovative therapy protocols or the use of adjuvanted vaccines have been reported over the years. Evidence for the clinical efficacy and good tolerability of AIT has been found in many clinical studies and is thoroughly documented in randomised controlled trials (RCTs).

However, there is a high degree of clinical and methodological heterogeneity among the (clinical) endpoints that have been used in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly-accepted (by both regulators and academia) standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints. The current EMA guideline states that, at present, no symptom scores or medication scores have been validated for clinical trials in AIT and that any proposed method must be scientifically justified. As a consequence, different manufacturers are using their (‘in-house’) endpoints to analyse clinical efficacy in the clinical documentation of their products.

In order to increase the harmonisation of this definition, a Task Force (TF) of the EAACI Immunotherapy Interest Group, chaired by Oliver Pfaar (Germany), formed a paneuropean working group. The first achievement of this TF group was a thorough review of all (primary and secondary) endpoints which have so far been reported in clinical trials on AIT. Based on this work, the TF drafted a Position Paper (PP) highlighting the pro’s and con’s of each endpoint described in the trials and, furthermore, reported clear recommendations/unmet needs to improve the usage of the respective endpoint in future clinical trials of AIT. In this PP, the nine most relevant endpoints are reported. These nine ‘domains’ include i) Total Symptom Scores (TSS), ii) Medication Scores (MS), iii) Combined Symptom Medication Scores (CSMS), iv) Health-Related Quality of Life (HRQL), v) Visual Analogue Scale (VAS), vi) Well and Severe Days, vii) Global Assessments and Patient Satisfaction, viii) Rhinitis Control and ix) Allergen Provocation Tests.

As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardised method that balances both symptoms and the need for anti-allergic medication in an equally weighted manner (table 1). In principle, this composite score is based on and modified from the “Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases” by the European Medicines Agency (EMA) and a draft guidance document by the US Department of Health and Human Services Food and Drug Administration (FDA). Furthermore, this score considers standards addressed in a statement as proposed by the World Allergy Organization (WAO). The proposed terminology for the individual symptoms (dSS) in this score was elaborated with the European Federation of Allergy and Airways Diseases Patients’ Associations (EFA). The EAACI Position Paper recommends this standardised and harmonised CSMS as the primary endpoint for future clinical trials in AIT (mainly in pivotal phase III-trials).

Acknowledgements: The Task Force was financed by EAACI. The authors would like to thank EAACI for their financial support in the development of this Task Force report and also Ms Anna Bedbrook for her assistance with the English language which was financed by a grant provided by EAACI.
We warmly thank Prof. Dr. Stefan Vieths and Dr. Susanne Kaul (Paul Ehrlich Institut, Langen, Germany) for their helpful comments. We also thank Breda Flood and Susanna Palkonen from the European Federation of Allergy and Airways Diseases Patients' Asscociation (EFA) for their advice on the proposed terminology for the individual symptoms as well as for their review and fruitful comments on this document. Additionally, we thank Simon Lawton (ALK Abello, Hørsholm, Denmark) for his critical review and comments. Table: The Task Force recommendation providing (a) a homogeneous terminology for nasal and conjunctival symptoms using the six organ-related categories in the daily symptom score (dSS), (b) a stepwise use of rescue medication summed in the daily medication score (dMS) and (c) a scoring system for a combined symptom and medication score (CSMS), which is based on an equal weight of the dSS and of the dMS

a) SYMPTOM SCORE
Nasal Symptoms (SCORE 0 - 3) 0 = no symptoms 1 = mild symptoms (sign/symptom clearly present, but minimal awareness; easily tolerated) 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but tolerable) 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping)
Itchy nose 0-3
Sneezing 0-3
Runny nose 0-3
Blocked nose 0-3
 
Conjunctival Symptoms Itchy/Red Eyes 0-3
Watery Eyes 0-3
 
(total) daily symptom score (dSS)* 0-3 (max score is 3, i.e. 18 points/ divided by 6 symptoms)
 
b) MEDICATION SCORE
Oral and/or topical (eyes or nose) non-sedative H1 antihistamines 1
Intranasal corticosteroids 2
Oral corticosteroids 3
 
(total) daily medication score (dMS) 0-3 (max score is 3)
c) COMBINED SYMPTOM AND MEDICATION SCORE
CSMS dSS (0-3) + dMS (0-3) 0 -6


* Max score 18/6 (i.e. 4 nasal symptoms, max score 12 and 2 conjunctival symptoms, max score 6) is optimal for studies of seasonal pollinosis. This could possibly be modified for studies of perennial allergies (e.g. in mite-allergic patients), for example max score 12/4 (i.e. 4 nasal symptoms with omission of eye symptoms). By assigning 0–3 for all individual symptoms and dividing by total number of symptoms, the symptom range 0–3 and maximum symptom score 3 would remain the same.

Task Force background

Coordinator: Oliver Pfaar

Start date: 2011
Finish date: 2013

Participants: Hans Jorg Malling, Jörg Kleine Tebbe, Moises Calderon, Oliver Pfaar, Pablo Rodriguez del Rio, Pascal Demoly, Roy Gerth van Wijk and Sabina Rak. The expert panel review board will comprise Desire Larenas-Linnemann, Erkka Valovirta, Gianni Passalaqua, Jean Bousquet, Linda Cox, Ludger Klimek, Marek Jutel, Stephen Durham and Tom Casale.

Rationale for establishing a Task Force: Specific subcutaneous immunotherapy (SCIT) and specific sublingual immunotherapy (SLIT) represent the only immune-modifying and causal treatments available for allergic patients. The evidence for the effects of SIT is based on controlled and randomized clinical trials using specific primary and secondary outcome measures (end points). Primary end points for evaluating clinical outcome are the severity of symptoms and the need for concomitant medication, and are usually obtained on a daily basis by keeping diaries. Secondary end points may include the specific and general (generic) quality of life (QoL) or impact on work-related abilities, and are usually obtained by questionnaires at follow-up. Some trials have also included allergen provocation tests, provocation chambers or other surrogate markers. However, there is a large and inevitable clinical and methodological heterogeneity on outcome parameter used amongst studies on both SLIT and SCIT. The different manufacturers have devised better or less validated outcome measures, which makes it difficult to compare or to perform metaanalyses of the clinical immunotherapy trials.In line with this, in the 2008 Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases the European Medicines Agency (EMA) states that to date, there are no symptoms scores thoroughly validated for clinical trials on SIT. However, for the evaluation of AR the 4 individual nasal symptoms “congestion,” “sneezing,” “itching,” and “secretion,” and 2 conjunctival symptoms “itching of eyes” and “ocular secretions,” are generally accepted. Shortness of breath, cough, wheezing, and chest tightness as concomitant lower airway symptoms are also considered in some clinical trials on SIT.Moreover, there is a complex and multifactorial connection between symptom scores and the use of concomitant medication. Therefore, it is recommended by the WAO-task force on SIT that symptom scores should always be combined with the concomitant medication scores to provide clinically more relevant information on SIT than assessing each of these two outcome parameters separately. This is achievable by a combined score (weighted sum scores of symptoms and rescue medications) or a symptom score adjusted for the use of medication, using a predefined algorithm. However, to date no standardized method for combined scores has been generally accepted. Taken together, generally accepted and authoritative national and international guidelines are still lacking with respect to the assessment of the therapeutic effects of SIT by using clearly defined symptom- and medication-scores. Therefore, the aim of the task-force would be to propose a position statement clearly defining how symptoms and medications should be assessed, analysed and weighted in prospective clinical trials on SLIT and SCIT

Main objectives: To gather present scoring-systems used in trials on SLIT and SCIT to produce an EAACI position paper on the “optimal“ (primary) outcome parameters (combined SMS) recommended for clinical research.

Outcomes and possible benefits to EAACI: Position statement on “EAACI-recommendation for outcome parameters in clinical trials on SIT” for SLIT and SCIT.

Updates:First meeting of this Group: MADRID 10th and 11th of March, 2012. An intense meeting with an interesting discussion was held among the following attendees: Moises Calderon, Oliver Pfaar, Pablo Rodriguez del Rio, Pascal Demoly, and Roy Gerth van Wijk. In the first session Oliver Pfaar gave a lecture based on a review of current Clinical Outcomes used in SIT trials. During the rest of the session and in the second session each outcome was critically examined and the plan of action of the team, as well as possible involvement of other experts, was established. Other meetings have been conducted in the last year, London the 2nd of June and Geneve the 18th of June 2012.
Last updated 01 October 2014