Clinical Management Review
Allergen Immunotherapy: Clinical Outcomes Assessment Melina Makatsori, MDa, Oliver Pfaar, MDb, and Moises A. Calderon, MD, PhDa London, United Kingdom; and Mannheim, Germany Assessment of clinical outcomes is essential to evaluate the efficacy of allergen immunotherapy, both in clinical trials and in daily clinical practice. “Primary outcomes” used in sublingual and subcutaneous immunotherapy trials include the measurement of symptoms, the use of concomitant medications, and/or a combination of both of these measures. “Secondary outcomes” that have been measured include individual symptom scores, provocation allergen tests, visual analog scales, and health-related quality of life assessments. Currently, there is a lack of consistency in the selection of outcome parameters used, which represents a major problem when comparing the same therapeutic intervention. In this review, we examined the different primary and secondary outcome parameters that have been used in clinical trials; reviewed recommendations by European and US guidelines, and allergy groups; and explored which outcomes may be applicable for use in clinical practice. Ó 2014 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2014;2:123-9) Key words: Outcome parameters; Allergen immunotherapy; Sublingual immunotherapy; Sublingual immunotherapy; Healthrelated quality of life
Allergen immunotherapy (AIT) has been found to be effective in the treatment of allergic rhinitis (AR), allergic conjunctivitis, allergic asthma, and Hymenoptera venom allergy. A beneficial effect has been shown in both adults and children. In contrast to pharmacological therapies, which provide only temporary relief of symptoms, AIT is the only currently available treatment that can modify the allergic disease process, and thus is worth considering as a possible treatment in affected individuals.1
a
Section of Allergy and Clinical Immunology, Imperial College London, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom b Centre for Rhinology and Allergology Wiesbaden, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Mannheim, Germany No funding was received for this work. Conflicts of interest: O. Pfaar has received consultancy fees from Stallergenes, HAL, Bencard/Allergy-Therapeutics, LETI/Novartis, and MEDA-Pharma; has received lecture fees from ALK-Abello, Allergopharma, Stallergenes, HAL, AllergyTherapeutics/Bencard, Hartington, Lofarma, Novartis/Leti, Glaxo-Smith-Kline, Roxall, and MEDA-Pharma GmbH; has received travel support from HALAllergy and Allergopharma. M. A. Calderon has received consultancy and lecture fees from ALK, Stallergenes, Merck, Allergopharma, HAL allergy, Therapeutics. M. Makatsori declares that she has no relevant conflicts. Received for publication November 18, 2013; revised January 20, 2014; accepted for publication January 22, 2014. Corresponding author: Moises A. Calderon, MD, PhD, Section of Allergy and Clinical Immunology, Imperial College London, NHLI, Royal Brompton Hospital, London, UK. E-mail: [email protected]. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.01.005
Assessment of clinical outcomes is essential to evaluate the effectiveness of AIT both in clinical trials and in daily clinical practice. Various clinical parameters are commonly used to provide evidence of the clinical efficacy of AIT.2,3 “Primary outcomes” usually include the measurement of symptoms and the use of concomitant medications, whereas quality of life measures or surrogate markers have usually been used as “secondary outcome” parameters.4,5 In practice, clinical outcomes are very important to evaluate the effect of AIT. They enable assessment of the patient’s condition and response to immunotherapy so that an appropriate schedule of treatment and monitoring can be planned. In clinical trials, they allow for collection of data to measure efficacy and enable comparison of different treatments. It is widely accepted that the personal burden of illness, as perceived by the patient with allergy, cannot be fully assessed by traditional measures, such as clinical symptoms, which correlate only moderately with patients’ perceptions and functional capabilities on a daily basis. For this reason, it is essential to include the patient’s self-rated health-related quality of life (HRQL) in evaluations of AIT interventions.6 In this review, we will examine the different primary and secondary outcome parameters that have been used in clinical trials and the ones that have been recommended by European as well as US guidelines and allergy groups.3-5,7 Furthermore, we will explore which outcomes may be useful to also apply in clinical practice.
PRIMARY OUTCOMES According to recommendations published by the European Medicines Agency (EMA) in 2008,4 the preferred primary outcome measure for AIT clinical trials is the total combined score (TCS), which is the sum of the total symptom score (TSS) and total medication score. Because the severity of symptoms and the use of relief medication are interdependent, it is important to combine these into a single score. Furthermore, the TCS is considered optimal because it shows the largest effect size and, therefore, the highest power to show significant treatment efficacy.8 A TCS has been used in some clinical trials of AR9-11; however, there currently is no agreed scoring system. The TSS commonly used for assessment of AR includes 4 individual nasal symptoms (sneezing, rhinorrhea, nasal congestion, nasal pruritus) and 2 conjunctival symptoms (ocular pruritus and watery eyes). These symptoms are scored by patients on a diary card by using a 4-point rating scale between 0 (no symptoms) and 3 (severe symptoms) so that the (combined) sum of the 6 individual symptom scores for a given day results in a rhinoconjunctivitis TSS that ranges from 0 to 18 points.2 Patients should record scores in a diary at least as often as the daily dosing interval. The US Food and Drug Administration recommends collection of both reflective symptom scores (ie, an evaluation of symptom severity after a predefined time period, 123
124
MAKATSORI ET AL
Abbreviations used AIT- allergen immunotherapy AR- Allergic rhinitis BAP- Bronchial allergen provocation EMA- European Medicines Agency HRQL- Health-related quality of life NPT- Nasal provocation test RQLQ- Rhinoconjunctivitis Quality-of-Life Questionnaire SCIT- Subcutaneous immunotherapy SLIT- Sublingual immunotherapy TCS- Total combined score TSS- Total symptom score VAS- Visual Analog Scale
eg, 12 hours) and instantaneous symptom scores (ie, an evaluation of symptom severity immediately before the next dose). This is because reflective symptom scores assess the overall degree of effectiveness over a prespecified time interval, whereas instantaneous scores assess effectiveness at the end-of-dosing interval.7 Similarly to the TSS, the total medication score is often used separately as a primary outcome parameter. A recent review of the outcomes used in well-powered immunotherapy clinical trials has found great variability between the rescue medication itself and the scoring systems used.11 The use of rescue medications is an important measure of immunotherapy efficacy because it is anticipated that patients will require reduced amounts of medical treatment if immunotherapy is effective. It is important that, to be able to compare clinical trials and also, more significantly for clinicians to be able to assess efficacy of different immunotherapy preparations and response to AIT, a standardized and validated TCS scoring system should be available. One possible approach that has been proposed is the adjusted symptom score, which is primarily based on the rhinoconjunctivitis TSS, which is calculated forward.12 By adjusting the rhinoconjunctivitis TSS for rescue medication use, the adjusted symptom score can estimate symptom severity and the treatment effect more accurately. A novel combined symptom-medication score that has recently been validated is the Allergy-Control-SCORE, which has been shown to be a reliable instrument to assess the severity of respiratory allergic diseases in clinical trials as well as in daily practice.13
SECONDARY OUTCOMES Scores of individual symptoms Changes in the score of individual symptoms (ocular, nasal, bronchial) can be a useful secondary outcome. This procedure allows separately assessing the effect of the treatment on each target organ. Also, in rhinitis, the effect of the treatment on each symptom (rhinorrhea, itching, sneezing, and obstruction) can be assessed.5 Visual Analog Scale A Visual Analog Scale (VAS) is a simple but valuable instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. It usually is a horizontal line, 100 mm in length, anchored by word descriptors at each end, for example, that represent the severity of symptoms from 0 “no symptoms” to 10 “very severe symptoms.” The patient marks on the line the point that the patient believes represents his or her perception of
J ALLERGY CLIN IMMUNOL PRACT MARCH/APRIL 2014
his or her current state. The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks.14 These scales are most useful when looking at change within individuals and are of less value for comparing across a group of individuals at one time point. The VAS has been extensively investigated and validated in AR and has been shown to significantly correlate with the severity of rhinitis graded by the Allergic Rhinitis and its Impact on Asthma criteria as well as quality of life.15 In addition, it is a useful measure to assess the effect of pharmacotherapies on symptoms.16,17 A recent observational prospective study in 990 patients who consulted their general practitioners for symptomatic rhinitis found that the VAS is a practical, sensitive, and valid tool to monitor the burden of AR in clinical practice. It was concluded that changes in VAS more than 23 mm should be considered of clinical importance and reflects responsiveness to treatments. Furthermore, changes in VAS values, after 14 days of treatment, were strongly correlated with changes in Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) and TSS, which means that these measures are similarly responsive to changes at the single-patient level.17 Furthermore, VAS has been used in AIT clinical trials as a secondary outcome in both adults and children.11,18-21 A venom immunotherapy study has also used a VAS to assess anxiety levels of being re-stung.22 One of the advantages of VAS is its ease of use and provision of a quick assessment. However, a disadvantage of using such a scale is the lack of extreme values of the VAS because patients tend to rate their symptom severity by avoiding the extremes.2
Well days and severe symptoms days The evaluation of well days, described as “days without intake of rescue medication and a symptom score below a predefined and clinically justified threshold” has been recommended by the EMA as a secondary end point.4 This outcome has been used in both sublingual and subcutaneous, well-powered, randomized controlled immunotherapy trials.10,23,24 The main concern with the use of well days as an outcome is the unclear definition of “clinically justified threshold,” which can lead to different interpretations.2 It has been proposed that, for pollen-induced rhinoconjunctivitis, given the significant day-to-day variation in the severity of symptoms due to changes in pollen exposure, “days with severe symptoms” is a more appropriate measure. The “days with severe symptoms” end point describes the treatment effect on the most troublesome days in the pollen season.25 It is an additional end point that can be used in immunotherapy trials to support the clinical interpretation of commonly used efficacy end points. It has been shown that the percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the group that received sublingual grass immunotherapy than in the placebo group, with relative differences of 49% to 63%.26 Provocation tests Provocation tests such as nasal, conjunctival, bronchial, or allergen exposure in allergen challenge chambers can be used for outcome assessment. The EMA guidance suggests that these may be used as primary end points in early stage, proof-of-concept, and dose-ranging (phase II) trials.4 Nasal provocation test. A nasal provocation test (NPT) or nasal allergen challenge involves the delivery of a small quantity of an allergen into the nose to elicit an allergic reaction if
J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 2
allergen-specific IgE is present in the nasal mucosa. Progressively increasing amounts (or concentrations) of the allergen are used to establish a threshold dose.27 Nasal symptoms can then be recorded. A quantitative assessment also can be made by instrumentally measuring the nasal flow or resistance by nasal peak flow meter, acoustic rhinometry, or rhinomanometry. An assessment of the inflammatory infiltrate by nasal scraping and/or brushing or the measurement of specific mediators in nasal lavage can be carried out.28 NPT performed with increasing threshold concentrations and then the response compared with the results at baseline have been used in several pollen as well as house dust mite AIT clinical trials.29-32 Overall, these have shown that specific nasal reactivity decreases after AIT. Uniform standards are of particular importance in the clinical setting and for the comparability of clinical and basic allergy research. These standards should cover the composition, dosage, and pharmacologic formulation of provocative substances (eg, allergen extracts), the necessity of titration, allergen application methods, and the evaluation criteria for a positive NPT reaction.33
Skin reactivity. A significant reduction of skin reactivity to allergen has been recorded in several controlled studies with sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) in both seasonal and perennial AR and/or asthma.34-36 However, the different biologic potency of different diagnostic extracts is a potential drawback in this evaluation. In addition, even if there is a trend in reduction of early and late skin reactivity in successful immunotherapy in individual patients, this parameter cannot predict the clinical outcome of the treatment.37 Conjunctival provocation test. Conjunctival provocation tests are less laborious than NPTs. They have been found to provide reproducible results while being a safe and acceptable alternative to NPTs.38,39 Conjunctival provocation tests have been used as an outcome in many trials both for seasonal and perennial allergens.29,40-42 A meta-analysis of SLIT for allergic conjunctivitis found that participants in the active treatment group showed an increase in the threshold dose for the conjunctival provocation test.43 Conjunctival challenges have also been used as an outcome in randomized double-blind placebo controlled trials of latex SCIT and SLIT.44-46 The main drawback, however, is the lack of an objective outcome measure because positive or negative results are only clinically assessed.2 These subjective parameters merit further evaluation. Bronchial allergen provocation. Bronchial allergen provocation (BAP) has traditionally been performed in immunotherapy trials to evaluate asthma symptoms. A Cochrane review on SCIT for asthma supports the use of BAP to determine the success of treatment by accurately evaluating the severity of bronchial sensitivity to a certain allergen.47 A recently published study on children treated with a house dust mite allergoid preparation concluded that BAP is a useful tool with which to define patients with asthma who are responders and nonresponders to SCIT. It is the only test available to objectively define responders, and, in contrast to the subjective rating, it is not influenced by the placebo effect.48 However, BAP is likely to remain an outcome only in clinical trials rather than daily clinical practice due to concerns regarding safety, feasibility, and expertise required to perform this.
MAKATSORI ET AL
125
Allergen challenge chambers. For patients with seasonal allergy, the assessment of clinical efficacy is complicated by the variability of pollen seasons. A specific challenge performed in a pollen challenge chamber with controlled exposure has been suggested as a reliable method to avoid these difficulties.49-51 The use of standardized pretreatment and posttreatment allergen challenges in such a chamber allows precise determination of efficacy, including onset, magnitude, and duration of action of any antiallergic treatment.52 Environmental exposure chambers have been used for assessment of grass pollen,53 ragweed,54 silver birch pollen,55 and recombinant hypoallergenic Bet v1 immunotherapy56 as well as cat Fel d 1-derived peptide antigen desensitization.57 The level of evidence that concerns the validity and reliability of allergen chamber systems is steadily growing, especially for specific allergen models, priming effects, and reproducibility of results in the same study population at different time points and with different challenge systems.52 Functional measures Although functional measures cannot replace the combined symptom and medication scores, they can provide supportive evidence for the effects of immunotherapy and, therefore, are recommended as secondary outcomes whenever possible. Furthermore, they are easy to measure in an allergy clinic setting. Examples of suitable objective functional measurements include the following: peak nasal inspiratory flow; nasal airway resistance; acoustic rhinometry; and, for asthma, spirometry and peak expiratory flow rate.5 In vitro parameters, such as allergen-specific IgE and specific IgG levels, cytokines such as INF-g, interleukins, tryptase, eosinophil cationic protein, and other inflammatory parameters are valuable additional secondary outcome measures that assess the immunologic effect of AIT in clinical trials but cannot replace the primary end points for efficacy.37 Health Related Quality of Life The personal burden of illness as perceived by patients with allergy extends beyond clinical symptoms, with an impact on sleep; daily activities, including work and school performance; and emotional consequences.58 Recently increased interest has been shown to the patient’s viewpoint about his or her illness and treatment options. All these viewpoints, which include illness perception, adherence or satisfaction to treatment, and quality of life, are grouped under the definition of Patient Reported Outcomes. Among them, quality of life has been the one most extensively studied.37,59 Quality of life is a broad concept and the term used to evaluate the general well-being of individuals. The component of overall quality of life that pertains to an individual’s health is known as “health-related quality of life.” This includes the psychologic, physical, and social aspects of one’s quality of life that are related to one’s health. HRQL instruments, therefore, can be used to assess the impact of an illness on a patient as perceived by the patient. These instruments are the only systemic scientific way to study differences in HRQL among patients with a similar level of objective clinical impairment.60,61 HRQL instruments also can be used as outcome measures for studying the impact of diagnostic or management interventions from the patient’s perspective and have been suggested as one of the most relevant secondary outcomes in AIT trials.5 HRQL can be measured with 2 types of questionnaires: generic and disease-specific. Generic questionnaires are intended
126
MAKATSORI ET AL
for general use and can be used to evaluate and compare different diseases. However, the disadvantages are that they may not focus adequately on problems specific to a particular disease and that they simultaneously measure the impact of comorbid conditions. Disease-specific instruments are more likely to detect clinically important impairments specific for a particular disease or HRQL differences over time and are better suited to evaluate the impact of interventions for specific diseases.62
Generic questionnaires. The best validated and most commonly applied generic questionnaire is the Health Status Questionnaire Short Form-36. This questionnaire comprises 36 questions in 9 health domains and renders mental component summary scores as well as a psychometrically based physical component summary. This has been shown to be a valuable tool in discriminating between patients with perennial AR and healthy subjects63 and has been used in AIT trials.2,64 Other generic HRQL questionnaires that have been used in allergic disorders are the Medical Outcome Study Short Form-2065; the Satisfaction Profile64; the Munich Life Dimension List; and the Work Productivity and Activity Impairment Questionnaire, used to assess the extent of the patient’s occupational impairment caused by the disease.2 Disease-specific questionnaires. For patients with AR and rhinoconjunctivitis, the RQLQ developed by Juniper et al66-69 is the most widely used tool in assessment of HRQL. This instrument has been adapted in several forms: the standardized form of RQLQ, Nocturnal RQLQ for measurement of nocturnal rhinitis, age-specific: the Adolescent RQLQ for patients 12-17 years of age and the Paediatric RQLQ for patients 612 years and the miniRQLQ.66-69 The standardized version of the RQLQ has 28 questions in 7 domains (practical problems, activity limitations, sleep problems, emotional condition, nasal symptoms, eye symptoms, and non-nose/eye symptoms) all of which are scored by the patients with a 7-point Likert scale that ranges from 0 (not troubled/none of the time) to 6 (extremely troubled/all the time). For the domain “activities,” 3 items can be freely selected of a list of 29 activities by the patient. These activities should be the 3 considered by the patient to be most affected by the disease.66 This instrument has been translated into many languages; has been tested in adult patients with seasonal, perennial, intermittent, and persistent AR; and is used extensively in both clinical studies and clinical practice.62 In controlled clinical trials, a difference of 0.5 or more in RQLQ domains between active and placebo-treated patients is regarded as clinically relevant.66 The miniRQLQ only has 14 of the 28 questions of the standardized version of the RQLQ. This is useful for group studies such as clinical trials and cross-sectional surveys, but the standardized version is considered to be more sensitive for use in clinical practice.70 The RQLQ has been used in many well-powered clinical trials as a secondary outcome both for SCIT18,19 and SLIT71-74 in adults and children.75 These studies showed that immunotherapy improves HRQL in patients with allergic rhinoconjunctivitis. Furthermore, this seems to parallel the clinical outcomes of a reduction in symptoms and/or medication intake. A recent real-life study with prospective follow up of 248 patients treated with SCIT with grass-pollene and/or house-dust-mitee induced allergic rhinoconjunctivitis and/or an asthma diagnosis found that the mean RQLQ score was reduced from 3.02 at baseline to 2.00 at follow-up. The average annual days with
J ALLERGY CLIN IMMUNOL PRACT MARCH/APRIL 2014
symptoms were reduced from 189 to 145 days, whereas annual sick days were reduced from 3.7 to 1.2 days.6 Of note, the RQLQ only evaluates HRQL in relation to allergic rhinoconjunctivitis symptoms but not to allergic asthma, although both diseases are linked and often coexist. The Rhinasthma questionnaire has been developed and validated for assessing the functional, physical, and emotional status of adult patients with AR and asthma.76 The German adapted version of this (RHINASTHMA GAV) was used in a prospective observational immunotherapy study, which showed significant improvement in HRQL during seasonal SLIT.77 Following on from the Rhinasthma questionnaire, the RhinAsthma Patient Perspective, a simple 8-question questionnaire with good measurement properties and sensitivity to health changes, has been found to provide a valid, reliable, and standardized HRQL measurement in patients with asthma and comorbid AR in clinical practice.78 Another tool that assesses disease control of both asthma and rhinitis is the Control of Allergic Rhinitis and Asthma Test. The shorter version, Control of Allergic Rhinitis and Asthma Test 10, can be used to assess control of AR and asthma, which can be used to compare groups in clinical studies and to evaluate individual patients in clinical practice.79 Other control tools likely to be useful in clinical care are the Rhinitis Control Assessment Test80 and the Allergic Rhinitis Control Test,81 which was developed based on the Asthma Control Test. Patient satisfaction has been shown to affect patients’ health-related decisions and treatment-related behaviors, which in turn have a substantial effect on the success of treatment outcomes. The Satisfaction Scale for Patients Receiving Allergen Immunotherapy questionnaire has been developed. This has been found to have good sensitivity to change for improved health status and can be used in clinical practice.82
Hymenoptera venom immunotherapy outcomes When using the Vespid Allergy Quality of Life Questionnaire, it has been found that the experience of anaphylaxis, the diagnosis of wasp venom allergy, and the potential dangers associated with wasp stings reduce the HRQL in patients allergic to wasp venom, regardless of the severity of the reaction.83 Recently, a children’s Hymenoptera venom allergy quality of life scale has also been developed.84 Venom immunotherapy has been shown to improve HRQL. A study of patients allergic to yellow jacket venom found a clinically important improvement in HRQL, whereas treatment with an adrenaline autoinjector resulted in deterioration in HRQL.85 A Cochrane meta-analysis has also found that venom immunotherapy is effective for preventing systemic allergic reaction to an insect sting.86 To check the clinical efficacy of venom immunotherapy, a sting challenge test can be performed with a live insect in a setting with available emergency care after the maintenance dose has been reached and according to agreed procedure guidelines.87,88 A tolerated sting challenge has a higher predictive value in terms of the results of later stings but does not prove that the patient is protected.89 Furthermore, these can only be performed in highly specialized units. Interestingly, it has been shown that the experience of having tolerated a sting challenge test also improves the HRQL, especially in patients who report high impairment in HRQL before the sting challenge test.90 DISCUSSION It is clear from this review that a variety of tools are available, all aiming to measure efficacy of AIT. However, there currently is
J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 2
a lack of consistency in the selection of primary and secondary outcome parameters used in SCIT and SLIT trials. Different primary outcomes, including TSS, medication score, and TCS have been used. The TCS is considered optimal because it shows the largest effect size and, therefore, the highest power to show significant treatment efficacy.8 However, there currently is no agreed scoring system. Standardized and validated primary outcomes are required to improve the comparability of study results. Furthermore, there is a need for clear guidelines as to the most appropriate primary outcome to be used. Secondary outcomes that have been measured include provocation allergen tests, individual symptom scores, well days and/or severe symptoms days, VAS, and HRQL questionnaires. The main drawback of provocation allergen tests is the lack of reproducibility and standardization. Currently, the EMA guidance suggests that these may be used as primary end points in early stage, proof-of-concept, and dose-ranging trials.4 Their use in daily clinical practice is less feasible. The evidence about the validity and reliability of allergen exposure chamber systems is increasing. These allergen chambers are likely to have an additive role in studying specific allergen models, priming effects, and reproducibility of results in the same study population at different time points. It is well established that allergic diseases have a significant impact on the affected individual’s HRQL and well-being. In recent years, more weight has appropriately been placed on patient recorded outcomes such as HRQL, satisfaction with or adherence to treatment, and control of disease reported directly by the patient. There are several validated HRQL questionnaires that can be used in clinical trials and clinical practice. Disease-specific instruments, for example, the RQLQ, have gained acceptance as methods to obtain a measure of disease perception in individuals with AR and have been validated in different age groups. It is important that such measures are included as secondary outcomes in clinical trials, but there also are versions that can easily be applied in daily practice. Furthermore, recently there has been an increased interest in measures of disease control. Various AR control measures (Allergic Rhinitis Control Test, Rhinitis Control Assessment Test, Control of Allergic Rhinitis and Asthma Test) have been developed and validated. These vary in the number of questions as well as the period of evaluation assessed. However, there are no studies currently that compared these tools with each other. In addition, they have not yet been tested in AIT randomized controlled trials; therefore, their use as an outcome is not yet established. Patient satisfaction with treatment is important because it can also be closely linked to adherence. The Satisfaction Scale for Patients Receiving Allergen Immunotherapy questionnaire specifically developed for AIT has been found to be sensitivity to change for improved health status and can be used in clinical practice, but further guidance is required about its role in randomized clinical trials. In conclusion, it is important to agree on outcome measures appropriate for clinical trials by consulting all parties involved, including regulatory bodies, the pharmaceutical industry, clinicians, and allergy associations. This will allow for improved comparability of studies as well as enable clinicians and patients to decide whether AIT would be an appropriate treatment option for them. REFERENCES 1. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/ European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013;131:1288-96.
MAKATSORI ET AL
127
2. Pfaar O, Kleine-Tebbe J, Hörmann K, Klimek L. Allergen-specific immunotherapy: which outcome measures are useful in monitoring clinical trials? Immunol Allergy Clin North Am 2011;31:289-309. 3. Bousquet J, Schünemann HJ, Bousquet PJ, Bachert C, Canonica GW, Casale TB, et al. How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement. Allergy 2011;66:765-74. 4. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. CHMP/EWP/18504/2006. London, 20 November 2008. Available from: http://www.ema.europa.eu/docs/en_ GB/document_library/Scientific_guideline/2009/09/WC500003605.pdf. Accessed February 5, 2014. 5. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ, Lockey RF, Malling HJ, et al. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy 2007;62:317-24. 6. Petersen KD, Kronborg C, Larsen JN, Dahl R, Gyrd-Hansen D. Patient related outcomes in a real life prospective follow up study: allergen immunotherapy increase quality of life and reduce sick days. World Allergy Organ J 2013;6:15. 7. Guidance for Industry. Allergic rhinitis: clinical development programs for drug products. Draft guidance. U.S. Department of Health and Human Serviced. FDA Food and Drug Administration. Center for Drug Evaluation and Research (CDER). 2000. Available from: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm071293.pdf. Accessed February 5, 2014. 8. Clark J, Schall R. Assessment of combined symptom and medication scores for rhinoconjunctivitis immunotherapy clinical trials. Allergy 2007;62:1023-8. 9. Pfaar O, Robinson DS, Sager A, Emuzyte R. Immunotherapy with depigmented polymerized mixed tree pollen extract: a clinical trial and responder analysis. Allergy 2010;65:1614-21. 10. DuBuske LM, Frew AJ, Horak F, Keith PK, Corrigan CJ, Aberer W, et al. Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc 2011;32:239-47. 11. Calderon MA, Eichel A, Makatsori M, Pfaar O. Comparability of subcutaneous and sublingual immunotherapy outcomes in allergic rhinitis clinical trials. Curr Opin Allergy Clin Immunol 2012;12:249-56. 12. Grouin JM, Vicaut E, Jean-Alphonse S, Demoly P, Wahn U, Didier A, et al. The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials. Clin Exp Allergy 2011;41:1282-8. 13. Häfner D, Reich K, Matricardi PM, Meyer H, Kettner J, Narkus A. Prospective validation of ‘Allergy-Control-SCORE(TM)’: a novel symptom-medication score for clinical trials. Allergy 2011;66:629-36. 14. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health 1990;13:227-36. 15. Bousquet PJ, Combescure C, Neukirch F, Klossek JM, Méchin H, Daures JP, et al. Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines. Allergy 2007;62:367-72. 16. Bousquet PJ, Combescure C, Klossek JM, Daures JP, Bousquet J. Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis. J Allergy Clin Immunol 2009;123:1349-54. 17. Demoly P, Bousquet PJ, Mesbah K, Bousquet J, Devillier P. Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis. Clin Exp Allergy 2013;43:881-8. 18. Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A. Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid. Allergy 2005;60:801-7. 19. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:319-25. 20. Kuna P, Kaczmarek J, Kupczyk M. Efficacy and safety of immunotherapy for allergies to Alternaria alternata in children. J Allergy Clin Immunol 2011;127:502-8. 21. Moller C, Dreborg S, Ferdousi HA, Halken S, Høst A, Jacobsen L, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251-6. 22. Sacha M, Czarnobilska E, Stobiecki M, Dyga W. Influence of venom immunotherapy on anxiety level of being re-stung. Przegl Lek 2012;69:1261-5. 23. Didier A, Malling HJ, Worm M, Horak F, Jäger S, Montagut A, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007; 120:1338-45. 24. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M, Klimek L, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol 2009;123:167-73.
128
MAKATSORI ET AL
25. Durham SR, Birk AO, Andersen JS. Days with severe symptoms: an additional efficacy endpoint in immunotherapy trials. Allergy 2011;66:120-3. 26. Durham SR, Emminger W, Kapp A, de Monchy JG, Rak S, Scadding GK, et al. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol 2012;129:717-25. 27. Hellings PW, Scadding G, Alobid I, Bachert C, Fokkens WJ, Gerth van Wijk R, et al. Executive summary of European Task Force document on diagnostic tools in rhinology. Rhinology 2012;50:339-52. 28. Scadding GW, Calderon MA, Bellido V, Koed GK, Nielsen NC, Lund K, et al. Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes. J Immunol Methods 2012;384:25-32. 29. Pfaar O, Barth C, Jaschke C, Hörmann K, Klimek L. Sublingual allergenspecific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study. Int Arch Allergy Immunol 2011;154:336-44. 30. Klimek L, Mewes T, Wolf H, Hansen I, Schnitker J, Mann WJ. The effects of short-term immunotherapy using molecular standardized grass and rye allergens compared with symptomatic drug treatment on rhinoconjunctivitis symptoms, skin sensitivity, and specific nasal reactivity. Otolaryngol Head Neck Surg 2005;133:538-43. 31. Amar SM, Harbeck RJ, Sills M, Silveira LJ, O’Brien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol 2009;124: 150-6. 32. Aydogan M, Eifan AO, Keles S, Akkoc T, Nursoy MA, Bahceciler NN, et al. Sublingual immunotherapy in children with allergic rhinoconjunctivitis monosensitized to house-dust-mites: a double-blind-placebo-controlled randomised trial. Respir Med 2013;107:1322-9. 33. Riechelmann H, Bachert C, Goldschmidt O, Hauswald B, Klimek L, Schlenter WW, et al. Application of the nasal provocation test on diseases of the upper airways. Position paper of the German Society for Allergology and Clinical Immunology (ENT Section) in cooperation with the Working Team for Clinical Immunology. Laryngorhinootologie 2003;82:183-8. 34. Loureiro G, Tavares B, Chieira C, Pereira C. Effect of dermatophagoides specific immunotherapy on cutaneous reactivity. Eur Ann Allergy Clin Immunol 2007;39:5-8. 35. Francis JN, James LK, Paraskevopoulos G, Wong C, Calderon MA, Durham SR, et al. Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol 2008;121:1120-5. 36. Lima MT, Wilson D, Pitkin L, Roberts A, Nouri-Aria K, Jacobson M, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 2002;32:507-14. 37. Senna G, Calderon M, Makatsori M, Ridolo E, Passalacqua G. An evidencebased appraisal of the surrogate markers of efficacy of allergen immunotherapy. Curr Opin Allergy Clin Immunol 2011;11:375-80. 38. Riechelmann H, Epple B, Gropper G. Comparison of conjunctival and nasal provocation test in allergic rhinitis to house dust mite. Int Arch Allergy Immunol 2003;130:51-9. 39. Moller C, Bjorksten B, Nilsson G, Dreborg S. The precision of the conjunctival provocation test. Allergy 1984;39:37-41. 40. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebocontrolled trial. Clin Exp Allergy 1997;27:860-7. 41. Durham SR, Walker SM, Varga EM, Jacobson MR, O’Brien F, Noble W, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341:468-75. 42. Riechelmann H, Schmutzhard J, van der Werf JF, Distler A, Kleinjans HA. Efficacy and safety of a glutaraldehyde-modified house dust mite extract in allergic rhinitis. Am J Rhinol Allergy 2010;24:104-9. 43. Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham S. Sublingual immunotherapy for treating allergic conjunctivitis. Cochrane Database Syst Rev 2011;(7):CD007685. 44. Gastaminza G, Algorta J, Uriel O, Audicana MT, Fernandez E, Sanz ML, et al. Randomized, double-blind, placebo-controlled clinical trial of sublingual immunotherapy in natural rubber latex allergic patients. Trials 2011;12:191. 45. Leynadier F, Herman D, Vervloet D, Andre C. Specific immunotherapy with a standardized latex extract versus placebo in allergic healthcare workers. J Allergy Clin Immunol 2000;106:585-90. 46. Tabar AI, Anda M, Bonifazi F, Bilo MB, Leynadier F, Fuchs T, et al. Specific immunotherapy with standardized latex extract versus placebo in latex-allergic patients. Int Arch Allergy Immunol 2006;14:369-76. 47. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 2010;(8):CD001186.
J ALLERGY CLIN IMMUNOL PRACT MARCH/APRIL 2014
48. Rosewich M, Arendt S, El Moussaoui S, Schulze J, Schubert R, Zielen S. Bronchial allergen provocation: a useful method to assess the efficacy of specific immunotherapy in children. Pediatr Allergy Immunol 2013;24:434-40. 49. Hohlfeld JM, Holland-Letz T, Larbig M, Lavae-Mokhtari M, Wierenga E, Kapsenberg M, et al. Diagnostic value of outcome measures following allergen exposure in an environmental challenge chamber compared with natural conditions. Clin Exp Allergy 2010;40:998-1006. 50. Krug N, Hohlfeld JM, Larbig M, Buckendahl A, Badorrek P, Geldmacher H, et al. Validation of an environmental exposure unit for controlled human inhalation studies with grass pollen in patients with seasonal allergic rhinitis. Clin Exp Allergy 2003;33:1667-74. 51. Jacobs RL, Harper N, He W, Andrews CP, Rather CG, Ramirez DA, et al. Responses to ragweed pollen in a pollen challenge chamber versus seasonal exposure identify allergic rhinoconjunctivitis endotypes. J Allergy Clin Immunol 2012;130:122-7. 52. Zieglmayer PU. Are results of environmental exposure units transferable to reallife exposure? Curr Opin Allergy Clin Immunol 2013;13:244-8. 53. Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Devillier P, Montagut A, et al. Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol 2009;124:471-7. 54. Donovan JP, Buckeridge DL, Briscoe MP, Clark RH, Day JH. Efficacy of immunotherapy to ragweed antigen tested by controlled antigen exposure. Ann Allergy Asthma Immunol 1996;77:74-80. 55. Horak F, Stubner P, Berger UE, Marks B, Toth J, Jäger S. Immunotherapy with sublingual birch pollen extract. A short-term double-blind placebo study. J Investig Allergol Clin Immunol 1998;8:165-71. 56. Meyer W, Narkus A, Salapatek AM, Häfner D. Double-blind, placebocontrolled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber. Allergy 2013;68:724-31. 57. Patel D, Couroux P, Hickey P, Salapatek AM, Laidler P, Larché M, et al. Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. J Allergy Clin Immunol 2013;131:103-9. 58. Ozdoganoglu T, Songu M, Inancli HM. Quality of life in allergic rhinitis. Ther Adv Respir Dis 2012;6:25-39. 59. Baiardini I, Bousquet PJ, Brzoza Z, Canonica GW, Compalati E, Fiocchi A, et al. Global Allergy and Asthma European Network. Recommendations for assessing patient-reported outcomes and health-related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper. Allergy 2010;65:290-5. 60. van Oene CM, van Reij EJ, Sprangers MA, Fokkens WJ. Quality-assessment of disease-specific quality of life questionnaires for rhinitis and rhinosinusitis: a systematic review. Allergy 2007;62:1359-71. 61. Flokstra-de Blok BM, Dubois AE. Quality of life measures for food allergy. Clin Exp Allergy 2012;42:1014-20. 62. Dietz de Loos DA, Segboer CL, Gevorgyan A, Fokkens WJ. Disease-specific quality-of-life questionnaires in rhinitis and rhinosinusitis: review and evaluation. Curr Allergy Asthma Rep 2013;13:162-70. 63. Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 Health Status Questionnaire. Allergy Clin Immunol 1994;94:182-8. 64. Passalacqua G, Pasquali M, Ariano R, Lombardi C, Giardini A, Baiardini I, et al. Randomized double-blind controlled study with sublingual carbamylated allergoid immunotherapy in mild rhinitis due to mites. Allergy 2006;61:849-54. 65. Bousquet J, Scheinmann P, Guinnepain MT, Perrin-Fayolle M, Sauvaget J, Tonnel AB, et al. Sublingual-swallow immunotherapy (SLIT) in patients with asthma due to house-dust mites: a double-blind, placebo-controlled study. Allergy 1999;54:249-60. 66. Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991;21:77-83. 67. Juniper EF, Guyatt H, Dolovich J. Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials. J Allergy Clin Immunol 1994;93:413-23. 68. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol 1999;104:364-9. 69. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measure quality of life in adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2003;111:484-90. 70. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Development and validation of the mini Rhinoconjunctivitis Quality of Life Questionnaire. Clin Exp Allergy 2000;30:132-40. 71. Rak S, Yang WH, Pedersen MR, Durham SR. Once-daily sublingual allergenspecific immunotherapy improves quality of life in patients with grass
J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 2
72.
73.
74.
75.
76.
77.
78.
79.
80.
pollen-induced allergic rhinoconjunctivitis: a double-blind, randomised study. Qual Life Res 2007;16:191-201. Didier A, Melac M, Montagut A, Lhéritier-Barrand M, Tabar A, Worm M. Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy. Allergy 2009;64:166-71. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802-9. Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol 2011;127:72-80. Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. J Allergy Clin Immunol 2011;127:64-71. Baiardini I, Pasquali M, Giardini A, Specchia C, Passalacqua G, Venturi S, et al. Rhinasthma: a new specific QoL questionnaire for patients with rhinitis and asthma. Allergy 2003;58:289-94. Sieber J, Gross A, Shah-Hosseini K, Mösges R. The RHINASTHMA GAV scores without SLIT, at the beginning and at the end of seasonal SLIT. Asian Pac J Allergy Immunol 2010;28:232-6. Braido F, Baiardini I, Stagi E, Scichilone N, Rossi O, Lombardi C, et al. RhinAsthma patient perspective: a short daily asthma and rhinitis QoL assessment. Allergy 2012;67:1443-50. Fonseca JA, Nogueira-Silva L, Morais-Almeida M, Sa-Sousa A, Azevedo LF, Ferreira J, et al. Control of Allergic Rhinitis and Asthma Test (CARAT) can be used to assess individual patients over time. Clin Transl Allergy 2012;2:16. Meltzer EO, Schatz M, Nathan R, Garris C, Stanford RH, Kosinski M. Reliability, validity, and responsiveness of the Rhinitis Control Assessment Test in patients with rhinitis. Allergy Clin Immunol 2013;131:379-86.
MAKATSORI ET AL
129
81. Demoly P, Jankowski R, Chassany O, Bessah Y, Allaert FA. Validation of a self-questionnaire for assessing the control of allergic rhinitis. Clin Exp Allergy 2011;41:860-8. 82. Justicia JL, Cardona V, Guardia P, Ojeda P, Olaguíbel JM, Vega JM, et al. Validation of the first treatment-specific questionnaire for the assessment of patient satisfaction with allergen-specific immunotherapy in allergic patients: the ESPIA questionnaire. J Allergy Clin Immunol 2013;131:1539-46. 83. Oude Elberink JN, Dubois AE. Quality of life in insect venom allergic patients. Curr Opin Allergy Clin Immunol 2003;3:287-93. 84. Cichocka-Jarosz E, Brzyski P, Tobiasz-Adamczyk B, Lis G, Pietrzyk JJ. Development of children’s Hymenoptera venom allergy quality of life scale (CHVAQoLS). Clin Transl Allergy 2013;3:25. 85. Oude Elberink JN, De Monchy JG, Van Der Heide S, Guyatt GH, Dubois AE. Venom immunotherapy improves health-related quality of life in patients allergic to yellow jacket venom. J Allergy Clin Immunol 2002;110:174-82. 86. Boyle RJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, Daniels M, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev 2012;(10):CD008838. 87. Ruëff F, Przybilla B, Müller U, Mosbech H. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy 1996;51:216-25. 88. Muller U, Golden DB, Lockey RF, Shin B. Immunotherapy for Hymenoptera venom hypersensitivity. Clin Allergy Immunol 2008;21:377-92. 89. Przybilla B, Ruëff F. Hymenoptera venom allergy. J Dtsch Dermatol Ges 2010; 8:114-27. 90. Fischer J, Teufel M, Feidt A, Giel KE, Zipfel S, Biedermann T. Tolerated wasp sting challenge improves health-related quality of life in patients allergic to wasp venom. J Allergy Clin Immunol 2013;132:489-90.
Allergen Immunotherapy: Clinical Outcomes Assessment Melina Makatsori, MDa, Oliver Pfaar, MDb, and Moises A. Calderon, MD, PhDa London, United Kingdom; and Mannheim, Germany Assessment of clinical outcomes is essential to evaluate the efficacy of allergen immunotherapy, both in clinical trials and in daily clinical practice. “Primary outcomes” used in sublingual and subcutaneous immunotherapy trials include the measurement of symptoms, the use of concomitant medications, and/or a combination of both of these measures. “Secondary outcomes” that have been measured include individual symptom scores, provocation allergen tests, visual analog scales, and health-related quality of life assessments. Currently, there is a lack of consistency in the selection of outcome parameters used, which represents a major problem when comparing the same therapeutic intervention. In this review, we examined the different primary and secondary outcome parameters that have been used in clinical trials; reviewed recommendations by European and US guidelines, and allergy groups; and explored which outcomes may be applicable for use in clinical practice. Ó 2014 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2014;2:123-9) Key words: Outcome parameters; Allergen immunotherapy; Sublingual immunotherapy; Sublingual immunotherapy; Healthrelated quality of life
Allergen immunotherapy (AIT) has been found to be effective in the treatment of allergic rhinitis (AR), allergic conjunctivitis, allergic asthma, and Hymenoptera venom allergy. A beneficial effect has been shown in both adults and children. In contrast to pharmacological therapies, which provide only temporary relief of symptoms, AIT is the only currently available treatment that can modify the allergic disease process, and thus is worth considering as a possible treatment in affected individuals.1
a
Section of Allergy and Clinical Immunology, Imperial College London, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom b Centre for Rhinology and Allergology Wiesbaden, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Mannheim, Germany No funding was received for this work. Conflicts of interest: O. Pfaar has received consultancy fees from Stallergenes, HAL, Bencard/Allergy-Therapeutics, LETI/Novartis, and MEDA-Pharma; has received lecture fees from ALK-Abello, Allergopharma, Stallergenes, HAL, AllergyTherapeutics/Bencard, Hartington, Lofarma, Novartis/Leti, Glaxo-Smith-Kline, Roxall, and MEDA-Pharma GmbH; has received travel support from HALAllergy and Allergopharma. M. A. Calderon has received consultancy and lecture fees from ALK, Stallergenes, Merck, Allergopharma, HAL allergy, Therapeutics. M. Makatsori declares that she has no relevant conflicts. Received for publication November 18, 2013; revised January 20, 2014; accepted for publication January 22, 2014. Corresponding author: Moises A. Calderon, MD, PhD, Section of Allergy and Clinical Immunology, Imperial College London, NHLI, Royal Brompton Hospital, London, UK. E-mail: [email protected]. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.01.005
Assessment of clinical outcomes is essential to evaluate the effectiveness of AIT both in clinical trials and in daily clinical practice. Various clinical parameters are commonly used to provide evidence of the clinical efficacy of AIT.2,3 “Primary outcomes” usually include the measurement of symptoms and the use of concomitant medications, whereas quality of life measures or surrogate markers have usually been used as “secondary outcome” parameters.4,5 In practice, clinical outcomes are very important to evaluate the effect of AIT. They enable assessment of the patient’s condition and response to immunotherapy so that an appropriate schedule of treatment and monitoring can be planned. In clinical trials, they allow for collection of data to measure efficacy and enable comparison of different treatments. It is widely accepted that the personal burden of illness, as perceived by the patient with allergy, cannot be fully assessed by traditional measures, such as clinical symptoms, which correlate only moderately with patients’ perceptions and functional capabilities on a daily basis. For this reason, it is essential to include the patient’s self-rated health-related quality of life (HRQL) in evaluations of AIT interventions.6 In this review, we will examine the different primary and secondary outcome parameters that have been used in clinical trials and the ones that have been recommended by European as well as US guidelines and allergy groups.3-5,7 Furthermore, we will explore which outcomes may be useful to also apply in clinical practice.
PRIMARY OUTCOMES According to recommendations published by the European Medicines Agency (EMA) in 2008,4 the preferred primary outcome measure for AIT clinical trials is the total combined score (TCS), which is the sum of the total symptom score (TSS) and total medication score. Because the severity of symptoms and the use of relief medication are interdependent, it is important to combine these into a single score. Furthermore, the TCS is considered optimal because it shows the largest effect size and, therefore, the highest power to show significant treatment efficacy.8 A TCS has been used in some clinical trials of AR9-11; however, there currently is no agreed scoring system. The TSS commonly used for assessment of AR includes 4 individual nasal symptoms (sneezing, rhinorrhea, nasal congestion, nasal pruritus) and 2 conjunctival symptoms (ocular pruritus and watery eyes). These symptoms are scored by patients on a diary card by using a 4-point rating scale between 0 (no symptoms) and 3 (severe symptoms) so that the (combined) sum of the 6 individual symptom scores for a given day results in a rhinoconjunctivitis TSS that ranges from 0 to 18 points.2 Patients should record scores in a diary at least as often as the daily dosing interval. The US Food and Drug Administration recommends collection of both reflective symptom scores (ie, an evaluation of symptom severity after a predefined time period, 123
124
MAKATSORI ET AL
Abbreviations used AIT- allergen immunotherapy AR- Allergic rhinitis BAP- Bronchial allergen provocation EMA- European Medicines Agency HRQL- Health-related quality of life NPT- Nasal provocation test RQLQ- Rhinoconjunctivitis Quality-of-Life Questionnaire SCIT- Subcutaneous immunotherapy SLIT- Sublingual immunotherapy TCS- Total combined score TSS- Total symptom score VAS- Visual Analog Scale
eg, 12 hours) and instantaneous symptom scores (ie, an evaluation of symptom severity immediately before the next dose). This is because reflective symptom scores assess the overall degree of effectiveness over a prespecified time interval, whereas instantaneous scores assess effectiveness at the end-of-dosing interval.7 Similarly to the TSS, the total medication score is often used separately as a primary outcome parameter. A recent review of the outcomes used in well-powered immunotherapy clinical trials has found great variability between the rescue medication itself and the scoring systems used.11 The use of rescue medications is an important measure of immunotherapy efficacy because it is anticipated that patients will require reduced amounts of medical treatment if immunotherapy is effective. It is important that, to be able to compare clinical trials and also, more significantly for clinicians to be able to assess efficacy of different immunotherapy preparations and response to AIT, a standardized and validated TCS scoring system should be available. One possible approach that has been proposed is the adjusted symptom score, which is primarily based on the rhinoconjunctivitis TSS, which is calculated forward.12 By adjusting the rhinoconjunctivitis TSS for rescue medication use, the adjusted symptom score can estimate symptom severity and the treatment effect more accurately. A novel combined symptom-medication score that has recently been validated is the Allergy-Control-SCORE, which has been shown to be a reliable instrument to assess the severity of respiratory allergic diseases in clinical trials as well as in daily practice.13
SECONDARY OUTCOMES Scores of individual symptoms Changes in the score of individual symptoms (ocular, nasal, bronchial) can be a useful secondary outcome. This procedure allows separately assessing the effect of the treatment on each target organ. Also, in rhinitis, the effect of the treatment on each symptom (rhinorrhea, itching, sneezing, and obstruction) can be assessed.5 Visual Analog Scale A Visual Analog Scale (VAS) is a simple but valuable instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. It usually is a horizontal line, 100 mm in length, anchored by word descriptors at each end, for example, that represent the severity of symptoms from 0 “no symptoms” to 10 “very severe symptoms.” The patient marks on the line the point that the patient believes represents his or her perception of
J ALLERGY CLIN IMMUNOL PRACT MARCH/APRIL 2014
his or her current state. The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks.14 These scales are most useful when looking at change within individuals and are of less value for comparing across a group of individuals at one time point. The VAS has been extensively investigated and validated in AR and has been shown to significantly correlate with the severity of rhinitis graded by the Allergic Rhinitis and its Impact on Asthma criteria as well as quality of life.15 In addition, it is a useful measure to assess the effect of pharmacotherapies on symptoms.16,17 A recent observational prospective study in 990 patients who consulted their general practitioners for symptomatic rhinitis found that the VAS is a practical, sensitive, and valid tool to monitor the burden of AR in clinical practice. It was concluded that changes in VAS more than 23 mm should be considered of clinical importance and reflects responsiveness to treatments. Furthermore, changes in VAS values, after 14 days of treatment, were strongly correlated with changes in Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) and TSS, which means that these measures are similarly responsive to changes at the single-patient level.17 Furthermore, VAS has been used in AIT clinical trials as a secondary outcome in both adults and children.11,18-21 A venom immunotherapy study has also used a VAS to assess anxiety levels of being re-stung.22 One of the advantages of VAS is its ease of use and provision of a quick assessment. However, a disadvantage of using such a scale is the lack of extreme values of the VAS because patients tend to rate their symptom severity by avoiding the extremes.2
Well days and severe symptoms days The evaluation of well days, described as “days without intake of rescue medication and a symptom score below a predefined and clinically justified threshold” has been recommended by the EMA as a secondary end point.4 This outcome has been used in both sublingual and subcutaneous, well-powered, randomized controlled immunotherapy trials.10,23,24 The main concern with the use of well days as an outcome is the unclear definition of “clinically justified threshold,” which can lead to different interpretations.2 It has been proposed that, for pollen-induced rhinoconjunctivitis, given the significant day-to-day variation in the severity of symptoms due to changes in pollen exposure, “days with severe symptoms” is a more appropriate measure. The “days with severe symptoms” end point describes the treatment effect on the most troublesome days in the pollen season.25 It is an additional end point that can be used in immunotherapy trials to support the clinical interpretation of commonly used efficacy end points. It has been shown that the percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the group that received sublingual grass immunotherapy than in the placebo group, with relative differences of 49% to 63%.26 Provocation tests Provocation tests such as nasal, conjunctival, bronchial, or allergen exposure in allergen challenge chambers can be used for outcome assessment. The EMA guidance suggests that these may be used as primary end points in early stage, proof-of-concept, and dose-ranging (phase II) trials.4 Nasal provocation test. A nasal provocation test (NPT) or nasal allergen challenge involves the delivery of a small quantity of an allergen into the nose to elicit an allergic reaction if
J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 2
allergen-specific IgE is present in the nasal mucosa. Progressively increasing amounts (or concentrations) of the allergen are used to establish a threshold dose.27 Nasal symptoms can then be recorded. A quantitative assessment also can be made by instrumentally measuring the nasal flow or resistance by nasal peak flow meter, acoustic rhinometry, or rhinomanometry. An assessment of the inflammatory infiltrate by nasal scraping and/or brushing or the measurement of specific mediators in nasal lavage can be carried out.28 NPT performed with increasing threshold concentrations and then the response compared with the results at baseline have been used in several pollen as well as house dust mite AIT clinical trials.29-32 Overall, these have shown that specific nasal reactivity decreases after AIT. Uniform standards are of particular importance in the clinical setting and for the comparability of clinical and basic allergy research. These standards should cover the composition, dosage, and pharmacologic formulation of provocative substances (eg, allergen extracts), the necessity of titration, allergen application methods, and the evaluation criteria for a positive NPT reaction.33
Skin reactivity. A significant reduction of skin reactivity to allergen has been recorded in several controlled studies with sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) in both seasonal and perennial AR and/or asthma.34-36 However, the different biologic potency of different diagnostic extracts is a potential drawback in this evaluation. In addition, even if there is a trend in reduction of early and late skin reactivity in successful immunotherapy in individual patients, this parameter cannot predict the clinical outcome of the treatment.37 Conjunctival provocation test. Conjunctival provocation tests are less laborious than NPTs. They have been found to provide reproducible results while being a safe and acceptable alternative to NPTs.38,39 Conjunctival provocation tests have been used as an outcome in many trials both for seasonal and perennial allergens.29,40-42 A meta-analysis of SLIT for allergic conjunctivitis found that participants in the active treatment group showed an increase in the threshold dose for the conjunctival provocation test.43 Conjunctival challenges have also been used as an outcome in randomized double-blind placebo controlled trials of latex SCIT and SLIT.44-46 The main drawback, however, is the lack of an objective outcome measure because positive or negative results are only clinically assessed.2 These subjective parameters merit further evaluation. Bronchial allergen provocation. Bronchial allergen provocation (BAP) has traditionally been performed in immunotherapy trials to evaluate asthma symptoms. A Cochrane review on SCIT for asthma supports the use of BAP to determine the success of treatment by accurately evaluating the severity of bronchial sensitivity to a certain allergen.47 A recently published study on children treated with a house dust mite allergoid preparation concluded that BAP is a useful tool with which to define patients with asthma who are responders and nonresponders to SCIT. It is the only test available to objectively define responders, and, in contrast to the subjective rating, it is not influenced by the placebo effect.48 However, BAP is likely to remain an outcome only in clinical trials rather than daily clinical practice due to concerns regarding safety, feasibility, and expertise required to perform this.
MAKATSORI ET AL
125
Allergen challenge chambers. For patients with seasonal allergy, the assessment of clinical efficacy is complicated by the variability of pollen seasons. A specific challenge performed in a pollen challenge chamber with controlled exposure has been suggested as a reliable method to avoid these difficulties.49-51 The use of standardized pretreatment and posttreatment allergen challenges in such a chamber allows precise determination of efficacy, including onset, magnitude, and duration of action of any antiallergic treatment.52 Environmental exposure chambers have been used for assessment of grass pollen,53 ragweed,54 silver birch pollen,55 and recombinant hypoallergenic Bet v1 immunotherapy56 as well as cat Fel d 1-derived peptide antigen desensitization.57 The level of evidence that concerns the validity and reliability of allergen chamber systems is steadily growing, especially for specific allergen models, priming effects, and reproducibility of results in the same study population at different time points and with different challenge systems.52 Functional measures Although functional measures cannot replace the combined symptom and medication scores, they can provide supportive evidence for the effects of immunotherapy and, therefore, are recommended as secondary outcomes whenever possible. Furthermore, they are easy to measure in an allergy clinic setting. Examples of suitable objective functional measurements include the following: peak nasal inspiratory flow; nasal airway resistance; acoustic rhinometry; and, for asthma, spirometry and peak expiratory flow rate.5 In vitro parameters, such as allergen-specific IgE and specific IgG levels, cytokines such as INF-g, interleukins, tryptase, eosinophil cationic protein, and other inflammatory parameters are valuable additional secondary outcome measures that assess the immunologic effect of AIT in clinical trials but cannot replace the primary end points for efficacy.37 Health Related Quality of Life The personal burden of illness as perceived by patients with allergy extends beyond clinical symptoms, with an impact on sleep; daily activities, including work and school performance; and emotional consequences.58 Recently increased interest has been shown to the patient’s viewpoint about his or her illness and treatment options. All these viewpoints, which include illness perception, adherence or satisfaction to treatment, and quality of life, are grouped under the definition of Patient Reported Outcomes. Among them, quality of life has been the one most extensively studied.37,59 Quality of life is a broad concept and the term used to evaluate the general well-being of individuals. The component of overall quality of life that pertains to an individual’s health is known as “health-related quality of life.” This includes the psychologic, physical, and social aspects of one’s quality of life that are related to one’s health. HRQL instruments, therefore, can be used to assess the impact of an illness on a patient as perceived by the patient. These instruments are the only systemic scientific way to study differences in HRQL among patients with a similar level of objective clinical impairment.60,61 HRQL instruments also can be used as outcome measures for studying the impact of diagnostic or management interventions from the patient’s perspective and have been suggested as one of the most relevant secondary outcomes in AIT trials.5 HRQL can be measured with 2 types of questionnaires: generic and disease-specific. Generic questionnaires are intended
126
MAKATSORI ET AL
for general use and can be used to evaluate and compare different diseases. However, the disadvantages are that they may not focus adequately on problems specific to a particular disease and that they simultaneously measure the impact of comorbid conditions. Disease-specific instruments are more likely to detect clinically important impairments specific for a particular disease or HRQL differences over time and are better suited to evaluate the impact of interventions for specific diseases.62
Generic questionnaires. The best validated and most commonly applied generic questionnaire is the Health Status Questionnaire Short Form-36. This questionnaire comprises 36 questions in 9 health domains and renders mental component summary scores as well as a psychometrically based physical component summary. This has been shown to be a valuable tool in discriminating between patients with perennial AR and healthy subjects63 and has been used in AIT trials.2,64 Other generic HRQL questionnaires that have been used in allergic disorders are the Medical Outcome Study Short Form-2065; the Satisfaction Profile64; the Munich Life Dimension List; and the Work Productivity and Activity Impairment Questionnaire, used to assess the extent of the patient’s occupational impairment caused by the disease.2 Disease-specific questionnaires. For patients with AR and rhinoconjunctivitis, the RQLQ developed by Juniper et al66-69 is the most widely used tool in assessment of HRQL. This instrument has been adapted in several forms: the standardized form of RQLQ, Nocturnal RQLQ for measurement of nocturnal rhinitis, age-specific: the Adolescent RQLQ for patients 12-17 years of age and the Paediatric RQLQ for patients 612 years and the miniRQLQ.66-69 The standardized version of the RQLQ has 28 questions in 7 domains (practical problems, activity limitations, sleep problems, emotional condition, nasal symptoms, eye symptoms, and non-nose/eye symptoms) all of which are scored by the patients with a 7-point Likert scale that ranges from 0 (not troubled/none of the time) to 6 (extremely troubled/all the time). For the domain “activities,” 3 items can be freely selected of a list of 29 activities by the patient. These activities should be the 3 considered by the patient to be most affected by the disease.66 This instrument has been translated into many languages; has been tested in adult patients with seasonal, perennial, intermittent, and persistent AR; and is used extensively in both clinical studies and clinical practice.62 In controlled clinical trials, a difference of 0.5 or more in RQLQ domains between active and placebo-treated patients is regarded as clinically relevant.66 The miniRQLQ only has 14 of the 28 questions of the standardized version of the RQLQ. This is useful for group studies such as clinical trials and cross-sectional surveys, but the standardized version is considered to be more sensitive for use in clinical practice.70 The RQLQ has been used in many well-powered clinical trials as a secondary outcome both for SCIT18,19 and SLIT71-74 in adults and children.75 These studies showed that immunotherapy improves HRQL in patients with allergic rhinoconjunctivitis. Furthermore, this seems to parallel the clinical outcomes of a reduction in symptoms and/or medication intake. A recent real-life study with prospective follow up of 248 patients treated with SCIT with grass-pollene and/or house-dust-mitee induced allergic rhinoconjunctivitis and/or an asthma diagnosis found that the mean RQLQ score was reduced from 3.02 at baseline to 2.00 at follow-up. The average annual days with
J ALLERGY CLIN IMMUNOL PRACT MARCH/APRIL 2014
symptoms were reduced from 189 to 145 days, whereas annual sick days were reduced from 3.7 to 1.2 days.6 Of note, the RQLQ only evaluates HRQL in relation to allergic rhinoconjunctivitis symptoms but not to allergic asthma, although both diseases are linked and often coexist. The Rhinasthma questionnaire has been developed and validated for assessing the functional, physical, and emotional status of adult patients with AR and asthma.76 The German adapted version of this (RHINASTHMA GAV) was used in a prospective observational immunotherapy study, which showed significant improvement in HRQL during seasonal SLIT.77 Following on from the Rhinasthma questionnaire, the RhinAsthma Patient Perspective, a simple 8-question questionnaire with good measurement properties and sensitivity to health changes, has been found to provide a valid, reliable, and standardized HRQL measurement in patients with asthma and comorbid AR in clinical practice.78 Another tool that assesses disease control of both asthma and rhinitis is the Control of Allergic Rhinitis and Asthma Test. The shorter version, Control of Allergic Rhinitis and Asthma Test 10, can be used to assess control of AR and asthma, which can be used to compare groups in clinical studies and to evaluate individual patients in clinical practice.79 Other control tools likely to be useful in clinical care are the Rhinitis Control Assessment Test80 and the Allergic Rhinitis Control Test,81 which was developed based on the Asthma Control Test. Patient satisfaction has been shown to affect patients’ health-related decisions and treatment-related behaviors, which in turn have a substantial effect on the success of treatment outcomes. The Satisfaction Scale for Patients Receiving Allergen Immunotherapy questionnaire has been developed. This has been found to have good sensitivity to change for improved health status and can be used in clinical practice.82
Hymenoptera venom immunotherapy outcomes When using the Vespid Allergy Quality of Life Questionnaire, it has been found that the experience of anaphylaxis, the diagnosis of wasp venom allergy, and the potential dangers associated with wasp stings reduce the HRQL in patients allergic to wasp venom, regardless of the severity of the reaction.83 Recently, a children’s Hymenoptera venom allergy quality of life scale has also been developed.84 Venom immunotherapy has been shown to improve HRQL. A study of patients allergic to yellow jacket venom found a clinically important improvement in HRQL, whereas treatment with an adrenaline autoinjector resulted in deterioration in HRQL.85 A Cochrane meta-analysis has also found that venom immunotherapy is effective for preventing systemic allergic reaction to an insect sting.86 To check the clinical efficacy of venom immunotherapy, a sting challenge test can be performed with a live insect in a setting with available emergency care after the maintenance dose has been reached and according to agreed procedure guidelines.87,88 A tolerated sting challenge has a higher predictive value in terms of the results of later stings but does not prove that the patient is protected.89 Furthermore, these can only be performed in highly specialized units. Interestingly, it has been shown that the experience of having tolerated a sting challenge test also improves the HRQL, especially in patients who report high impairment in HRQL before the sting challenge test.90 DISCUSSION It is clear from this review that a variety of tools are available, all aiming to measure efficacy of AIT. However, there currently is
J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 2
a lack of consistency in the selection of primary and secondary outcome parameters used in SCIT and SLIT trials. Different primary outcomes, including TSS, medication score, and TCS have been used. The TCS is considered optimal because it shows the largest effect size and, therefore, the highest power to show significant treatment efficacy.8 However, there currently is no agreed scoring system. Standardized and validated primary outcomes are required to improve the comparability of study results. Furthermore, there is a need for clear guidelines as to the most appropriate primary outcome to be used. Secondary outcomes that have been measured include provocation allergen tests, individual symptom scores, well days and/or severe symptoms days, VAS, and HRQL questionnaires. The main drawback of provocation allergen tests is the lack of reproducibility and standardization. Currently, the EMA guidance suggests that these may be used as primary end points in early stage, proof-of-concept, and dose-ranging trials.4 Their use in daily clinical practice is less feasible. The evidence about the validity and reliability of allergen exposure chamber systems is increasing. These allergen chambers are likely to have an additive role in studying specific allergen models, priming effects, and reproducibility of results in the same study population at different time points. It is well established that allergic diseases have a significant impact on the affected individual’s HRQL and well-being. In recent years, more weight has appropriately been placed on patient recorded outcomes such as HRQL, satisfaction with or adherence to treatment, and control of disease reported directly by the patient. There are several validated HRQL questionnaires that can be used in clinical trials and clinical practice. Disease-specific instruments, for example, the RQLQ, have gained acceptance as methods to obtain a measure of disease perception in individuals with AR and have been validated in different age groups. It is important that such measures are included as secondary outcomes in clinical trials, but there also are versions that can easily be applied in daily practice. Furthermore, recently there has been an increased interest in measures of disease control. Various AR control measures (Allergic Rhinitis Control Test, Rhinitis Control Assessment Test, Control of Allergic Rhinitis and Asthma Test) have been developed and validated. These vary in the number of questions as well as the period of evaluation assessed. However, there are no studies currently that compared these tools with each other. In addition, they have not yet been tested in AIT randomized controlled trials; therefore, their use as an outcome is not yet established. Patient satisfaction with treatment is important because it can also be closely linked to adherence. The Satisfaction Scale for Patients Receiving Allergen Immunotherapy questionnaire specifically developed for AIT has been found to be sensitivity to change for improved health status and can be used in clinical practice, but further guidance is required about its role in randomized clinical trials. In conclusion, it is important to agree on outcome measures appropriate for clinical trials by consulting all parties involved, including regulatory bodies, the pharmaceutical industry, clinicians, and allergy associations. This will allow for improved comparability of studies as well as enable clinicians and patients to decide whether AIT would be an appropriate treatment option for them. REFERENCES 1. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/ European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013;131:1288-96.
MAKATSORI ET AL
127
2. Pfaar O, Kleine-Tebbe J, Hörmann K, Klimek L. Allergen-specific immunotherapy: which outcome measures are useful in monitoring clinical trials? Immunol Allergy Clin North Am 2011;31:289-309. 3. Bousquet J, Schünemann HJ, Bousquet PJ, Bachert C, Canonica GW, Casale TB, et al. How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement. Allergy 2011;66:765-74. 4. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. CHMP/EWP/18504/2006. London, 20 November 2008. Available from: http://www.ema.europa.eu/docs/en_ GB/document_library/Scientific_guideline/2009/09/WC500003605.pdf. Accessed February 5, 2014. 5. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ, Lockey RF, Malling HJ, et al. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy 2007;62:317-24. 6. Petersen KD, Kronborg C, Larsen JN, Dahl R, Gyrd-Hansen D. Patient related outcomes in a real life prospective follow up study: allergen immunotherapy increase quality of life and reduce sick days. World Allergy Organ J 2013;6:15. 7. Guidance for Industry. Allergic rhinitis: clinical development programs for drug products. Draft guidance. U.S. Department of Health and Human Serviced. FDA Food and Drug Administration. Center for Drug Evaluation and Research (CDER). 2000. Available from: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm071293.pdf. Accessed February 5, 2014. 8. Clark J, Schall R. Assessment of combined symptom and medication scores for rhinoconjunctivitis immunotherapy clinical trials. Allergy 2007;62:1023-8. 9. Pfaar O, Robinson DS, Sager A, Emuzyte R. Immunotherapy with depigmented polymerized mixed tree pollen extract: a clinical trial and responder analysis. Allergy 2010;65:1614-21. 10. DuBuske LM, Frew AJ, Horak F, Keith PK, Corrigan CJ, Aberer W, et al. Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc 2011;32:239-47. 11. Calderon MA, Eichel A, Makatsori M, Pfaar O. Comparability of subcutaneous and sublingual immunotherapy outcomes in allergic rhinitis clinical trials. Curr Opin Allergy Clin Immunol 2012;12:249-56. 12. Grouin JM, Vicaut E, Jean-Alphonse S, Demoly P, Wahn U, Didier A, et al. The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials. Clin Exp Allergy 2011;41:1282-8. 13. Häfner D, Reich K, Matricardi PM, Meyer H, Kettner J, Narkus A. Prospective validation of ‘Allergy-Control-SCORE(TM)’: a novel symptom-medication score for clinical trials. Allergy 2011;66:629-36. 14. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health 1990;13:227-36. 15. Bousquet PJ, Combescure C, Neukirch F, Klossek JM, Méchin H, Daures JP, et al. Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines. Allergy 2007;62:367-72. 16. Bousquet PJ, Combescure C, Klossek JM, Daures JP, Bousquet J. Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis. J Allergy Clin Immunol 2009;123:1349-54. 17. Demoly P, Bousquet PJ, Mesbah K, Bousquet J, Devillier P. Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis. Clin Exp Allergy 2013;43:881-8. 18. Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A. Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid. Allergy 2005;60:801-7. 19. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:319-25. 20. Kuna P, Kaczmarek J, Kupczyk M. Efficacy and safety of immunotherapy for allergies to Alternaria alternata in children. J Allergy Clin Immunol 2011;127:502-8. 21. Moller C, Dreborg S, Ferdousi HA, Halken S, Høst A, Jacobsen L, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251-6. 22. Sacha M, Czarnobilska E, Stobiecki M, Dyga W. Influence of venom immunotherapy on anxiety level of being re-stung. Przegl Lek 2012;69:1261-5. 23. Didier A, Malling HJ, Worm M, Horak F, Jäger S, Montagut A, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007; 120:1338-45. 24. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M, Klimek L, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol 2009;123:167-73.
128
MAKATSORI ET AL
25. Durham SR, Birk AO, Andersen JS. Days with severe symptoms: an additional efficacy endpoint in immunotherapy trials. Allergy 2011;66:120-3. 26. Durham SR, Emminger W, Kapp A, de Monchy JG, Rak S, Scadding GK, et al. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol 2012;129:717-25. 27. Hellings PW, Scadding G, Alobid I, Bachert C, Fokkens WJ, Gerth van Wijk R, et al. Executive summary of European Task Force document on diagnostic tools in rhinology. Rhinology 2012;50:339-52. 28. Scadding GW, Calderon MA, Bellido V, Koed GK, Nielsen NC, Lund K, et al. Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes. J Immunol Methods 2012;384:25-32. 29. Pfaar O, Barth C, Jaschke C, Hörmann K, Klimek L. Sublingual allergenspecific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study. Int Arch Allergy Immunol 2011;154:336-44. 30. Klimek L, Mewes T, Wolf H, Hansen I, Schnitker J, Mann WJ. The effects of short-term immunotherapy using molecular standardized grass and rye allergens compared with symptomatic drug treatment on rhinoconjunctivitis symptoms, skin sensitivity, and specific nasal reactivity. Otolaryngol Head Neck Surg 2005;133:538-43. 31. Amar SM, Harbeck RJ, Sills M, Silveira LJ, O’Brien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol 2009;124: 150-6. 32. Aydogan M, Eifan AO, Keles S, Akkoc T, Nursoy MA, Bahceciler NN, et al. Sublingual immunotherapy in children with allergic rhinoconjunctivitis monosensitized to house-dust-mites: a double-blind-placebo-controlled randomised trial. Respir Med 2013;107:1322-9. 33. Riechelmann H, Bachert C, Goldschmidt O, Hauswald B, Klimek L, Schlenter WW, et al. Application of the nasal provocation test on diseases of the upper airways. Position paper of the German Society for Allergology and Clinical Immunology (ENT Section) in cooperation with the Working Team for Clinical Immunology. Laryngorhinootologie 2003;82:183-8. 34. Loureiro G, Tavares B, Chieira C, Pereira C. Effect of dermatophagoides specific immunotherapy on cutaneous reactivity. Eur Ann Allergy Clin Immunol 2007;39:5-8. 35. Francis JN, James LK, Paraskevopoulos G, Wong C, Calderon MA, Durham SR, et al. Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol 2008;121:1120-5. 36. Lima MT, Wilson D, Pitkin L, Roberts A, Nouri-Aria K, Jacobson M, et al. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 2002;32:507-14. 37. Senna G, Calderon M, Makatsori M, Ridolo E, Passalacqua G. An evidencebased appraisal of the surrogate markers of efficacy of allergen immunotherapy. Curr Opin Allergy Clin Immunol 2011;11:375-80. 38. Riechelmann H, Epple B, Gropper G. Comparison of conjunctival and nasal provocation test in allergic rhinitis to house dust mite. Int Arch Allergy Immunol 2003;130:51-9. 39. Moller C, Bjorksten B, Nilsson G, Dreborg S. The precision of the conjunctival provocation test. Allergy 1984;39:37-41. 40. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebocontrolled trial. Clin Exp Allergy 1997;27:860-7. 41. Durham SR, Walker SM, Varga EM, Jacobson MR, O’Brien F, Noble W, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341:468-75. 42. Riechelmann H, Schmutzhard J, van der Werf JF, Distler A, Kleinjans HA. Efficacy and safety of a glutaraldehyde-modified house dust mite extract in allergic rhinitis. Am J Rhinol Allergy 2010;24:104-9. 43. Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham S. Sublingual immunotherapy for treating allergic conjunctivitis. Cochrane Database Syst Rev 2011;(7):CD007685. 44. Gastaminza G, Algorta J, Uriel O, Audicana MT, Fernandez E, Sanz ML, et al. Randomized, double-blind, placebo-controlled clinical trial of sublingual immunotherapy in natural rubber latex allergic patients. Trials 2011;12:191. 45. Leynadier F, Herman D, Vervloet D, Andre C. Specific immunotherapy with a standardized latex extract versus placebo in allergic healthcare workers. J Allergy Clin Immunol 2000;106:585-90. 46. Tabar AI, Anda M, Bonifazi F, Bilo MB, Leynadier F, Fuchs T, et al. Specific immunotherapy with standardized latex extract versus placebo in latex-allergic patients. Int Arch Allergy Immunol 2006;14:369-76. 47. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 2010;(8):CD001186.
J ALLERGY CLIN IMMUNOL PRACT MARCH/APRIL 2014
48. Rosewich M, Arendt S, El Moussaoui S, Schulze J, Schubert R, Zielen S. Bronchial allergen provocation: a useful method to assess the efficacy of specific immunotherapy in children. Pediatr Allergy Immunol 2013;24:434-40. 49. Hohlfeld JM, Holland-Letz T, Larbig M, Lavae-Mokhtari M, Wierenga E, Kapsenberg M, et al. Diagnostic value of outcome measures following allergen exposure in an environmental challenge chamber compared with natural conditions. Clin Exp Allergy 2010;40:998-1006. 50. Krug N, Hohlfeld JM, Larbig M, Buckendahl A, Badorrek P, Geldmacher H, et al. Validation of an environmental exposure unit for controlled human inhalation studies with grass pollen in patients with seasonal allergic rhinitis. Clin Exp Allergy 2003;33:1667-74. 51. Jacobs RL, Harper N, He W, Andrews CP, Rather CG, Ramirez DA, et al. Responses to ragweed pollen in a pollen challenge chamber versus seasonal exposure identify allergic rhinoconjunctivitis endotypes. J Allergy Clin Immunol 2012;130:122-7. 52. Zieglmayer PU. Are results of environmental exposure units transferable to reallife exposure? Curr Opin Allergy Clin Immunol 2013;13:244-8. 53. Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Devillier P, Montagut A, et al. Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol 2009;124:471-7. 54. Donovan JP, Buckeridge DL, Briscoe MP, Clark RH, Day JH. Efficacy of immunotherapy to ragweed antigen tested by controlled antigen exposure. Ann Allergy Asthma Immunol 1996;77:74-80. 55. Horak F, Stubner P, Berger UE, Marks B, Toth J, Jäger S. Immunotherapy with sublingual birch pollen extract. A short-term double-blind placebo study. J Investig Allergol Clin Immunol 1998;8:165-71. 56. Meyer W, Narkus A, Salapatek AM, Häfner D. Double-blind, placebocontrolled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber. Allergy 2013;68:724-31. 57. Patel D, Couroux P, Hickey P, Salapatek AM, Laidler P, Larché M, et al. Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. J Allergy Clin Immunol 2013;131:103-9. 58. Ozdoganoglu T, Songu M, Inancli HM. Quality of life in allergic rhinitis. Ther Adv Respir Dis 2012;6:25-39. 59. Baiardini I, Bousquet PJ, Brzoza Z, Canonica GW, Compalati E, Fiocchi A, et al. Global Allergy and Asthma European Network. Recommendations for assessing patient-reported outcomes and health-related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper. Allergy 2010;65:290-5. 60. van Oene CM, van Reij EJ, Sprangers MA, Fokkens WJ. Quality-assessment of disease-specific quality of life questionnaires for rhinitis and rhinosinusitis: a systematic review. Allergy 2007;62:1359-71. 61. Flokstra-de Blok BM, Dubois AE. Quality of life measures for food allergy. Clin Exp Allergy 2012;42:1014-20. 62. Dietz de Loos DA, Segboer CL, Gevorgyan A, Fokkens WJ. Disease-specific quality-of-life questionnaires in rhinitis and rhinosinusitis: review and evaluation. Curr Allergy Asthma Rep 2013;13:162-70. 63. Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 Health Status Questionnaire. Allergy Clin Immunol 1994;94:182-8. 64. Passalacqua G, Pasquali M, Ariano R, Lombardi C, Giardini A, Baiardini I, et al. Randomized double-blind controlled study with sublingual carbamylated allergoid immunotherapy in mild rhinitis due to mites. Allergy 2006;61:849-54. 65. Bousquet J, Scheinmann P, Guinnepain MT, Perrin-Fayolle M, Sauvaget J, Tonnel AB, et al. Sublingual-swallow immunotherapy (SLIT) in patients with asthma due to house-dust mites: a double-blind, placebo-controlled study. Allergy 1999;54:249-60. 66. Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991;21:77-83. 67. Juniper EF, Guyatt H, Dolovich J. Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials. J Allergy Clin Immunol 1994;93:413-23. 68. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol 1999;104:364-9. 69. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measure quality of life in adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2003;111:484-90. 70. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Development and validation of the mini Rhinoconjunctivitis Quality of Life Questionnaire. Clin Exp Allergy 2000;30:132-40. 71. Rak S, Yang WH, Pedersen MR, Durham SR. Once-daily sublingual allergenspecific immunotherapy improves quality of life in patients with grass
J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 2
72.
73.
74.
75.
76.
77.
78.
79.
80.
pollen-induced allergic rhinoconjunctivitis: a double-blind, randomised study. Qual Life Res 2007;16:191-201. Didier A, Melac M, Montagut A, Lhéritier-Barrand M, Tabar A, Worm M. Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy. Allergy 2009;64:166-71. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802-9. Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol 2011;127:72-80. Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. J Allergy Clin Immunol 2011;127:64-71. Baiardini I, Pasquali M, Giardini A, Specchia C, Passalacqua G, Venturi S, et al. Rhinasthma: a new specific QoL questionnaire for patients with rhinitis and asthma. Allergy 2003;58:289-94. Sieber J, Gross A, Shah-Hosseini K, Mösges R. The RHINASTHMA GAV scores without SLIT, at the beginning and at the end of seasonal SLIT. Asian Pac J Allergy Immunol 2010;28:232-6. Braido F, Baiardini I, Stagi E, Scichilone N, Rossi O, Lombardi C, et al. RhinAsthma patient perspective: a short daily asthma and rhinitis QoL assessment. Allergy 2012;67:1443-50. Fonseca JA, Nogueira-Silva L, Morais-Almeida M, Sa-Sousa A, Azevedo LF, Ferreira J, et al. Control of Allergic Rhinitis and Asthma Test (CARAT) can be used to assess individual patients over time. Clin Transl Allergy 2012;2:16. Meltzer EO, Schatz M, Nathan R, Garris C, Stanford RH, Kosinski M. Reliability, validity, and responsiveness of the Rhinitis Control Assessment Test in patients with rhinitis. Allergy Clin Immunol 2013;131:379-86.
MAKATSORI ET AL
129
81. Demoly P, Jankowski R, Chassany O, Bessah Y, Allaert FA. Validation of a self-questionnaire for assessing the control of allergic rhinitis. Clin Exp Allergy 2011;41:860-8. 82. Justicia JL, Cardona V, Guardia P, Ojeda P, Olaguíbel JM, Vega JM, et al. Validation of the first treatment-specific questionnaire for the assessment of patient satisfaction with allergen-specific immunotherapy in allergic patients: the ESPIA questionnaire. J Allergy Clin Immunol 2013;131:1539-46. 83. Oude Elberink JN, Dubois AE. Quality of life in insect venom allergic patients. Curr Opin Allergy Clin Immunol 2003;3:287-93. 84. Cichocka-Jarosz E, Brzyski P, Tobiasz-Adamczyk B, Lis G, Pietrzyk JJ. Development of children’s Hymenoptera venom allergy quality of life scale (CHVAQoLS). Clin Transl Allergy 2013;3:25. 85. Oude Elberink JN, De Monchy JG, Van Der Heide S, Guyatt GH, Dubois AE. Venom immunotherapy improves health-related quality of life in patients allergic to yellow jacket venom. J Allergy Clin Immunol 2002;110:174-82. 86. Boyle RJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, Daniels M, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev 2012;(10):CD008838. 87. Ruëff F, Przybilla B, Müller U, Mosbech H. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy 1996;51:216-25. 88. Muller U, Golden DB, Lockey RF, Shin B. Immunotherapy for Hymenoptera venom hypersensitivity. Clin Allergy Immunol 2008;21:377-92. 89. Przybilla B, Ruëff F. Hymenoptera venom allergy. J Dtsch Dermatol Ges 2010; 8:114-27. 90. Fischer J, Teufel M, Feidt A, Giel KE, Zipfel S, Biedermann T. Tolerated wasp sting challenge improves health-related quality of life in patients allergic to wasp venom. J Allergy Clin Immunol 2013;132:489-90.
