Subcutaneous Allergen Immunotherapy for Allergic Disease

Examining Efficacy, Safety and Cost-Effectiveness of Current and Novel Formulations

Linda Cox; Moisés Calderón; Oliver Pfaar

Disclosures

Immunotherapy. 2012;4(6):601-616. 

In This Article

Assessment of Immunotherapy Outcomes

In performing clinical studies on allergen-specific immunotherapy (SIT), a variety of clinical outcome parameters are utilized for the evaluation of the clinical efficacy of the therapy.[5,6] It is common practice to define 'primary' as well as 'secondary' outcome parameters before initiation of the SIT trial.

'Primary outcome measures' include the daily severity of symptoms as well as the daily consumption of antiallergic concomitant medication as documented in patients' (paper or electronic) diaries. The EMA guidance on statistical principles for clinical trials states that "The primary variable ('target' variable, primary endpoint) should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial".[201] The 2008 guidance of the EMA indicated that, to date, there has been no validated symptom and medication scoring method for clinical trials for SIT.[202] However, the guidance points out that "measurement of symptoms on a 4-point rating scale … is generally accepted," which should include itching, sneezing, rhinorrhea, nasal obstruction for nasal symptoms and, furthermore, itching/grittiness/redness and ocular tearing for conjunctival symptoms. Each symptom can be scored by patients between 0 (absent symptoms) and 3 (severe symptoms) (Box 2). All symptoms together may sum between 0 and 18 points as Rhinoconjunctivitis Total Symptom Score. A World Allergy Organization (WAO) Taskforce position paper on recommendations for standardization of clinical trials with SIT suggests that pulmonary symptoms, such as chest tightness, shortness of breath, cough and wheezing, may also be included in the symptom score.[7]

An important consideration in assessing outcomes is that there is an interdependence between allergic symptoms and the use of antiallergic medication. The WAO Taskforce recommendation clearly states that both scores should not be evaluated separately but be calculated in a combined score.[7] The use of a combined score was endorsed by the EMA guidance, which stated that "a weighted sum of the symptom and medication score" shall be used.[202] Again, currently there is no standardized and widely accepted method for the reporting of combined symptom and medication scores.[8]

One approach used to report combined symptom–medication scores is the Adjusted Symptom Score, which is primarily based on the Rhinoconjunctivitis Total Symptom Score calculated forward ('last observation carried forward'),[9] with an adjustment in the symptoms score if the patient had taken an allergy medication the subsequent day.[10] A novel instrument, the Allergy-Control-SCORE™, designed to assess patients' allergy severity by recording symptoms and rescue medication, has recently been validated.[11] The Allergy-Control-SCORE, which takes into account the global allergy severity, allergy-related consultations and the validated Rhinoconjunctivitis Quality of Life Questionnaire,[12] was found to be a "valid and reliable instrument to assess allergy severity in clinical trials and observational studies of respiratory allergic diseases".[11]

Secondary outcome parameters may also be evaluated as important outcome measures in clinical trials on SIT. These include Rhinoconjunctivitis Quality of Life, 'well/hell days', allergen provocation tests and other surrogate markers, such as allergen-specific IgG antibodies or inflammatory parameters.[7]

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