Severe/Uncontrolled Asthma From General Population to Clinical Setting: Update and Follow-up of the RItA Registry

Within the AGAVE project (2010-2014), funded by the 2008 AIFA (Italian Medicines Agency) Call (contract No. FARM8YRYZC), a severe/uncontrolled asthma online Registry (RItA) was implemented to assess the appropriateness of therapeutic strategies for severe/uncontrolled asthma patients, according to GINA (Global Initiative for Asthma) guidelines, in epidemiological and clinical samples. The online RItA Registry is a database containing information on patients' general characteristics, medical history, clinical data, risk factors, comorbidity, asthma exacerbations, current asthma treatment. Currently, it contains information on severe/uncontrolled asthma subjects, enrolled at national level, performing baseline (n tot=1018) and follow-up interviews (n tot=402).

Aim of the RISER study is to increase knowledge about the risk factors, diagnosis, and management of severe/uncontrolled asthma in general population and clinical setting through the update and follow-up of the RItA registry.

The RISER study is an observational longitudinal study involving a clinical setting and an epidemiological one.

The field survey will comprise one or two follow-ups according to the sample.

1. Observational longitudinal study in hospital specialist centres (clinical sample). Clinical cases of severe/uncontrolled asthma already included in the online RItA Registry and new clinical cases of severe/uncontrolled asthma attending the clinical centres and not yet included in the online RItA Registry, will be investigated at T0, T6 and T12 through a clinical form in order to collect information in accordance with the online RItA registry, and routine clinical/functional tests of asthma control.
2. Observational longitudinal study in a general population sample (epidemiological sample). Epidemiological cases of severe/uncontrolled asthma from Pisa cohort already inserted in the online RItA Registry and new epidemiological cases of severe/uncontrolled asthma from pre-existing Pisa cohort not yet included in the online RItA Registry will be investigated at T0 and T12 through a questionnaire to collect information for feeding the online RItA registry. Subjects fitting the epidemiological definition of severe/uncontrolled asthma will be invited at the Pisa clinical centre to have routine clinical/functional tests.

All data collected from clinical/epidemiological centres will be included in the RItA registry.

Overall, it is expected to enroll 422 patients.

RISER study is an observational longitudinal study in epidemiological and clinical samples investigated through questionnaires/clinical forms and routine clinical/functional assessments at baseline and at follow-ups.

The study is constituted by two arms:

1. observational longitudinal study in hospital specialist centres (clinical sample);
2. observational longitudinal study in a general population sample (epidemiological sample).

The clinical sample will provide a new characterization of severe/uncontrolled asthma phenotypes through clinical and functional assessments and biomarkers.

The epidemiological sample will allow to obtain new information about risk/protective factors for severe/uncontrolled asthma and to identify new cases who have not been yet referred to clinical centres.

RISER study is not a clinical trial, but it is an observational study without any specific drug administration by the investigators. Participants will receive interventions, which can include medical products, such as drugs or devices, or procedures, as part of their routine medical care, but they will not be assigned to specific interventions by the investigator as in a clinical trial.

Sample size Considering a possible loss to follow-up and a refusal rate of 20%, the expected number of subjects in the clinical sample will be 287 (195 cases already included in the online RItA Registry and 92 new uncontrolled/severe asthma cases not yet included in the Registry).

Considering a possible loss to follow-up and a refusal rate of 30%, the expected number of subjects in the epidemiological sample will be 135 (112 cases already included in the online RItA Registry and 23 new uncontrolled/severe asthma cases not yet included in the Registry).

Data collection tools:

1. Clinical form (clinical sample): a modified and updated version of the RItA Registry implemented during the AGAVE study will be used;
2. Questionnaire (epidemiological sample): a modified and updated version of the questionnaire implemented during the AGAVE study will be used. The questionnaire will be structured according to the data required by the online RItA registry.

   The clinical form and the questionnaire will take into account the following aspects, as in the pre-existing RItA Registry: demographic characteristics, asthma severity and level of control, current asthma therapy, comorbidities, risk factors, health services utilization.

   New information, to answer to new specific aspects addressed in the RISER study, will be integrated: asthma indirect costs, quality of life, biological drugs use, reason of changing therapy, use of electronic cigarettes or of heat-not-burn tobacco.
3. Routine clinical /functional tests of asthma control (clinical and epidemiological sample):

serum total IgE, spirometry, reversibility test, blood cell count, fractional exhaled nitric oxide (FeNO), oscillometry.

Data collected from clinical and epidemiological centres will be included in the online RiTA registry.

Field survey The field survey will be organized in three or two phases, according to the type of sample. In particular, the field study will comprise T0, baseline, T6, follow-up at 6 months from baseline (only for the clinical sample), T12, follow-up at 12 months from baseline.

1. Observational longitudinal study in hospital specialist centres (clinical sample): eligible subjects will be contacted from physicians, by telephone or directly when they attend the clinical centre for control visits. Once the patients have provided their signed informed consent, they will have to fill in the clinical form; routine functional/clinical tests will be performed. In particular, subjects will be investigated at T0, T6 and T12 through the clinical form in order to collect information in accordance with the online RItA Registry and routine clinical/functional tests of asthma control.

   All the possible variations that could occur in the patients' disease status and disease management, according to the routine medical care, will be registered and taken into account in the RISER study.
2. Observational longitudinal study in a general population sample (epidemiological sample): eligible subjects will be contacted by telephone from trained personnel of the Research Unit.

Once the signed informed consent is obtained by each enrolled subject, they will be invited to answer the phone questionnaire and to perform a medical examination at the local clinical centre.

In particular, subjects will be investigated at T0 and T12 through the questionnaire to collect information for feeding the online RItA Registry. Subjects fitting the epidemiological definition of severe/uncontrolled asthma will be invited at the Pisa clinical centre (CC) to have routine clinical/functional tests.

Each subject performing baseline clinical/functional tests at the Pisa clinical centre (CC) will be clinically and functionally re-assessed.

. Statistical analysis: data quality control will be carried out before statistical analysis performance.

Descriptive analysis will comprise: frequency distribution and Chi-square test for categorical variables; analysis of variance and Wilcoxon's rank test for continuous variables.

Multivariable analysis will be carried out through logistic regression analysis and survival analysis, taking into account the independent effects of potential confounders. Analyses to assess asthma phenotypes/endotypes and presence of risk factors clusters will be performed (i.e. cluster analysis, network analysis, principal component analysis) as well.

Analysis on cross-sectional and longitudinal data will be carried out. The longitudinal analysis will take into account a follow-up period of 6 and 12 months. For subjects already included in the online RItA Registry, a longer follow-up will be assessed (from 5 to 9 years).

Comparisons between the different phases of the study will permit to collect information about changes in asthma condition; in particular, the following statistical analysis will be carried out:

1. assessment of incidence and prevalence of severe/uncontrolled asthma and related risk factors in asthmatic cohorts;
2. comparison between different therapeutic approaches and related effectiveness in terms of asthma control, in the whole sample and taking into account comorbidity and polypharmacy;
3. assessment of possible risk factors for severe/uncontrolled asthma (i.e. demographic characteristics, environmental/occupational exposure, comorbidity) related to a different effectiveness of the therapeutic approach;
4. assessment of treatable traits related to different effectiveness of the therapeutic approach;
5. assessment of severe/uncontrolled asthma average indirect costs, in the whole sample and in specific subgroups of patients, in relation to gender, age, environmental exposures, comorbidity;
6. assessment of risk factors (i.e. demographic characteristics, environmental/occupational exposure, comorbidity) related to different disease prognosis;
7. characterization of specialist clinical setting and epidemiological setting in terms of risk factors exposure, therapeutic approaches and asthma control;
8. assessment of characteristics of new cases, enrolled from the epidemiological cohort and clinically confirmed, who have not been yet referred to clinical centres.

Ethical aspects: No issue about the safety of the protocol has to be forecasted, since all the protocol procedures are routine analyses for severe/uncontrolled asthma patients.

Study subjects will not undergo any risk for their physical or psychological domains, as they will perform questionnaire interview and a regular medical examination under safe procedures.

According to the General Data Protection Regulation (GDPR 25 May 2018), informed consent for data collection and analysis will be requested to the subjects involved in the study.

Eligibility Criteria:
Inclusion Criteria

1. Observational longitudinal study in hospital specialist centres (clinical sample) Target population consists of asthmatic adult patients managed by clinical centres in Pisa (Unit of Pulmonology, Cardio-Thoracic and Vascular Department), Perugia (Section of Occupational Medicine, Respiratory Diseases and Toxicology, Medicine Department), Ancona (Unit of Allergology, Internal Medicine Department).

   In particular, the eligible patients for RISER study are:
   1. clinical cases of severe/uncontrolled asthma already included in the online RItA Registry (number: 244 total; n=75 Pisa; n=114 Perugia; n=55 Ancona)
   2. new clinical cases of severe/uncontrolled asthma attending the clinical centres and not yet included in the online RItA Registry, with the following characteristics: adult subjects with a diagnosis of asthma since at least one year with a) uncontrolled asthma, despite regular treatment with GINA step 4 level, in the last three months or b) controlled asthma with a step 5 level treatment according to GINA. The expected number will be of 115 in total: n=50 Pisa; n=35 Perugia; n=30 Ancona.
2. Observational longitudinal study in a general population sample (epidemiological sample) Target population consists of adults suffering from asthmatic symptoms or having an asthma diagnosis within a general population sample investigated in three subsequent cross-sectional surveys in Pisa (the 1st survey (PI1) performed in 1985-1988 on 3865 subjects; the 2nd survey(PI2) in 1991-1993 on 2841 subjects; the 3rd survey (PI3) in 2009-2011 on 1620 subjects).

In particular, the eligible subjects for RISER study are:

1. epidemiological cases of severe/uncontrolled asthma from Pisa cohort already inserted in the online RItA Registry (n=160)
2. new epidemiological cases of severe/uncontrolled asthma from pre-existing Pisa cohort not yet included in the online RItA Registry, with the following characteristics: adult subjects with at least one asthma attack in the last 12 months or wheezing and/or asthma therapy in the last 12 months. The expected number, on the basis of the severe/uncontrolled asthma prevalence obtained in previous studies, is 34.

Exclusion Criteria

1. subjects of age \< 18 yrs
2. subjects unable to participate in the study or to sign the consent form
3. subjects refusing to fill in the consent form
4. untraceable subjects (for the epidemiological sample)

No other specific exclusion criterion will be considered, in order to capture all potential variables influencing severe/uncontrolled asthma outcomes in real life.