Real-life Ecological Momentary Assessment of Lived Burden in Hereditary AngioEdema (REAL-HAE)

The aim of this study is to conduct an in-depth analysis of the Burden of Disease (BoD) perceived by patients with Hereditary Angioedema (HAE), through daily prospective observations based on Ecological Momentary Assessment (EMA) via digital surveys and standardised questionnaires.

Participants will answer online survey questions about their perceived burden of disease for 8 consecutive weeks. The main hypothesis is that daily prospective observation (EMA) will reveal a higher and more fluctuating burden of disease compared to traditional retrospective scales, providing a more accurate representation of the impact of HAE on patients' daily lives.

Study Overview

• Status: Recruiting
• Conditions: Hereditary Angioedema With C1 Esterase Inhibitor Deficiency; Hereditary Angioedema - Type 1; Hereditary Angioedema - Type 2
• Intervention / Treatment: Other: ecological momentary assessment

Detailed Description

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent attacks of non-pruritic edema, localized at the subcutaneous, submucosal, and visceral levels. These attacks, caused by a temporary and localized increase in vascular permeability mediated by bradykinin, can affect the skin, gastrointestinal tract, face, genitals, and upper airways, resulting in a risk of asphyxiation. The most common forms of HAE are Type 1 (85-90%), caused by a quantitative deficiency of C1-inhibitor (HAE-C1INH-Type1), and Type 2 (10-15%), due to a qualitative dysfunction of the same (HAE-C1INH-Type2). In Italy, the overall prevalence is estimated at approximately 1:65,000.

HAE attacks occur unpredictably, with an average frequency that is highly heterogeneous between subjects, ranging on average from 1 to 26 episodes per year; some severe cases can reach 100 attacks per year. These manifestations have an average duration of about 2-5 days and are often debilitating, significantly compromising quality of life (QoL) and the subject's functional abilities. The impact of the disease is not limited to the presence, duration, or frequency of attacks but persists during intercritical periods, often accompanied by anticipatory anxiety and a constant sense of vulnerability, which can lead to a state of hypervigilance.

Numerous studies describe the Burden of Disease (BoD) as multidimensional. The impact on QoL concerns physical, psychological, social, and professional dimensions. From a psychological and emotional perspective, many HAE patients report high levels of stress, anxiety, and depressive symptoms, often linked to the unpredictability of attacks and the perception of poor control over their condition. Furthermore, despite therapeutic progress, the potential risk of fatal laryngeal edema remains a significant source of concern for many patients, contributing to a persistent emotional burden.

At the professional level, a reduction in productivity is observed due to both absenteeism and presenteeism, with European studies documenting an average of up to 20 days lost per year between school and work. Finally, on a social level, some patients report experiences of stigmatization or discrimination, with a negative impact on relational well-being and social integration.

Until now, BoD in HAE has been assessed primarily through retrospective questionnaires and standardized measures administered at single time points, such as the Angioedema Quality of Life (AE-QoL), the Angioedema Activity Score (AAS), or the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH). While validated and widely used, these instruments present several methodological limitations. In particular, they rely on subjective estimates reported within more or less broad time windows (e.g., the last two weeks or the previous month) and are therefore susceptible to recall bias, the mnemonic distortion in the reconstruction of past experiences. Moreover, these tools are developed to provide a static snapshot of subjective BoD, which may fail to capture the dynamic trends and the intra- and inter-individual fluctuations typical of the HAE experience, especially concerning emotional, social, or symptomatic events occurring in daily life.

In light of these considerations, this study will apply the Ecological Momentary Assessment (EMA) method. This is an innovative observational data collection method that allows for the repeated collection of self-report data over time through brief questionnaires sent to the participant's smartphone at specific and/or random moments of the day. EMAs are based on simple, intuitive, and quick items, similar to those found in traditional psychometric tools, but administered multiple times over time and within the context of the patient's real life.

This approach offers a twofold advantage:

1. It reduces recall bias, as the person is prompted to respond in real-time or in close temporal proximity to the experience.
2. It allows for the collection of data with high ecological validity, meaning data that is relevant to the subject's behavior and experience in their natural environment.

This allows for a more precise exploration of the characteristics that constitute BoD in HAE and, consequently, the daily impact of the disease. The present protocol aims to analyze in depth the Burden of Disease (BoD) perceived by HAE patients through daily and prospective observation based on EMAs and standardized scales.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20138
    • Recruiting
    • Istituti Clinici Scientifici Maugeri, Milan, Milan 20138
    • Contact: Francesca Perego, MD, PhD; Phone Number: +39 0250725239; Email: francesca.perego@icsmaugeri.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study involves the participation of adult patients with a confirmed diagnosis of hereditary angioedema, belonging to the ITACA (Italian Network for Hereditary and Acquired Angioedema) national cohort and receiving follow-up care at the IRCCS Maugeri Milano (Via Camaldoli) center. Participation in the study is voluntary and subject to the signing of informed consent. Patients will complete the questionnaires independently via their own smartphones, with no requirement for in-person visits.

Description

Inclusion Criteria:

• Confirmed diagnosis of Type 1 or Type 2 hereditary angioedema;
• Age ≥ 18 years;
• Ability to understand instructions and provide informed consent;
• Ownership and proficiency in using a personal smartphone compatible with the m-Path application (Android or iOS);
• Willingness to participate in the study for the entire duration of the observation period (8 weeks).

Exclusion Criteria:

• Diagnosis of acquired angioedema or other forms of angioedema unrelated to C1-inhibitor deficiency;
• Severe cognitive or psychiatric disorders that compromise the ability to complete the questionnaires independently;
• Age < 18 years;

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emotional Burden via Ecological Momentary Assessment (EMA)	Evaluation of emotional states (anxiety, mood, stress, and fear of attacks) through a Visual Analogue Scale (VAS). Each item is scored on a range from 0 to 100, where 0 indicates "no emotional impact" and 100 indicates "maximum emotional distress.	Every other day for 8 weeks
Socio-occupational Impairment via Ecological Momentary Assessment (EMA)	Assessment of the impact of Hereditary Angioedema (HAE) on daily, social, and professional activities. Measured via a scale ranging from 1 to 10, where 1 indicates "no impairment" and 10 indicates "maximum perceived impairment"	Every other day for 8 weeks
Disease Activity	Assessment of the physical burden using the Angioedema Activity Score (AAS): A daily symptom diary, total score from 0 to 15.	AAS is collected every other day for 8 weeks
Angioedema Quality of Life	Assessment of quality of life impairment using the AE-QoL questionnaire. The total score ranges from 17 to 85, where higher scores indicate greater impairment.	After 4 weeks and at the end of the 8 weeks
Disease Control	Assessment of disease control using the AECT. The total score ranges from 0 to 16, where lower scores indicate poorer disease control.	After 4 weeks and at the end of the 8 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anxiety and Depressive Symptoms	Measured via the Patient Health Questionnaire-4 (PHQ-4), a 4-item screening scale for anxiety and depression. Each item is scored from 0 to 3. The total score ranges from 0 to 12, where higher scores indicate more severe symptoms of anxiety and depression.	Every other week for 8 weeks
Work Productivity and Activity Impairment (WPAI:GH)	The WPAI:GH measures the impact of health problems on work productivity and daily activities. It yields four scores: absenteeism, presenteeism, overall work impairment, and activity impairment. Results are expressed as percentages (0-100%), where higher percentages indicate greater impairment.	Once a week for 8 weeks
Within-person Variability of Emotional States (EMA)	Calculated as the standard deviation or Mean Successive Difference (MSSD) of the daily emotional VAS scores (0-100) collected via EMA over the 8-week period. This measures the "fluctuations" of the patient's emotional state.	Every other day for 8 weeks
Difference in Burden of Disease between LTP and ODT groups	Comparison of the mean Burden of Disease (BoD) scores across all dimensions (physical, emotional, socio-occupational) between patients receiving Long-Term Prophylaxis (LTP) and those receiving On-Demand Treatment (ODT).	8 weeks
Correlation between EMA scores and Traditional Questionnaires	Comparison between the real-time daily scores (EMA) and the retrospective scores (AE-QoL, WPAI:GH, PHQ-4) to measure the difference in patient perception of disease burden.	8 weeks

Collaborators and Investigators

• Sponsor: Istituti Clinici Scientifici Maugeri SpA

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2026
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: February 26, 2026
• First Submitted That Met QC Criteria: March 3, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Quality of Life; Hereditary Angioedema; Ecological Momentary Assessment; Burden of disease
• Additional Relevant MeSH Terms: Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immunologic Deficiency Syndromes; Skin Diseases; Urticaria; Skin Diseases, Vascular; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Angioedema; Angioedemas, Hereditary; Behavioral Disciplines and Activities; Psychological Tests; Ecological Momentary Assessment
• Other Study ID Numbers: 2025-3.11/388

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No