Abstract
Background: Hereditary angioedema (HAE) is a rare, debilitating, potentially life-threatening condition characterized by recurrent acute attacks of edema of the skin, face/upper airway, and gastrointestinal and urogenital tracts. During a laryngeal attack, people with HAE may be at risk of suffocation, while other attacks are often associated with intense pain, disfigurement, disability, and/or vomiting. The intensity of some symptoms is known only to the person experiencing them. Thus, interview studies are needed to explore such experience and patient-reported outcome measures (PROMs) are required for systematic assessment of symptoms in the clinical setting and in clinical trials of treatments for acute HAE attacks.
Objective: The aim of this interview study was to assess the content validity and suitability of four visual analog scale (VAS) instruments for use in clinical studies. The VAS instruments were designed to assess symptoms at abdominal, oro-facial-pharyngeal-laryngeal, peripheral, and urogenital attack locations. This is the first known study to report qualitative data about the patient’s experience of the rare disorder, HAE.
Methods: Semi-structured exploratory and cognitive debriefing interviews were conducted with 27 adults with a confirmed clinical/laboratory diagnosis of HAE (baseline plasma level of functional plasma protein C1 esterase inhibitor [C1INH] <50% of normal without evidence for acquired angioedema). There were 17 participants from the US and 10 from Italy, with mean age 42.5 (SD 14.5) years, range 18–72 years, mean HAE duration 21.3 (SD 14.1) years, range 1–45 years, 67% female, and 44% VAS-naïve. Experience of acute angioedema attacks was first explored, noting spontaneous mentions by participants of HAE symptomatology. Cognitive debriefing of the VAS instruments was undertaken to assess the suitability, comprehensibility, and relevance of the VAS items. Asymptomatic participants completed the VAS instruments relevant to their angioedema experience, reporting as if they were experiencing an acute angioedema attack at the time. Interviews were conducted in the clinic setting in the US and Italy over an 8-month period.
Results: Participants mentioned spontaneously almost all aspects of acute angioedema attacks covered by the four VAS instruments, thus providing strong support for inclusion of nearly all VAS items, with no important symptoms missing. Predominant symptoms found to be associated with acute angioedema attacks were edema and pain, and there was evidence of varying degrees of disruption to everyday activities supporting the inclusion of an overall severity item reflecting the disabling effects of HAE symptoms. VAS item wording was understood by participants.
Conclusion: This interview study explored and reported the patient experience of HAE attacks. It demonstrated the content validity of the four anatomical location HAE VAS instruments and their suitability for use in clinical trials of recombinant human C1INH (rhC1INH) treatment for ascertaining trial participants’ assessments of the severity of acute angioedema symptoms.
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Notes
Where participants speak spontaneously about a subject (e.g. use a particular term to describe a symptom) without prior prompting.
HAE is a rare condition and recruiting patients who had not previously participated in any HAE research or not completed a VAS instrument would prove to be very difficult.
The Appendix, available as Supplemental Digital Content (SDC), http://links.adisonline.com/PBZ/A36, contains the full US and Italian VAS instruments.
Nessun danneggiato/estremamente disabilitanti (Peripheral VAS instrument) versus Nessun sintomo/estremamente disabilitanti (Abdominal, OFPL, and Urogenital VAS instruments).
Forward translation into Italian by a native Italian speaker, followed by two back translations into English (performed by certified translators specializing in medical translations who were fluent in Italian and whose mother tongue was English); checks for discrepancies; and then production of final versions.
Reference to VAS items includes their respective response options unless otherwise stated.
The US sample of 17 patients was representative in terms of socio-demographic characteristics given the rarity of the HAE condition. Age range was 18–67 years. Thirteen participants (76.5%) were women; four (23.5%) were men. The majority of participants (n = 13; 76%) were Caucasian. Two (12%) were Black, one person was of Asian origin, and one other described himself as ‘White (Mexican/German).’ The majority of participants (n = 9; 52.9%) had the equivalent of college education or less but a further six participants (47%) had at least university-level education (Bachelor’s or advanced degree). Ten (59%) were employed, three (18%) were students in full-time higher education, one was self-employed, one was unemployed, one was a homemaker/carer, and one was retired. The overall preponderance of women in the US sample was not unusual in HAE studies:[19] women tend to experience more acute angioedema attacks, perhaps due to hormonal factors.[20] The Italian sample of ten patients was representative given the small size of the sample and rarity of the condition. Equal numbers of males and females were enrolled, with a range in age (33–72 years), education, cultural, and occupational backgrounds (with five not employed), and with variation in ethnicity (Caucasian, 60% and other unspecified, 40%).
There is a higher proportion of people with experience of urogenital attacks in this study than is generally found because we wanted to ensure that most participants would be able to discuss attacks in all locations.
Wording of both US and Italian VAS instruments is shown in the Appendix (SDC), but only the US wording is shown here for ease of reference.
Both terms in Italian have the same root (gonfiarsi/gonfio).
This might be because the Italian male (as in quanto male sente? = how ill do you feel?) has multiple interpretations in Italian: ill, evil, pain, or harm.
See figure S1 in the SDC.
Given the frequency and severity of HAE attacks, recall was not expected to be problematic, as diabetes mellitus studies have noted that recall of severe hypoglycemic events (of similar magnitude and distress to HAE attacks) is robust up to 1 year or more.[23]
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Acknowledgments
This study and manuscript preparation were funded by Pharming Technologies BV who were involved in the design and conduct of the study, and the review and approval of the manuscript.
CVM is a Consultant Health Psychologist at AHP Research and JS is Director of Research at AHP Research, an independent research company that received funding from Pharming to conduct this study and received consultancy fees related to contributions to other aspects of Pharming’s clinical studies. AR is a Medical Director at Pharming Technologies BV and has also received stock options in the company. GH is an independent consultant who was engaged by Pharming and received fees and expenses from the study sponsor throughout the conduct and reporting of the study. MC has or has had consultancy agreements with Pharming, Jerini, and Dyax and is on the advisory board for Jerini/Shire, CSL Behring, Pharming, Viro Pharma, and Dyax. Università degli Studi di Milano (= The University of Milan) received a payment from Pharming for performing the study. LB has a consultancy agreement with Pharming for running research and development activities.
The authors acknowledge valuable assistance from staff at all clinics (Family Allergy & Asthma Center P.C., Atlanta, GA, USA; Asthma, Allergy & Immunology Clinical Research Unit, Tampa, FL, USA; Allergy, Asthma & Immunology Clinic P.A., Irving, TX, USA; and Dipartimento di Scienze Cliniche “Luigi Sacco,” Ospedale Luigi Sacco, Milan, Italy) where people with HAE were recruited and interviews carried out. The authors thank Adele Succetti for conducting the interviews in Italy and all 27 participants for sharing their experiences and insights into HAE and contributing their time to aid our understanding of this condition.
GH and AR conceived the need for the interview study, which was designed by JS, CVM, AR, and GH and coordinated by CVM. MC reviewed the study protocol. JS and CVM conducted the interviews in the US and LB coordinated the interviews in Italy. CVM and JS analyzed the data and wrote the report upon which this manuscript is based. CVM drafted the manuscript, JS and AR contributed to the manuscript development, and all authors read and approved the final manuscript. CVM is the guarantor of the overall content of this article.
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Key points for decision makers
• In this interview study, participants spoke of the often severe and distressing symptoms associated with a hereditary angioedema (HAE) attack, including (depending on the attack location) pain, swelling and associated disfigurement, vomiting, and difficulty breathing, and their debilitating impact on everyday activities
• There was strong support for inclusion of nearly all the visual analog scale (VAS) items in the four attack location patient-completed instruments, with no important symptoms missing; VAS items were comprehensible to participants
• The four VAS instruments have good content validity and are considered suitable for use in clinical trials of recombinant human C1 esterase inhibitor (rhC1INH) treatment for ascertaining participants’ assessments of the severity of acute angioedema symptoms
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McMillan, C.V., Speight, J., Relan, A. et al. Content Validity of Visual Analog Scales to Assess Symptom Severity of Acute Angioedema Attacks in Adults with Hereditary Angioedema. Patient 5, 113–126 (2012). https://doi.org/10.2165/11597490-000000000-00000
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DOI: https://doi.org/10.2165/11597490-000000000-00000