Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: findings from the COMPACT open-label extension study

William R Lumry, Bruce Zuraw, Marco Cicardi, Timothy Craig, John Anderson, Aleena Banerji, Jonathan A Bernstein, Teresa Caballero, Henriette Farkas, Richard G Gower, Paul K Keith, Donald S Levy, H Henry Li, Markus Magerl, Michael Manning, Marc A Riedl, John-Philip Lawo, Subhransu Prusty, Thomas Machnig, Hilary Longhurst, on behalf of the COMPACT Investigators, William R Lumry, Bruce Zuraw, Marco Cicardi, Timothy Craig, John Anderson, Aleena Banerji, Jonathan A Bernstein, Teresa Caballero, Henriette Farkas, Richard G Gower, Paul K Keith, Donald S Levy, H Henry Li, Markus Magerl, Michael Manning, Marc A Riedl, John-Philip Lawo, Subhransu Prusty, Thomas Machnig, Hilary Longhurst, on behalf of the COMPACT Investigators

Abstract

Background: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.

Results: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within "normal" range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], - 1.23 [- 2.08, - 0.38]), HADS depression scale (- 0.95 [- 1.57, - 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], - 23.33% [- 34.86, - 11.81]), work productivity loss (- 26.68% [- 39.92, - 13.44]), and activity impairment (- 16.14% [- 26.36, - 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135.

Conclusions: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://ichgcp.net/clinical-trials-registry/NCT02316353 .

Keywords: Anxiety; C1-inhibitor protein; Depression; HAEGARDA; Health-related quality of life; Hereditary angioedema; Patient-reported outcomes; Productivity; Subcutaneous.

Conflict of interest statement

W Lumry is a consultant for Adverum, Attune, BioCryst, CSL Behring, Kalvista, Pharming, and Takeda; a speaker for CSL Behring, Pharming, and Takeda; and has received research grants from BioCryst, CSL Behring, Pharming, Ionis, and Takeda. B Zuraw has served as a consultant for Adverum, Attune, BioCryst, CSL Behring, and Takeda. M Cicardi was a PI, consultant, and speaker for CSL Behring, Shire/Takeda, and Pharming; a consultant PI for BioCryst, Kalvista, Attune, and Pharvaris; and conducted research with Pharming and Shire/Takeda. T Craig is a consultant and speaker for CSL Behring, Shire/Takeda, Spark, and Pharming; has conducted research for CSL Behring, Shire/Takeda, Ionis, and BioCryst; and is on the Medical Advisory Board for the HAEA, Board of Directors for the AAAAI and the Board of Directors for ALA- Mid Atlantic. J Anderson is a PI, consultant, and speaker for CSL Behring, Shire/Takeda, and Pharming and a PI for BioCryst. A Banerji conducted research with Shire/Takeda, BioCryst and served as a consultant for Shire/Takeda, BioCryst, Pharming, CSL, and Kalvista. JA Bernstein is a PI, consultant, and speaker for CSL Behring, Shire/Takeda, and Pharming; a consultant and PI for BioCryst; and a consultant for Kalvista. T Caballero is a speaker for CSL Behring, Merck, Novartis, and Shire/Takeda; consultant for BioCryst, CSL Behring, Novartis, Octapharma, Pharming, and Shire/Takeda; she has been a PI in clinical trials/registries for BioCryst, CSL Behring, Novartis, Pharming, and Shire/Takeda; she has received educational funding from CSL Behring, Novartis, and Shire/Takeda; and she is a researcher from the IdiPAZ program for promoting research activities. H Farkas has received honoraria, speaker fees, and travel grants from CSL Behring, Shire/Takeda, Swedish Orphan Biovitrum, and Pharming and/or served as a consultant for these companies and has participated in clinical trials/registries for BioCryst, CSL Behring, Pharming, and Shire/Takeda. RG Gower has conducted research with Shire/Takeda and BioCryst; he has served as a consultant with Shire/Takeda and CSL Behring; is on the advisory board for Shire/Takeda, BioCryst, and Fresenius Kabi; and he has received speakers’ fees from Shire/Takeda. PK Keith has conducted research with, served as a consultant for, and has received speakers’ fees from Shire/Takeda and CSL Behring. DS Levy has served as a consultant, speaker, and has received research grants from CSL Behring; he has served as a consultant for BioCryst; he has served as a speaker for Takeda. HH Li has conducted research with and has served as a consultant/received speakers’ fees from Shire/Takeda, BioCryst, and CSL Behring; he has served as a consultant/received speakers’ fees from Pharming. M Magerl is a PI, consultant, and/or speaker for CSL Behring, BioCryst, Kalvista, Shire/Takeda, and Pharming. M Manning is a researcher/PI and speaker/consultant at CSL Behring, Shire/Takeda, BioCryst, and Pharming. M Riedl is a research investigator with CSL Behring, Takeda, BioCryst, and Ionis; he has served as a consultant for CSL Behring, Takeda, BioCryst, Pharming, Adverum, Attune, Kalvista, and Pharvaris; and he has received speakers’ fees from CSL Behring, Takeda, and Pharming. J-P Lawo, S Prusty, and T Machnig are/were employees of and stockholders at CSL Behring during study conduct. H Longhurst served as a consultant for, participated in research with or accepted educational funding support from Adverum, BioCryst, CSL Behring, GSK, Kalvista, Pfizer, Pharming, Pharvaris, and Shire/Takeda.

Figures

Fig. 1
Fig. 1
COMPACT open-label study design and timing of HRQoL assessments. AE-QoL Angioedema Quality of Life Questionnaire, C1-INH(SC) subcutaneous C1-inhibitor, EQ-5D European Quality of Life-5 Dimensions Questionnaire, HADS Hospital Anxiety and Depression Scale, HAE-QoL Hereditary Angioedema Quality of Life Questionnaire, HRQoL health-related quality of life, TSQM Treatment Satisfaction Questionnaire for Medication, TP treatment period, US United States, WPAI Work Productivity and Activity Impairment Questionnaire
Fig. 2
Fig. 2
Mean intra-subject change from baseline (95% CI) in patient-reported outcomes, baselinea to end of studyb. Note Mean and 95% CI values can be found in Additional file 1. aBaseline was visit 1 (week 1) of the open-label study. bFinal visit (week 53 or extension period week 88 for subjects who participated in the extension period). C1-INH(SC) subcutaneous C1-inhibitor, CI confidence interval, EQ-5D European Quality of Life-5 Dimensions Questionnaire, HADS Hospital Anxiety and Depression Scale, TSQM Treatment Satisfaction Questionnaire for Medication, WPAI Work Productivity and Activity Impairment Questionnaire, CI confidence interval
Fig. 3
Fig. 3
Percentages of patients using C1-INH(SC) who demonstrated minimal clinically important difference (MCID) improvements from baseline to end-of-study. C1-INH(SC) subcutaneous C1-inhibitor, EQ-5D European Quality of Life-5 Dimensions Questionnaire, HADS Hospital Anxiety and Depression Scale, TSQM Treatment Satisfaction Questionnaire for Medication, WPAI Work Productivity and Activity Impairment Questionnaire
Fig. 4
Fig. 4
Published mean AE-QoL (a) and HAE-QoL (b) scores in different patient cohorts. C1-INH(SC) subcutaneous C1-inhibitor, ext extension, HAE hereditary angioedema, HRQoL health-related quality of life, pdC1-INH(IV) plasma-derived intravenous C1-INH, TXA tranexamic acid. Note Mean scores for individual domains for the AE-QoL and HAE-QoL are presented in Additional file 6 and Additional file 8. SC subcutaneous, C1-INH C1-inhibitor, C1-INH(IV) intravenous C1-INH, RhUPH20 recombinant human hyaluronidase, AE-QoL Angioedema Quality of Life Questionnaire, HAE-QoL hereditary Angioedema Quality of Life Questionnaire

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