Background
Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1‐INH‐HAE) by reducing the frequency of ...angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS‐2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo.
Methods
OPuS‐2 was a Phase 3, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator‐confirmed attacks.
Results
A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack‐free during the 84‐day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE‐QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated.
Conclusions
Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1‐INH‐HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.
Background
Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long‐term prophylaxis with twice‐weekly ...intravenous injections of plasma‐derived C1‐inhibitor (pdC1‐INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1‐INH has not been studied in patients with HAE.
Methods
This open‐label, dose‐ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice‐weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume‐reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1‐INH functional activity, C1‐INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model‐derived steady‐state trough C1‐INH functional activity.
Results
After SC CSL830 administration, a dose‐dependent increase in trough functional C1‐INH activity was observed. C1‐INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1‐INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1‐INH SC injection with CSL830 showed a lower peak‐to‐trough ratio and more consistent exposures. All doses were well tolerated. Mild‐to‐moderate local site reactions were noted with pain and swelling being the most common adverse event.
Conclusions
Subcutaneous volume‐reduced CSL830 was well tolerated and led to a dose‐dependent increase in physiologically relevant functional C1‐INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation.
The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1‐INH deficiency (C1‐INH‐HAE) represent one of the oldest unsolved problems of the disease. ...Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12‐46C/T in disease phenotype. We studied 258 C1‐INH‐HAE patients from 113 European families, and we explored possible associations of F12‐46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within‐subject correlation. F12‐46C/T carriers exhibited a significantly delayed disease onset (P < 0.001) and did not need long‐term treatment (P = 0.02). In a GEE linear regression model, the presence of F12‐46C/T was significantly associated with a 7‐year delay in disease onset (P < 0.0001) regardless of SERPING1 mutational status. It is concluded that F12‐46C/T carriage acts as an independent modifier of C1‐INH‐HAE severity.
Summary
Background Chronic urticaria (CU), one of the most common skin disorders, is characterized by spontaneous recurrent bouts of weals and pruritus and associated with severely impaired quality ...of life (QoL).
Objectives To determine what aspects of life quality are affected and to characterize the factors that impact on QoL in CU patients.
Subjects and methods This interdisciplinary interview/questionnaire‐based study included 100 patients admitted to a University Hospital Dermatology Department for the identification of underlying causes of CU; 96 healthy subjects matched for age and sex were used as controls. QoL was assessed using Skindex‐29, a validated instrument to measure the effects of skin disease on overall QoL (composite score) and three defined QoL aspects (emotions, symptoms, functioning).
Results CU patients exhibited markedly reduced overall QoL compared with healthy control subjects. CU had distinct effects on the three QoL aspects assessed (functioning = emotions > symptoms). The age or sex of patients, the absence or presence of angio‐oedemas, and the duration or cause of CU did not significantly influence QoL impairment. Interestingly, psychiatric comorbidity (depression, anxiety, somatoform disorders) was associated with a more pronounced reduction of QoL compared with CU patients without a psychiatric diagnosis and the severity of psychiatric disease was found to correlate with QoL impairment.
Conclusions Our data confirm that overall QoL is markedly reduced in CU patients. Social functioning and emotions were found to be the areas of QoL most affected in CU patients. Psychiatric comorbidity significantly increased QoL impairment, whereas QoL in CU patients was not significantly affected by age or sex, the absence or presence of angio‐oedema, or the course or cause of CU.
At an international hereditary angioedema (HAE) expert meeting, results from a survey were used to guide discussion on how best to advise patients on self-administering intravenous C1 esterase ...inhibitor therapy. Treatment differences across Europe were highlighted, together with the practicalities of self-administration and useful resources for patients in the future. The international HAE experts noted an increase in the uptake of self-administration, with patients being trained by nursing staff. All patients who are willing and able to self-administer should be offered this treatment option and patients should be encouraged to treat attacks early. Several initiatives were suggested regarding support for patients who self-administer therapy, including a 24-hour helpline and home care agencies.
Summary
Background
Hereditary angio‐oedema (HAE), C1 inhibitor HAE (C1‐INH‐HAE) type I and C1‐INH‐HAE type II, are inherited disorders characterised by potentially life‐threatening recurrent ...swellings, caused by a deficiency of C1 inhibitor. Management includes attack treatment or prevention using prophylaxis/routine prevention.
Aim
To evaluate the success of self‐administration training as part of a home care programme for treatment of HAE using intravenous C1 inhibitor.
Methods
In total, 18 patients (7 men, 11 women; aged 18–72 years) were trained to self‐administer a plasma‐derived C1 inhibitor concentrate for acute treatment or routine prevention of HAE attacks. The number of training sessions needed to learn intravenous self‐administration, delay in time to treatment and reduction in attack frequency (per month) were evaluated after completion of the training.
Results
All patients successfully completed training. The median number of training sessions required to be capable of unassisted/independent self‐injection was 5 (range 2–30). Time to treatment was reduced from a median of 4.5 h (270 min) by medical professionals to 15 min by patients after self‐administration training). Using the treatment as routine prevention resulted in a reduction of median frequency of attacks from 8 to 0.5 attacks/month.
Conclusion
C1 inhibitor self‐administration for the treatment of HAE allows patients to quickly treat attacks at home, potentially reducing attack severity. The results also demonstrate the benefit of self‐administered routine prevention therapy in a real‐world patient population. Self‐administered therapy potentially allows patients to gain greater control over their attacks, resulting in a reduction in healthcare utilization.
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