Reference - COMPACT trial (N Engl J Med 2017 Mar 23;376(12):1131) (level 1 [likely reliable] evidence)
- Hereditary angioedema, characterized by recurrent angioedema attacks due to impaired C1 inhibitor protein activity, can be disabling and, potentially, fatal. Practical long-term prophylactic therapies that reduce attack frequency with minimal adverse events are needed.
- In the COMPACT trial, 90 patients ≥ 12 years old with hereditary angioedema were randomized to self-administered C1 inhibitor CSL830 subcutaneous injection twice weekly vs. placebo for 16 weeks followed by crossover to the other treatment for 16 weeks. CSL830 doses of 40 units/kg and 60 units/kg were investigated.
- CSL830 40 units/kg compared to placebo reduced the frequency of angioedema attacks (1.19 vs. 3.61 attacks/month), need for rescue medication (1.13 vs. 5.55 uses/month), and days with symptoms (1.57 vs. 7 days/month). Consistent results were observed with CSL830 60 units/kg.
Hereditary angioedema is an uncommon chronic condition characterized by impaired C1 inhibitor protein activity causing recurrent angioedema attacks unresponsive to antihistamines, epinephrine, or steroids (J Allergy Clin Immunol. 2013 Jun;131(6):1491, Lancet 2012 Feb 4;379(9814):474). The attacks can lead to disability lasting several days at a time and, potentially, death, depending on the location of swelling. On-demand medications to treat attacks are available, but swelling may take several hours to resolve. Long-term prophylactic therapies that reduce the frequency of attacks include oral steroids and antifibrinolytics, which may have significant adverse effects, and C1 inhibitor replacement therapy, which has good efficacy and safety but requires IV administration (J Allergy Clin Immunol. 2013 Jun;131(6):1491). To assess the efficacy of C1 inhibitor replacement with a more practical administration, 90 patients ≥ 12 years old (mean age 40 years) with types I or II hereditary angioedema were randomized in the COMPACT trial to 1 of 2 crossover groups. The first group was randomized to self-administered C1 inhibitor CSL830 40 units/kg subcutaneous injection twice weekly vs. placebo for 16 weeks, followed by crossover to other treatment for 16 weeks without a washout. The second group followed the same design except had CSL830 dose 60 units/kg. All patients had ≥ 4 attacks over 2 months within the previous 3 months and were allowed treatment, including IV C1 inhibitor replacement, as rescue medication or preprocedure prophylaxis during the trial. The trial protocol was amended during enrollment to allow patients to continue with established stable prophylactic oral medication (in 42%), but patients were excluded for routine IV C1 inhibitor prophylaxis within the previous 3 months or planned use during the trial. Patients were also excluded for C1 inhibitory activity ≥ 50%, normal C4 antigen levels, features of acquired C1 inhibitor deficiency, history of poor response to C1 inhibitor therapy, and medication-refractory attacks. Efficacy assessment was based on patient-reported daily diaries, excluding the first 2 weeks of treatment periods to account for run-in/washout from the previous treatment. Eleven patients (12%) did not complete both treatment periods.
For patients allocated to CSL830 40 units/kg, the mean number of attacks per month was 1.19 while taking CSL830 vs. 3.61 with placebo (p< 0.001), with complete remission from attacks in 38% vs. 9% (statistical comparison not reported). The frequency of attacks while taking CSL830 40 units/kg was reduced by ≥ 50% compared to placebo in 76% of patients, and by ≥ 90% in 43%. While on CSL830 40 units/kg, the patients used rescue medications less frequently (mean 1.13 vs. 5.55 uses/month, p = 0.02) and had fewer days/month with symptoms (mean 1.57 vs. 7, statistical comparison not reported). CSL830 dose 60 units/kg had a greater benefit on most outcomes, but not significantly so. Adverse events were reported in 69% while on CSL830 (both doses) and 66% with placebo (statistical comparison not reported), and serious events included urosepsis in 1 patient with CSL830 and pulmonary embolism, angioedema, and syncope in 2 patients with placebo.
The COMPACT trial demonstrated that twice-weekly self-administered subcutaneous injections of the C1 inhibitor CSL830 decreases the frequency of angioedema attacks in patients ≥ 12 years old with types I or II hereditary angioedema, providing a potential prophylactic C1 inhibitor replacement option that is more practical than previous options. Additional studies are needed to assess long-term efficacy and safety, optimal dosing, treatment adherence among patients who do not choose to participate in a clinical trial, and comparisons with established long-term prophylactic options. Nonetheless, subcutaneous CSL830, when it becomes available, may be an option for long-term prophylactic therapy for types I or II hereditary angioedema.
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