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Indirect comparison of intravenous vs. subcutaneous C1-inhibitor placebo-controlled trials for routine prevention of hereditary angioedema attacks.

ABSTRACT: Introduction:For prophylaxis of hereditary angioedema (HAE) attacks, replacement therapy with human C1-inhibitor (C1-INH) treatment is approved and available as intravenous [C1-INH(IV)] (Cinryze®) and subcutaneous [C1-INH(SC)] HAEGARDA® preparations. In the absence of a head-to-head comparative study of the two treatment modalities, an indirect comparison of data from 2 independent but similar clinical trials was undertaken. Methods:Two similar randomized, double-blind, placebo-controlled, crossover studies were identified which evaluated either C1-INH(SC) (COMPACT; NCT01912456; 16 weeks) or C1-INH(IV) (CHANGE; NCT01005888; 14 weeks) vs. placebo (on-demand treatment only) for routine prevention of HAE attacks. Individual patient data from each trial were used to conduct an indirect comparison of treatment effects. Attack reductions (absolute and percent of mean/median number of monthly HAE attacks reduction over placebo) were compared between the two C1-INH formulations at approved/recommended doses: C1-INH(SC) 60 IU/kg twice weekly (n?=?45) and 1000 U of C1-INH(IV) twice weekly (n?=?22). Point estimates were adjusted using mixed and quantile regression models that controlled for study design. Results:The absolute mean monthly numbers of HAE attack reductions were 3.6 (95% CI 2.9, 4.2) for C1-INH(SC) 60 IU/kg vs. placebo and 2.3 (1.4, 3.3) for C1-INH(IV) vs. placebo; between-product difference, 1.3 (0.1, 2.4; P?=?0.034). The mean percent reduction in monthly attack rate was significantly greater with C1-INH(SC) as compared with C1-INH(IV) (84% vs. 51%; P?

SUBMITTER: Bernstein JA

PROVIDER: S-EPMC6407188 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:BackgroundHereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA®, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported.MethodsThis is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response.ResultsSubgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect.ConclusionsC1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden.Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.

Project description:BackgroundHereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.MethodsInformation collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.ResultsForty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 10(9)/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 10(9)/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77 ± 33 versus 29 ± 65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.ConclusionsHAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.Trials registrationThe data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

Project description:ImportanceCurrent treatments for long-term prophylaxis in hereditary angioedema have limitations.ObjectiveTo assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.Design, setting, and participantsPhase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.InterventionsTwenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.Main outcome and measuresPrimary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.ResultsAmong 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).Conclusions and relevanceAmong patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.Trial registrationEudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

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Indirect comparison of intravenous vs. subcutaneous C1-inhibitor placebo-controlled trials for routine prevention of hereditary angioedema attacks.

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