Table 3.
Summary of clinical trials of C1-INH replacement therapy as short-term or long-term prophylaxis for HAE attacks.
| Therapy | Study and inclusion criteria | Treatments | Efficacy outcome(s) | Safety |
|---|---|---|---|---|
| pdC1-INH (Berinert) | Short-term prophylaxis | |||
| Farkas H, et al. (46) Retrospective analysis of pts with angioedema before HAE dx, and prospective analysis of the same pts after HAE dx receiving STP for medical procedures |
STP with pdC1-INH 500 IU IV pre-procedure (n = 137) 20 pediatric pts (mean age, 12.2 y; range, 2.2–17.3 y) 117 adults (mean age, 41.3 y; range, 18.5–81.2 y) |
HAE attacks decreased with pdC1-INH vs. pre-STP: 9% (5/54) vs. 58.7% (74/126) |
No tx-related AEs No discontinuations |
|
| Magerl M, et al. (47) Retrospective analysis of Berinert registry (US and Europe) 2010–2014 |
STP with pdC1-INH (median dose per infusion, 14.6 [range, 3.6–33.9] IU/kg or 1,000 [range, 500–3,500] IU) 79 patients (mean age, 42.4 y; range, 8–76 y) |
Cumulative HAE attack rate after STP (attacks per infusion): Within 1 d: 0.04 (95% CI, 0.015–0.088) Within 2 d: 0.06 (95% CI, 0.028–0.115) Within 3 d: 0.11 (95% CI, 0.061–0.174) |
6 AEs reported in 5/79 patients (6.3%), 2 (both headache) of which were considered tx related | |
| Long-term prophylaxis | ||||
| Bork K and Hardt J (52) Prospective observational study End December 2008 Pts with type I or II HAE (n = 19) Mean age at end of study: 51.8 y (range, 35–78) |
LTP with pdC1-INH IV ≥ once/wk Mean (SD) weekly dose: Tx onset: 1,253 U (641 U; range, 500–2,300 U) Tx end: 2,564 U (1,835 U; range, 500–7,000 U) Mean (SD) tx duration: 9 y (4.2); range, 4–19 y |
8/14 pts had fewer attacks with LTP 12 mo after starting tx vs. pre-LTP
Mean (SD) attacks/mo: beginning, 1.9 (0.8) vs. end, 9.7 (10.2) 1/14 pts discontinued after 5 y because of attacks |
Not reported | |
| Craig T, et al. (53) MC, observational patient registry (US and Europe) 2010–2014 47 pts w/mean age 44.8 y (range, 13–79 y) |
Total LTP duration for 47 pts: 430.2 mo Mean LTP duration: 9.2 mo/pt pdC1-INH IV dosing: Median absolute dose: 1,000 IU (range, 500–3,000 IU) |
Pts with ≥1 attack within 7 d of tx: 68.1% (32/47) HAE attack rates among pts receiving pdC1-INH: 5.2 attacks/pt 0.06 attacks/infusion 0.6 attacks/mo Interval between pdC1-INH administration and attack: Mean (SD): 73.7 h (32.5 h) Median (range): 72.0 h (0–166.4 h) |
Pts with ≥1 AE: 34.0% (16/47) Tx-related AEs: 3.7% (3/81)
|
|
| pdC1-INH (Cinryze) | Long-term prophylaxis | |||
| Zuraw BL, et al. (40) DB, PBO-C, crossover Pts ≥6 y with ≥2 HAE attacks/mo (moderate or severe attacks affecting abdomen, face, or external genitalia) |
Two consecutive 12-wk tx periods pdC1-INH 1,000 U/10 ml (n = 11) or PBO (n = 11) administered IV q3–4 d |
Mean number of HAE attacks during tx period (pdC1-INH vs. PBO): 6.3 vs. 12.7 (i.e., ∼2 vs. 4/mo) Mean difference in attack rates vs. PBO: 6.5 (95% CI, 4.2–8.7; P < 0.001) Mean (SD) duration of attacks (pdC1-INH vs. PBO): 2.1 (1.1) d vs. 3.4 (1.4); P = 0.002 |
AEs possibly related to pdC1-INH:
|
|
| Zuraw BL and Kalfus I (49) OL, single arm Pts ≥1 y with ≥1 HAE attack/month, or any laryngeal attack Mean age: 36.5 y (range 3–82) |
pdC1-INH 1,000 U administered IV q3–7 d at study site (n = 146) LTP duration up to 2.6 y |
Number of HAE attacks/mo at baseline vs. during the study: Mean (SD): 4.7 (5.2) vs. 0.5 (0.8) 90% decrease from baseline Median (IQR): 3 (2–4) vs. 0.19 (0.0–0.64) 93.7% decrease from baseline |
No AE-related study discontinuations 2 deaths not related to study drug (pulmonary arterial embolization of foreign material from IV injection of oral medication [n = 1]; HCC [n = 1]) 99/101 SAEs not related to pdC1-INH (2 of unknown relationship: musculoskeletal chest pain, major depression) |
|
| pdC1-INH (Haegarda) | Long-term prophylaxis | |||
| Longhurst H, et al. (50) COMPACT trial R, DB, PBO-C, crossover, ph 3 Pts ≥12 y with type I or II HAE w/ ≥4 attacks in 2-mo period ≤3 mo before screening Number of HAE attacks in 3 mo before screening, mean (SD): pdC1-INH 40 U/kg or 60 U/kg: 10.8 (6.7) or 8.8 (6.4) (i.e., ∼3 to 4/mo) |
Two 16 wk tx periods: pdC1-INH 40 IU/kg bw SC (n = 45), or pdC1-INH 60 IU/kg bw SC (n = 45), followed by PBO, or vice versa, administered twice weekly |
Number of HAE attacks per month: pdC1-INH 40 IU/kg (n = 43) vs. PBO (n = 44): 1.2 vs. 3.6 (P < 0.001; within-pt difference, −2.4) Mean/median decrease in attacks vs. PBO: 55%/89% pdC1-INH 60 IU/kg (n = 43) vs. PBO (n = 42): 0.5 vs. 4.0 (P < 0.001; within-pt difference, −3.5) Mean/median decrease in attacks vs. PBO: 84%/95% Pts with response (≥50% decrease in number of attacks with pdC1-INH 40 IU/kg or 60 IU/kg, vs. PBO): 76% or 90% Use of rescue medication/mo: pdC1-INH 40 IU/kg vs. PBO: 1.1 vs. 5.6 (P = 0.02; within-pt difference, −4.4) Mean/median decrease in use of rescue medication vs. PBO: 70%/89% pdC1-INH 60 IU/kg vs. PBO: 0.3 vs. 3.9 (P < 0.001; within-pt difference, −3.6) Mean/median decrease in use of rescue medication vs. PBO: 89%/100% |
pdC1-INH 40 IU/kg (n = 43) pdC1-INH 60 IU/kg (n = 43) PBO (n = 86) AEs with onset ≤24 h of administration
Injection-site reaction: 28% (n = 12), 35% (n = 15), vs. 24% (n = 21) Dizziness: 9% (n = 4), 0, vs. 1% (n = 1) Upper respiratory tract infection: 7% (n = 3), 7% (n = 3), vs. 7% (n = 6) Hypersensitivity: 5% (n = 2), 7% (n = 3), vs. 1% (n = 1) Nasopharyngitis: 2% (n = 1), 19% (n = 8), vs. 7% (n = 6) Fatigue: 2% (n = 1), 2% (n = 1), vs. 7% (n = 6) Back pain: 2% (n = 1), 2% (n = 1), vs. 6% (n = 5) |
|
| Craig T, et al. (51) OL extension of COMPACT trial R, OL, ph 3 December 2014–December 2017 Pts ≥6 y with type I or II HAE w/ ≥4 attacks in 2-mo period before enrollment into COMPACT trial or treatment-naïve pts Number of HAE attacks in 3 mo before screening, mean (SD): pdC1-INH 40 IU/kg: 12.8 (8.4) pdC1-INH 60 IU/kg: 12.7 (10.2) Overall, mean of 4.3 attacks/mo in the 3 mo before study entry |
pdC1-INH 40 IU/kg bw SC (n = 63) pdC1-INH 60 IU/kg bw SC (n = 63) |
745 HAE attacks (observation period of up to 2.7 y) Number of HAE attacks/mo (mean [SD]): pdC1-INH 40 IU/kg: 0.4 (0.7) pdC1-INH 60 IU/kg: 0.5 (0.9) Number of HAE attacks/y (median [range]): pdC1-INH 40 IU/kg: 1.3 (0.0–40.6) pdC1-INH 60 IU/kg: 1.0 (0.0–48.0) Time-normalized reduction in HAE attack rate from baseline (mean [SD]): pdC1-INH 40 IU/kg: −6.8 (−9.8 to −3.8) pdC1-INH 60 IU/kg: −6.8 (−10.9 to −2.7) Pts with response (≥50% decrease in number of attacks with pdC1-INH 40 IU/kg or 60 IU/kg) 94% or 92% |
pdC1-INH 40 IU/kg (n = 63) pdC1-INH 60 IU/kg (n = 70)a Any AE: pdC1-INH 40 IU/kg, 89% (n = 56); pdC1-INH 60 IU/kg, 83% (n = 58) Events (events/patient-year): pdC1-INH 40 IU/kg, 948 (11.3); pdC1-INH 60 IU/kg, 849 (8.5) Any SAE: pdC1-INH 40 IU/kg, 6% (n = 4); pdC1-INH 60 IU/kg, 7% (n = 5) Any tx-related SAE: 0 (both groups) AEs leading to discontinuation: pdC1-INH 40 IU/kg, 0; pdC1-INH 60 IU/kg, 1% (n = 1) Most common AEs (pdC1-INH 40 IU/kg, pdC1-INH 60 IU/kg) Nasopharyngitis: 19% (n = 12), 30% (n = 21) Injection-site pain: 27% (n = 17), 14% (n = 10) Injection-site erythema: 16% (n = 10), 17% (n = 12) Headache: 16% (n = 10), 14% (n = 10) Injection-site bruising: 14% (n = 9), 10% (n = 7) UTI: 13% (n = 8), 11% (n = 8) |
|
| rhC1-INH (Ruconest) | Short-term prophylaxis | |||
| Valerieva A, et al. (48) Retrospective study Pts with HAE (51 pts received rhC1-INH) Median age 44 y (range, 17–73) Procedures (e.g., medical/dental) with rhC1-INH prophylaxis (n = 70) vs. procedures with no prophylaxis (n = 26) |
Median rhC1-INH IV dose: 3,075 IU (range, 2,100–4,200 IU) Administered median 60 min pre-procedure |
rhC1-INH vs. no rhC1-INH Attack-free procedures
|
No AEs in the 70 treated procedures | |
| Long-term prophylaxis | ||||
| Riedl MA, et al. (54) R, DB, PBO-C, crossover, ph 2 Pts ≥13 y with HAE w/ ≥4 attacks/mo for 3 consecutive mo before study initiation (n = 32) Mean (SD) attacks ≤3 mo: 17.9 (7.2) Median (range) attacks ≤3 mo: 14.5 (12–33) |
Three 4-wk tx periods, with 1-wk washout before crossover: rhC1-INH 50 IU/kg bw (pts <84 kg) or 4,200 IU (pts ≥84 kg) once or twice weekly IV, vs. PBO |
Mean (SD) number of HAE attacks in each 4-wk tx period (n = 31): Once weekly, 4.4 (3.2) Twice weekly: 2.7 (2.4) PBO: 7.2 (3.6) Mean differences vs. PBO: −2.8 (P = 0.0004) and −4.4 (P < 0.0001), respectively Mean decrease in attack frequency (once weekly, twice weekly vs. PBO) (n = 31): 34.9% and 63.3% Pts with clinical response (≥50% decrease in number of attacks with rhC1-INH vs. PBO): Once weekly tx: 13/31 (42%) Twice weekly tx: 23/31 (74%) |
rhC1-INH once weekly (n = 29) rhC1-INH twice weekly (n = 29) PBO (n = 28) Any AEs: once weekly, 45% (n = 13); twice weekly, 34% (n = 10) vs. PBO 29% (n = 8) Tx-related AEs: 0, 7% (n = 2), vs. 0 SAEs: 0, 3% (n = 1), vs. 0 AEs occurring in ≥5% pts:
|
|
AE, adverse event; bw, body weight; C1-INH, C1 esterase inhibitor; COMPACT, Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy; DB, double-blind; dx, diagnosis; GI, gastrointestinal; HAE, hereditary angioedema; HAE-nC1, normal hereditary angioedema; HCC, hepatocellular carcinoma; IQR, interquartile range; IV, intravenous; LTP, long-term prophylaxis; MC, multicenter; OL, open-label; PBO, placebo; PBO-C, placebo-controlled; pdC1-INH, plasma-derived C1 esterase inhibitor; ph, phase; pts, patients; R, randomized; rhC1-INH, recombinant human C1 esterase inhibitor; SAE, serious adverse event; SC, subcutaneous; STP, short-term prophylaxis; tx, treatment; UTI, urinary tract infection.
a
Included 7 patients whose treatment was uptitrated from 40 IU/kg to 60 IU/kg and were included in both treatment arms in the safety population.