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. 2022 Sep 12;3:952233. doi: 10.3389/falgy.2022.952233

Table 2.

Summary of clinical trials of C1-INH replacement therapy as on-demand treatment for HAE attacks.

Therapy Study and inclusion criteria Treatments Efficacy outcome(s) Safety
pd C1-INH (Berinert) Craig TJ, et al. (38)
IMPACT1
August 2005–December 2007
R, DB, PBO-C, ph 2/3 study
Pts ≥6 y with type I or II HAE with single abdominal or facial attacks		 pdC1-INH 10 U/kg bw IV (n = 39)
pdC1-INH 20 U/kg bw (n = 43) IV
PBO (n = 42)		 Time to onset of symptom reliefa:
Mean (SD):
pdC1-INH 10 U/kg: 7.5 h (10.5)
pdC1-INH 20 U/kg: 3.9 h (8.2)
PBO: 10.3 h (11.5)
Median (range):
pdC1-INH 10 U/kg: 1.2 h (0.2–24.0)
pdC1-INH 20 U/kg: 0.5 h (0.2–24.0)
PBO: 1.5 h (0.2–24.0)
P = 0.002 (20 U/kg vs. PBO)
Time to complete resolution of HAE symptoms:
Mean (SD):
pdC1-INH 10 U/kg: 216.1 h (494.2) pdC1-INH 20 U/kg: 81.8 h (314.3)
PBO: 125.1 h (382.8)
Median (range):
pdC1-INH 10 U/kg: 20.0 h (0.5–1,486.2)
pdC1-INH 20 U/kg: 4.9 h (0.5–1,486.2)
PBO: 7.8 h (0.3–1,486.2)
P = 0.02 (20 U/kg vs. PBO)		 pdC1-INH 10 U/kg (n = 39)
pdC1-INH 20 U/kg (n = 46)
PBO (n = 41)
Any AE ≤4 h of start of tx: pdC1-INH 10 U/kg, 25.6% (n = 10); pdC1-INH 20 U/kg, 19.6% (n = 9) vs. PBO 43.9% (n = 18)
Tx-related AEs: 20.5% (n = 8), 10.9% (n = 5), vs. 19.5% (n = 8), respectively
SAEs/AEs leading to discontinuation: 0 (all groups)
Most common AEsb:

  • Muscle spasms: 10.3% (n = 4), 2.2% (n = 1), vs. 4.9% (n = 2)

  • Pain: 10.3% (n = 4), 2.2% (n = 1), vs. 2.4% (n = 1)

  • Nausea: 2.6% (n = 1), 6.5% (n = 3), vs. 12.2% (n = 5)

  • Diarrhea: 2.6% (n = 1), 0, vs. 9.8% (n = 4)
Craig TJ, et al. (39)
(IMPACT2)
August 2005–February 2010
OL extension of IMPACT1
Pts ≥6 y with type I or II HAE who previously participated in IMPACT1 (n = 57; 1,085 attacks) with attacks at any body location		 pdC1-INH 20 U/kg bw IV
Median study duration: 24 mo (range, 0–51 mo)
Pts received tx for median 7 attacks (range, 1–184 attacks)		 Per-attack analysis:
Median (range) time to onset of symptom reliefa: 0.4 h (0.05–497.0c)
Median (range) time to complete resolution of HAE symptoms: 14.3 h (0.2–497.0c)
Single dose effective for 1,073/1,085 HAE attacks (99%)
Per-pt analysis:
Median time to onset of symptom reliefa: 0.46 h (95% CI, 0.39–0.53; range, 0.2–497.0c)
Median time to complete resolution of HAE symptoms: 15.5 h (95% CI, 11.6–21.6; range, 0.6–497.0c)		 AEs by no. of pts (n = 57)/no. of attacks (n = 1,085):
Any AE: 43.9% (n = 25)/5.4% (n = 59)
Tx-related AEs: 14.0% (n = 8)/0.8% (n = 9)
SAEs: 1.8% (n = 1)d/<0.1% (n = 1)d
AEs leading to discontinuation: 1.8% (n = 1)/<0.1% (n = 1)
Most common AEsc:

  • Headache: 8.8% (n = 5)/0.7% (n = 8)

  • Nasopharyngitis: 5.3% (n = 3)/0.3% (n = 3)
pdC1-INH (Cinryze) Zuraw BL, et al. (40)
14 March 2005–18 May 2007
R, DB, PBO-C
Pts ≥6 y with single HAE attacks (abdomen, external genitalia, extremities, face, throat)		 pdC1-INH 1,000 U/10 ml (n = 36)
PBO (n = 35)e

 Median time to onset of symptom relief:
pdC1-INH 1,000 U: 2 h
PBO: >4 h
Estimated success rate ratio, 2.4 (95% CI, 1.2–5.0; P = 0.02)
Pts with time to relief ≤4 h: 21/35 (60%) vs. 14/33 (42%; P = 0.06)
Median time to complete resolution of symptoms (after second dose of study drug [pdC1-INH: n = 23; PBO: n = 28]): 12.3 vs. 25.0 h (P = 0.004)		 pdC1-INH 1,000 U/10 ml (n = 36)
PBO (n = 35)
≥1 AEs: 17% (n = 6) vs. 20% (n = 7)
Possibly tx-related AEs

  • pdC1-INH:

  • Rash at injection site: 2.8% (n = 1)

  • PBO:

  • Contact dermatitis: 2.9% (n = 1)

  • Tetany: 2.9% (n = 1)
rhC1-INH Ruconest Zuraw B, et al. (41)
R, DB, C
2 independent trials with similar design, entry criteria, endpoints
Pts ≥12 y (US/Canada) or ≥16 y (Europe)		 rhC1-INH 50 U/kg bw IVf (n = 12)
rhC1-INH 100 U/kg bw IV (n = 29)
PBO (n = 29)		 Time to onset of symptom relief:
Median (range):
rhC1-INH 50 U/kg: 122 min (72–136)
P = 0.01 vs. PBO
rhC1-INH 100 U/kg: 66 min (61–122)
P < 0.001 vs. PBO
PBO: 495 min (245–520)		 rhC1-INH 50 U/kg (n = 12)
rhC1-INH 100 U/kg (n = 29)
PBO (n = 29)
Any AE ≤90 d of tx administration: rhC1-INH 50 U/kg, 33% (n = 4); rhC1-INH 100 U/kg, 24% (n = 7), vs. 48% (n = 14)
Tx-related AEs: 0, 3% (n = 1), vs. 10% (n = 3)
SAEs: 0, 3% (n = 1), vs. 10% (n = 3)
AEs leading to discontinuation: 0 (all groups)
Most common AEsb:

  • Headache: 0, 10% (n = 3), vs. 14% (n = 4)

  • Back pain: 8% (n = 1), 0, vs. 0

  • CRP: 8% (n = 1), 0, vs. 0

  • Erythema: 8% (n = 1), 0, vs. 0

  • Pruritus: 8% (n = 1), 0, vs. 0

  • Tooth abscess: 8% (n = 1), 0, vs. 0

  • UTI: 8% (n = 1), 0, vs. 0

AE, adverse event; bw, body weight; C, controlled; C1-INH, C1 esterase inhibitor; CRP, C-reactive protein; DB, double-blind; HAE, hereditary angioedema; IMPACT, International Multicenter Prospective Angioedema C1-INH Trial; IV, intravenous; 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; tx, treatment; UTI, urinary tract infection.

a

Time from the start of treatment to the onset of symptom relief, as determined by patients’ responses to a standard question posed at appropriate time intervals for as long as 24 h after the start of treatment.

b

In any group, the most common AEs.

c

One patient was discontinued from the study after receiving treatment for an abdominal attack, after genetic testing did not confirm an HAE diagnosis. The time to complete resolution of HAE symptoms for this patient’s attack was 497 h, which was included in the data analysis.

d

One patient (later determined to not have HAE) had 2 SAEs considered unrelated to treatment.

e

After treatment, 3 patients were determined to not have had a true HAE attack (pdC1-INH [n = 1]; PBO [n = 2]).

f

Patients in US or Canada only.