Pediatric Allergy and Immunology
ORIGINAL ARTICLE
Clinical immunology
Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema William Lumry1, Daniel Soteres2, Richard Gower3, Kraig W. Jacobson4, H. Henry Li5, Hongzi Chen6 & Jennifer Schranz6 1
AARA Research Center, Dallas, TX, USA; 2Asthma & Allergy Associates, Colorado Springs, CO, USA; 3Marycliff Allergy Specialists, Spokane, WA, USA; 4Oregon Allergy Associates, Eugene, OR, USA; 5Institute for Allergy and Asthma, Chevy Chase, MD, USA; 6ViroPharma Incorporated (part of the Shire Group of Companies), Exton, PA, USA
To cite this article: Lumry W, Soteres D, Gower R, Jacobson KW, Li HH, Chen H, Schranz J. Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema. Pediatr Allergy Immunol 2015: 26: 674–680.
Keywords acute treatment; C1 esterase inhibitor; children; hereditary angioedema; safety Correspondence William Lumry, AARA Research Center, 10100 N. Central Expressway, Suite 100, Dallas, TX 75231, USA Tel.: +1 214 365 0365 Fax: 214 373 7003 E-mail: [email protected] Accepted for publication 6 July 2015 DOI:10.1111/pai.12444
Abstract Background: Human plasma-derived nanofiltered C1 esterase inhibitor (C1 INH-nf) is used to treat acute angioedema attacks in patients with hereditary angioedema (HAE), but data regarding use in children are sparse. Methods: Patients 2 to 25 kg). Each weight category included 2 dosing levels: C1 INH-nf (500 units [U], 1000 U) and C1 INH-nf (1000 U, 1500 U), respectively. Patients experiencing an angioedema attack were given a single intravenous dose. Primary efficacy end-point was the onset of unequivocal relief of the defining symptom within 4 h following initiation of C1 INH-nf treatment. Results: Nine children were treated: 3 (10–25 kg) received 500 U; 3 (>25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. The lower weight/higher dose category (10–25 kg, 1000 U) was not successfully enrolled. All patients completed the study. Most angioedema attacks (n = 5) were abdominal. All patients met the primary endpoint; median time to unequivocal symptom relief was 0.5 (range: 0.25–2.5) h. Doses of C1 INH-nf ranged from 20.8 to 51.9 U/kg. Conclusions: Treatment of a single angioedema attack with C1 INH-nf doses of 500 U (in patients 10–25 kg), 1000 U, and 1500 U (in patients >25 kg) were well tolerated. Doses of C1 INH-nf 1 location, the defining symptom was selected using the following priority: laryngeal > gastrointestinal/ abdominal > facial > genitourinary > extremity. The overall severity of the angioedema attack at baseline was categorized as mild, moderate, or severe. Assessments continued until either the patient achieved relief sufficient to allow discharge from the study center or at 4 h post-infusion, whichever occurred earlier. Safety assessments included adverse event (AE) monitoring, physical examinations, vital signs, and clinical safety laboratory testing. Active monitoring for possible venous thromboembolism via medical history, physical examinations, and laboratory testing was conducted by the investigators. After complete resolution of the presenting angioedema attack, any subsequent attack that occurred during the study was recorded as an AE or serious AE. The occurrence of a thrombotic event, thromboembolic event, or anaphylactic reaction resulted in cessation of study drug administration pending a review of all available data.
Study patients Eligible patients were 2 to 25 kg) with 2 dosing regimens as described in Table 1. Within each weight category, the first 3 patients treated were to receive the lower dose in that category, and the second 3 patients treated were to receive the higher dose after a safety review. Recruitment within each weight category occurred in parallel.
Study end-points Table 1 Dosing of C1 INH-nf
Weight category ≥10 and ≤25 kg >25 kg
C1 INH-nf dose group (U)
Planned no. of patients
Enrolled patients
500 1000 1000 1500
3 3 3 3
3 0 3 3
C1 INH-nf, nanofiltered C1 esterase inhibitor; U, units.
The primary efficacy end-point was the onset of unequivocal relief of the defining symptom. Unequivocal relief of the defining symptom was achieved in 1 of 2 ways: (i) 3 consecutive assessments ≤4 h post-infusion indicating that symptoms/signs of the angioedema attack were improved from the previous assessments or (ii) single assessment of improved (or 2 consecutive assessments of improved) with no subsequent assessments, and investigator determination that the patient achieved sufficient relief to be discharged from the study center before the end of the 4-h post-infusion period. Secondary
Pediatric Allergy and Immunology 26 (2015) 674–680 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
675
C1 INH in pediatric acute attacks of HAE
efficacy end-points included time to onset of relief of the defining symptom and time to complete resolution of the angioedema attack.
Lumry et al.
in the 1000 and 1500 U C1 INH-nf groups) was assessed as severe. Efficacy
Pharmacokinetic/pharmacodynamic assessments Antigenic and functional C1 INH were measured pre-infusion and at 1 and 24 h (day 2) after the start of the study drug infusion from blood samples collected from a vein other than the one in the arm used for study drug infusion. Assays Blood samples (5 mL) were collected via venipuncture or through an indwelling venous catheter into collection tubes and stored at 80°C. C1 INH antigen concentration was determined using an automated nephelometric assay (Siemens/ Dade Behring BN II Nephelometer, Deerfield, IL, USA) with a validated calibration range of 0.03–0.4 g/L at a 1:5 sample dilution. C1 INH activity was determined using a chromogenic assay (Siemens) with a validated calibration range of 0.10–1.4 U/mL. Study samples were measured at a serial dilution of 1:12.5/1:25/1:50. If C1 INH activity was 25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. Patients in the lower weight category (10–25 kg) were not enrolled in the 1000-U dose group despite substantial recruitment efforts, and the dosage cohort was subsequently dropped. All 9 enrolled patients completed the study. All 9 patients were white (Table 2) with a median (range) age of 9 (6–11) years. Most (89%) patients were female. The median (range) time since diagnosis of HAE for the 9 patients at enrollment was 3.4 (0.1–7.4) years. The median (range) time since the last angioedema attack before enrollment was 125 (36–465), 73 (10–78), and 157 (39–176) days in the 500, 1000, and 1500 U C1 INH-nf groups, respectively. The anatomic locations of the defining symptoms were abdominal (n = 5), extremity (n = 3), and facial (n = 1; Table 3). At baseline, severity was assessed by the investigator as moderate for the majority of angioedema attacks (6/9 [67%], 2 in each C1 INH-nf dose group). One attack in 1 patient (500 U C1 INH-nf group) was assessed as mild and 2 attacks (1 each
676
Safety The median (range) weight-adjusted C1 INH-nf dose was 22.0 (20.8–28.3), 26.5 (26.0–29.0), and 31.6 (28.5–51.9) U/kg in the 500, 1000, and 1500 U C1 INH-nf groups, respectively. No deaths, serious AEs, discontinuations, or thromboembolic events occurred during the study. The only AEs were mild nausea and diarrhea in a 6-year-old girl receiving 500 U for an abdominal attack; symptoms were considered possibly related to study drug and resolved ≤1 day without additional treatment. In 1 patient creatinine rose from 0.62 mg/dL on day 1 to 0.94 mg/dL on day 2 (normal range: 0.37–0.62 mg/dL), and 2 patients had elevated D-dimer levels (above the reference range) on days 1 and 2; no laboratory abnormalities or changes in vital signs were considered by the investigator to be clinically significant. Discussion In pediatric patients, C1 INH-nf was safe and well tolerated in this study. Median time to onset of symptom relief was 30 min, consistent with the results of the pediatric subset in a pivotal
Pediatric Allergy and Immunology 26 (2015) 674–680 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Lumry et al.
C1 INH in pediatric acute attacks of HAE
Table 2 Demographics and relevant history C1 INH-nf dose
n Age (y), mean (s.d.) Female, n (%) Weight (kg), mean (s.d.) Female Male White, n (%) Years since HAE diagnosis, mean (s.d.) Days since previous attack* Mean (s.d.) Median (range) Average monthly attacks,† mean (s.d.) Distribution of previous attack locations,‡ n (%) Laryngeal GI/abdominal Facial Genitourinary Extremity Hospital/ED visits due to attack,§ mean (s.d.) Hospital/ED visits due to attack,§ n (%) 0 visits 1–5 visits Previous laryngeal attack§
10–25 kg
>25 kg
500 U
1000 U
3 7.3 (1.5) 3 (100)
3 8.3 (1.2) 3 (100)
21.5 (3.3)
36.9 (2.1) – 3 (100) 2.7 (4.1)
– 3 (100) 4.2 (3.6) 208.7 (226.4) 125.0 (36–465) 0.4 (0.5)
53.7 (37.9) 73.0 (10–78) 1.5 (2.2)
0 3 (100) 0 0 1 (33) 1 (1.0)
0 2 1 0 2 0.3
1 (33) 2 (67) 0
(67) (33) (67) (0.6)
2 (67) 1 (33) 0
1500 U 3 9.7 (1.5) 2 (67) 38.2 52.7 3 3.0
(13.2) (NA) (100) (2.3)
124.0 (74.2) 157.0 (39–176) 0.8 (1.1) 2 2 3 1 3 0.7
(67) (67) (100) (33) (100) (1.2)
2 (67) 1 (33) 2 (67)
All patients 9 8.4 (1.6) 8 (89) 31.4 52.7 9 3.3
(9.9) (NA) (100) (3.0)
128.8 (138.1) 78.0 (10–465) 0.9 (1.3) 2 7 4 1 6 0.7
(22) (78) (44) (11) (67) (0.9)
5 (56) 4 (44) 2 (22)
C1 INH-nf, nanofiltered C1 esterase inhibitor; ED, emergency department; GI, gastrointestinal; HAE, hereditary angioedema; NA, not available; U, units. *Last angioedema attack before enrollment. †In the year before enrollment. Patients reported weekly, monthly, or yearly attack frequencies: conversion from weekly to monthly = (number of attacks per week) 9 52/12; conversion from yearly to monthly = (number of attacks per year)/ 12. ‡In the year before enrollment. Patients may have had >1 attack location. §In the year before enrollment.
Table 3 Dosing, attack location, and time to complete resolution
Age (y)
Sex
Dose (U)
Weight (kg)
Weight-adjusted dose (U/kg)
Attack location
Attack severity
7 6 9 7 9 9 11 8 10
F F F F F F M F F
500 500 500 1000 1000 1000 1500 1500 1500
22.7 17.7 24.0 38.4 37.7 34.5 52.7 28.9 47.5
22 28.3 20.8 26.0 26.5 29.0 28.5 51.9 31.6
Extremity GI/abdominal GI/abdominal GI/abdominal GI/abdominal Extremity Extremity GI/abdominal Facial
Mild Moderate Moderate Severe Moderate Moderate Severe Moderate Moderate
F, female; GI, gastrointestinal; M, male; U, units.
study (10). Five of 7 patients 6–17 years of age in the pivotal study C1 INH-nf group achieved onset of symptom relief ≤4 h after treatment with 1000 U (10), and all 9 children in this study had onset of symptom relief ≤4 h. Most symptoms reported in this study occurred in the extremities and gastrointestinal tract, common locations for angioedema
presentation in children (12). Additionally, children in this study were 6–11 years of age and had been diagnosed with HAE for 2–4 years, consistent with the reported onset of angioedema episodes between 5 and 11 years of age (13). Four of 9 (44%) children in the study had ≥1 hospitalization or emergency department visit related to HAE in the year
Pediatric Allergy and Immunology 26 (2015) 674–680 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
677
C1 INH in pediatric acute attacks of HAE
Lumry et al.
(a) 8 yo F
1500 U
10 yo F 11 yo M 9 yo F
1000 U
7 yo F 9 yo F 9 yo F
500 U
6 yo F 7 yo F −8
−6
Time (hr) from symptom onset to study drug administration
−4
−2
2
Study drug administration
4
Time (hr) from study drug administration to unequivocal relief of symptoms
(b) 8 yo F
1500 U
10 yo F 11 yo M 9 yo F
1000 U
7 yo F 9 yo F 9 yo F
500 U
6 yo F 7 yo F 20 40 Study drug administration
60
80
Time (hr) to complete resolution of symptoms
before enrollment. These interactions with the healthcare system increase the burden of HAE on patients and their families and have implications for school and recreational activities. Among patients with HAE ≥18 years of age, 44% of students reported that their last angioedema attack caused them to miss ≥1 school day (4). In 2 previous multicenter studies of C1 INH-nf for the prevention of angioedema attacks (14, 15) and 2 multicenter studies of C1 INH-nf for the treatment of angioedema attacks (14, 16), C1 INH-nf was administered intravenously to 46 unique patients
ORIGINAL ARTICLE
Clinical immunology
Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema William Lumry1, Daniel Soteres2, Richard Gower3, Kraig W. Jacobson4, H. Henry Li5, Hongzi Chen6 & Jennifer Schranz6 1
AARA Research Center, Dallas, TX, USA; 2Asthma & Allergy Associates, Colorado Springs, CO, USA; 3Marycliff Allergy Specialists, Spokane, WA, USA; 4Oregon Allergy Associates, Eugene, OR, USA; 5Institute for Allergy and Asthma, Chevy Chase, MD, USA; 6ViroPharma Incorporated (part of the Shire Group of Companies), Exton, PA, USA
To cite this article: Lumry W, Soteres D, Gower R, Jacobson KW, Li HH, Chen H, Schranz J. Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema. Pediatr Allergy Immunol 2015: 26: 674–680.
Keywords acute treatment; C1 esterase inhibitor; children; hereditary angioedema; safety Correspondence William Lumry, AARA Research Center, 10100 N. Central Expressway, Suite 100, Dallas, TX 75231, USA Tel.: +1 214 365 0365 Fax: 214 373 7003 E-mail: [email protected] Accepted for publication 6 July 2015 DOI:10.1111/pai.12444
Abstract Background: Human plasma-derived nanofiltered C1 esterase inhibitor (C1 INH-nf) is used to treat acute angioedema attacks in patients with hereditary angioedema (HAE), but data regarding use in children are sparse. Methods: Patients 2 to 25 kg). Each weight category included 2 dosing levels: C1 INH-nf (500 units [U], 1000 U) and C1 INH-nf (1000 U, 1500 U), respectively. Patients experiencing an angioedema attack were given a single intravenous dose. Primary efficacy end-point was the onset of unequivocal relief of the defining symptom within 4 h following initiation of C1 INH-nf treatment. Results: Nine children were treated: 3 (10–25 kg) received 500 U; 3 (>25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. The lower weight/higher dose category (10–25 kg, 1000 U) was not successfully enrolled. All patients completed the study. Most angioedema attacks (n = 5) were abdominal. All patients met the primary endpoint; median time to unequivocal symptom relief was 0.5 (range: 0.25–2.5) h. Doses of C1 INH-nf ranged from 20.8 to 51.9 U/kg. Conclusions: Treatment of a single angioedema attack with C1 INH-nf doses of 500 U (in patients 10–25 kg), 1000 U, and 1500 U (in patients >25 kg) were well tolerated. Doses of C1 INH-nf 1 location, the defining symptom was selected using the following priority: laryngeal > gastrointestinal/ abdominal > facial > genitourinary > extremity. The overall severity of the angioedema attack at baseline was categorized as mild, moderate, or severe. Assessments continued until either the patient achieved relief sufficient to allow discharge from the study center or at 4 h post-infusion, whichever occurred earlier. Safety assessments included adverse event (AE) monitoring, physical examinations, vital signs, and clinical safety laboratory testing. Active monitoring for possible venous thromboembolism via medical history, physical examinations, and laboratory testing was conducted by the investigators. After complete resolution of the presenting angioedema attack, any subsequent attack that occurred during the study was recorded as an AE or serious AE. The occurrence of a thrombotic event, thromboembolic event, or anaphylactic reaction resulted in cessation of study drug administration pending a review of all available data.
Study patients Eligible patients were 2 to 25 kg) with 2 dosing regimens as described in Table 1. Within each weight category, the first 3 patients treated were to receive the lower dose in that category, and the second 3 patients treated were to receive the higher dose after a safety review. Recruitment within each weight category occurred in parallel.
Study end-points Table 1 Dosing of C1 INH-nf
Weight category ≥10 and ≤25 kg >25 kg
C1 INH-nf dose group (U)
Planned no. of patients
Enrolled patients
500 1000 1000 1500
3 3 3 3
3 0 3 3
C1 INH-nf, nanofiltered C1 esterase inhibitor; U, units.
The primary efficacy end-point was the onset of unequivocal relief of the defining symptom. Unequivocal relief of the defining symptom was achieved in 1 of 2 ways: (i) 3 consecutive assessments ≤4 h post-infusion indicating that symptoms/signs of the angioedema attack were improved from the previous assessments or (ii) single assessment of improved (or 2 consecutive assessments of improved) with no subsequent assessments, and investigator determination that the patient achieved sufficient relief to be discharged from the study center before the end of the 4-h post-infusion period. Secondary
Pediatric Allergy and Immunology 26 (2015) 674–680 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
675
C1 INH in pediatric acute attacks of HAE
efficacy end-points included time to onset of relief of the defining symptom and time to complete resolution of the angioedema attack.
Lumry et al.
in the 1000 and 1500 U C1 INH-nf groups) was assessed as severe. Efficacy
Pharmacokinetic/pharmacodynamic assessments Antigenic and functional C1 INH were measured pre-infusion and at 1 and 24 h (day 2) after the start of the study drug infusion from blood samples collected from a vein other than the one in the arm used for study drug infusion. Assays Blood samples (5 mL) were collected via venipuncture or through an indwelling venous catheter into collection tubes and stored at 80°C. C1 INH antigen concentration was determined using an automated nephelometric assay (Siemens/ Dade Behring BN II Nephelometer, Deerfield, IL, USA) with a validated calibration range of 0.03–0.4 g/L at a 1:5 sample dilution. C1 INH activity was determined using a chromogenic assay (Siemens) with a validated calibration range of 0.10–1.4 U/mL. Study samples were measured at a serial dilution of 1:12.5/1:25/1:50. If C1 INH activity was 25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. Patients in the lower weight category (10–25 kg) were not enrolled in the 1000-U dose group despite substantial recruitment efforts, and the dosage cohort was subsequently dropped. All 9 enrolled patients completed the study. All 9 patients were white (Table 2) with a median (range) age of 9 (6–11) years. Most (89%) patients were female. The median (range) time since diagnosis of HAE for the 9 patients at enrollment was 3.4 (0.1–7.4) years. The median (range) time since the last angioedema attack before enrollment was 125 (36–465), 73 (10–78), and 157 (39–176) days in the 500, 1000, and 1500 U C1 INH-nf groups, respectively. The anatomic locations of the defining symptoms were abdominal (n = 5), extremity (n = 3), and facial (n = 1; Table 3). At baseline, severity was assessed by the investigator as moderate for the majority of angioedema attacks (6/9 [67%], 2 in each C1 INH-nf dose group). One attack in 1 patient (500 U C1 INH-nf group) was assessed as mild and 2 attacks (1 each
676
Safety The median (range) weight-adjusted C1 INH-nf dose was 22.0 (20.8–28.3), 26.5 (26.0–29.0), and 31.6 (28.5–51.9) U/kg in the 500, 1000, and 1500 U C1 INH-nf groups, respectively. No deaths, serious AEs, discontinuations, or thromboembolic events occurred during the study. The only AEs were mild nausea and diarrhea in a 6-year-old girl receiving 500 U for an abdominal attack; symptoms were considered possibly related to study drug and resolved ≤1 day without additional treatment. In 1 patient creatinine rose from 0.62 mg/dL on day 1 to 0.94 mg/dL on day 2 (normal range: 0.37–0.62 mg/dL), and 2 patients had elevated D-dimer levels (above the reference range) on days 1 and 2; no laboratory abnormalities or changes in vital signs were considered by the investigator to be clinically significant. Discussion In pediatric patients, C1 INH-nf was safe and well tolerated in this study. Median time to onset of symptom relief was 30 min, consistent with the results of the pediatric subset in a pivotal
Pediatric Allergy and Immunology 26 (2015) 674–680 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Lumry et al.
C1 INH in pediatric acute attacks of HAE
Table 2 Demographics and relevant history C1 INH-nf dose
n Age (y), mean (s.d.) Female, n (%) Weight (kg), mean (s.d.) Female Male White, n (%) Years since HAE diagnosis, mean (s.d.) Days since previous attack* Mean (s.d.) Median (range) Average monthly attacks,† mean (s.d.) Distribution of previous attack locations,‡ n (%) Laryngeal GI/abdominal Facial Genitourinary Extremity Hospital/ED visits due to attack,§ mean (s.d.) Hospital/ED visits due to attack,§ n (%) 0 visits 1–5 visits Previous laryngeal attack§
10–25 kg
>25 kg
500 U
1000 U
3 7.3 (1.5) 3 (100)
3 8.3 (1.2) 3 (100)
21.5 (3.3)
36.9 (2.1) – 3 (100) 2.7 (4.1)
– 3 (100) 4.2 (3.6) 208.7 (226.4) 125.0 (36–465) 0.4 (0.5)
53.7 (37.9) 73.0 (10–78) 1.5 (2.2)
0 3 (100) 0 0 1 (33) 1 (1.0)
0 2 1 0 2 0.3
1 (33) 2 (67) 0
(67) (33) (67) (0.6)
2 (67) 1 (33) 0
1500 U 3 9.7 (1.5) 2 (67) 38.2 52.7 3 3.0
(13.2) (NA) (100) (2.3)
124.0 (74.2) 157.0 (39–176) 0.8 (1.1) 2 2 3 1 3 0.7
(67) (67) (100) (33) (100) (1.2)
2 (67) 1 (33) 2 (67)
All patients 9 8.4 (1.6) 8 (89) 31.4 52.7 9 3.3
(9.9) (NA) (100) (3.0)
128.8 (138.1) 78.0 (10–465) 0.9 (1.3) 2 7 4 1 6 0.7
(22) (78) (44) (11) (67) (0.9)
5 (56) 4 (44) 2 (22)
C1 INH-nf, nanofiltered C1 esterase inhibitor; ED, emergency department; GI, gastrointestinal; HAE, hereditary angioedema; NA, not available; U, units. *Last angioedema attack before enrollment. †In the year before enrollment. Patients reported weekly, monthly, or yearly attack frequencies: conversion from weekly to monthly = (number of attacks per week) 9 52/12; conversion from yearly to monthly = (number of attacks per year)/ 12. ‡In the year before enrollment. Patients may have had >1 attack location. §In the year before enrollment.
Table 3 Dosing, attack location, and time to complete resolution
Age (y)
Sex
Dose (U)
Weight (kg)
Weight-adjusted dose (U/kg)
Attack location
Attack severity
7 6 9 7 9 9 11 8 10
F F F F F F M F F
500 500 500 1000 1000 1000 1500 1500 1500
22.7 17.7 24.0 38.4 37.7 34.5 52.7 28.9 47.5
22 28.3 20.8 26.0 26.5 29.0 28.5 51.9 31.6
Extremity GI/abdominal GI/abdominal GI/abdominal GI/abdominal Extremity Extremity GI/abdominal Facial
Mild Moderate Moderate Severe Moderate Moderate Severe Moderate Moderate
F, female; GI, gastrointestinal; M, male; U, units.
study (10). Five of 7 patients 6–17 years of age in the pivotal study C1 INH-nf group achieved onset of symptom relief ≤4 h after treatment with 1000 U (10), and all 9 children in this study had onset of symptom relief ≤4 h. Most symptoms reported in this study occurred in the extremities and gastrointestinal tract, common locations for angioedema
presentation in children (12). Additionally, children in this study were 6–11 years of age and had been diagnosed with HAE for 2–4 years, consistent with the reported onset of angioedema episodes between 5 and 11 years of age (13). Four of 9 (44%) children in the study had ≥1 hospitalization or emergency department visit related to HAE in the year
Pediatric Allergy and Immunology 26 (2015) 674–680 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
677
C1 INH in pediatric acute attacks of HAE
Lumry et al.
(a) 8 yo F
1500 U
10 yo F 11 yo M 9 yo F
1000 U
7 yo F 9 yo F 9 yo F
500 U
6 yo F 7 yo F −8
−6
Time (hr) from symptom onset to study drug administration
−4
−2
2
Study drug administration
4
Time (hr) from study drug administration to unequivocal relief of symptoms
(b) 8 yo F
1500 U
10 yo F 11 yo M 9 yo F
1000 U
7 yo F 9 yo F 9 yo F
500 U
6 yo F 7 yo F 20 40 Study drug administration
60
80
Time (hr) to complete resolution of symptoms
before enrollment. These interactions with the healthcare system increase the burden of HAE on patients and their families and have implications for school and recreational activities. Among patients with HAE ≥18 years of age, 44% of students reported that their last angioedema attack caused them to miss ≥1 school day (4). In 2 previous multicenter studies of C1 INH-nf for the prevention of angioedema attacks (14, 15) and 2 multicenter studies of C1 INH-nf for the treatment of angioedema attacks (14, 16), C1 INH-nf was administered intravenously to 46 unique patients
