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Hereditary angioedema ("HAE") is a genetic disorder characterized by sudden recurrent attacks of local swelling (angioedema). These attacks are often painful and disabling, and, in some cases, life-threatening. "HAE" is caused by mutations in the "C1INH" gene that leads to a decrease in the blood level of functional "C1INH". This multi-center study was designed to assess the safety and tolerability, efficacy and pharmacodynamics/ pharmacokinetics of recombinant human C1 inhibitor ("rhC1INH") in the treatment of acute hereditary angioedema attacks.
A prospectively planned interim analysis will be performed on the double-blind data.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 100 IU/kg "rhC1INH" | Experimental | 100 IU/kg recombinant human C1 inhibitor |
|
| Saline | Placebo Comparator | Saline solution |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| recombinant human C1 inhibitor | Drug | IV |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Beginning of Relief of Symptoms | The time to beginning of relief of symptoms has been assessed by using a patient-reported visual analogue scale ("VAS") ranging from 0 mm (no symptoms at all) to 100 mm (extremely disabling). Time to beginning of relief of symptoms at the location that showed first "VAS" score decrease of at least 20 mm from baseline score (t= 0 min) to the next assessment time-point). Assessment time-points were taken on pre-scheduled time-points after drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to beginning of relief has been calculated as median time, by using the exact time-points on which each assessment was performed. | up to 48 hours after study drug administration |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Minimal Symptoms | the time to minimal symptoms was the time to minimal symptoms for an attack, assessed using the Visual Analogue Scale ("VAS") score. Symptoms were said to be minimal when the "VAS" score at all locations was below 20 mm. Assessment time-points were: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to minimal symptoms has been calculated by using the exact time-points on which each assessment was performed. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jan Nuijens, MD, PhD | Pharming Group N.V. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| For information on sites, please contact Pharming Medical Affairs Deparment | Leiden | 2300 AL | Netherlands | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20920772 | Result | Zuraw B, Cicardi M, Levy RJ, Nuijens JH, Relan A, Visscher S, Haase G, Kaufman L, Hack CE. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010 Oct;126(4):821-827.e14. doi: 10.1016/j.jaci.2010.07.021. | |
| 22909164 | Result |
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Patients could be enrolled into the open-label phase of the study after conclusion of the double-blind phase.
During the double-blind phase of the study, patients were randomized once to receive 100 IU/kg "rhC1INH" or Saline in a ratio of 1:1. After conclusion of the double-blind phase, patients with subsequent eligible attacks could be treated with open-label 1 vial (2100 IU) of "rhC1INH".
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| ID | Title | Description |
|---|---|---|
| FG000 | 100 IU/kg "rhC1INH" | Includes all subjects randomized and who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. |
| FG001 | Saline | Includes all subjects randomized and who received Saline solution in the double-blind phase. |
| FG002 | 1 Vial (2100 IU) "rhC1INH" | Includes all subjects who received, 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. Patients received 1 vial initially and could receive an additional 1-2 vials within 4 hours at the investigator's discretion. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double-blind Phase |
|
| |||||||||||||||||||||
| Open-label Phase |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 100 IU/kg "rhC1INH" | Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. |
| BG001 | Saline | Includes all subjects randomized and who received Saline solution in the double-blind phase. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Beginning of Relief of Symptoms | The time to beginning of relief of symptoms has been assessed by using a patient-reported visual analogue scale ("VAS") ranging from 0 mm (no symptoms at all) to 100 mm (extremely disabling). Time to beginning of relief of symptoms at the location that showed first "VAS" score decrease of at least 20 mm from baseline score (t= 0 min) to the next assessment time-point). Assessment time-points were taken on pre-scheduled time-points after drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to beginning of relief has been calculated as median time, by using the exact time-points on which each assessment was performed. | The full analysis set ("FAS" or "mITT") was defined as the set of patients who provided Informed Consent, were randomized and took at least one dose of the study drug administration. | Posted | Median | Full Range | minutes | up to 48 hours after study drug administration |
|
Treatment-Emergent-Adverse-Events ("TEAEs") were defined as events with start from onset of study drug administration. Serious Adverse events and Adverse events for each arm with onset dates within 7 days of study drug administration have been listed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 100 IU/kg "rhC1INH" | Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Prostate examination | Investigations | MedDRA (9.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| headache | Nervous system disorders | MedDRA (9.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Affairs Department | Pharming Technologies BV | +31715247400 | medicalinfo@pharming.com |
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| ID | Term |
|---|---|
| D054179 | Angioedemas, Hereditary |
| D000799 | Angioedema |
| D030342 | Genetic Diseases, Inborn |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000081208 | Hereditary Complement Deficiency Diseases |
| D000081207 | Primary Immunodeficiency Diseases |
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| ID | Term |
|---|---|
| D050718 | Complement C1 Inhibitor Protein |
| C571093 | conestat alfa |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D003174 | Complement C1 Inactivator Proteins |
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| Placebo | Drug | IV |
|
|
| up to 48 hours after study drug administration |
| Emergency County Hospital, Internal Medicin Clinica, Allergology-Immunology Department |
| Târgu Mureş |
| 541103 |
| Romania |
| Moldovan D, Reshef A, Fabiani J, Kivity S, Toubi E, Shlesinger M, Triggiani M, Montinaro V, Cillari E, Realdi G, Cancian M, Visscher S, Zanichelli A, Relan A, Cicardi M. Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. Clin Exp Allergy. 2012 Jun;42(6):929-35. doi: 10.1111/j.1365-2222.2012.03984.x. |
| 42159953 | Derived | Riedl MA, Narsipur N, Jones D, Tachdjian R, Relan A, Kilvert H, Aiello E, Habimana K, Roskell N, Gough A, Harper JR, Li HH, Harrington A. Post Hoc Analysis of Recombinant C1 Inhibitor Clinical Data Using Contemporary Endpoints for Hereditary Angioedema. Adv Ther. 2026 May 20. doi: 10.1007/s12325-026-03625-0. Online ahead of print. |
| 28284978 | Derived | Bernstein JA, Relan A, Harper JR, Riedl M. Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2017 Apr;118(4):452-455. doi: 10.1016/j.anai.2017.01.029. Epub 2017 Mar 9. |
| NOT COMPLETED |
|
| BG002 | 1 Vial (2100 IU) "rhC1INH" | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| 100 IU/kg "rhC1INH" |
Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. |
| OG001 | Saline | Includes all subjects randomized and who received Saline solution in the double-blind phase. |
| OG002 | 1 Vial (2100 IU) "rhC1INH" | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. |
|
|
|
| Secondary | Time to Minimal Symptoms | the time to minimal symptoms was the time to minimal symptoms for an attack, assessed using the Visual Analogue Scale ("VAS") score. Symptoms were said to be minimal when the "VAS" score at all locations was below 20 mm. Assessment time-points were: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to minimal symptoms has been calculated by using the exact time-points on which each assessment was performed. | The full analysis set ("FAS" or "mITT") was defined as the set of patients who provided Informed Consent, were randomized and took at least one dose of study drug administration. | Posted | Median | Full Range | minutes | up to 48 hours after study drug administration |
|
|
|
|
| 0 |
| 16 |
| 2 |
| 16 |
| EG001 | Saline | Includes all subjects randomized and who received Saline solution in the double-blind phase. | 2 | 16 | 5 | 16 |
| EG002 | 1 Vial (2100 IU) "rhC1INH" | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. | 0 | 57 | 6 | 57 |
| Biliary colic | Hepatobiliary disorders | MedDRA (9.1) | Systematic Assessment |
|
| nausea | Gastrointestinal disorders | MedDRA (9.1) | Systematic Assessment |
|
| menstrual disorder | Reproductive system and breast disorders | MedDRA (9.1) | Systematic Assessment |
|
| scrotal swelling | Reproductive system and breast disorders | MedDRA (9.1) | Systematic Assessment |
|
| pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (9.1) | Systematic Assessment |
|
| hypotension | Vascular disorders | MedDRA (9.1) | Systematic Assessment |
|
| pain | General disorders | MedDRA (9.1) | Systematic Assessment |
|
The investigator must provide a copy of any results communication to the sponsor for review at least 30 days prior to its submission or disclosure. The sponsor may request to delete information identified by sponsor as confidential information prior to submitting such manuscript and/or abstract for publication. For a multi-center study, the investigator must wait (i) at least 24 months after the study is completed at all sites or (ii) until after the multi-center publication.
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D014581 | Urticaria |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D015843 |
| Serpins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D003169 | Complement Inactivator Proteins |
| D003165 | Complement System Proteins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |