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NCT06679426

PHASE3

Safety and Efficacy of Conestat Alfa for ACE-Induced Angioedema

Sponsor: University of Cincinnati

View on ClinicalTrials.gov

Summary

Angiotensin-converting enzyme inhibitors (ACE-Is), prescribed most often to treat hypertension, have been used extensively since the 1980s. Additional indications for their use include heart failure, diabetes mellitus, chronic kidney disease, and post-myocardial infarction. It is estimated that up to 40 million patients take ACE-Is worldwide. C1-INH is a serine protease inhibitor that is normally found in the blood. Its primary function is the regulation of the complement and contact system pathways by binding irreversibly to target proteases. It additionally inhibits the fibrinolytic, clotting, and kinin pathways.31 Patients with the hereditary forms of AE (HAE) tend to have lower quantitative or functional levels of C1-INH. This results in decreased suppression of plasma kallikrein and factor XIIa leading to cleavage of high molecular weight kininogen to form increased circulating levels of bradykinin. Bradykinin binds to bradykinin 2 receptors resulting in separation of endothelial vascular cells and extravasation of fluid manifesting clinically as angioedema. Conestat alfa (Ruconest®) is a recombinant human C1-INH that has been purified from the breast milk of genetically modified rabbits. It is a single-chain soluble glycoprotein that is made of 478 amino acids. Administering conestat alfa increases the amount of C1-INH in these patients, repleting their levels, and acting as a treatment for AE due to C1-INH deficiency. Conestat alfa has been studied on asymptomatic patients with HAE and was shown to dose-dependently increase the level of functional C1-INH. Additionally, it was shown to restore the level of the complement C4 protein, which is also decreased in these patients. Since the same pathophysiological pathway is involved in patients with ACE-I-induced AE, it is reasonable to hypothesize its effectiveness in the treatment of patients with acute attacks.

Official title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the Safety and Efficacy of Conestat Alfa As a Treatment for Angiotensin-Converting Enzyme-Inhibitor-Induced Angioedema

Key Details

Gender

All

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

Start Date

2024-12-01

Completion Date

2025-12

Last Updated

2024-11-07

Healthy Volunteers

Conditions

ACE Inhibitor-Induced Angioedema

Interventions

DRUG

Conestat Alfa

See arm/group descriptions

Inclusion Criteria: 1\. Age 18 years or older 2. Currently being treated with an ACE-I and presenting with presumed ACE-I-induced AE involving the head and/or neck region as determined by the clinical team 3. ACE-I-induced AE of the head and/or neck region of at least moderate severity within 24 hours of onset (must be sufficiently less than 24 hours to allow study drug to be administered within the same time frame) 4. AE that is at least moderate in severity for no less than one of the AE-associated airway symptoms (difficulty breathing, difficulty swallowing, voice changes, tongue swelling)32 5. Be able to provide informed consent or obtain informed consent from a legally appointed representative \- Exclusion Criteria: 1\. History of anaphylaxis, hypersensitivity, or allergic reactions to rabbits/rabbit-derived products and C1-INH preparations 2. Urticaria present during the current illness 3. AE thought by the clinical team to be due to any other etiology i.e., HAE (types I, II, and HAE with normal C1-INH), acquired AE, allergic/histaminergic AE 4. History of recent trauma, abscess, infection, local inflammation, local tumor, postoperative or post-radiogenic edema, salivary gland disorders, and non-ACE-I drug-induced AE 5. Family history of recurrent AE 6. History of AE prior to ACE-I therapy initiation 7. Last dose of ACE-I taken more than 72 hours before the onset of AE symptoms 8. History of a major systemic disease that is not well controlled (left to the study team's discretion) 9. Anyone requiring immediate airway intervention according to the clinical team, such as endotracheal intubation 10. Women who are pregnant or breast-feeding (pregnancy must be ruled out by a negative test with the exception of those who have undergone total hysterectomy, bilateral oophorectomy, or are 2 years post-menopausal) 11. Concurrent participation in other investigational drug studies 12. Treatment with other targeted therapeutic agents for HAE (ecallantide/icatibant/C1-INH/fresh frozen plasma) 13. In the opinion of the investigator, there is adequate response to the usual care treatments (epinephrine, H1 and/or H2 antihistamine, corticosteroids) within one hour before dosing of the study drug 14. Prisoners 15. Non-English speaking \-