Safety and Efficacy of Conestat Alfa for ACE-Induced Angioedema

NCT06679426 | Not Yet Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: 2024-0561
• Study Type: interventional
• Target: 24
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

ACE Inhibitor-Induced Angioedema

Keywords

Ruconest, conestat alpha, ACE inhibitor, angioedema, treatment, outcome, safety

Outcome Measures

Primary Outcomes (1)

• The primary objective is to assess the efficacy of conestat alfa compared to placebo in the treatment of ACE-1-induced AE based on the Time to Onset of Symptom Relief (TOSR) endpoint.

  The TOSR is defined as the time at which the total severity score of four airway compromising symptoms (difficulty breathing, difficulty swallowing, voice changes, and tongue swelling) has decreased by at least 1 point overall and no individual component of the score has increased. The 5-point severity scale is: 0 = absence of symptoms, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.

  24 hours

Secondary Outcomes (1)

• The secondary objective is to compare the efficacy of conestat alfa to placebo for the treatment of ACE-1-induced AE based on the endpoint of Time to Meeting Discharge Criteria (TMDC).

  24 hours

Other Outcomes (2)

• Exploratory objective

  24 hours

• Safety outcome

  Every hour post treatment up to 8 hours and then every 2 hours from >8 to 24 hours; phone calls at day 7 and day 28.

Study Arms (2)

Investigational product

ACTIVE COMPARATOR

Human recombinant C1-INH, also known as conestat alfa (Ruconest™), has been purified from the breast milk of genetically modified rabbits. Conestat alfa targets activated C1s, kallikrein, factor XIIa, and factor XIa. Inhibition kinetics are comparable to plasma-derived human C1-INH. The elimination half-life is approximately 2.5 hours.37 One vial consists of 2100 units, which corresponds to 2100 units per 14 mL after reconstitution, resulting in a concentration of 150 units/mL. One unit of activity corresponds to C1 esterase inhibiting activity in 1 mL of normal plasma. Each vial also contains 19.5 mg of sodium.41 In order to administer 4200 IU of conestat alfa, 2 reconstituted vials are needed

Drug: Conestat Alfa

Placebo

PLACEBO COMPARATOR

The comparator in the study will be a placebo, an isotonic sterile solution (pH 5.5 ± 0.3) for IV injection. The solution does not contain any preservatives. The placebo is formulated to match the study drug (conestat alfa) and is supplied in an identical single-dose IV bag. To maintain the blinding of the study, the IV bag containing the placebo will be indistinguishable from that containing conestat alfa, in addition to the labeling

Drug: Conestat Alfa

Interventions

Conestat Alfa DRUG

See arm/group descriptions

Also known as: Ruconest

Investigational product; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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

You may not qualify if:

• \. 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

Sponsors & Collaborators

• University of Cincinnati: lead
• University of Maryland: collaborator

Related Publications (6)

• Bernstein JA, Moellman JJ, Collins SP, Hart KW, Lindsell CJ. Effectiveness of ecallantide in treating angiotensin-converting enzyme inhibitor-induced angioedema in the emergency department. Ann Allergy Asthma Immunol. 2015 Mar;114(3):245-9. doi: 10.1016/j.anai.2014.12.007. Epub 2015 Jan 16.

  PMID: 25601538 BACKGROUND

• Moellman JJ, Bernstein JA, Lindsell C, Banerji A, Busse PJ, Camargo CA Jr, Collins SP, Craig TJ, Lumry WR, Nowak R, Pines JM, Raja AS, Riedl M, Ward MJ, Zuraw BL, Diercks D, Hiestand B, Campbell RL, Schneider S, Sinert R; American College of Allergy, Asthma & Immunology (ACAAI); Society for Academic Emergency Medicine (SAEM). A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med. 2014 Apr;21(4):469-84. doi: 10.1111/acem.12341.

  PMID: 24730413 BACKGROUND

• Bonner N, Panter C, Kimura A, Sinert R, Moellman J, Bernstein JA. Development and validation of the angiotensin-converting enzyme inhibitor (ACEI) induced angioedema investigator rating scale and proposed discharge criteria. BMC Health Serv Res. 2017 May 22;17(1):366. doi: 10.1186/s12913-017-2274-4.

  PMID: 28532495 BACKGROUND

• Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, Schranz J, Baptista J, Kimura A, Nothaft W; CAMEO study group. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1402-1409.e3. doi: 10.1016/j.jaip.2017.03.003. Epub 2017 May 25.

  PMID: 28552382 BACKGROUND

• Mudd PA, Hooker EA, Stolz U, Hart KW, Bernstein JA, Moellman JJ. Emergency department evaluation of patients with angiotensin converting enzyme inhibitor associated angioedema. Am J Emerg Med. 2020 Dec;38(12):2596-2601. doi: 10.1016/j.ajem.2019.12.058. Epub 2020 Jan 7.

  PMID: 31932133 BACKGROUND

• Wilkerson RG, Dakessian A, Moellman JJ, Bernstein JA. Clinical trial of C1-INH for treatment of ACEi-induced angioedema. Am J Emerg Med. 2023 Jun;68:196-197. doi: 10.1016/j.ajem.2023.04.012. Epub 2023 Apr 11. No abstract available.

  PMID: 37061431 BACKGROUND

MeSH Terms

Conditions

Angioedema

Interventions

conestat alfa

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• Joseph A. Moellman, MD

  University of Cincinnati

  PRINCIPAL INVESTIGATOR

• Gentry Wilkerson, MD

  University of Maryland

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jonathan A. Bernstein, MD

CONTACT

5132357971; bernstja@ucmail.uc.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be conducted as a double-blind, placebo-controlled trial. The appearance of the prefilled device containing placebo will be indistinguishable from those containing conestat alfa. The blinding will be maintained throughout the duration of the study for the subject. As such, only investigators and study staff blinded to the treatment assignments will be responsible for monitoring the patient and assessing efficacy and safety outcomes.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Adjunct Professor

Model Details: This Phase III study is designed as a randomized, double-blind, two-armed, placebo-controlled study (Figure 2). It will be conducted at two centers in the United States. The primary aim is to compare the efficacy of conestat alfa with a placebo in the treatment of ACE-I-induced AE based on the TMDC endpoint, assess its safety and tolerability, as well as compare its efficacy compared to the placebo based on the TOSR endpoint. Moreover, the proportion of patients in each arm who are hospitalized, admitted to the ICU, or who require an airway intervention will be compared.

Study Record Dates

• First Submitted: November 5, 2024
• First Posted: November 7, 2024
• Study Start: December 1, 2024
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: November 7, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Study will enrol over 12 months and data analysis and publication 0ver 6 to 12 months. Data will be available after publication of the study
• Access Criteria: Contact the Protocol Chair Jonathan Bernstein or Co-PIs Drs. Joseph Moellman or Gentry Wilderson