A Phase 3 interventional study of Conestat Alfa in ACE Inhibitor-Induced Angioedema, sponsored by University of Cincinnati. Not yet recruiting. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-11-07.
Sponsored by University of Cincinnati · Phase 3, Interventional, and Treatment
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.
This phase III clinical trial is being conducted to assess the benefits of emergency administration of intravenous (IV) conestat alfa to treat ACE-I-induced AE during an ED visit. This will be a multi-center, randomized, double-blind, two-armed, placebo-controlled trial. It will enroll 24 patients at two clinical sites in the United States. The population will consist of adult patients (≥ 18 years of age) who present to the ED with acute ACE-I-induced AE of the head and/or neck. Eligible patients will be enrolled in the study and randomized at a ratio of 1:1 to either the active treatment or placebo groups. The treatment group will receive intravenous conestat alfa at a fixed dose of 4200 International Units (IU) IV along with usual ED care at the discretion of the clinical care team, which may include epinephrine, H1 and/or H2-antihistamines, and corticosteroids. The placebo group will receive the same volume of an isotonic, sterile, normal saline (pH 5.5 ± 0.3) solution without any preservatives via IV injection, in addition to the usual care. Fixed dosing was chosen for this study rather than weight-based dosing as is used for treatment of acute attacks of hereditary angioedema because it is hypothesized that higher doses may have greater efficacy in ACE-I-induced AE and is safe to administer.32 A second fixed dose (4200 IU) of open label study drug will be administered 2 hours after the initial dose as a rescue medication if the subject has not experienced symptom relief (based upon TOSR evaluation). Additional doses of study drug or placebo will not be used. The rationale behind the dosage is based on the fact that 4200 IU is the maximum dose irrespective of patient weight. A second dose of the same amount is recommended if symptoms persist.
The primary objective is to compare the Time to Onset of Symptom Relief (TOSR) of conestat alfa compared to placebo in the treatment of ACE-I-induced AE. The secondary objective is to evaluate the efficacy of conestat alfa compared to placebo in Time to Meeting Discharge Criteria (TMDC), based on investigator-assessment of upper airway symptoms. The study will also compare the proportion of patients in each arm who 1) are hospitalized for any level of care 2) are admitted to the intensive care unit (ICU) and 3) requiring airway intervention (e.g., intubation, cricothyrotomy, or tracheotomy). Safety and tolerability of conestat alfa treatment will also be assessed.
69 studies on the registry are indexed under Angioedema; 16 are open to participants now.
This study's planned enrollment of 24 is below the median of 45 across 44 interventional studies indexed under Angioedema.
Browse Angioedema studies →University of Cincinnati is the lead sponsor of 324 studies on the registry; 42 are open to participants now.
Of its 24 completed or terminated interventional studies of FDA-regulated products, 15 (63%) have results posted.
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Exclusion Criteria:
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Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
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Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
See arm/group descriptions
Also known as: Ruconest
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.
Time frame: 24 hours
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).
The criteria for discharge will be based on the assessment of the severity of four airway compromising symptoms, and will be calculated from the time of initiation of study drug administration to the earliest point at which the symptoms of difficulty breathing and difficulty swallowing have resolved (score = 0) and the symptoms of voice change and tongue swelling are mild or absent.
Time frame: 24 hours
Exploratory objective
Exploratory objectives include comparison of the proportion of patients in each arm who 1) are hospitalized to any level of care 2) are admitted to the intensive care unit (ICU) and 3) required an airway intervention (e.g., intubation, cricothyrotomy, or tracheotomy).
Time frame: 24 hours
Safety outcome
Safety and tolerability of conestat alfa treatment in patients experiencing ACE-I-induced AE will be assessed.
Time frame: 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.
No study locations are listed for this record.
Plan to share: Yes — Data will be published. Raw data will be provided upon request as appropriate.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report
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
Start is estimated for Dec 2024; primary completion for Dec 2025, 12 months later.
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This study is not yet recruiting, as verified in Jul 2024. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Conestat alfa