Description:
Rationale for Study Design and Comparator Group
This Phase III study has a double-blind, two-arm, placebo-controlled design. The following is a discussion of the rationale behind the design of the trial.
• The study is intended to determine whether a single dose of intravenous conestat alfa at 50IU/kg dose for weights <84kg and up to a maximum dose of 4200 IU for weights ≥84kg, when administered within 24 hours of the onset of ACE-I-induced AE, is significantly more effective than the placebo at resolving the attack as assessed by the primary endpoint of TOSR and secondarily by the TMDC. Because the symptoms selected for assessment reflect potential airway compromise, a more rapid resolution of these symptoms is a relevant and clinically meaningful outcome for the patient in distress, as well as the physician who is assessing the need for an emergency airway intervention.
• This trial incorporates a placebo comparator group to rigorously evaluate and interpret the efficacy of conestat alfa. To justify a placebo-controlled trial design, as per common clinical practice, patients are expected to have been treated with the usual care prior to enrolling in the study.10,33 Furthermore, conventional medications will not be withheld during the study and may be administered at any time at the discretion of the investigator or clinical care team. Conventional medications, defined as corticosteroids and antihistamines, are commonly used to treat ACE-induced AE, but have no proven therapeutic benefit.
• The inclusion/exclusion criteria are designed to decrease the probability of enrolling patients with AE from other etiologies, such as hereditary, acquired C1 inhibitor
deficiencies, and allergic AE. Patients with allergic AE are expected to clinically respond to H1-antihistamines and/or corticosteroids.
• To be eligible, at least one of the four airway symptoms must be assessed by the investigator as moderate in severity at baseline. The rationale for this is that patients
with moderate or severe attacks would be more responsive to conestat alfa treatment than those with milder symptoms and are more likely to be the population that would receive conestat alfa if approved for use in the treatment of ACE-induced AE.
• The study is intended to establish the tolerability and safety of conestat alfa in adult patients with ACE-I-induced AE. The half-life of conestat alpha is between 2.4-2.7
hours with a duration of action estimated to be around 12-13 hours (5 half-lives) after IV administration. As such, standard safety testing (physical examination, clinical
laboratory testing, clinical ECG) will be performed 8 hours after administration. The 8-hour time point also represents > 2 half-lives of conestat alfa elimination. Conestat alfa is currently FDA approved for treatment of HAE and commonly reported adverse reactions with chronic use are rare (headache, lipoma) and which are even less likely to be observed in this study as only a maximum of two dosses will be administered.
• Adverse events will be monitored for 28 days after the study drug administration. Based on the acute nature of the ACE-I-induced AE, the short half-life of conestat alfa,
as well as the current experience with HAE, this time interval is considered appropriate and practical for the safety follow-up. In addition, the safety follow-up calls on Day 7 (+/- 1 day) and Day 28 (+/- 1 day) will capture any symptoms that recur after discharge.
Conestat alfa Dose Rationale
The dose of conestat alfa selected for the present study is the currently approved FDA dose of 50IU/kg for weights < 84kg and up to a maximum dose of 4200 IU for subjects ≥84kg to be administered via IV injection in accordance with the dosing and administration for patients presenting with acute HAE, approved by the European Medicines Agency in 201036 and the US Food and Drug Administration (FDA) in 2014.37 The presumed pathophysiology of ACE-I-induced AE is unknown but is believed to be partially mediated by bradykinin-induced activation of vascular B2 receptors. Bradykinin, a potent vasodilator, increases vascular permeability and leads to a rapid accumulation of fluid in the interstitial tissues. However, based on lack of efficacy for ACE-induced AE in previous clinical trials that selectively targeted B2 receptors and kallikrein, it is believed the mechanism of ACEinduced AE is more complex involving pathways beyond the contact system such as the plasminogen and complement pathways which conestat alfa also targets.
All statistical analyses will be performed using SAS® Version 9.1 or higher (SAS Institute, Cary, North Carolina, US). The analysis methods for study data (demographic and pretreatment characteristics, efficacy variables, and safety variables) will be detailed in the statistical analysis plan (SAP). Unless otherwise specified, summary tabulations will be presented by treatment group. For categorical variables, the number and percentage of patients within each category (with a category for missing data as needed) will be presented. For continuous variables, the number of patients, mean, median, standard deviation (SD), minimum, and maximum values will be
presented. Time-to-event data will be summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% confidence intervals, as well as the percentage of censored observations. Plots of the Kaplan-Meier curves and supporting data listings detailing each patient’s contribution to the analysis will be provided.
Formal statistical hypothesis testing will be performed on the primary and key secondary efficacy endpoints with a two-tailed test. Statistical significance will be set at < 0.05.
The intent-to-treat (ITT) population will be the primary efficacy analysis population and will include all randomized patients. Patients will be analyzed according to their randomized treatment assignment, regardless of the treatment actually received.
The safety population will be used for the analysis of safety endpoints and will include all patients who receive study medication. Patients will be analyzed according to the treatment they actually received. If all patients received treatment according to their randomized assignment, then the safety population will be identical to the ITT population and will be omitted. Analyses planned for the safety population will be performed using the ITT population.
An alternative population to be used only for the analysis of the primary and key secondary efficacy endpoints will be the per-protocol (PP) population, which will consist of all patients in the ITT population and exclude those with major protocol violations. Patients will be analyzed according to their actual treatment. The PP population will be identified prior to unblinding the treatment assignments by a team consisting of, at a minimum, a physician and a statistician.
Keywords: Conestat alfa, Ruconest, Angioedema
