Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Deucrictibant XR for Prophylaxis of Angioedema Attacks in Hereditary Angioedema Patients
- Trial ID
- 2024-516247-62-00
- Protocol
- PHA022121-C305
- Sponsor
- Pharvaris Netherlands B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of deucrictibant 40 mg extended-release (XR) tablet compared with placebo for prophylaxis against angioedema attacks in individuals with **Hereditary Angioedema** (HAE). This is clinically relevant as it aims to provide a potential therapeutic option for reducing the frequency and severity of angioedema attacks, which can significantly impact the quality of life and health outcomes in affected patients.
Secondary objectives include:
- Characterizing the efficacy of deucrictibant 40 mg XR tablet in the prophylactic treatment of HAE.
- Evaluating the safety and tolerability of deucrictibant 40 mg XR tablet in the prophylactic treatment of HAE.
- Assessing the pharmacokinetics (PK) of deucrictibant 40 mg XR tablet in the prophylactic treatment of HAE.
- Evaluating the impact on health-related quality of life (HRQoL) of deucrictibant 40 mg XR tablet in the prophylactic treatment of HAE.
Participants
The clinical trial involves a total of **38 participants** diagnosed with **Hereditary Angioedema** (HAE). The study population includes both male and female subjects, with an age range starting from 12 years and above, encompassing adolescents and adults. Participants were selected based on a documented clinical history consistent with HAE, including nonpruritic swelling without urticaria, and diagnostic testing confirming a C1INH functional level below 50% of the normal level. The trial includes individuals who have experienced at least three HAE attacks in the three months prior to screening. Participants are required to have reliable access to standard care treatments for managing acute HAE attacks. The study population is characterized by its inclusion of a vulnerable population, with considerations for adherence to protocol requirements, including eDiary and ePRO data recording. Female participants of childbearing potential must comply with specified pregnancy testing and contraception requirements. The trial does not specify particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of orally administered deucrictibant extended-release tablets for the prophylaxis against angioedema attacks in adolescents and adults with **hereditary angioedema**. The trial aims to compare the efficacy of deucrictibant 40 mg extended-release tablets with a placebo over a 24-week treatment period. The primary endpoint is the time-normalized number of investigator-confirmed hereditary angioedema attacks during this period. Secondary endpoints include the number of attacks treated with on-demand medication, the severity of attacks, and the proportion of participants achieving significant reductions in attack rates.
The trial is expected to commence recruitment on January 13, 2025, and conclude by May 15, 2026. Participants will be involved in the study for a maximum of 24 weeks, with the possibility of early termination if they experience adverse events or fail to adhere to protocol requirements. The study includes a screening visit to confirm eligibility, followed by a run-in period where participants must experience a specified number of investigator-confirmed attacks. The treatment phase consists of regular follow-up visits to monitor safety and efficacy, with the final visit marking the end of the study.
Inclusion criteria require participants to provide written informed consent, be aged 12 years or older, and have a documented clinical history consistent with hereditary angioedema. Participants must have experienced at least three attacks in the three months prior to screening and demonstrate reliable access to standard care treatments. Exclusion criteria are not specified in the provided data. The study will utilize deucrictibant tablets and a placebo, with the active substance being administered orally. The trial is not classified as low intervention and is categorized as a Phase III therapeutic use confirmatory clinical trial.
Treatment
The clinical trial involves the evaluation of **Deucrictibant (PHA-022121)**, an experimental medication formulated as an extended-release tablet. The active substance, **deucrictibant**, is of chemical origin. The pharmaceutical form is a tablet, and it is administered orally. The maximum daily dose is 40 mg, with a total maximum dose of 6720 mg over a treatment period of up to 24 weeks. The trial aims to assess the efficacy of deucrictibant for prophylaxis against angioedema attacks in individuals with hereditary angioedema. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to the experimental treatment, the study includes the use of **ICATIBANT** as a comparator treatment. Icatibant is a solution for injection, administered subcutaneously. The active substance, **icatibant**, is also of chemical origin. The maximum daily dose is 90 mg, with a total maximum dose of 5760 mg over a treatment period of up to 8 weeks. Icatibant serves as a standard-of-care therapy in this trial, providing a basis for comparison with the experimental treatment.
The study also incorporates a placebo group, using tablets matched to the test product deucrictibant extended-release tablets, with the exception of the active substance. The placebo is administered orally, following the same dosing schedule as the experimental treatment, to ensure blinding and unbiased assessment of the treatment's efficacy. Participant adherence to the dosing regimen will be closely monitored to maintain the integrity of the trial results.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **time-normalized number of Investigator-confirmed Hereditary Angioedema (HAE) attacks** during the 24-week treatment period, from Day 1 through Day 168. This primary endpoint will be measured per 4 weeks to determine the frequency of HAE attacks. Secondary endpoints include the time-normalized number of HAE attacks treated with on-demand medication, the number of moderate or severe attacks, and the number of severe attacks during the same period. Additionally, the proportion of participants achieving a reduction in HAE attack rate by 50%, 70%, and 90% relative to baseline will be assessed, as well as the proportion of participants who remain attack-free and the proportion of time without angioedema symptoms.
Further efficacy assessments will involve changes in clinical laboratory tests, vital signs, and electrocardiogram (ECG) parameters from baseline. The study will also evaluate the plasma concentration-time profiles of deucrictibant. Patient-reported outcomes will be collected using validated instruments such as the Angioedema Quality of Life (AE-QoL) questionnaire, Patient Global Assessment of Change (PGA-Change), Angioedema Control Test 4-week version (AECT-4wk), Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP), and the Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9). These assessments will provide comprehensive data on the efficacy of deucrictibant in reducing the frequency and severity of HAE attacks and improving the quality of life for participants.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provision of written informed consent. At the time of signing informed consent, male and female participants must be aged ≥12 years. Adolescent participants (ie, aged ≥12 to <18 years or as determined by local law) must also be ≥40 kg in body weight at Screening. If the participant is an adolescent, written assent will be obtained from the participant and consent will be obtained from the participant’s parent/legally designated representative/guardian, per local regulations. A participant who is an adolescent will sign the ICF if they reach the age of 18 years or as determined by local law during their participation in the study.
- Participants who previously completed Study PHA022121-C306 may be eligible to be screened for this study. For these participants, there is no need to repeat HAE diagnostic test as described in Inclusion Criterion #3 if the C1INH function was confirmed by the central laboratory in Study PHA022121-C306.
- Diagnosis of HAE type 1/2 or type 3 based on the following: a. For participants with HAE type 1/2: • Documented clinical history consistent with HAE (cutaneous or submucosal, nonpruritic swelling without accompanying urticaria) • At least one of the following: − Age at reported onset of first angioedema symptoms ≤30 years − Family history consistent with HAE − C1q above the lower limit of the normal range by central laboratory as part of the Screening assessments • Diagnostic testing results to confirm HAE: − C1INH functional level <50% of the normal level must be shown by chromogenic assay performed by the central laboratory as part of the Screening procedures. Participants with functional C1INH level 40% to <50% of the normal level must also have a C4 level below the normal range. b. For participants with HAE type 3: • Recurrent angioedema attacks with diagnostic testing results obtained during Screening to confirm C1INH function ≥50% of normal and C4 level not below the lower level of the normal range performed by the central laboratory • Must meet one of the following: − Documented genetic mutation associated with HAE type 3 as listed in the HAEA and WAO/EAACI Guidelines (Appendix 2) Or − If no documented genetic mutation: - Clinical diagnosis with family history of HAE type 3 and an elevated BK peptide level previously confirmed by a commercially available liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay And - Attacks not responding to treatments with high-dose antihistamine (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine medication) and no clinical attack symptom relief if treated with corticosteroid, montelukast, or omalizumab • Documented effective attack symptom relief with on-demand icatibant treatment
- History of at least 3 HAE attacks within the 3 consecutive months prior to Screening Visit
- Participants must experience at least XX Investigator-confirmed attacks during the up to 8 week Run-in Period
- Participant is assessed by the Investigator to have reliable access and ability to use standard of care on-demand treatments to effectively manage acute HAE attacks.
- Investigator considers that the participant (and parent/legally designated representaive/guardian for adolescent participants) is willing and able to adhere to all protocol requirements, including ensuring that the participant is capable of, and compliant with, eDiary and ePRO data recording
- Female participants of childbearing potential (or who become of childbearing potential during the study) must agree to the protocol specified pregnancy testing and to be abstinent from heterosexual intercourse or to use a highly effective contraception method as defined in the protocol (Section 8.2.2) and as available locally, from enrollment until 30 days after the last study drug administration.
Exclusion Criteria
- Any diagnosis of angioedema other than HAE
- Participation in a clinical study with any other investigational drug within the last 30 days or within 5 half-lives of the investigational drug at Screening (whichever was longer)
- Has received prior prophylactic treatment or on-demand treatment with deucrictibant, with the exception of participants from Study PHA022121-C306
- Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks of Screening
- Prior gene therapy for any indication at any time
- Receiving prophylactic treatment for HAE and are satisfied with this treatment. Patients who are not satisfied (eg, tolerability issues, lack of efficacy) and have previously stopped long-term prophylactic HAE treatment can sign the ICF and begin the Screening Period only if their last dose of treatment was received prior to the time point before Screening indicated below: a. Long-term prophylactic therapy for HAE (with C1INH, oral kallikrein inhibitors, or anti fibrinolytics): 2 weeks prior to Screening b. Long-term prophylactic therapy for HAE with attenuated androgens: 4 weeks prior to Screening c. Long-term prophylactic monoclonal antibody therapy for HAE (ie, lanadelumab): 5 half-lives prior to Screening d. Short-term prophylaxis for HAE: 7 days prior to Screening Note: Short-term prophylaxis is defined as intravenous (iv) C1INH to avoid angioedema complications from medically indicated procedures
- Any females who are pregnant, plan to become pregnant, or are currently breast-feeding
- Abnormal hepatic function (aspartate aminotransferase [AST] >2× upper limit of normal [ULN], alanine aminotransferase [ALT] >2× ULN, or total bilirubin >1.5× ULN or any hepatic impairment via Child-Pugh Scoring System. Participants with Gilbert’s syndrome, defined as isolated increase of total bilirubin ≤3× ULN and AST and ALT within the normal range, are not excluded
- Moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2)
- Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, uncontrolled hypertension, bradycardia, or any other clinically significant cardiovascular abnormality within the previous year that, in the opinion of the Investigator, would interfere with the participant's safety or ability to participate in the study
- History of epilepsy and/or other significant neurological diseases
- Any clinically significant and uncontrolled gastrointestinal dysfunction (eg, chronic diarrhea, inflammatory bowel disease) which impacts study drug absorption
- History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse
- Use of concomitant medications with systemic absorption and foods that are moderate and strong inhibitors of cytochrome P450 (CYP) 3A4 such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, and grapefruit juice or strong inducers of CYP3A4 such as carbamazepine, phenytoin, and rifampin within the last 30 days or within 5 half-lives (whichever is longer) of the time of randomization
- Known hypersensitivity to deucrictibant or any of the excipients of the study drug
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 13 Jan 2025 | 4 |
 France | Not Recruiting | 13 Jan 2025 | 2 |
 Germany | Not Recruiting | 13 Jan 2025 | 2 |
 Hungary | Not Recruiting | 13 Jan 2025 | 5 |
 Ireland | Not Recruiting | 13 Jan 2025 | 1 |
 Italy | Not Recruiting | 13 Jan 2025 | 10 |
 Poland | Not Recruiting | 13 Jan 2025 | 3 |
 Romania | Not Recruiting | 13 Jan 2025 | 2 |
 Slovakia | Not Recruiting | 13 Jan 2025 | 2 |
 Spain | Not Recruiting | 13 Jan 2025 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Matched to test Product Deucrictibant extended release tablets with the exception of active substance | Placebo | N/A | — | — | — | N/A |
DeucrictibantPHA-022121 | Test | TABLET | ORAL | 40 | 24 | PRD10561204 |
ICATIBANT | Other | — | SUBCUTANEOUS INJECTION | 90 | 8 | SUB08104MIG |