Phase II Double-Blind, Placebo-Controlled Study of PHA-022121 for Prophylaxis of Hereditary Angioedema Attacks in C1-Inhibitor Deficiency Patients
- Trial ID
- 2023-505549-18-00
- Protocol
- PHA022121-C301
- Sponsor
- Pharvaris Netherlands B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of two dose regimens of PHA-022121 when administered as prophylaxis against attacks of **hereditary angioedema** (HAE) due to C1-Inhibitor Deficiency (Type I or Type II). Additionally, the study aims to assess the efficacy of these dose regimens in preventing HAE attacks. The clinical relevance of this objective lies in the potential to provide a safe and effective prophylactic treatment option for patients suffering from HAE, a condition characterized by recurrent episodes of severe swelling.
The secondary objectives include:
- Characterizing the pharmacokinetics/pharmacodynamics (PK/PD) of two dose regimens of PHA-022121 administered as prophylaxis against HAE attacks.
- Evaluating the impact on quality of life (QoL) of these dose regimens.
- Assessing the efficacy of PHA-022121 as a long-term prophylactic treatment for HAE.
- Evaluating the PK/PD of PHA-022121 when used as a long-term prophylactic treatment.
- Assessing the impact on QoL of PHA-022121 administered as long-term prophylactic treatment.
Participants
The clinical trial involves a total of **13 participants** diagnosed with **hereditary angioedema** due to C1-Inhibitor Deficiency (Type I or Type II). The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on a documented clinical history consistent with hereditary angioedema, with diagnostic testing confirming the condition. The trial population is characterized by a history of at least three hereditary angioedema attacks within the last three months prior to screening. Participants are required to have a body weight of at least 40 kg and must demonstrate the ability to manage acute attacks with standard care treatments. The study includes individuals who are assessed to have reliable access to healthcare and the capability to adhere to protocol requirements, including data recording. Female participants of childbearing potential are required to adhere to specific contraceptive measures during the study. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are capable of complying with the study's demands and have provided informed consent. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety and efficacy of PHA-022121, a **Bradykinin B2 receptor antagonist**, administered orally for the prophylaxis of angioedema attacks in patients with **hereditary angioedema** due to C1-Inhibitor Deficiency (Type I or Type II). The trial is structured in two parts, with Part 1 focusing on dose-ranging and Part 2 on long-term safety. The study is expected to last approximately 36 months, with participant involvement spanning from the initial screening to the end-of-study visit.
Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and history of hereditary angioedema attacks. Following successful screening, participants will be randomized to receive either PHA-022121 or a placebo. The treatment period in Part 1 will last 84 days, during which the primary efficacy endpoint will be the number of investigator-confirmed hereditary angioedema attacks, expressed as the normalized number of attacks per month. Secondary endpoints include the number of moderate or severe attacks and the number of attacks requiring acute treatment.
Follow-up visits will be scheduled to monitor safety and efficacy, with data collected through electronic Patient Reported Outcome (ePRO) tools. The end-of-study visit will conclude the participant's involvement, assessing long-term safety and summarizing the efficacy endpoints. Participants are expected to adhere to protocol requirements, including reliable access to standard care treatments for acute attacks and compliance with data recording. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse events that compromise participant safety.
Treatment
The clinical trial involves the administration of **PHA-022121**, an experimental medication designed as a **Bradykinin B2 receptor antagonist** for the oral treatment of **hereditary angioedema**. The pharmaceutical form of PHA-022121 is a soft capsule, and it is administered orally. The dosing regimen includes a maximum daily dose of 20 mg, with a total maximum dose of 40 mg over a treatment period of up to 36 weeks. The active substance in PHA-022121 is chemically synthesized and identified as (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide. The medication is developed by Pharvaris Netherlands B.V.
The study also includes a **placebo** group for comparison purposes. The placebo is designed to match the experimental medication in appearance but does not contain any active pharmaceutical ingredients. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered in the same manner as PHA-022121, following the same oral route and dosing schedule. This allows for an accurate assessment of the safety and efficacy of PHA-022121 in comparison to a non-active treatment.
Efficacy
The efficacy of PHA-022121 in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint in Part 1 of the study is the number of investigator-confirmed **hereditary angioedema (HAE)** attacks during the treatment period, expressed as the normalized number of attacks per month (4 weeks) of exposure. Secondary efficacy endpoints include the number of moderate or severe HAE attacks, the number of attacks requiring acute treatment, and the number of patients achieving significant reductions in attack rates relative to baseline. Additionally, the time to the first investigator-confirmed HAE attack and the number of attacks resulting in emergency department visits or hospital admissions will be evaluated.
In Part 2 of the study, efficacy endpoints include the number of investigator-confirmed angioedema attacks, the number of moderate or severe attacks, and the number of attacks requiring acute treatment. The incidence of HAE attacks and the proportion of days with angioedema symptoms will also be assessed. The analysis of these endpoints will be performed descriptively, with the number of attacks expressed as the normalized number per month of exposure. The efficacy assessments will be conducted using an intention-to-treat (ITT) analysis set, and all statistical tests comparing treatments will be descriptive without adjustment for multiplicity.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Each patient must meet the following criteria to be enrolled in this study. 1. Male or female patients aged ≥ 18 to ≤ 75 years at screening.
- Diagnosis of HAE (type I or II) based upon all of the following: a. Documented clinical history consistent with HAE (subcutaneous and/or mucosal swelling without accompanying wheals) b. At least one of the following: - Age at reported onset of first angioedema symptoms ≤ 30 years - Family history consistent with HAE type I or II - C1q within normal range c. Diagnostic testing results to confirm HAE type I or II: - C1-INH functional level < 50% of the normal level. The diagnosis should be documented prior to randomization by a local or central laboratory value documented in the medical records Note: For patients who receive any form of C1-INH replacement, the last dose before the confirmatory C1-INH testing should be given at least 5 half-lives before the date of sampling.
- Documented history of at least 3 HAE attacks within the last 3 consecutive months prior to screening. If the patient has no documentation or has less than 3 attacks in the 3 months before the screening visit, or was on prophylactic treatment, patient must experience a minimum of 2 HAE attacks during the screening period (up to 8 weeks).
- Is assessed by the investigator to have reliable access and ability to use standard of care treatments alone to effectively manage acute HAE attacks.
- Body weight of ≥ 40 kg at screening.
- Investigator considers that the patient is willing and able to adhere to all protocol requirements, including being capable of and compliant with data recording into an electronic Patient Reported Outcome (ePRO) tool.
- Female patients of childbearing potential must agree to the protocol specified pregnancy testing and to practice abstinence from heterosexual intercourse in line with the preferred and usual lifestyle of the patient or to use a medically acceptable form of contraception methods from enrollment until 30 days after the last IMP administration. Methods acceptable for this study include male condom with or without spermicide, cervical cap, diaphragm or sponge with spermicide, a combination of male condom with cap, diaphragm or sponge with spermicide (double-barrier methods), combined or progestin-only hormonal methods (oral, injectable, or implantable), intrauterine device (IUD, all types), intrauterine hormone releasing systems (IUS). Females of non-childbearing potential, defined as surgically sterile(status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal (defined as no menses for at least 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) test result indicative of post-menopausal status) do not require contraception during the study. There are no contraceptive requirements for male patients.
- The patient has provided informed consent.
Exclusion Criteria
- Patients who meet any of the following criteria will be excluded from the study. 1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE) with C1-INH deficiency, angioedema with normal C1-INH levels (HAE type III), idiopathic nonhistaminergic angioedema, or recurrent angioedema associated with urticaria.
- Participation in a clinical trial with any other investigational drug within the last 30 days or within 5 half-lives of IMP at screening (whichever was longer). Previous participation in the Study PHA022121- C201 is permitted.
- Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks of screening.
- Receiving prophylactic treatment for HAE. Patients who have previously received prophylactic therapy but have stopped, can participate in this study provided a sufficiently long washout period is observed before the patient is screened. Exclusion includes use of: a. long-term prophylactic therapy for HAE (C1-INH, oral kallikrein inhibitors, attenuated androgens, or anti-fibrinolytics) within 2 weeks prior to screening b. long-term prophylactic monoclonal therapy for HAE (i.e., lanadelumab) within 11 weeks prior to screening c. short-term prophylaxis for HAE within 7 days prior to screening Short-term prophylaxis is defined as intravenous C1-INH, attenuated androgens, or antifibrinolytics to avoid angioedema complications from medically indicated procedures. Note: Patients who are receiving long-term prophylactic treatment for HAE and are satisfied with this treatment, are not eligible for this study. Patients who have previously stopped long-term prophylactic HAE treatment because of intolerance or lack of efficacy can enter the study with a sufficiently long wash-out period as defined in Exclusion Criterion #4 for the different HAE therapies.
- Clinically significant abnormal electrocardiogram (ECG), most notably a QTcF > 470 milliseconds (for women) or > 450 milliseconds (for men).
- Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, uncontrolled hypertension (systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg), bradycardia (heart rate < 50 beats per minute) or any other cardiovascular abnormality within the previous year.
- Any other systemic disease (e.g., gastrointestinal, renal, respiratory, neurological) or significant disease or disorder that would interfere with the patient's safety or ability to participate in the study.
- 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). Patients with Gilbert's syndrome, being defined as isolated increase of total bilirubin ≤3xULN and AST and ALT within the normal range, are not excluded.
- Abnormal renal function (estimated glomerular filtration rate [eGFR] CKD-EPI < 60 mL/min/1.73 m2).
- History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse.
- Use of concomitant medications that are strong inhibitors of CYP3A4 such as clarithromycin, itraconazole, ketoconazole, ritonavir, and grapefruit as well as inducers of CYP3A4 such as phenobarbital, phenytoin, rifampicin, and St. John's Wort.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 09 Mar 2022 | 2 |
 Bulgaria | Not Recruiting | 09 Mar 2022 | 5 |
 Germany | Not Recruiting | 09 Mar 2022 | 2 |
 Ireland | Not Recruiting | 09 Mar 2022 | 1 |
 Italy | Not Recruiting | 09 Mar 2022 | 6 |
 Poland | Not Recruiting | 09 Mar 2022 | 5 |
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 |
|---|---|---|---|---|---|---|
PHA-022121 | Test | CAPSULE, SOFT | ORAL USE | 20 | 36 | PRD8312853 |
Placebo for PHA-022121 | Placebo | N/A | — | — | — | N/A |