Efficacy and Safety of Deucrictibant for Prophylaxis and On-demand Treatment of Angioedema Attacks in Adults with Acquired Angioedema due to C1 Inhibitor Deficiency
- Trial ID
- 2025-522051-26-00
- Protocol
- PHA022121-C308
- Sponsor
- Pharvaris Netherlands B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this study are to evaluate the efficacy of deucrictibant extended-release (XR) tablet for the prophylaxis of attacks in adults with acquired angioedema due to C1 inhibitor deficiency, and to assess the efficacy of deucrictibant soft capsule for on-demand treatment, specifically measuring the time to symptom relief during attacks. Additionally, the study aims to evaluate the safety and tolerability of the deucrictibant soft capsule for on-demand use. Secondary objectives include:
- Characterization of the efficacy of deucrictibant XR tablet in prophylactic treatment.
- Evaluation of safety and tolerability for both prophylactic and on-demand administration.
- Assessment of the pharmacokinetics of deucrictibant XR tablet during prophylaxis and the single-dose pharmacokinetics of the soft capsule in a non-attack state.
- Evaluation of the impact on health-related quality of life and disease control.
- Characterization of symptom relief and resolution of attacks during on-demand treatment.
Participants
This clinical trial includes 14 participants diagnosed with acquired angioedema due to C1 inhibitor deficiency. The study population consists of male and female patients aged 18 years or older. Eligible individuals must demonstrate a clinical history of nonpruritic swelling and undergo diagnostic confirmation through a C1INH functional level below 40%. Further diagnostic requirements include a low C1q level or positive anti-C1INH autoantibody results, alongside the absence of a family history of angioedema. For the prophylaxis phase, participants must have a history of attacks and a stable underlying condition, such as lymphoproliferative disease or immune complex disorders. Those enrolling in the on-demand treatment phase must have experienced at least two attacks within the 12 consecutive weeks preceding the screening visit.
Plans and Procedures
This Phase 3, randomized, double-blind, placebo-controlled study is organized into three distinct parts to evaluate the efficacy and safety of deucrictibant in adults with acquired angioedema due to C1 inhibitor deficiency. Part 1 is a double-blind prophylaxis phase utilizing an extended-release tablet to compare deucrictibant against a placebo in reducing the frequency of attacks over a 12-week period. Part 2 is a double-blind phase assessing the on-demand treatment efficacy of deucrictibant soft capsules compared to a placebo, specifically measuring the time to symptom relief during attacks. Part 3 consists of an open-label extension phase to evaluate the long-term safety and tolerability of the on-demand soft capsule treatment. The study sequence begins with a screening visit to confirm diagnosis through clinical history and laboratory testing, such as C1INH functional level and C1q assessments. Following successful screening and entry into the treatment phases, participants may transition through the designated parts of the protocol. The overall trial duration is estimated to conclude by September 2027. Early termination may occur based on clinical requirements or safety considerations as defined by the investigator.
Treatment
Deucrictibant (PHA-022121) is an investigational medicinal product administered via two distinct formulations. For prophylaxis, deucrictibant is provided as an extended-release (XR) tablet at a dose of 40 mg, administered through the oral route. For on-demand treatment of angioedema attacks, deucrictibant is administered as a 40 mg soft capsule via the oral route.
Placebo formulations are utilized in the double-blind phases of the study. This includes a placebo corresponding to the 40 mg extended-release tablet and a placebo corresponding to the soft capsule formulation.
Efficacy
Efficacy assessment in this study of acquired angioedema due to C1 inhibitor deficiency is divided into three distinct parts. In Part 1, which focuses on prophylaxis, the primary endpoint is the time-normalized number of investigator-confirmed attacks per 4 weeks during a 12-week treatment phase. Secondary parameters include the proportion of participants who remain attack-free, the number of attacks requiring on-demand medication, and the frequency of moderate or severe attacks. Reductions in attack rates of 50%, 70%, and 90% relative to baseline are also evaluated. Additional assessments involve plasma concentrations of deucrictibant and its metabolites at Week 6 and Week 12, urine concentrations at Week 12, and changes from baseline in the Angioedema Quality of Life (AE-QoL) total, functioning, and fears/shame domain scores at Weeks 4, 8, and 12. Other measures include the Angioedema Control Test 4-week version (AECT-4wk) at Week 12, the Patient Global Assessment (PGA), and the EuroQol 5 Dimension 5 Level (EQ-5D-5L) at Week 12.
In Part 2, which evaluates on-demand treatment, the primary endpoint is the time to symptom relief, defined as a Patient Global Impression of Change (PGI-C) rating of at least "better" sustained within 12 hours post-treatment. Secondary endpoints include the time to complete symptom resolution, defined by a Patient Global Impression of Severity (PGI-S) rating of "no symptoms" within 24 hours, and the time to onset of symptom relief. The study also monitors the time to end of progression in symptoms and the proportion of attacks achieving complete resolution. Plasma concentration-time profiles for deucrictibant and its metabolites are also analyzed.
Part 3, an open-label extension, assesses efficacy through the time to symptom relief using both PGI-C and PGI-S ratings, as well as the proportion of attacks achieving complete symptom resolution.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provision of written informed consent
- Male or female (sex at birth) aged ≥18 years at the time of providing written informed consent
- Diagnosis of AAE-C1INH based upon all of the following: a. Documented clinical history consistent with AAE-C1INH (subcutaneous or mucosal, nonpruritic swelling without accompanying urticaria) b. Diagnostic testing results to confirm AAE-C1INH: - C1INH functional level <40%, as demonstrated by chromogenic assay performed by the central laboratory as part of the screening procedures c. Absence of family history of angioedema d. At least 1 of the following: - C1q performed by the central laboratory is below the lower limit of the normal range - Documented positive anti-C1INH autoantibody test result within 6 months before the Screening Visit Note: If applicable, the confirmatory C1INH functional testing should be performed at least 5 half-lives after the last dose of C1INH therapy.
- AAE-C1INH Attacks Requirement a. Participants enrolling in Part 1 must have a history of AAE-C1INH Attacks b. New deucrictibant treatment-naïve participants enrolling directly into Part 2 must have a history of at least 2 AAE-C1INH attacks within 12 consecutive weeks prior to the Screening Visit.
- Participants enrolling in Part 1 must have stable underlying disease of AAE-C1INH, if diagnosed, defined as: a. Lymphoproliferative disease: Participant did not receive chemotherapy or immunotherapy in the 6 months before the Screening Visit. b. Immune complex disorders or monoclonal gammopathy of undetermined significance: Participant did not receive specific treatment (eg, rituximab) in the 6 months before the Screening Visit. c. Other diseases (eg, Systemic Lupus Erythematosus): Maintenance treatment should be stable for at least 6 months before the Screening Visit. In addition, the underlying condition can reasonably be expected to remain stable for the duration of Part 1 of the study in the opinion of the Investigator. This inclusion criterion is not applicable for new deucrictibant treatment-naïve participants enrolling directly into Part 2.
- Participant is assessed by the Investigator to have reliable access and ability to use available therapy to effectively manage AAE-C1INH attacks
- Female participants of childbearing potential must agree to the protocol-specified pregnancy testing and to be abstinent from heterosexual intercourse or to use an acceptable contraception method from enrollment until 30 days after the last study drug administration. There are no contraceptive requirements for male participants. Females of non-childbearing potential, defined as prepubertal, surgically sterile (status after hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or postmenopausal (defined as no menses for at least 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) test result indicative of postmenopausal status) do not require contraception during the study
- Capable of recording, without assistance, eDiary and ePRO data using an electronic device, as evidenced by the eDiary and ePRO training conducted during the Screening Period and upon entry/rollover to Part 2 and Part 3, as applicable
Exclusion Criteria
- Any concomitant diagnosis of recurrent angioedema other than AAE-C1INH
- 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 the Screening Visit (whichever is longer).
- Participants who have previously received prophylactic therapy but have stopped can participate in this study provided the last dose of the treatment was received prior to the timepoint before the Screening Visit indicated below: a. LTP therapy for AAE-C1INH (C1INH, oral kallikrein inhibitors, or anti-fibrinolytics) within 2 weeks prior to the Screening Visit b. LTP therapy for AAE-C1INH with attenuated androgens within 4 weeks prior to the Screening Visit c. LTP monoclonal antibody therapy for AAE-C1INH (ie, lanadelumab) within 10 weeks prior to the Screening Visit d. Short-term prophylaxis for AAE-C1INH within 1 week prior to the Screening Visit. Short-term prophylaxis is defined as intravenous C1INH, or attenuated androgens to avoid angioedema complications from medically indicated procedures Note: In case of prophylactic treatments not listed above, please consult with the Sponsor. Participants who are receiving LTP treatment for AAE-C1INH and are satisfied with this treatment are not eligible for this study. This exclusion criterion is not applicable to participants enrolling directly into Part 2.
- 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 the Child-Pugh Scoring System), or history of clinically significant abnormal hepatic function. Participants with Gilbert’s syndrome, defined as an 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 calculated by CKD-EPI formula] <60 mL/min/1.73 m2 )
- Any current clinically significant cardiovascular disease (eg, angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, uncontrolled hypertension, bradycardia, or any other clinically significant cardiovascular abnormality) 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) that may impact study drug absorption
- Evidence of current alcohol or drug 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) at the time of the Screening Visit
- Known hypersensitivity to deucrictibant or any of the excipients of the study drug
- Use of angiotensin-converting enzyme inhibitors or any estrogen-containing medications with systemic absorption within 5 half-lives before the Screening Visit
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 23 Feb 2026 | 1 |
 Bulgaria | Recruiting | 23 Feb 2026 | 1 |
 France | Recruiting | 23 Feb 2026 | 3 |
 Germany | Recruiting | 23 Feb 2026 | 2 |
 Hungary | Recruiting | 23 Feb 2026 | 1 |
 Italy | Recruiting | 23 Feb 2026 | 5 |
 The Netherlands | Recruiting | 23 Feb 2026 | — |
 Poland | Recruiting | 23 Feb 2026 | 2 |
 Spain | Recruiting | 23 Feb 2026 | 2 |
| Netherlands | — | — | 1 |
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 |
|---|---|---|---|---|---|---|
Placebo for Deucrictibant 40mg extended release tablets | Placebo | N/A | — | — | — | N/A |
DeucrictibantPHA-022121 | Test | TABLET | ORAL | 40 | 12 | PRD10561204 |
DeucrictibantPHA-022121 | Test | SOFT CAPSULE | ORAL | 40 | 40 | PRD11078990 |
Placebo for Deucrictibant
20mg soft
capsules | Placebo | N/A | — | — | — | N/A |