Phase 3 Randomized Double-Blind Placebo-Controlled Crossover Study of Deucrictibant for On-Demand Treatment of Hereditary Angioedema Attacks in Adolescents and Adults
- Trial ID
- 2023-507268-37-00
- Protocol
- PHA022121-C306
- Sponsor
- Pharvaris Netherlands B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of deucrictibant as an on-demand treatment compared with placebo for the onset of symptom relief during **hereditary angioedema** (HAE) attacks. This is clinically relevant as it aims to provide a rapid therapeutic option for managing acute HAE episodes, potentially improving patient outcomes and quality of life.
Secondary objectives include:
- Evaluating the efficacy of deucrictibant compared with placebo on symptom relief and resolution of HAE attacks.
- Assessing the safety and tolerability of deucrictibant compared with placebo for on-demand treatment of HAE attacks.
- Assessing the pharmacokinetics of deucrictibant in adolescent participants (aged 12 to <18 years) in a non-attack state.
Participants
The clinical trial involves a total of **71 participants** diagnosed with **Hereditary Angioedema** (HAE). The study population includes both male and female subjects, aged between 12 and 75 years. Participants were selected based on a documented clinical history consistent with HAE, with diagnostic testing confirming HAE-1/2. The trial includes individuals who have experienced at least two HAE attacks in the three months prior to screening and have experience with standard-of-care treatment for managing on-demand HAE attacks. Participants receiving long-term prophylactic therapy with specific medications for HAE must have been on a stable dose for at least six months before the screening visit. The study population is capable of independently recording electronic HAE diary and ePRO data. The trial includes a vulnerable population, with adolescent participants aged 12 to less than 18 years required to have a body weight of at least 40 kg. The selection criteria ensure that participants are willing and able to comply with the study protocol, with female participants of childbearing potential agreeing to specified pregnancy testing and contraception requirements.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, crossover study** to evaluate the efficacy of **deucrictibant** as an on-demand treatment for attacks in adolescents and adults with **hereditary angioedema** (HAE). The trial aims to assess the time to onset of symptom relief, with the primary endpoint being the time to achieve a Patient Global Impression of Change (PGI-C) rating of at least "a little better" for two consecutive timepoints within 12 hours post-treatment. Secondary endpoints include various measures of symptom relief and resolution, such as the proportion of attacks achieving substantial symptom relief and the time to complete symptom resolution.
The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of HAE, and history of HAE attacks. Participants will be required to provide written informed consent, and for minors, consent will be obtained from a parent or legal guardian. Following the screening, participants will be randomized to receive either deucrictibant or a placebo in a crossover design, ensuring each participant receives both treatments at different times. Follow-up visits will be scheduled to monitor the participants' response to the treatment and to collect data on the efficacy and safety of the intervention. The end-of-study visit will conclude the trial, where final assessments will be conducted.
The expected duration of participant involvement is up to 42 days, with the trial estimated to end by September 2025. Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with the study protocol, or choose to withdraw consent. The trial will adhere to strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study period.
Treatment
The clinical trial involves the administration of **Deucrictibant (PHA-022121)**, an experimental medication formulated as a soft capsule. The active substance, **deucrictibant**, is of chemical origin. The medication is administered orally with a maximum daily dose of 40 mg, and the treatment period extends up to 42 days. The primary objective of the trial is to evaluate the efficacy of deucrictibant as an on-demand treatment for symptom relief during attacks of hereditary angioedema (HAE) in adolescents and adults. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to deucrictibant, the trial includes the use of **Icatibant**, a non-experimental treatment serving as a comparator. Icatibant is also of chemical origin and is administered orally. The maximum daily dose for icatibant is 60 mg, with a treatment period of up to 42 days. This comparator treatment is included to assess the relative efficacy of deucrictibant in managing HAE attacks.
A **placebo** is also utilized in this study, designed to match the deucrictibant soft capsules in appearance but lacking the active substance. The placebo is used in a double-blind manner to ensure unbiased assessment of the treatment's efficacy. The placebo administration follows the same oral route and dosing schedule as the experimental medication, providing a control for evaluating the onset of symptom relief during HAE attacks.
Efficacy
The efficacy of Deucrictibant (PHA-022121) in the treatment of **Hereditary Angioedema (HAE)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to onset of symptom relief, which is defined as a Patient Global Impression of Change (PGI-C) rating of at least "a little better" for two consecutive timepoints within 12 hours post-treatment. Secondary endpoints include the proportion of study drug-treated attacks achieving a PGI-C rating of at least "a little better" at 4 hours post-treatment, time to substantial symptom relief, and time to complete symptom resolution, among others.
These efficacy parameters will be measured using validated scales such as the PGI-C and the Patient Global Impression of Severity (PGI-S), as well as the Angioedema SyMptom Rating Scale (AMRA). The assessments will be conducted at various timepoints, including 4 hours, 12 hours, and 24 hours post-treatment, to capture the progression and resolution of symptoms. The data collected will be analyzed to determine the effectiveness of Deucrictibant in providing on-demand relief during HAE attacks compared to placebo.
Inclusion and Exclusion Criteria
Inclusion Criteria
- In the opinion of the Investigator, the participant (and parent/caregiver for adolescent participants) is willing and able to comply with the protocol.
- Male or female, aged ≥12 to ≤75 years at the time of providing written informed consent/assent.
- Diagnosis of HAE based upon the following: a. For participants with HAE type 1 or type 2 (type 1/2): • Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling without accompanying urticaria) • At least one of the following: − Age ≤30 years at reported onset of first angioedema symptoms − Family history consistent with HAE type 1/2 − C1q performed by the central laboratory is above the lower limit of the normal range • Diagnostic testing results to confirm HAE type 1/2: − Participants on long-term prophylactic HAE therapies with C1-INH or danazol at the time of study entry must provide documentation of a historical laboratory test showing C1-INH functional level <50%. Note: If a confirmatory C1-INH test is required, the sample should be collected at least 5 half-lives after the last dose of C1-INH or danazol. This procedure will not be considered an interruption of stable LTP treatment. For all other participants with HAE type 1/2, C1-INH functional level of <50% must be shown by chromogenic assay performed by the central laboratory as part of the screening procedures. b. For participants with HAE type 3: • Recurrent angioedema attacks with diagnostic testing results obtained during screening to confirm C1-INH function ≥50% of normal and C4 level not below lower level of normal range performed by the central laboratory Note: The C1-INH sample should be collected at least 5 half-lives after the last dose of C1-INH therapy, if applicable. • Must meet one of the following: − Documented genetic mutation associated with HAE type 3 as listed in the Hereditary Angioedema Association (HAEA) and World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) Guidelines (Appendix 1) OR − If no documented mutation: o Clinical diagnosis with family history of HAE type 3 and an elevated BK peptide level confirmed by a commercially available assay AND o 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 symptoms relief if treated with corticosteroid, montelukast, or omalizumab • Documented effective attack symptom relief with on-demand icatibant treatment
- History of at least 2 HAE attacks in the last 3 months before screening.
- Experience with using standard-of-care treatment to effectively manage on-demand treatment for HAE attacks.
- Either: Is on a stable dose and regimen of long-term prophylactic therapy with one of the following medications indicated for HAE: plasma-derived C1-INH, ≤ 200 mg/day, anti-fibrinolytics, berotralstat, or lanadelumab, for at least 6 months before the Screening Visit and intend to remain on the same dose for the duration of the study. OR Is receiving only on-demand treatment, and has not used long-term prophylactic treatment within the following durations before the Screening Visit, as specified below: − Plasma-derived C1-INH, berotralstat, anti-fibrinolytics, or attenuated androgens for at least 2 weeks − Lanadelumab for at least 10 weeks
- Capable of recording, without assistance, electronic HAE diary and ePRO data using an electronic device, as evidenced by the competency assessment conducted during the Screening Phase.
- For adolescent participants aged ≥12 to <18 years: body weight ≥40 kg.
- Provision of written informed consent. If the participant is a minor (i.e., <18 years of age or as determined by local law), consent will be obtained from the participant’s parent/legally designated representative/guardian, and written assent will be obtained from the participant, per country regulations.
- 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 an acceptable contraception method, as defined in the protocol and as available locally, from enrollment until 30 days after the last study drug administration. There are no contraceptive requirements for male participant.
Exclusion Criteria
- Any female who is pregnant, plans to become pregnant, or is breastfeeding.
- Any diagnosis of angioedema other than HAE.
- Any clinically significant comorbidity or systemic dysfunction (e.g., cardiovascular, gastrointestinal, renal, neurological, respiratory) that, in the opinion of the Investigator, would interfere with the participant’s safety or ability to participate in the study.
- Use of attenuated androgens for short-term prophylaxis within 2 weeks before screening.
- Abnormal hepatic function (aspartate aminotransferase [AST] >2×upper limit of normal [ULN], alanine aminotransferase [ALT] >2×ULN, or total bilirubin >1.5×ULN, or Child-Pugh class B or C). Participants with Gilbert’s syndrome, being defined as an isolated increase in total bilirubin ≤3×ULN, with AST and ALT in the normal range, will not be excluded.
- Abnormal renal function (estimated glomerular filtration rate <60 mL/min/1.73 m2).
- History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse.
- Has received prior on-demand HAE treatment with deucrictibant.
- Currently participating in any other investigational drug study or receiving other investigational treatment within the last 30 days, or within 5 half-lives (whichever is longer) of the time of randomization.
- Prior gene therapy for any indication at any time.
- Use of concomitant medications with systemic absorption that are strong inhibitors of CYP3A4, (such as clarithromycin, itraconazole, ketoconazole, and ritonavir) or strong inducers of CYP3A4 (such as carbamazepine and phenytoin) 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 study drug.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 24 Jun 2024 | 6 |
 Bulgaria | Not Recruiting | 24 Jun 2024 | 9 |
 Czechia | Not Recruiting | 24 Jun 2024 | 3 |
 France | Not Recruiting | 24 Jun 2024 | 4 |
 Germany | Not Recruiting | 24 Jun 2024 | 8 |
 Hungary | Not Recruiting | 24 Jun 2024 | 3 |
 Ireland | Not Recruiting | 24 Jun 2024 | 2 |
 Italy | Not Recruiting | 24 Jun 2024 | 16 |
 The Netherlands | Not Recruiting | 24 Jun 2024 | — |
 Poland | Not Recruiting | 24 Jun 2024 | 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 |
|---|---|---|---|---|---|---|
DeucrictibantPHA-022121 | Test | SOFT CAPSULE | ORAL | 40 | 42 | PRD11078990 |
ICATIBANT | Other | PHF00231MIG | ORAL | 60 | 42 | SCP51825813 |
Placebo matches Deucritibant soft capsules with exception of active substance. | Placebo | N/A | — | — | — | N/A |