CHAPTER-3 – A randomised clinical trial to assess efficacy and safety of deucrictibant treatment in prophylaxis against HAE attacks in adults and adolescents

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharvaris Netherlands B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

10 Mar 2025 → ongoing

Decision date (initial)

2025-02-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharvaris Netherlands B.V.

External identifiers

EU CT number

2024-516247-62-00

ClinicalTrials.gov

NCT06669754

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Prophylaxis, Efficacy

To evaluate the efficacy of deucrictibant 40 mg extended release (XR) tablet compared with placebo for prophylaxis against angioedema attacks

Secondary objectives 4

1. To characterize the efficacy of deucrictibant 40 mg XR tablet in prophylactic treatment of hereditary angioedema (HAE)
2. To evaluate the safety and tolerability of deucrictibant 40 mg XR tablet in prophylactic treatment of HAE
3. To evaluate the pharmacokinetics (PK) of deucrictibant 40 mg XR tablet in prophylactic treatment of HAE
4. To evaluate the impact on health-related quality of life (HRQoL) of deucrictibant 40 mg XR tablet in prophylactic treatment of HAE

Conditions and MedDRA coding

Hereditary Angioedema

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003090-PIP02-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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.
2. 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.
3. 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
4. History of at least 3 HAE attacks within the 3 consecutive months prior to Screening Visit
5. Participants must experience at least XX Investigator-confirmed attacks during the up to 8 week Run-in Period
6. 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.
7. 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
8. 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 15

1. Any diagnosis of angioedema other than HAE
2. 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)
3. Has received prior prophylactic treatment or on-demand treatment with deucrictibant, with the exception of participants from Study PHA022121-C306
4. 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
5. Prior gene therapy for any indication at any time
6. 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
7. Any females who are pregnant, plan to become pregnant, or are currently breast-feeding
8. 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
9. Moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2)
10. 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
11. History of epilepsy and/or other significant neurological diseases
12. Any clinically significant and uncontrolled gastrointestinal dysfunction (eg, chronic diarrhea, inflammatory bowel disease) which impacts study drug absorption
13. History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse
14. 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
15. Known hypersensitivity to deucrictibant or any of the excipients of the study drug

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time-normalized (per 4 weeks) number of Investigator confirmed HAE attacks during the 24 week Treatment Period (Day 1 through Day 168)

Secondary endpoints 18

1. Time-normalized number of Investigator confirmed HAE attacks treated with on-demand medication during the 24 week Treatment Period
2. Time-normalized number of Investigator confirmed moderate or severe HAE attacks during the 24 week Treatment Period
3. Time-normalized number of Investigator confirmed severe HAE attacks during the 24 week Treatment Period
4. Proportion of participants achieving ≥50% reduction in HAE attack rate relative to baseline during the 24 week Treatment Period
5. Proportion of participants achieving ≥70% reduction in HAE attack rate relative to baseline during the 24 week Treatment Period
6. Proportion of participants achieving ≥90% reduction in HAE attack rate relative to baseline during the 24 week Treatment Period
7. Proportion of participants that are HAE attack-free during the 24 week Treatment Period
8. Proportion of time without angioedema symptoms during the 24 week Treatment Period
9. Treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), adverse events of special interest (AESIs), and TEAEs leading to study drug discontinuation
10. Changes in clinical laboratory tests from baseline
11. Changes in vital signs from baseline
12. Changes in electrocardiogram (ECG) parameters from baseline
13. Deucrictibant plasma concentration-time profiles
14. Angioedema Quality of Life (AE-QoL) questionnaire
15. Patient Global Assessment of Change (PGA-Change)
16. Angioedema Control Test 4-week version (AECT-4wk)
17. Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)
18. Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharvaris Netherlands B.V.

Sponsor organisation

Pharvaris Netherlands B.V.

Address

J.H. Oortweg 21

City

Leiden

Postcode

2333 CH

Country

Netherlands

Scientific contact point

Organisation

Pharvaris Netherlands B.V.

Contact name

Clinical Trials Information

Public contact point

Organisation

Pharvaris Netherlands B.V.

Contact name

Clinical Trials Information

Third parties 5

Locations

10 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 182 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications