An extension phase 2/3 study to test the safety of long term administration of oral PHA-022121 for acute treatment of angioedema attacks in patients with hereditary angioedema

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], Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

10 Oct 2022 → ongoing

Decision date (initial)

2024-12-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharvaris Netherlands BV

External identifiers

EU CT number

2023-505766-28-00

EudraCT number

2021-006906-58

WHO UTN

U1111-1293-1013

ClinicalTrials.gov

NCT05396105

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Therapy, Safety

To evaluate the safety of long-term on-demand treatment with deucrictibant for acute HAE attacks including laryngeal attacks (without breathing difficulties).

Secondary objectives 3

1. 1. To evaluate the efficacy of deucrictibant in achieving symptom relief in participants with acute HAE attacks including laryngeal attacks (without breathing difficulties).
2. 2. To evaluate the maintenance of deucrictibant efficacy in achieving symptom relief for any subsequent acute HAE attacks including laryngeal attacks (without breathing difficulties).
3. 3. To evaluate the proportion of deucrictibant-treated attacks requiring a second dose of deucrictibant or rescue medication to achieve symptom relief.

Conditions and MedDRA coding

Hereditary angioedema

Regulatory references

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 5

1. 1. Provision of the signed informed consent form by the participant and/or legally designated representative. 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 signed assent will be obtained from the participant, per country regulations.
2. 2. For participants from Study C201, received at least one dose of study drug (including the non-attack visit) in Study C201. For participants from Study C306, participant was randomized (and for adolescent participants (≥12 to <18 years received a dose of study drug in a non-attack state at Visit 1) and completed Study C306, with 2 attacks treated, or after closure of that study by the Sponsor. Enrollment of adolescents (≥12 to <18 years or age of adulthood as defined locally) from these studies is with consideration of local age requirements.
3. 3. 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.
4. 4. In the opinion of the Investigator, the participant (and parent/caregiver for adolescent participants) is willing and able to comply with the protocol.
5. 5. Adult participants with HAE type 3 (HAE-nC1INH) who are deucrictibant-treatment naïve, must have: • 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. • Documented genetic mutation associated with HAE-nC1INH as listed in the Hereditary Angioedema Association (HAEA) and World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) Guidelines • 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 • A history of at least 1 HAE attack in the last 3 months prior to Screening

Exclusion criteria 8

1. 1. Any female who is pregnant, plans to become pregnant, or is breast-feeding.
2. 2. Any other systemic disease (e.g., cardiovascular, gastrointestinal, renal, respiratory, neurological) or significant disease or disorder that, in the opinion of the Investigator, would interfere with the participant’s safety or ability to participate in the study.
3. 3. Use of lanadelumab for long-term HAE prophylactic therapy within 12 weeks prior to enrollment in Part A.
4. 4. Participants who have recently used short or long-term HAE prophylaxis or on-demand HAE treatment will not be excluded from the study provided the following washout period is observed (i.e., study screening or enrollment/rollover should be delayed allowing for washout): • For Part A: − 2-week washout period before enrollment should be respected for participants who have used any C1-INH product, oral kallikrein inhibitors, attenuated androgens, or anti-fibrinolytics for long-term prophylactic HAE therapy. − 1-week washout period before enrollment should be respected for participants who have used plasma derived C1-INH concentrates (Berinert, Cinryze, Haegarda) for on-demand treatment or short-term prophylaxis. − 24-hour washout period before enrollment should be respected for participants who have used recombinant C1-INH (Ruconest) for on-demand treatment or short-term prophylaxis. • For Part B: − If a participant is receiving long-term prophylactic therapy with one of the following medications indicated for HAE: plasma-derived C1INH, danazol at less than or equal to 200 mg/day, anti-fibrinolytics, berotralstat, or lanadelumab, they must be on a stable dose and regimen for at least 3 months before screening and intends to remain on the same dose for the duration of the study.
5. 6. Participation in any other investigational drug study (except with deucrictibant) currently, within the last 30 days prior to the first deucrictibant dose or within 5 half-lives of study drug at enrollment, whichever is longer.
6. 5. History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse.
7. 7. Discontinued from parent study after enrollment for any study drug-related safety reason or non-compliance including significant protocol deviation.
8. 8. Use of concomitant medications with systemic absorption that are strong CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole, ritonavir) or strong CYP3A4 inducers (e.g., carbamazepine and phenytoin).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. 1. AEs, including treatment-emergent adverse events (TEAEs), treatment-related TEAEs, treatment-emergent serious adverse events (TESAEs), treatment-related TESAEs, and TEAEs leading to deucrictibant discontinuation
2. 4. Vital signs
3. 2. Clinical laboratory tests
4. 5. ECG
5. 3. Physical examination

Secondary endpoints 10

1. 1. Part A, Efficacy: Time to onset of symptom relief, defined as Patient Global Impression of Change (PGI-C) rating of at least “a little better” for 2 consecutive timepoints within 12 hours post treatment.
2. 2. Part A, Efficacy: Time to substantial symptom relief, defined as achieving PGI-C rating of at least “better” for 2 consecutive timepoints within 12 hours post-treatment
3. 3. Part A, Efficacy: Time to substantial symptom relief by Patient Global Impression of Severity (PGI-S), defined as achieving ≥1 point reduction in PGI-S from pre-treatment for 2 consecutive timepoints within 12 hours post-treatment.
4. 4. Part A, Efficacy: Time to onset of symptom relief by VAS-3/ VAS-5 (defined as a reduction of ≥30% from pretreatment in VAS composite score, sustained for 2 consecutive timepoints)
5. 5. Part A, Efficacy: Time to symptom relief by VAS (based on achieving ≥50% reduction from pretreatment in VAS composite score sustained for 2 consecutive timepoints).
6. 6. Part B, Efficacy: Time to onset of symptom relief, defined as Patient Global Impression of Change (PGI C) rating of at least “a little better” for 2 consecutive timepoints within 12 hours post treatment
7. 7. Part B, Efficacy: Time to substantial symptom relief, defined as achieving PGI-C rating of at least “better” for 2 consecutive timepoints within 12 hours post-treatment
8. 8. Part B, Efficacy: Time to substantial symptom relief by Patient Global Impression of Severity (PGI-S), defined as achieving ≥1 point reduction in PGI-S from pre-treatment for 2 consecutive timepoints within 12 hours post-treatment
9. 9. Part B, Efficacy: Time to onset of symptom relief by AMRA (defined as a reduction of ≥30% from pretreatment in AMRA composite score, sustained for 2 consecutive timepoints)
10. 10. Part B, Efficacy: Time to symptom relief by AMRA (based on achieving ≥50% reduction from pretreatment in AMRA composite score sustained for 2 consecutive timepoints).

Investigational products

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

Test 2

Placebo 1

Auxiliary 2

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

Pharvaris Clinical Team

Public contact point

Organisation

Pharvaris Netherlands B.V.

Contact name

Pharvaris Clinical Team

Third parties 11

Locations

14 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 280 files

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

Application history

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