A Phase 3, Placebo-controlled, Cross-over Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Attacks in Adolescents and Adults 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

29 Jul 2024 → 17 Oct 2025

Decision date (initial)

2024-07-22

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharvaris Netherlands B.V

External identifiers

EU CT number

2023-507268-37-00

WHO UTN

U1111-1295-6497

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety, Therapy

To evaluate the efficacy of deucrictibant as on-demand treatment compared with placebo on the onset of symptom relief during hereditary angioedema (HAE) attacks.

Secondary objectives 3

1. 1. To evaluate the efficacy of deucrictibant as on-demand treatment compared with placebo on symptom relief and resolution of HAE attacks.
2. 2. To evaluate the safety and tolerability of deucrictibant compared with placebo for on demand treatment of HAE attacks.
3. 3. To assess the pharmacokinetics (PK) of deucrictibant in adolescent participants (≥12 to <18 years) in a non-attack state.

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 10

1. 10. In the opinion of the Investigator, the participant (and parent/caregiver for adolescent participants) is willing and able to comply with the protocol.
2. 2. Male or female, aged ≥12 to ≤75 years at the time of providing written informed consent/assent.
3. 3. 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
4. 4. History of at least 2 HAE attacks in the last 3 months before screening.
5. 5. Experience with using standard-of-care treatment to effectively manage on-demand treatment for HAE attacks.
6. 6. 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
7. 7. 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.
8. 8. For adolescent participants aged ≥12 to <18 years: body weight ≥40 kg.
9. 1. 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.
10. 9. 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 12

1. 1. Any female who is pregnant, plans to become pregnant, or is breastfeeding.
2. 2. Any diagnosis of angioedema other than HAE.
3. 3. 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.
4. 4. Use of attenuated androgens for short-term prophylaxis within 2 weeks before screening.
5. 5. 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.
6. 6. Abnormal renal function (estimated glomerular filtration rate <60 mL/min/1.73 m2).
7. 7. History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse.
8. 8. Has received prior on-demand HAE treatment with deucrictibant.
9. 9. 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.
10. 10. Prior gene therapy for any indication at any time.
11. 11. 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.
12. 12. Known hypersensitivity to deucrictibant or any of the excipients of study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 11

1. 1. Proportion of study drug-treated attacks achieving PGI-C rating of at least “a little better” at 4 hours post-treatment
2. 2. 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. 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. Time to complete symptom resolution, defined as achieving PGI-S rating of “none” within 48 hours post-treatment.
5. 5. Time to End of Progression (EoP) in attack symptoms within 12 hours, with EoP time defined as the earliest post-treatment timepoint after which all subsequent PGI-C ratings are stable or improved.
6. 6. Proportion of study drug-treated attacks requiring rescue medication within 24 hours post treatment.
7. 7. Proportion of attacks achieving symptom resolution, defined as achieving PGI-S rating of “none” with one dose of study drug at 24 hours post-treatment.
8. 8. Time to substantial symptom relief by Angioedema SyMptom Rating scAle (AMRA), defined as a ≥50% reduction in AMRA composite score from pre-treatment for 2 consecutive timepoints within 12 hours post-treatment.
9. 9. Time to almost complete or complete symptom relief by AMRA, defined as all item scores in AMRA having a value ≤10 for 2 consecutive timepoints within 24 hours post-treatment.
10. 10. Proportion of study drug-treated attacks reaching almost complete or complete symptom relief by AMRA, defined as all item scores in AMRA having a value ≤10 at 24 hours post treatment.
11. 11. Time to EoP in attack symptoms within 12 hours, with EoP time defined as the earliest post-treatment timepoint after which every individual AMRA item is stable or improved at all subsequent timepoints

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

Pharvaris Netherlands BV - Pharvaris Clinical

Public contact point

Organisation

Pharvaris Netherlands B.V.

Contact name

Pharvaris Netherlands BV - Pharvaris Clinical

Third parties 9

Locations

14 EU/EEA countries · 27 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 257 files

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

Application history

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