A blinded, placebo-controlled and randomized phase 2 study to test different doses of oral PHA-022121 for acute treatment of angioedema attacks in patients with hereditary angioedema (HAE).

• Register: EUCTR
• Last refreshed on: 5 April 2021
• Main ID: EUCTR2020-003445-11-HU
• Date of registration: 30/11/2020
• Prospective Registration: Yes
• Primary sponsor: Pharvaris Netherlands BV
• Public title: A blinded, placebo-controlled and randomized phase 2 study to test different doses of oral PHA-022121 for acute treatment of angioedema attacks in patients with hereditary angioedema (HAE).
• Scientific title: A Phase II, double-blind, placebo-controlled, Randomized, cross-over, dose-ranging study of oral PHA-022121 for Acute treatment of angioedema attacks in Patients with hereditary angioedema due to C1-Inhibitor Deficiency type I and II - RAPIDe-1
• Date of first enrolment: 27/01/2021
• Target sample size: 54
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-003445-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: yes; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 9
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Spain, United Kingdom

Contacts

• Name: Pharvaris Clinical
• Affiliation: Pharvaris Netherlands BV

• Name: Pharvaris Clinical
• Affiliation: Pharvaris Netherlands BV

Key inclusion & exclusion criteria

Inclusion criteria:
1. Provision of signed and dated informed consent form
2. Male or female, aged = 18 and = 75 years at enrollment
3. Diagnosis of HAE (type I or II) based upon all of the following:
a. Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling without accompanying urticaria)
b. At least one of the following:
? Age at reported onset of first angioedema symptoms = 40 years
? Family history consistent with HAE type I or II
? C1q within normal range
c. Diagnostic testing results to confirm HAE type I or II:
? C1-INH functional level < 50% of the normal level
The diagnosis may be established by local laboratory values documented in the medical records or by genotyping of the C1-INH gene (SERPING1). Before entering Part II of the study (home treatment), the diagnosis needs to be confirmed by a central laboratory assessment or by genotyping of the C1-INH gene (SERPING1).
4. Documented history of at least three HAE attacks in the last 4 months, or at least two HAE attacks in the last 2 months.
5. Reliable access and experience to use standard of care treatment to effectively manage acute HAE attacks
6. Capable to record PRO data using the ePRO device
7. Female patients of childbearing potential must agree to be abstinent or to use highly effective forms of contraception methods from enrollment through the end of the study. This includes progestin-only oral contraceptive associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device (IUD, all types) or intrauterine hormone releasing systems (IUS). A female of childbearing potential whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception.
Male patients, including males who are surgically sterile (post vasectomy), who have a female partner of childbearing potential must agree to be sexually abstinent or use a medically acceptable form of barrier contraception for 2 weeks after each administration of study drug. In addition, they must agree to not donate sperm during study participation.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 40
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 14

Exclusion criteria:
1. Pregnancy or breast-feeding
2. Clinically significant abnormal ECG, most notably a QTcF > 470 ms (for females) or > 450 ms (for males)
3. Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, or any other cardiovascular abnormality within the previous year
4. Any other systemic disease (e.g., gastrointestinal, renal, respiratory, neurological) or significant disease or disorder that would interfere with the patient’s safety or ability to participate in the study
5. Use of:
a. long-term prophylactic therapy for HAE (C1-INH, oral kallikrein inhibitors, attenuated androgens, or anti-fibrinolytics) within 2 weeks prior to enrollment
b. long-term prophylactic monoclonal therapy for HAE (e.g., lanadelumab) within 12 weeks prior to enrollment
c. acute C1-INH treatment or short-term prophylaxis for HAE within 7 days prior to enrollment
Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics to avoid angioedema complications from medically indicated procedures.
6. Clinical history of resistance to B2 receptor antagonists
7. Positive serology for human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
8. Abnormal hepatic function (AST > 2×ULN, ALT > 2×ULN, or total bilirubin > 1.5×ULN)
9. Abnormal renal function (eGFR CKD-EPI < 60 mL/min/1.73 m2)
10. History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse (self-reported alcoholic intake > 3 drinks/day)
11. History of documented severe hypersensitivity to any medicinal product
12. Participation in any other investigational drug study currently, within the last 30 days or within 5 half-lives of study drug at enrollment (whichever was longer)
13. Regular use of corticosteroids, antihistamines, narcotics, and other pain relief medications for acute HAE attack treatment
14. Use of concomitant medication that are moderate or potent inhibitors/inducers of CYP3A4 or are metabolized by CYP3A4 and have a narrow therapeutic range, such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit as well as phenobarbital, phenytoin, rifampicin, St. John's Wort, and glucocorticoids (not for topical use or inhalation)



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Immune system processes [G12]

Hereditary angioedema attacks caused by Type 1 and 2 C1-Inhibitor Deficiency
MedDRA version: 23.1 Level: PT Classification code 10019860 Term: Hereditary angioedema System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 21.0 Level: LLT Classification code 10080956 Term: Hereditary angioedema type I System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 21.0 Level: LLT Classification code 10080957 Term: Hereditary angioedema C1 inhibitor deficiency System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 21.0 Level: LLT Classification code 10080960 Term: Hereditary angioedema type II System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: PHVS416
Product Code: PHA-022121
Pharmaceutical Form: Capsule, soft
CAS Number: 2340111-58-0
Current Sponsor code: PHA-022121
Other descriptive name: PHA-022121
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Capsule, soft
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): The primary endpoint of the study is the change of the 3-symptom composite visual analogue scale (VAS-3) score from pre-treatment to 4 h post-treatment.

Timepoint(s) of evaluation of this end point: 4h post treatment of an attack during the home treatment phase (Part II).

Main Objective: To evaluate the efficacy of three different single doses of PHA-022121 versus placebo in achieving angioedema symptom relief during acute attacks in patients with hereditary angioedema (HAE) type I/II

Secondary Objective: • To further explore the clinical efficacy of three different single doses of PHA-022121 versus placebo with regard to onset of symptom relief, time to complete symptom relief, and differences between the doses
• To evaluate the safety of three different single doses of PHA-022121 versus placebo
• To evaluate the pharmacokinetics, dose-effect relationship, and concentration-effect relationship of PHA-022121
• To evaluate the frequency and timing of HAE rescue medication use of three different single doses of PHA-022121 versus placebo

Secondary Outcome(s)

Secondary end point(s): The secondary efficacy endpoints of the study are:
• Time to onset of symptom relief by VAS-3 score
Symptom relief is defined as the earliest of three consecutive non-missing measurements where the VAS 3 score was reduced by > 50% from pre-treatment.
• Time to onset of primary symptom relief by VAS
Primary symptom relief is defined as any reduction above 6/7*[pre-treatment value] 16 for pre-treatment VAS = 30. The symptom with the highest pre-treatment VAS score is considered the primary symptom.
• Time to almost complete and complete symptom relief by VAS
Almost complete symptom relief is defined as the earliest of three consecutive non-missing measurements for which all VAS scores are < 10.
Complete symptom relief is defined as the earliest of three consecutive non-missing measurements for which all VAS scores are 0.
• Change of the individual VAS scores (skin pain, skin swelling, abdominal pain) from pre-treatment to 4 h post-treatment
• MSCS score at 4 h and 24 h post-treatment
• TOS at 4 h and 24 h post-treatment
• TSQM scores
• Number of attacks requiring HAE rescue medication
• Time to HAE rescue medication use, if applicable

The (secondary) safety endpoints of the study are:
• Occurrence of treatment-emergent adverse events (TEAEs), treatment-related adverse events (AEs), and treatment-emergent serious adverse events (TESAEs).
• Occurrence of clinically significant changes in clinical laboratory tests reported as AE
• Occurrence of clinically significant changes in vital signs reported as AE
• Occurrence of clinically significant changes in ECG

Timepoint(s) of evaluation of this end point: Safety: All AEs with onset after signing informed consent (including SAEs) are to be recorded. Last follow-up for AEs will occur 10±5 days after the last attack treatment.
Efficacy:
• VAS score: every 30±10 min from 0 to 4 h post-treatment, and at 5±0.5, 6±0.5, 8±1, 24±4 and 48±6 h post-treatment
• MSCS score: pre-treatment, and at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 48±6 h post-treatment
• TOS: pre-treatment, and at 1±0.25, 2±0.25, 4±0.25, 6±1, 8±1, 24±4, and 48±6 h post-treatment
• TSQM scores: at 48±6 h post-treatment

Secondary ID(s)

PHA022121-C201

Source(s) of Monetary Support

Pharvaris Netherlands BV

Ethics review

Status: Approved
Approval date: 29/12/2020
Contact: