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    Summary
    EudraCT Number:2020-003445-11
    Sponsor's Protocol Code Number:PHA022121-C201
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-12-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-003445-11
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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).
    A.3.2Name or abbreviated title of the trial where available
    RAPIDe-1
    A.4.1Sponsor's protocol code numberPHA022121-C201
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPharvaris Netherlands BV
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPharvaris Netherlands BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharvaris Netherlands BV
    B.5.2Functional name of contact pointPharvaris Clinical
    B.5.3 Address:
    B.5.3.1Street AddressJ.H. Oortweg 21
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CH
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 (0)712036410
    B.5.6E-mailclinical@pharvaris.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePHVS416
    D.3.2Product code PHA-022121
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 2340111-58-0
    D.3.9.2Current sponsor codePHA-022121
    D.3.9.3Other descriptive namePHA-022121
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hereditary angioedema attacks caused by Type 1 and 2 C1-Inhibitor Deficiency
    E.1.1.1Medical condition in easily understood language
    Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling.
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10019860
    E.1.2Term Hereditary angioedema
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10080956
    E.1.2Term Hereditary angioedema type I
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10080957
    E.1.2Term Hereditary angioedema C1 inhibitor deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10080960
    E.1.2Term Hereditary angioedema type II
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of three different single doses of PHA-022121 versus placebo in achieving angioedema symptom reduction, defined as change of VAS-3 score during acute attacks in patients with hereditary angioedema (HAE) type I/II
    E.2.2Secondary objectives of the trial
    Key Objectives
    To evaluate the clinical efficacy of 3 different single doses of PHA-022121 vs placebo with regards to:
    •Onset of symptom relief
    •The proportion of attacks requiring the use of HAE rescue medication
    •Time to almost complete and complete symptom relief
    •Change in MSCS at 4 h post-treatment
    •Change in TOS at 4 h post-treatment
    Other objectives:
    •To evaluate the safety of 3 different single doses of PHA-022121 vs placebo
    •To evaluate the pharmacokinetics, dose-effect relationship, and concentration-effect relationship of PHA-022121
    •To evaluate the timing of HAE rescue medication use after 3 different single doses of PHA-022121 vs placebo
    •To evaluate the time to onset of primary symptom relief by VAS
    •To evaluate the change of the individual VAS scores from pre-treatment to 4 h post-treatment
    •To evaluate the change of MSCS score at 24 h post-treatment
    •To evaluate the change of TOS at 24 h post-treatment
    •To evaluate the TSQM scores at 48 h post-treatment
    E.2.3Trial contains a sub-study No
    E.3Principal 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 prior to screening.
    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 until 30 days after the last study drug administration. 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 during the study and for 90 days after the last administration of study drug. In addition, they must agree to not donate sperm during study participation and within 90 days after the last study drug administration.
    E.4Principal exclusion criteria
    1. Pregnant 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, uncontrolled arterial hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg), bradycardia (< 50 bpm), 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 screening.
    Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics to avoid angioedema complications from medically indicated procedures.
    Patients who receive long-term prophylactic treatment for HAE are not eligible for the study. Patients who have previously stopped long-term prophylactic HAE treatment because of intolerance or lack of efficacy can enter the study with a sufficiently long wash-out period as defined above for the different drugs.
    6. Positive serology for human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
    7. Abnormal hepatic function (AST > 2×ULN, ALT > 2×ULN, or total bilirubin > 1.5×ULN)
    8. Abnormal renal function (eGFR CKD-EPI < 60 mL/min/1.73 m2)
    9. 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)
    10. History of documented severe hypersensitivity to any medicinal product
    11. 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)
    12. Regular use of corticosteroids, antihistamines, narcotics, and other pain relief medications for acute HAE attack treatment
    13. 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)
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    4h post treatment of an attack during the home treatment phase (Part II).
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints of the study are:
    •Time to onset of symptom relief by VAS-3 score Symptom relief by VAS-3 score is defined as a reduction of > 50% from the pre-treatment value of the VAS-3 score.
    • Proportion of study drug treated attacks requiring HAE rescue medication
    • Time to almost complete and complete symptom relief by VAS-3 score Almost complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 having a value < 10. Complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 having a value of 0.
    • MSCS score at 4 h post-treatment
    • TOS at 4 h post-treatment
    Other secondary efficacy endpoints of the study are as follows:
    • Time to onset of primary symptom relief by VAS
    • Time to HAE rescue medication use for IMP treated attacks, if applicable
    • Change of the individual VAS scores (skin pain, skin swelling, abdominal pain) from pre-treatment to 4 h post-treatment
    • MSCS score at 24 h post-treatment
    • TOS at 24 h post-treatment
    • TSQM scores at 48 h post-treatment
    The (secondary) safety endpoints of the study are:
    • Treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and treatment-emergent serious adverse events (TESAEs), and treatment-related TESAEs
    • Clinically significant changes in clinical laboratory tests
    • Clinically significant changes in vital signs
    • Clinically significant changes in ECG
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial9
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Israel
    United States
    Bulgaria
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    Czechia
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end-of-study visit will take place remotely 10±5 days post-treatment of the last attack and if possible in case of withdrawal from the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 54
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 72
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will continue with standard of care after trial participation ends.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-03-01
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