E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hereditary angioedema attacks caused by Type 1 and 2 C1-Inhibitor Deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019860 |
E.1.2 | Term | Hereditary angioedema |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080956 |
E.1.2 | Term | Hereditary angioedema type I |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080957 |
E.1.2 | Term | Hereditary angioedema C1 inhibitor deficiency |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080960 |
E.1.2 | Term | Hereditary angioedema type II |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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 |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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)
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
4h post treatment of an attack during the home treatment phase (Part II). |
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E.5.2 | Secondary 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 |
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E.5.2.1 | 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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 9 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |