| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary angioedema due to C1-Inhibitor Deficiency (Type I or Type II) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. |
|
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 26.0 |
| 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 |
|
| 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 |
|
| 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 |
|
| 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 |
Primary Objective(s):
Part-1
• To evaluate the safety and tolerability of two dose regimens of PHA-022121 administered as prophylaxis against hereditary angioedema (HAE) attacks.
• To evaluate the efficacy of two dose regimens of PHA-022121 administered as prophylaxis against HAE attacks.
Part-2
• To evaluate the safety of PHA-022121 administered as long-term prophylactic HAE treatment.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objective:
Part-1
• To characterize the pharmacokinetics/pharmacodynamics (PK/PD) of two dose regimens of PHA-022121 administered as prophylaxis against HAE attacks.
• To evaluate the impact on quality of life (QoL) of two dose regimens of PHA-022121 administered as prophylaxis against HAE attacks.
Part 2
• To evaluate the efficacy of PHA-022121 administered as long-term prophylactic HAE treatment.
• To evaluate the PK/PD of PHA-022121 administered as long-term prophylactic HAE treatment.
• To evaluate the impact on QoL of PHA-022121 administered as long-term prophylactic HAE treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet the following criteria to be enrolled in this study. 1. Male or female patients aged ≥ 18 to ≤ 75 years at screening.
2. Diagnosis of HAE (type I or II) based upon all of the following:
a. Documented clinical history consistent with HAE (subcutaneous and/or mucosal swelling without accompanying wheals)
b. At least one of the following: - Age at reported onset of first angioedema symptoms ≤ 30 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 should be documented prior to randomization by a local or central laboratory value documented in the medical records
Note: For patients who receive any form of C1-INH replacement, the last dose before the confirmatory C1-INH testing should be given at least 5 half-lives before the date of sampling.
3. Documented history of at least 3 HAE attacks within the last 3 consecutive months prior to screening. If the patient has no documentation or has less than 3 attacks in the 3 months before the screening visit, or was on prophylactic treatment, patient must experience a minimum of 2 HAE attacks during the screening period (up to 8 weeks).
4. Is assessed by the investigator to have reliable access and ability to use standard of care treatments alone to effectively manage acute HAE attacks.
5. Body weight of ≥ 40 kg at screening.
6. Investigator considers that the patient is willing and able to adhere to all protocol requirements, including being capable of and compliant with data recording into an electronic Patient Reported Outcome (ePRO) tool.
7. Female patients of childbearing potential must agree to the protocol specified pregnancy testing and to practice abstinence from heterosexual intercourse in line with the preferred and usual lifestyle of the patient or to use a medically acceptable form of contraception methods from enrollment until 30 days after the last IMP administration. Methods acceptable for this study include male condom with or without spermicide, cervical cap, diaphragm or sponge with spermicide, a combination of male condom with cap, diaphragm or sponge with spermicide (double-barrier methods), combined or progestin-only hormonal methods (oral, injectable, or implantable), intrauterine device (IUD, all types), intrauterine hormone releasing systems (IUS).
Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal (defined as no menses for at least 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) test result indicative of post-menopausal status) do not require contraception during the study.
There are no contraceptive requirements for male patients.
8. The patient has provided informed consent. |
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from the study.
1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE) with C1-INH deficiency, angioedema with normal C1-INH levels (HAE type III), idiopathic nonhistaminergic angioedema, or recurrent angioedema associated with urticaria.
2. Participation in a clinical trial with any other investigational drug within the last 30 days or within 5 half-lives of IMP at screening (whichever was longer). Previous participation in the Study PHA022121-C201 is permitted.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks of screening.
4. Receiving prophylactic treatment for HAE. Patients who have previously received prophylactic therapy but have stopped, can participate in this study provided a sufficiently long washout period is observed before the patient is screened. Exclusion includes use of:
a. long-term prophylactic therapy for HAE (C1-INH, oral kallikrein inhibitors, attenuated androgens, or anti-fibrinolytics) within 2 weeks prior to screening
b. long-term prophylactic monoclonal therapy for HAE (i.e., lanadelumab) within 11 weeks prior to screening
c. short-term prophylaxis for HAE within 7 days prior to screening
Short-term prophylaxis is defined as intravenous C1-INH, attenuated androgens, or antifibrinolytics to avoid angioedema complications from medically indicated procedures.
Note: Patients who are receiving long-term prophylactic treatment for HAE and are satisfied with this treatment, are not eligible for this 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 in Exclusion Criterion #4 for the different HAE therapies.
5. Clinically significant abnormal electrocardiogram (ECG), most notably a QTcF > 470 milliseconds (for women) or > 450 milliseconds (for men).
6. Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, uncontrolled hypertension (systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg), bradycardia (heart rate < 50 beats per minute) or any other cardiovascular abnormality within the previous year.
7. 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.
8. Any females who are pregnant, plan to become pregnant, or are currently breast-feeding.
9. Abnormal hepatic function (aspartate aminotransferase [AST] > 2×upper limit of normal [ULN], alanine aminotransferase [ALT] > 2×ULN, or total bilirubin > 1.5×ULN). Patients with Gilbert's syndrome, being defined as isolated increase of total bilirubin ≤3xULN and AST and ALT within the normal range, are not excluded.
10. Abnormal renal function (estimated glomerular filtration rate [eGFR] CKD-EPI < 60 mL/min/1.73 m2).
11. History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse.
12. Use of concomitant medications that are strong inhibitors of CYP3A4 such as clarithromycin, itraconazole, ketoconazole, ritonavir, and grapefruit as well as inducers of CYP3A4 such as phenobarbital, phenytoin, rifampicin, and St. John's Wort. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part-1
The primary efficacy endpoint will be the number of investigator-confirmed HAE attacks during the treatment period in Part-1 (Day 0 through Day 84) and will be expressed as the normalized number of attacks per month (4 weeks) of exposure. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analyses of the efficacy endpoints in this study require documentation of specific information regarding the patient’s symptoms of any HAE attacks experienced during the study.
In both Part 1 and Part 2 of the study, the evaluation of safety includes the following endpoints:
• Treatment-emergent adverse events (TEAEs), treatment-related AEs, and treatment-emergent SAEs
• Clinical laboratory tests
• Vital signs
• ECG data |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints in Part-1 of the study are listed below.
• Number of investigator-confirmed moderate or severe HAE attacks during the treatment period in Part 1 (Day 0 to Day 84).
• Number of investigator-confirmed HAE attacks requiring acute treatment during the treatment period in Part 1.
• Number of patients achieving ≥50% reduction in attack rate relative to baseline during the treatment period in Part 1.
• Number of patients achieving ≥70% reduction in attack rate relative to baseline during the treatment period in Part 1.
• Number of patients achieving ≥90% reduction in attack rate relative to baseline during the treatment period in Part 1.
• Number of patients that are attack-free during the treatment period in Part 1.
• Number and proportion of days with angioedema symptoms during the treatment period in Part 1.
• Time to first investigator-confirmed HAE attack in the treatment period in Part 1.
• Number of investigator-confirmed HAE attacks resulting in a visit to the emergency department or an admission to hospital during the treatment period in Part 1.
The analyses of these secondary efficacy endpoints are considered supportive, all statistical tests comparing treatments are descriptive in nature and will be made without adjustment for multiplicity
Part 2
The efficacy endpoints in Part 2 of the study are:
• Number of investigator-confirmed angioedema attacks during the treatment period in Part 2 (from time of the first open-label dose to the last dose, excluding the treatment gap in Part 2).
• Number of investigator-confirmed moderate or severe angioedema attacks during the treatment period in Part 2.
• Number of investigator-confirmed angioedema attacks requiring acute treatment during the treatment period in Part 2.
• Incidence of HAE attacks during the treatment period in Part 2 (attack rate trend over time).
• Number and proportion of days with angioedema symptoms during the treatment period in Part 2.
The analysis of the efficacy endpoints in Part 2 will be performed based on the ITT analysis set. The number of investigator-confirmed HAE attacks during the treatment period in Part 2 will be expressed as the normalized number of attacks per month (4 weeks) of exposure. The normalized number of investigator-confirmed HAE attacks during the treatment period in Part 2 will be descriptively summarized. Similarly, normalized number of investigator-confirmed moderate or severe HAE attacks during the treatment period in Part 2, normalized number of investigator-confirmed HAE attacks requiring acute treatment during the treatment period in Part 2, and proportion of days with HAE symptoms during the treatment period in Part 2 will be summarized.
All efficacy analyses in Part 2 will be descriptive. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The safety endpoints will be summarized using the Safety population. Usage of concomitant medications (other than rescue medications) in Part 1 will be summarized descriptively for each of the treatment groups and the combined active treatment group.
Clinical laboratory data, vital signs, physical examination, and ECG data will be presented in summary tables and/or individual listings.
Other endpoints evaluated during each part of the study:
• Pharmacokinetic parameters based on plasma concentration of PHA-022121 - determined using an existing population PK model for PHA-022121
• Change from baseline in the AE-QoL questionnaire
• PGA-QoL and PGA-change questions
• AECT-4wk scores
• TSQM scores |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| 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 | 10 |
| 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 Kingdom |
| United States |
| Austria |
| Bulgaria |
| Germany |
| Ireland |
| Italy |
| Poland |
| Spain |
|
| 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
|
The end of the study is defined as the last visit of the last patient participating in the study.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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