| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary Angioedema (HAE) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Disease that causes episodes of severe swelling in the body |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To describe the pharmacokinetic (PK) parameters of berotralstat administered orally to pediatric subjects with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of berotralstat administered orally to pediatric subjects with HAE aged 2 to < 12 years old and weighing ≥ 12 kg.
- To describe the effectiveness of berotralstat in pediatric subjects with HAE aged 2 to < 12 years old and weighing ≥ 12 kg. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and non-pregnant, non-lactating females 2 to < 12 years of age and weighing ≥ 12 kg.
2. Parent/caregiver willing and able to provide written, informed consent (with assent from the child where appropriate).
3. Subjects with a clinical diagnosis of HAE. A clinical diagnosis of HAE is defined as:
• Laboratory documentation of historical C1-INH deficiency results (<50% of normal levels) and a complement 4 (C4) level below the lower limit of the normal (LLN) reference range.
OR
• Historical or new laboratory documentation of historical C1-INH functional level below the assay lower limit of normal
OR
• For subjects with C1-INH function ≥ 50% but less than the assay LLN, a SERPING-1 gene mutation known or likely to be associated with HAE Type I or II, as assessed during the screening period OR a repeat C1-INH functional level < 50% will be considered acceptable for enrollment.
OR
• Historical or new laboratory documentation of a SERPING-1 mutation known or likely to be associated with HAE
OR
• For subjects who currently use plasma-derived or recombinant C1-INH-based therapies, a confirmed family history of C1-INH deficiency.
4. For subjects who are not currently receiving prophylaxis for HAE, documented history of ≥ 2 HAE attacks in the 6 months prior to the enrollment visit.
5. Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE.
6. In the opinion of the investigator, the subject would benefit from long-term oral prophylaxis.
7. Females who had started their menses and males must be either:
- Sexually abstinent (Section 9.2.2.2 of the protocol ); OR
- If sexually active , or become sexually active during the study, must agree to the use of effective contraception (Section 9.2.2.2 of the protocol ) |
|
| E.4 | Principal exclusion criteria |
1. Concurrent diagnosis of any other type of recurrent angioedema.
2. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, myocarditis, pericarditis, congenital heart defects, or any other clinically significant cardiovascular abnormality such as poorly controlled hypertension.
3. Known family history of sudden cardiac death. Family history of sudden death from HAE is not exclusionary.
4. History of or current implanted defibrillator or pacemaker.
5. Moderate to severe hepatic impairment (Child-Pugh B or C).
6. A calculated creatinine clearance using the Modified Schwartz formula of ≤ 30 mL/min/1.73 m2 or aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the age-appropriate normal reference range value.
7. History of severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear etiology.
8. Current participation in any other investigational drug study or received another investigational drug within 30 days of enrollment; not willing to refrain from participation in another clinical study after enrollment and for the duration of the study. [Note: drugs/vaccines approved under FDA emergency use authorization (or country-specific analogous regulations) are not considered excluded or prohibited under this criterion.]
9. An immediate family relationship to either sponsor employees, the investigator, or employees of the study site named on the delegation log.
10. Any clinically significant medical condition or medical history (including altered mental status) that, in the opinion of the investigator or sponsor, would interfere with the subject’s safety or ability to participate in the study. Examples include but are not limited to active malignancy under treatment, uncontrolled cardiovascular disease, organ dysfunction requiring supportive care.
11. Clinically significant abnormal ECG including but not limited to, a corrected QT interval calculated using Fridericia’s correction (QTcF = QT/RR0.33) > 450 msec, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping.
12. Any result at screening that, in the opinion of the investigator, is clinically significant and relevant for this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PK : The primary endpoint is the characterization of the PK profile of berotralstat in subjects aged 2 to < 12 years. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be evaluated at week 2, part 1 and at week 48, part 2 of the study for each cohort of patients. |
|
| E.5.2 | Secondary end point(s) |
Safety : The frequency and severity of adverse events (AEs) and serious adverse events (SAEs), laboratory analyses (clinical chemistry, hematology, coagulation), height, weight, vital signs, electrocardiograms (ECGs), and physical examination findings
Effectiveness: The frequency of attacks, duration of symptoms, anatomical location of attack, on-demand treatment, number of days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety endpoints will be assessed at the end of each Part (ie, Weeks 12, 48, and 144/end of study [EOS]).
The other secondary endpoint of effectiveness will be measured by assessing the frequency of attacks, duration of symptoms, anatomical location, on-demand treatment required, number of days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, effectiveness |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Austria |
| France |
| Poland |
| Romania |
| Spain |
| Germany |
| Italy |
| Hungary |
| North Macedonia |
| United Kingdom |
|
| 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 study will be defined as when the last subject completes the last protocol-scheduled visit or sponsor-defined last visit should study be terminated early. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 35 |
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