E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hereditary Angioedema (HAE) |
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E.1.1.1 | Medical condition in easily understood language |
HAE is a long-term and life-threatening disease. HAE manifests clinically as unpredictable, intermittent attacks of edema of the face, larynx, gastrointestinal tract, limbs and/or genitalia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
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 | 23.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075280 |
E.1.2 | Term | Hereditary angioedema attack |
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 |
The primary objective of the study is to evaluate the safety and pharmacokinetics (PK) of lanadelumab in children (2 to <12 years of age) with HAE. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To evaluate the clinical outcomes of lanadelumab in preventing HAE attacks in children (2 to <12 years of age) with HAE.
• To characterize the pharmacodynamics (PD) of lanadelumab in children (2 to <12 years of age) with HAE.
• To assess the immunogenicity of chronically administered lanadelumab and its effect on PK, PD, clinical outcomes, and safety.
The exploratory objectives are:
• To evaluate the effect of lanadelumab on health-related quality of life (HRQoL).
• To evaluate the effect of lanadelumab on exploratory biomarker(s) of angioedema disease-state bioactivity. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Be a child (male or female) 2 to <12 years of age at the time of screening.
2. Documented diagnosis of HAE (Type I or II) based upon both of the following:
• Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes without accompanying urticaria);
• Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH functional level <40% of the normal level. Subjects with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. With prior sponsor approval, subjects may be retested during the baseline observation period if results are incongruent with clinical history or believed by the investigator to be confounded by recent C1 inhibitor use.
3. A historical baseline HAE attack rate of at least 1 attack per 3 months. Note: In addition, subjects who experience ≥1.0 angioedema attacks per three months during the 12-week baseline observation period and who remain eligible per the inclusion criteria will enter the lanadelumab treatment period.
4. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
5. Have a parent(s)/legal guardian who is informed of the nature of the study and can provide written informed consent for the child to participate in the study before any study-specific procedures are performed (with assent from the child when appropriate).
6. Females of childbearing potential must agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol through the duration of the study from screening through 30 days after the final study visit. |
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E.4 | Principal exclusion criteria |
1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH, idiopathic angioedema, or recurrent angioedema associated with urticaria.
2. Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
3. Be pregnant or breastfeeding.
4. Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and testosterone) within 2 weeks prior to entering the observation period.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
6. Have any active infectious illness or fever defined as an oral temperature >38°C (100.4°F), tympanic >38.5°C (101.3°F), axillary >38°C (100.4°F), or rectal/core >38.5°C (101.3°F) within 24 hours prior to the first dose of study drug in Treatment Period A.
7. Have any HAE attack that is not resolved prior to the first dose of study drug in Treatment Period A.
8. Have any of the following liver function test abnormalities: alanine aminotransferase (ALT) >3x upper limit of normal (ULN), or aspartate aminotransferase (AST) >3x ULNl, or total bilirubin >2x ULN (unless the bilirubin elevation is a result of Gilbert’s syndrome).
9. Have any condition (any surgical or medical condition) that, in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude the successful conduct of the study, or interfere with interpretation of the results (eg, significant pre-existing illness or other major comorbidity that the investigator considers may confound the interpretation of study results).
10. Subject has a known hypersensitivity to the investigational product or its components. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Measures of safety include:
• Adverse events including SAEs and AESI.
• Clinical laboratory testing (hematology, clinical chemistry, coagulation)
• Vital signs including blood pressure, heart rate, body temperature, and respiratory rate.
Measures of PK include:
• Plasma concentrations of lanadelumab
• PK parameters in plasma, by age group, will be determined by a modelling and simulation approach and reported separately:
o Cmax,ss: Maximum observed concentration at steady state
o Cavg,ss: Average concentration over dosing interval at steady state
o Ctrough,ss: Predose concentration at steady state
o tmax: Time to reach Cmax in plasma
o AUCtau,ss: Area under the concentration-time curve over the dosing interval at steady state
o t½: Terminal half-life
o CL/F: Apparent clearance
o V/F: Apparent volume of distribution
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52])
• Treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26])
• Treatment Period B (Day 183 through Day 364 [Week 52])
• Overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52])
• Presumed steady state period for Treatment Period A (Day 70 [Week 10] through Day 182 [Week 26]). |
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E.5.2 | Secondary end point(s) |
• Normalized number of investigator-confirmed HAE attacks.
• Time to the first attack, ie, duration that a subject is attack-free until their first attack.
• Normalized number of investigator-confirmed HAE attacks requiring acute therapy use.
• Normalized number of moderate or severe investigator-confirmed HAE attacks.
• Normalized number of high morbidity investigator-confirmed HAE attacks.
• Characteristics of investigator-confirmed HAE attacks, including duration, severity, attack location, and rescue medication use.
• Achievement of attack-free status.
• Plasma kallikrein activity (as measured by cHMWK level). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Overall treatment period (Day 0 [after study drug administration] through Day 364 [Week 52])
• Treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 26])
• Treatment Period B (Day 183 through Day 364 [Week 52])
• Overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52])
• Presumed steady state period for Treatment Period A (Day 70 [Week 10] through Day 182 [Week 26]). |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 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) | 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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
United States |
Germany |
Hungary |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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 Study Completion Date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |