| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-histaminergic angioedema with normal C1-INH and acquired angioedema due to C1-INH deficiency |
| nem-hisztaminerg angioödéma normál C1-INH-val és C1-INH-hiány miatt szerzett angioödéma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Angioedema is a long-term and life-threatening disease. It manifests clinically as unpredictable, intermittent attacks of edema of the face, larynx, gastrointestinal tract, limbs and/or genitalia. |
|
| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10002425 |
| E.1.2 | Term | Angioedemas |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 repeated SC administrations of lanadelumab in preventing
angioedema attacks in adolescents (12 to <18 years of age) and adults with non-histaminergic
angioedema with normal C1-INH and in adults with AAE due to C1-INH deficiency. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of repeated SC administrations of lanadelumab in preventing
angioedema attacks in adolescents and adults with normal C1-INH angioedema and in adults
with AAE due to C1-INH deficiency.
- To evaluate the PK of repeated SC administrations of lanadelumab in preventing angioedema attacks
- To evaluate the PD of repeated SC administrations of lanadelumab in preventing angioedema attacks
- To evaluate the immunogenicity of repeated SC administrations of lanadelumab in preventing angioedema attacks
- To evaluate the effect of lanadelumab on health-related quality of life (HR-QoL) assessments |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria 1 through 3 and 6 through 10 are identical for the 2 study populations, non-histaminergic normal C1-INH angioedema and AAE due to C1-INH deficiency:
1. Males and females, 12 years of age and older for subjects with non-histaminergic normal C1-INH angioedema or 30 years of age and older for subjects with AAE due to C1-INH deficiency at the time of signing of the informed consent form (ICF).
2. Documented clinical history of recurrent attacks of angioedema in the absence of wheals/urticaria.
3. Investigator-confirmed diagnosis of non-histaminergic bradykinin-mediated angioedema:
A) non-histaminergic angioedema with normal C1-INH or
B) AAE due to C1-INH deficiency, as documented by a history of angioedema attacks at screening and occurrence of attack(s) during the observation period.
4. Subjects with non-histaminergic normal C1-INH angioedema must also meet the specific inclusion criteria below unique to this study population:
- History of recurrent angioedema with at least an average of 1 angioedema attack per 4 weeks prior to screening and this attack rate must be confirmed during the observation period while treated with chronic high-dose antihistamine (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine medication).
- Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH antigen and function ≥50% of normal and normal C4. With prior sponsor approval, subjects may be retested during the observation period if results are incongruent with clinical history.
- Clinical history of not responding to high-dose antihistamine treatment (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine medication), which must be confirmed during the observation period with at least 1 angioedema attack per 4 weeks with chronic high-dose antihistamine treatment and no significant difference (as assessed by the investigator and in consultation with the sponsor’s medical monitor, as necessary) from the historic attack rate without high-dose antihistamine treatment.
5. Subjects with AAE due to C1-INH deficiency must also meet the specific inclusion criteria below unique to this study population:
- History of recurrent angioedema with at least an average of 1 angioedema attack per 4 weeks prior to screening and this attack rate must be confirmed during the observation period.
- No family history of angioedema or C1-INH deficiency.
- Onset of angioedema symptoms and attacks after the age of 30 years.
- Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm C1-INH function below 50% of normal (decreased functional C1-INH) and low C4 levels (below the normal range). Subjects may be retested if results are incongruent with clinical history or believed by the investigator to be confounded by recent C1-INH use.
6. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
7. Subjects ≥18 years of age must be willing to use icatibant as the rescue medication during the
observation and treatment period. During the observation period, subjects need to be treated with icatibant for at least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the investigator, subjects with no response to icatibant for acute angioedema attacks in the past medical history/screening, or no improvement or worsened attack severity 2 hours after icatibant treatment during the observation period (based on totality of assessments), will not be included. Note: For subjects 12 to <18 years of age, standard of care therapy per local protocols should be provided.
8. Males, or non-pregnant, non-lactating females who are of child-bearing potential and who agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and must be willing to undergo pregnancy tests throughout the study. Females of non- childbearing potential are defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months.
9. The subject (or the subject’s parent/legal guardian, if applicable) has provided written informed consent approved by the institutional review board/research ethics board/ethics committee (IRB/REB/EC).
10. If the subject is an adult, be informed of the nature of the study and provide written informed
consent before any study-specific procedures are performed.
OR
If the subject is a minor (ie, <18 years of age), have a parent/legal guardian who is informed of the nature of the study provide written informed consent (ie, permission) for the minor to participate in the study before any study-specific procedures are performed. Assent will be obtained from minor subjects. |
|
| E.4 | Principal exclusion criteria |
Except for exclusion criterion 4, all other exclusion criteria listed below are identical for the 2 study populations.
1. Concomitant diagnosis of Type I or Type II HAE, or recurrent angioedema associated with urticaria.
2. Dosing with any investigational drug or exposure to an investigational device within 4 weeks prior to screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or rituximab within 6 months prior to screening.
4. For patients with normal C1-INH angioedema only: use of any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 6 months prior to screening.
5. Response to omalizumab (prophylactic) or corticosteroid (acute/prophylactic) or epinephrine (acute) or anti-leukotrienes (prophylactic) treatments in the past.
6. Use of long-term prophylactic therapy for HAE, eg, C1-INH, attenuated androgens (eg, danazol, methyltestosterone, testosterone), or anti-fibrinolytics within 2 weeks prior to entering the observation period.
7. Any exposure to prophylactic plasma kallikrein inhibitors prior to screening.
8. Use of short-term prophylaxis for HAE within 7 days prior to entering the observation period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or antifibrinolytics used to avoid angioedema complications from medically indicated procedures.
9. 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 the treatment period. Any angioedema attack must be resolved prior to the first dose in the treatment period.
10. Any of the following liver function test abnormalities: ALT >3x upper limit of normal, or AST >3x upper limit of normal, or total bilirubin >2x upper limit of normal (unless the bilirubin elevation is a result of Gilbert’s syndrome).
11. Pregnancy or breast feeding.
12. Subject has a known hypersensitivity to the investigational product or its components.
13. Have any uncontrolled underlying medical condition which would require treatment adjustment during the study treatment period, that, in the opinion of the investigator or sponsor, may confound the results of the safety assessments or may place the subject at risk. Subjects with stable treatment for at least 3 months prior to screening and NOT expecting any change to their treatment regimen for 6 months during the study treatment period, will not be excluded.
14. Have any condition (surgical or medical) 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 comorbidities that the investigator considers may confound the interpretation of study results). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Number of investigator-confirmed angioedema attacks during the treatment period (Day 0 through Day 182) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Subjects that are attack-free during the treatment period (Day 0 through Day 182)
2. Number of investigator-confirmed moderate or severe angioedema attacks during the treatment period (Day 0 through Day 182)
3. Number of investigator-confirmed angioedema attacks during the presumed steady state period (Day 70 through Day 182)
4. Subjects that are attack-free during the presumed steady state period (Day 70 through Day 182)
5. Number of investigator-confirmed moderate or severe angioedema attacks during the presumed steady state period (Day 70 through Day 182) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| multiple timepoints as specified above under each point |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Australia |
| Canada |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Last visit of the last subject |
| Utolsó beteg utolsó vizitje |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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