E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hereditary angioedema (HAE) is a rare genetic condition, where the body has local swellings in various body parts including the hands, feet, face and airway, (throat). |
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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 | 16.0 |
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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the PK, tolerability, and safety of a single SC dose of icatibant in children and adolescents with HAE |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with HAE
- To evaluate the effect on reproductive hormone levels after a single SC dose of icatibant in children and adolescents with HAE
- To evaluate the continued safety of icatibant in pubertal/postpubertal children after repeated exposures.
- To evaulate the efficacy of icatibant in the treatment of acute HAE attacks in pubertal/postpubertal children after repeated exposures.
- To evaluate the effect on reproductive hormone levels in pubertal/postpubertal children after repeated exposure. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Two to <18 years of age (ie, from the second birthday through the day prior to the eighteenth birthday) at the time of enrollment and treatment with icatibant.
- Prepubertal and pubertal/postpubertal subjects experiencing an acute cutaneous, abdominal, or laryngeal HAE attack treated with icatibant as part of this study.
- Pubertal/postpubertal subjects with HAE who are treated with icatibant as part of this study, but not during an attack.
2. Documented diagnosis of HAE type I or II. Diagnosis may be on the basis of historical data: family history, characteristic attack manifestations, recurrent attacks, historical C1-INH deficiency, and exclusion of other forms of angioedema. Inclusion will be permitted initially based on medical history only if a clear diagnosis has been made based on all of the preceding criteria. However, the diagnosis must be confirmed prior to treatment by documented immunogenic and/or functional C1-INH deficiency (C1-INH protein level below the lower limit of normal and/or functional level <50% of normal) as performed by the Sponsor’s central laboratory.
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) or legal guardian(s).
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E.4 | Principal exclusion criteria |
1. Diagnosis of angioedema other than HAE.
2. Participation in another clinical trial that involves use of any investigational product (drug or device) within 30 days prior to study enrollment or at any time during the study.
3. Any known factor/disease that might interfere with the treatment compliance, study conduct, or result interpretation.
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac function.
5. Treatment with angiotensin converting enzyme (ACE) inhibitors within 7 days prior to treatment.
6. Use of hormonal contraception within the 90 days prior to treatment.
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone within the 90 days prior to treatment).
8. Pregnancy or breastfeeding.
9. A physical condition that interferes with pubertal status determination. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The PK profile of icatibant after a single SC injection in pediatric subjects (in prepubertal children with an acute attack of HAE and pubertal/postpubertal children with or without an acute attack of HAE).
The tolerability and safety of SC icatibant as assessed by injection site reactions, AEs, vital signs, ECG recordings, physical examination, clinical laboratory parameters (serum chemistry [including liver function tests], hematology, urinalysis), reproductive hormone levels, and immunogenicity (presence of anti-icatibant antibodies). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Post-Treatment Day 1 through Day 8 (±1 days)
Follow-up Day 9 through Day 90 (±7 days)
Two additional icatibant-treated attacks for a total of 3 icatibant-treated attacks
(Pubertal/postpubertal subjects only)
Treatment Day 1
Post-Treatment Day 1 through Day 8 (±1 days)
Follow-up Day 9 through Day 90 (±7 days) |
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E.5.2 | Secondary end point(s) |
Only for subjects treated with icatibant during an HAE attack
Time to onset of relief of symptoms and time to minimal symptoms, as measured by investigator- and subject-reported outcomes
• For subjects 2 to less than 18 years of age: investigator assessment and scoring of cutaneous, abdominal and laryngeal symptoms of acute HAE attacks by an investigator-rated symptom score.
• For subjects 4 years of age and older: subject self-assessment of HAE related pain using the Faces Pain Scale-Revised (FPS-R).
• For subjects less than 4 years of age: investigator assessment of HAE-related pain (cutaneous, abdominal and laryngeal) using a validated pain scale (Faces, Legs, Activity, Cry, and Consolability [FLACC].
Incidence of rescue medication use.
Proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 4 hours after treatment with icatibant.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Post-Treatment Day 1 through Day 8 (±1 days)
Follow-up Day 9 through Day 90 (±7 days)
Two additional icatibant-treated attacks for a total of 3 icatibant-treated attacks
(Pubertal/postpubertal subjects only)
Treatment Day 1
Post-Treatment Day 1 through Day 8 (±1 days)
Follow-up Day 9 through Day 90 (±7 days) |
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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 | 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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | 6 |
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 |
Germany |
Hungary |
Israel |
Italy |
Spain |
United States |
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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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Once the tenth prepubertal subject and the twentieth pubertal/postpubertal subject have completed the 6-month follow-up after the initial treatment, and the tenth pubertal/postpubertal subject has completed the 6-month follow-up after his or her third and final treatment for an attack, the study will be closed. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |