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 |
Genetic disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
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 |
The primary objective of the study is to evaluate the clinical efficacy of ISIS 721744 in patients with HAE. |
|
E.2.2 | Secondary objectives of the trial |
Evaluate the effects of ISIS 721744 on the quality and pattern of HAE attacks and their impact on Quality of Life. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must be aged ≥ 12 years at the time of informed consent, and, as applicable, assent Patients must have a documented diagnosis of HAE-1/HAE-2 based upon ALL of the following: a. Documented clinical history consistent with HAE (subcutaneous [SC] or mucosal, non-pruritic swelling episodes without accompanying urticaria) b. Diagnostic testing results that confirm HAE-1/HAE-2: C1-INH functional level < 40% normal level. Patients with a functional level of 40% to 50% of normal can be enrolled if their complement factor C4 level is below the lower limit of normal (LLN) or if a known pathogenic mutation in the SERPING1 gene has been demonstrated c. At least 1 of the following: age at reported HAE onset ≤ 30 years; a family history consistent with HAE-1/HAE-2; or complement component 1q within the normal range Patients must: a. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the Screening Period b. Be willing to complete the PRO assessments throughout the study Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) to treat angioedema attacks |
|
E.4 | Principal exclusion criteria |
• Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the Screening, Treatment or Post-Treatment Periods • Concurrent diagnosis of any other type of recurrent angioedema, including acquired, idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III) • Anticipated change in the use of concurrent androgen prophylaxis used to treat angioedema attacks • Participation in a prior ISIS 721744 study • Exposure to any of the following medications: a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to Screening b. Chronic prophylaxis with Takhzyro (lanadelumab), Haegarda (C1esterase inhibitor SQ), Cinryze and Ruconest (C1 esterase inhibitor) or Orladeyo (berotralstat) within 5 half-lives prior to Screening (i.e., Takhzyro within 10 weeks prior to Screening, Haegarda/Cinryze/Ruconest within 2 weeks prior to screening, Orladeyo within 3 weeks prior to Screening) c. Oligonucleotides (including small interfering ribonucleic acid) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received. This exclusion does not apply to vaccines |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 1 to Week 25 compared to placebo. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints are described within the text in section E.5.1 |
|
E.5.2 | Secondary end point(s) |
The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 5 to Week 25 compared to placebo • The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to Week 25 compared to placebo • The time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per month) from Week 5 to Week 25 compared to placebo • The number of patients with a clinical response defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline (i.e., screening rate) in Investigator-confirmed HAE attack rate between Week 5 to Week 25 compared to placebo • Percent of patients who are well-controlled based on the AECT at Week 25 • Change in AE-QoL questionnaire total score at Week 25 • The number of Investigator-confirmed HAE attacks requiring acute HAE therapy from Week 5 to Week 25 compared to placebo. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints are described within the text in section E.5.1 |
|
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 | Yes |
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 | No |
E.6.12 | Pharmacoeconomic | Yes |
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
| 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 States |
France |
Poland |
Bulgaria |
Netherlands |
Spain |
Germany |
Italy |
Belgium |
Denmark |
Turkey |
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 is defined as the date of the last visit of the last patient in the study. For individual patients, End-of-Study is defined as completion of their last study visit. |
|
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 | 4 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |