OASIS-HAE: A Study to Evaluate the Safety and Efficacy of Donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in Participants With Hereditary Angioedema (HAE)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of donidalorsen in participants with HAE and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).

Detailed Description
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This is a Phase 3, multi-center, double-blind, randomized, placebo-controlled study of donidalorsen in up to 84 participants. Participants will be randomized in a 2:1 ratio to Cohort A (donidalorsen or placebo every 4 weeks) or Cohort B (donidalorsen or placebo every 8 weeks), respectively. Within each Cohort, participants will be randomized in a 3:1 ratio to receive donidalorsen or matching-placebo. The length of participation in the study is approximately 11 months, which includes an up to 8-week Screening Period, a 25-week Treatment Period, and an up to 13-week Post-treatment Period.

Official Title
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A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Drug: Donidalorsen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants, or their legally appointed and authorized representatives, must provide written and signed informed consent form (ICF)/assent Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent Participants must have a documented diagnosis of hereditary angioedema type 1 (HAE-1)/hereditary angioedema type 2 (HAE-2) Participants must: Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the Screening Period Be willing to complete the participant reported outcomes (PRO) assessments throughout the study Participants must have access to, and the ability to use acute medication(s) to treat angioedema attacks Exclusion Criteria 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) Any clinically-significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion in the study Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of Screening Participated in a prior ISIS 721744 study Exposure to any of the following medications: Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption within 4 weeks prior to Screening Chronic prophylaxis with Takhzyro, Haegarda, Cinryze and Ruconest or Orladeyo within 5 half-lives prior to Screening Oligonucleotides (including small interfering ribonucleic acid [siRNA]) 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 Recent history (3 years) of, or current drug or alcohol abuse

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donidalorsen: Cohort A<br>Participants will be administered donidalorsen by subcutaneous (SC) injection for up to 25 weeks. | Drug: Donidalorsen<br>* Donidalorsen will be administered by SC injection.<br>|
| Experimental: Donidalorsen: Cohort B<br>Participants will be administered donidalorsen by subcutaneous (SC) injection for up to 25 weeks. | Drug: Donidalorsen<br>* Donidalorsen will be administered by SC injection.<br>|
| Placebo Comparator: Placebo: Cohort A<br>Participants will be administered donidalorsen-matching placebo by subcutaneous (SC) injection for up to 25 weeks. | Drug: Placebo<br>* Donidalorsen-matching placebo will be administered by SC injection.<br>|
| Placebo Comparator: Placebo: Cohort B<br>Participants will be administered donidalorsen-matching placebo by subcutaneous (SC) injection for up to 25 weeks. | Drug: Placebo<br>* Donidalorsen-matching placebo will be administered by SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Normalized Number of Investigator-Confirmed HAE Attacks (per Month) From Week 1 to Week 25 |  | Week 1 to Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Normalized Number of Investigator-Confirmed HAE Attacks (per Month) From Week 5 to Week 25 |  | Week 5 to Week 25 | 
| Percentage of Investigator-Confirmed HAE Attack-Free Participants From Week 5 to Week 25 |  | Week 5 to Week 25 | 
| Time-Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks (per Month) From Week 5 to Week 25 |  | Week 5 to Week 25 | 
| Number of Participants With a Clinical Response Defined as a ≥ 50%, ≥ 70%, or ≥ 90% Reduction From Baseline (Screening Rate) in Investigator-confirmed HAE Attack Rate Between Week 5 to Week 25 |  | Week 5 to Week 25 | 
| Number of Investigator-Confirmed HAE Attacks Requiring Acute HAE Therapy From Week 5 to Week 25 |  | Week 5 to Week 25 | 
| Percentage of Participants who are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | The AECT is a validated participant-reported outcome instrument to assess disease activity in participants with recurrent angioedema. The questionnaire consists of four questions asking about the frequency and severity of angioedema experienced in the prior month. Each question has 5 response choices. The AECT can be used to identify participants with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Participants who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas participants with controlled disease score 10-16 points. Higher scores will indicate well controlled disease. | Week 25 | 
| Change in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL impairment in participants suffering from recurrent angioedema. The AE-QoL is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 1 to 5 where, 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = very often. Total and domain scores range from 0 to 100, with higher scores indicating greater impairment. | Week 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HAE