An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)

Phase 1

Conditions: Hereditary Angioedema (HAE)
MedDRA version: 23.1Level: PTClassification code 10019860Term: Hereditary angioedemaSystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

Registration Number: EUCTR2022-000757-93-PL

Lead Sponsor: IONIS PHARMACEUTICALS, INC.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 144

Inclusion Criteria

1. Participants and, as applicable, legally authorized representatives (i.e., parent(s)/legal guardian), must provide written and signed informed consent form (ICF).
2. Participants must have access to, and the ability to use, = 1 acute medication(s) (e.g., plasma-derived or recombinant C1-INH concentrate or a bradykinin receptor (BK) 2-receptor antagonist) to treat angioedema attacks
Open-Label Extension Participants ONLY:
3. Satisfactory completion of ISIS 721744-CS5 (randomized placebo-controlled index study) through Week 25 or participants who are allowed to exit ISIS 721744-CS5 study per protocol with an acceptable safety and tolerability profile
New (not previously on donidalorsen) Participants ONLY
4. Participants must be aged = 12 years at the time of informed consent and, as applicable, assent
5. Participants must have a documented diagnosis of HAE-1/HAE-2
6. Participants must be on a stable dose (= 12 weeks) of prophylaxis treatment with lanadelumab or berotralstat or C1-esterase inhibitor prior to the Screening Period
Are the trial subjects under 18? yes
Number of subjects for this age range: 13
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 125
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 6

Exclusion Criteria

1. Have any new condition or worsening of an existing condition or change or anticipated change in medication
De-novo Participants:
2. 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)
3. Anticipated change in the use of concurrent androgen or tranexamic acid prophylaxis used to prevent angioedema attacks
Any clinically-significant abnormalities in screening laboratory values.
4. Malignancy within 5 years of Screening, except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has been successfully treated.
5. Hypersensitivity to the active substance (donidalorsen) or to any of the excipients
6. Treatment with another investigational drug (non-oligonucleotide) or biological agent within 1 month of Screening or 5 half-lives of investigational agent, whichever is longer
7. Recent history of, or current drug or alcohol abuse
8. Participated in a prior donidalorsen study
9. Exposure to any of the following medications:
Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption
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

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of the study is to evaluate the safety of long-term dosing with donidalorsen in patients with HAE;Secondary Objective: To evaluate the long-term efficacy and the effects of donidalorsen on the number of HAE attacks and their impact on the quality of life (QoL) of patients with HAE.;Primary end point(s): Incidence and severity of treatment-emergent adverse events (TEAEs).;Timepoint(s) of evaluation of this end point: From week 1 to week 157

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 1 to Week 53<br>• The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 5 to Week 53<br>• The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to Week 53<br>• The time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per month) from Week 5 to Week 53<br>• The number of Investigator-confirmed HAE attacks requiring acute therapy from Week 5 to Week 53<br>• Angioedema Quality of Life (AE-QoL) questionnaire total score over 53 weeks;Timepoint(s) of evaluation of this end point: From week 1 to week 53

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