Clinical trial NCT05392114: A Study to Assess the Long-Term Safety and Efficacy of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
Official title: An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hereditary Angioedema
Keywords: HAE
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2022-05-26
Enrollment: 144
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the long-term safety and efficacy of donidalorsen in people with HAE and the effects of donidalorsen on the number of HAE attacks and their impact on quality of life (QoL).

Detailed description: This is a Phase 3, multi-center, open-label, global study with donidalorsen in up to approximately 144 participants with HAE-1 (Type I) and HAE-2 (Type II). There are two groups in this study: 1) participants who roll over from another study of donidalorsen (open-label extension \[OLE\] participants), and 2) new participants who are not rolling over from another study of donidalorsen and were previously maintained on HAE prophylactic therapy with lanadelumab, berotralstat, or a C1-esterase inhibitor (C1-INH). The length of participation in the study is approximately 70 weeks for OLE participants and 76 weeks for other participants. Participants will receive donidalorsen in an Extended Treatment Period for up to an additional 104 weeks.

Eligibility criteria: 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 SC C1-esterase inhibitor prior to the Screening Period.

Exclusion Criteria

Open-Label Extension Participants:

1. Have any new condition or worsening of an existing condition or change or anticipated change in medication.

   New (not previously on donidalorsen) Participants ONLY:
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.
4. Any clinically-significant abnormalities in screening laboratory values.
5. 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.
6. Hypersensitivity to the active substance (donidalorsen) or to any of the excipients.
7. 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.
8. Recent history of, or current drug or alcohol abuse.
9. Participated in a prior donidalorsen study.
10. Exposure to any of the following medications:

    1. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption.
    2. 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.

Primary outcomes:
measure: Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE), Graded by Severity
timeFrame: Up to approximately 70 weeks, plus 104 weeks for Group 1; up to approximately 76 weeks, plus 104 weeks for Group 2
Secondary outcomes:
measure: Time-normalized Number of Investigator-confirmed HAE Attacks (per Month)
timeFrame: Week 1 to Week 157 for Group 1 and Group 2
measure: Percentage of Investigator-confirmed HAE Attack-free Participants
timeFrame: Week 1 to Week 157 for Group 1 and Group 2
measure: Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (per Month)
timeFrame: Week 1 to Week 157 for Group 1 and Group 2
measure: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy
timeFrame: Week 1 to Week 157 for Group 1 and Group 2
measure: Angioedema Quality of Life (AE-QoL) Questionnaire Total Score
timeFrame: Up to 157 weeks for Group 1 and Group 2
Other outcomes:
Locations:
city: Paradise Valley
country: United States
facility: Ionis Investigative Site
state: Arizona
city: La Jolla
country: United States
facility: Ionis Investigative Site
state: California
city: Santa Monica
country: United States
facility: Ionis Investigative Site
state: California
city: Walnut Creek
country: United States
facility: Ionis Investigative Site
state: California
city: Tampa
country: United States
facility: Ionis Investigative Site
state: Florida
city: Kansas City
country: United States
facility: Ionis Investigative Site
state: Kansas
city: Boston
country: United States
facility: Ionis Investigative Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Ionis Investigative Site
state: Michigan
city: Detroit
country: United States
facility: Ionis Investigative Site
state: Michigan
city: Saint Louis
country: United States
facility: Ionis Investigative Site
state: Missouri
city: Mooresville
country: United States
facility: Ionis Investigative Site
state: North Carolina
city: Cincinnati
country: United States
facility: Ionis Investigative Site
state: Ohio
city: Columbus
country: United States
facility: Ionis Investigative Site
state: Ohio
city: Hershey
country: United States
facility: Ionis Investigative Site
state: Pennsylvania
city: Dallas
country: United States
facility: Ionis Investigative Site
state: Texas
city: Murray
country: United States
facility: Ionis Investigative Site
state: Utah
city: Edegem
country: Belgium
facility: Ionis Investigative Site
city: Sofia
country: Bulgaria
facility: Ionis Investigative Site
city: Sofia
country: Bulgaria
facility: Ionis Investigative Site
city: Ottawa
country: Canada
facility: Ionis Investigative Site
state: Ontario
city: Edmonton
country: Canada
facility: Ionis Investigative Site
city: La Tronche
country: France
facility: Ionis Investigative Site
city: Marseille
country: France
facility: Ionis Investigative Site
city: Paris
country: France
facility: Ionis Investigative Site
city: Berlin
country: Germany
facility: Ionis Investigative Site
city: Frankfurt
country: Germany
facility: Ionis Investigative Site
city: München
country: Germany
facility: Ionis Investigative Site
city: Ashkelon
country: Israel
facility: Ionis Investigative Site
city: Haifa
country: Israel
facility: Ionis Investigative Site
city: Tel Aviv
country: Israel
facility: Ionis Investigative Site
city: Catania
country: Italy
facility: Ionis Investigative Site
city: Napoli
country: Italy
facility: Ionis Investigative Site
city: Padova
country: Italy
facility: Ionis Investigative Site
city: Palermo
country: Italy
facility: Ionis Investigative Site
city: San Donato Milanese
country: Italy
facility: Ionis Investigative Site
city: Amsterdam
country: Netherlands
facility: Ionis Investigative Site
city: Groningen
country: Netherlands
facility: Ionis Investigative Site
city: Krakow
country: Poland
facility: Ionis Investigative Site
city: San Juan
country: Puerto Rico
facility: Ionis Investigative Site
city: Barcelona
country: Spain
facility: Ionis Investigative Site
city: Barcelona
country: Spain
facility: Ionis Investigative Site
city: Madrid
country: Spain
facility: Ionis Investigative Site
city: Sevilla
country: Spain
facility: Ionis Investigative Site
city: Valencia
country: Spain
facility: Ionis Investigative Site
city: Altındağ
country: Turkey
facility: Ionis Investigative Site
city: Bornova
country: Turkey
facility: Ionis Investigative Site
city: Istanbul
country: Turkey
facility: Ionis Investigative Site
city: Birmingham
country: United Kingdom
facility: Ionis Investigative Site
city: Bristol
country: United Kingdom
facility: Ionis Investigative Site
city: London
country: United Kingdom
facility: Ionis Investigative Site
Study officials:
References: