Hereditary AngioedemaPhase 3NCT05392114
A Study to Assess the Long-Term Safety and Efficacy of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
A Phase 3 study testing Donidalorsen in people with Hereditary Angioedema, run by Ionis Pharmaceuticals, Inc. at 50 sites in 14 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Hereditary Angioedema
- What is being tested?
- Donidalorsen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 154 participants
- Where
- 50 sitesin 14 countries
- Study dates
- 13 Jul 2022to Mar 2027
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Participants and, as applicable, legally authorized representatives (i.e., parent(s)/legal guardian), must provide written and signed informed consent form (ICF).
- 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:
- 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:
- Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent.
- Participants must have a documented diagnosis of HAE-1/HAE-2.
- 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.
Who cannot join
- Open-Label Extension Participants:
- Have any new condition or worsening of an existing condition or change or anticipated change in medication.
- New (not previously on donidalorsen) Participants ONLY:
- 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 or tranexamic acid prophylaxis used to prevent angioedema attacks.
- Any clinically-significant abnormalities in screening laboratory values.
Show all 14Show fewer
- 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.
- Hypersensitivity to the active substance (donidalorsen) or to any of the excipients.
- 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.
- Recent history of, or current drug or alcohol abuse.
- Participated in a prior donidalorsen study.
- 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.
Trial locations and contacts
50 sites in 14 countries.
50 sites in 14 countries
United States16 sites
Ionis Investigative Site
Ann Arbor, Michigan, 48109
Ionis Investigative Site
Boston, Massachusetts, 02114
Ionis Investigative Site
Cincinnati, Ohio, 45236
Ionis Investigative Site
Columbus, Ohio, 43235
Ionis Investigative Site
Dallas, Texas, 75231
Ionis Investigative Site
Detroit, Michigan, 48202
Ionis Investigative Site
Hershey, Pennsylvania, 17033
Ionis Investigative Site
Kansas City, Kansas, 66103
Ionis Investigative Site
La Jolla, California, 92037
Ionis Investigative Site
Mooresville, North Carolina, 28117
Ionis Investigative Site
Murray, Utah, 84107
Ionis Investigative Site
Paradise Valley, Arizona, 85253
Ionis Investigative Site
Santa Monica, California, 90404
Ionis Investigative Site
St Louis, Missouri, 63141
Ionis Investigative Site
Tampa, Florida, 33613
Ionis Investigative Site
Walnut Creek, California, 94598
Italy5 sites
Ionis Investigative Site
Catania, 95123
Ionis Investigative Site
Naples, 80131
Ionis Investigative Site
Padova, 35128
Ionis Investigative Site
Palermo, 90146
Ionis Investigative Site
San Donato Milanese, 20097
Spain5 sites
Ionis Investigative Site
Barcelona, 08035
Ionis Investigative Site
Barcelona, 08907
Ionis Investigative Site
Madrid, 28046
Ionis Investigative Site
Seville, 41013
Ionis Investigative Site
Valencia, 46026
France3 sites
Ionis Investigative Site
La Tronche, 38700
Ionis Investigative Site
Marseille, 13385
Ionis Investigative Site
Paris, 75012
Germany3 sites
Ionis Investigative Site
Berlin, 12203
Ionis Investigative Site
Frankfurt, 60590
Ionis Investigative Site
München, 81675
Israel3 sites
Ionis Investigative Site
Ashkelon, 7830604
Ionis Investigative Site
Haifa, 3104802
Ionis Investigative Site
Tel Aviv, 6423906
Turkey (Türkiye)3 sites
Ionis Investigative Site
Altındağ, 06230
Ionis Investigative Site
Bornova, 35100
Ionis Investigative Site
Istanbul, 34093
United Kingdom3 sites
Ionis Investigative Site
Birmingham, B9 5SS
Ionis Investigative Site
Bristol, BS10 5NB
Ionis Investigative Site
London, E1 2ES
Bulgaria2 sites
Ionis Investigative Site
Sofia, 1431
Ionis Investigative Site
Sofia, 1680
Canada2 sites
Ionis Investigative Site
Edmonton, AB T6G 1Z1
Ionis Investigative Site
Ottawa, Ontario, K1H 1E4
Netherlands2 sites
Ionis Investigative Site
Amsterdam, 1105
Ionis Investigative Site
Groningen, 9713 AP
About this study
Official title: An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
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).
Read the 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.
- Conditions
- Hereditary Angioedema
- Being tested
- Donidalorsen
- Keywords
- HAE
- Medical subject headings
- Angioedemas, Hereditary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DonidalorsenDrug
Also called ISIS 721744, IONIS-PKK-LRx
Donidalorsen will be administered by SC injection.
| Study group | Role | What they receive |
|---|---|---|
| OLE Participants | Experimental | Group 1 and Group 2 participants will be administered donidalorsen by SC injection for up to 157 weeks. Receives: Drug: Donidalorsen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE), Graded by Severity
Measured: Up to approximately 70 weeks, plus 104 weeks for Group 1; up to approximately 76 weeks, plus 104 weeks for Group 2
Secondary outcomes (5)
Time-normalized Number of Investigator-confirmed HAE Attacks (per Month)
Measured: Week 1 to Week 157 for Group 1 and Group 2
Percentage of Investigator-confirmed HAE Attack-free Participants
Measured: Week 1 to Week 157 for Group 1 and Group 2
Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (per Month)
Measured: Week 1 to Week 157 for Group 1 and Group 2
Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy
Measured: Week 1 to Week 157 for Group 1 and Group 2
Angioedema Quality of Life (AE-QoL) Questionnaire Total Score
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.
Measured: Up to 157 weeks for Group 1 and Group 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 May 2022
- Study start13 Jul 2022
- Primary completionDec 2026 (estimated)
- Study completionMar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hereditary AngioedemaStudies of the same condition, open and under way.
- More trials run by Ionis Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 154 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ionis Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05392114
- Sponsor's protocol ID
- ISIS 721744-CS7
- Other IDs
- 2022-000757-93
- Status last verified
- Dec 2025
- First submitted
- 23 May 2022
- Last updated
- 12 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.
- Expanded access
- Available
Publications
Lumry WR, Tachdjian R, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Manning ME, Grammatikos A, Giardino F, Guilarte M, Baptist AP, Bordone L, Newman KB, Treadwell S, Lin T, Yarlas A, Riedl MA, Cohn DM. Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1. J Asthma Allergy. 2026 Feb 23;19:592079. doi: 10.2147/JAA.S592079. eCollection 2026.
PubMed 41767175Riedl MA, Bernstein JA, Jacobs JS, Craig T, Banerji A, Perego F, Lumry WR, Wedner HJ, Gierer S, Manning ME, Bordone L, Treadwell S, Lin T, Newman KB, Yarlas A, Cohn DM. Donidalorsen Treatment of Hereditary Angioedema in Patients Previously on Long-Term Prophylaxis. J Allergy Clin Immunol Pract. 2025 Sep;13(9):2381-2389.e3. doi: 10.1016/j.jaip.2025.06.018. Epub 2025 Jul 17.
PubMed 40673861
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
- ClinicalTrials.gov ID
- NCT05392114
- Acronym / sponsor ID
- ISIS 721744-CS7
- Conditions
- Hereditary Angioedema
- Keywords
- HAE
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 154 participants (actual)
- Lead sponsor
- Ionis Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 13 Jul 2022 (actual)
- Primary completion
- Dec 2026 (estimated)
- Study completion
- Mar 2027 (estimated)
- First posted
- 26 May 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| OLE Participants | Experimental | Drug: DonidalorsenGroup 1 and Group 2 participants will be administered donidalorsen by SC injection for up to 157 weeks. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- Participants and, as applicable, legally authorized representatives (i.e., parent(s)/legal guardian), must provide written and signed informed consent form (ICF).
- 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.
- 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.
- Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent.
- Participants must have a documented diagnosis of HAE-1/HAE-2.
Key exclusion criteria (14 listed)
- Have any new condition or worsening of an existing condition or change or anticipated change in medication.
- 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 or tranexamic acid prophylaxis used to prevent angioedema attacks.
- Any clinically-significant abnormalities in screening laboratory values.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DonidalorsenAlso: ISIS 721744, IONIS-PKK-LRxDonidalorsen will be administered by SC injection. | Drug | OLE Participants |
Primary outcome
Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE), Graded by Severity
Time frame: Up to approximately 70 weeks, plus 104 weeks for Group 1; up to approximately 76 weeks, plus 104 weeks for Group 2
5 secondary outcomes
Time-normalized Number of Investigator-confirmed HAE Attacks (per Month)
Time frame: Week 1 to Week 157 for Group 1 and Group 2
Percentage of Investigator-confirmed HAE Attack-free Participants
Time frame: Week 1 to Week 157 for Group 1 and Group 2
Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (per Month)
Time frame: Week 1 to Week 157 for Group 1 and Group 2
Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy
Time frame: Week 1 to Week 157 for Group 1 and Group 2
Angioedema Quality of Life (AE-QoL) Questionnaire Total Score
Time frame: Up to 157 weeks for Group 1 and Group 2
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Dec 2025.
- Derived from this study: PubMed 41767175Lumry WR, Tachdjian R, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Manning ME, Grammatikos A, Giardino F, Guilarte M, Baptist AP, Bordone L, Newman KB, Treadwell S, Lin T, Yarlas A, Riedl MA, Cohn DM. Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1. J Asthma Allergy. 2026 Feb 23;19:592079. doi: 10.2147/JAA.S592079. eCollection 2026.
- Derived from this study: PubMed 40673861Riedl MA, Bernstein JA, Jacobs JS, Craig T, Banerji A, Perego F, Lumry WR, Wedner HJ, Gierer S, Manning ME, Bordone L, Treadwell S, Lin T, Newman KB, Yarlas A, Cohn DM. Donidalorsen Treatment of Hereditary Angioedema in Patients Previously on Long-Term Prophylaxis. J Allergy Clin Immunol Pract. 2025 Sep;13(9):2381-2389.e3. doi: 10.1016/j.jaip.2025.06.018. Epub 2025 Jul 17.
- Individual participant dataSharing planned: Yes. Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
50 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Donidalorsen in people with Hereditary Angioedema, run by Ionis Pharmaceuticals, Inc. at 50 sites in 14 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 12 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 50 sites in United States, Italy, Spain, France, Germany and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE), Graded by Severity (time frame: Up to approximately 70 weeks, plus 104 weeks for Group 1; up to approximately 76 weeks, plus 104 weeks for Group 2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05392114, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2025.