Hereditary AngioedemaPhase 2NCT04307381
An Extension Study of Donidalorsen (IONIS-PKK-LRx) in Participants With Hereditary Angioedema
A Phase 2 study testing Donidalorsen in people with Hereditary Angioedema, run by Ionis Pharmaceuticals, Inc. at 7 sites in 2 countries.
Trial summary
The purpose of this study was to evaluate the safety and efficacy of extended dosing of donidalorsen administered subcutaneously (SC), with alternative dosing and/or dose frequency with donidalorsen in participants with hereditary angioedema (HAE). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hereditary Angioedema
- What is being tested?
- Donidalorsen
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 7 sitesin 2 countries
- Study dates
- 31 Mar 2020to 24 Jan 2025
- Phase
- Phase 2
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Satisfactory completion of ISIS 721744-CS2 (index study) through Week 17 with an acceptable safety and tolerability profile, per Sponsor and Investigator judgement
- Able and willing to participate in a 64-week study
- Females must be non-pregnant, non-lactating and either surgically sterile or post-menopausal
- Males must be surgically sterile or abstinent* or if engaged in sexual relations with a female of child-bearing potential, participant is utilizing an acceptable contraceptive method
- Participants must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1- inhibitor (C1-INH) concentrate or a bradykinin-2 [BK-2] antagonist) to treat angioedema attacks
Who cannot join
- 1. Have any new condition or worsening of an existing condition or change or anticipated change in medication, which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study
Trial locations and contacts
7 sites in 2 countries.
7 sites in 2 countries
United States6 sites
Ionis Investigative Site
Cincinnati, Ohio, 45231
Ionis Investigative Site
Dallas, Texas, 75231
Ionis Investigative Site
Hershey, Pennsylvania, 17033
Ionis Investigative Site
Plymouth, Minnesota, 55446
Ionis Investigative Site
Santa Monica, California, 90404
Ionis Investigative Site
Scottsdale, Arizona, 85251
About this study
Official title: An Open-Label Extension Study of ISIS 721744 in Patients With Hereditary Angioedema
The purpose of this study was to evaluate the safety and efficacy of extended dosing of donidalorsen administered subcutaneously (SC), with alternative dosing and/or dose frequency with donidalorsen in participants with hereditary angioedema (HAE).
Read the detailed description
This was an open-label extension study of donidalorsen in 20 participants with HAE. The length of participation in the study was approximately 68 weeks, which included an up to 4-week qualification period, a 52-week treatment period, and a 12-week post-treatment period. Following the Week 53 treatment period visit, participants received donidalorsen in an extended treatment period for up to an additional 156 weeks. Participants taking part in the extended treatment period entered the 12-week post-treatment period after completion of, or early termination from, the extended treatment period.
- Conditions
- Hereditary Angioedema
- Being tested
- Donidalorsen
- Keywords
- Hereditary Angioedema, 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 administered SC
| Study group | Role | What they receive |
|---|---|---|
| HAE-1/HAE-2 | Experimental | Participants with hereditary angioedema Type I/Type II (HAE-1/HAE-2) who received placebo or donidalorsen, 80 milligrams (mg), SC once every 4 weeks, in the previous study ISIS 721744-CS2 (NCT04030598), received donidalorsen, 80 mg, SC once every 4 weeks, from Week 1 to Week 13 (Fixed Dosing Period). Starting From Week 17 (Flexible Dosing Period), participants had 3 different dosing options as: 80 mg every 4 weeks, 80 mg every 8 weeks for participants who were attack-free for ≥12 weeks, 100 mg every 4 weeks for participants who were not attack-free for ≥12 weeks up to Week 53 based on the investigator and sponsor medical monitor recommendation. Participants continued flexible dosing from Week 53 for up to approximately 209 weeks. Receives: Drug: Donidalorsen |
| HAE-nC1-INH | Experimental | Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) who received donidalorsen, 80 mg, SC, once every 4 weeks, in the previous study ISIS 721744-CS2 (NCT04030598), continued to receive donidalorsen, 80 mg, SC once every 4 weeks, from Week 1 to Week 13 (Fixed Dosing Period). Starting From Week 17 (Flexible Dosing Period), participants had 2 different dosing options as: 80 mg every 4 weeks, and 100 mg every 4 weeks for participants who were not attack-free for ≥12 weeks up to Week 53 based on the investigator and sponsor medical monitor recommendation. Participants continued flexible dosing from Week 53 for up to approximately 209 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 Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. TEAEs were defined as those AEs that either started or worsened in severity on or after the date/time of first administration of study drug in this OLE Study. TEAEs included both serious and non-serious TEAEs.
Measured: Up to Week 221
Percentage of Participants With Clinically Meaningful Changes in Clinical Laboratory Assessments
Clinical laboratory tests including clinical chemistry, hematology, coagulation, complement, inflammatory, urinalysis were performed. The percentage of participants with clinically meaningful changes were reported. Clinical meaningfulness was determined by the investigator.
Measured: Up to Week 221
Percentage of Participants With Clinically Meaningful Changes in Vital Signs
Vital sign measurements including heart rate, respiratory rate, body temperature, systolic and diastolic blood pressure and pulse pressure were assessed. Percentage of participants with clinically meaningful changes in the vital signs were reported. Clinically meaningfulness was determined by the investigator.
Measured: Up to Week 221
Percentage of Participants With Clinically Meaningful Changes in Electrocardiograms (ECGs) Parameters
The ECG parameters included ventricular rate, PR interval, QRS duration, QTc, QT corrected using the Fridericia's formula (QTcF), QT corrected using the Bazett's formula (QTcB), and overall interpretation. Percentage of participants with clinically meaningful changes in the ECG parameters were reported. Clinical meaningfulness was determined by the investigator.
Measured: Up to Week 221
Percentage of Participants Who Received At Least One Concomitant Medication
Concomitant medications include medications that participants were exposed to on or after the first dose of ISIS 721744 in the OLE study. Percentage of participants who received at least one concomitant medication were reported.
Measured: Up to Week 221
Secondary outcomes (2)
Percent Change From Baseline in Time-normalized HAE Attack (Per 4 Weeks) Rate
HAE attack rate was calculated for each participant as the number of HAE attacks occurring during the respective period divided by the number of days the participant contributed to this period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). A negative change from baseline in HAE attacks indicates an improvement in HAE attacks.
Measured: Up to Week 221
Percentage of Participants Who Used On-demand Medications
The most commonly used on-demand medications during the On-Treatment Period were C1 esterase inhibitors (human) and icatibant, which were allowed per-protocol for treatment of acute attacks.
Measured: Up to Week 221
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2020
- Study start31 Mar 2020
- Primary completion24 Jan 2025
- Study completion24 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 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
- NCT04307381
- Sponsor's protocol ID
- ISIS 721744-CS3
- Other IDs
- 2020-000197-14
- Status last verified
- Apr 2026
- First submitted
- 11 Mar 2020
- Last updated
- 8 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- 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
Manning ME, de Lange M, Bernstein JA, Craig T, Lumry WR, Raasch J, Tachdjian R, Bordone L, Deng Y, Newman KB, Cohn DM. Donidalorsen for hereditary angioedema: Long-term results from a 4-year, phase 2, open-label extension study. Ann Allergy Asthma Immunol. 2026 Jun;136(6):699-705.e1. doi: 10.1016/j.anai.2026.02.019. Epub 2026 Mar 7.
PubMed 41802598Petersen RS, Bordone L, Riedl MA, Tachdjian R, Craig TJ, Lumry WR, Manning ME, Bernstein JA, Raasch J, Zuraw BL, Deng Y, Newman KB, Alexander VJ, Lui C, Schneider E, Cohn DM. A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema. Allergy. 2024 Mar;79(3):724-734. doi: 10.1111/all.15948. Epub 2023 Nov 27.
PubMed 38009241