A Phase 3 interventional study of Donidalorsen and Placebo in Hereditary Angioedema, sponsored by Ionis Pharmaceuticals, Inc.. Completed at 51 sites in 14 countries. Open to participants aged 12 Years and older. Per ClinicalTrials.gov, last updated 2025-03-06.
Sponsored by Ionis Pharmaceuticals, Inc. · Phase 3, Interventional, and Treatment
The purpose of this study was 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).
This was a Phase 3, multi-center, double-blind, randomized, placebo-controlled study of donidalorsen in 91 participants. Participants were randomly assigned 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 were randomized in a 3:1 ratio to receive donidalorsen or matching-placebo. The study included an up to 8-week Screening Period, a 24-week Treatment Period, and an up to 13-week Post-treatment Period.
171 studies on the registry are indexed under Angioedemas, Hereditary; 24 are open to participants now.
This study's enrollment of 91 is above the median of 48 across 116 interventional studies indexed under Angioedemas, Hereditary.
Browse Angioedemas, Hereditary studies →Ionis Pharmaceuticals, Inc. is the lead sponsor of 118 studies on the registry; 10 are open to participants now.
Of its 49 completed or terminated interventional studies of FDA-regulated products, 22 (45%) have results posted.
Counted across the registry records on this site, refreshed daily.
Key Inclusion Criteria
Participants must:
Key Exclusion Criteria
Exposure to any of the following medications:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Weeks 1, 5, 9, 13, 17, and 21) or 8 weeks (Weeks 1, 9, and 17)
Drug: Donidalorsen
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.
Drug: Donidalorsen
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Drug: Placebo
Donidalorsen was administered by SC injection.
Donidalorsen-matching placebo was administered by SC injection.
Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, divided by the number of days the participant contributed to the 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).
Time frame: Week 1 to Week 25
Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the 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).
Time frame: Week 5 to Week 25
Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25
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). Percentages are rounded off to the nearest decimal.
Time frame: Week 5 to Week 25
Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25
The time-adjusted HAE attack rate was calculated as number of investigator-confirmed moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the 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).
Time frame: Week 5 to Week 25
Number of Participants With a Clinical Response From Week 5 to Week 25
Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. The HAE attack rate between Week 5 and Week 25 for each participant is calculated as number of HAE attacks occurring from Week 5 to week 25 divided by the number of days the participant contributed to the 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). Baseline= Run-in period which is the period from screening to the last day prior to Study Day 1.
Time frame: Week 5 to Week 25
IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25
Time-adjusted HAE attack rate is calculated as number of IC HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days the participant contributed to 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). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist.
Time frame: 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 4 questions asking about the frequency and severity of angioedema experienced in last 4 weeks. Each question has 5 response choices with total score ranging from 0 to 16. 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 well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal.
Time frame: Week 25
Change From Baseline 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. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0 = never, 1 = rarely, 2 = occasionally, 3 = often, 4 = very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. The calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline is defined as the score on Study Day 1.
Time frame: Week 25
Participants took part in the study at 39 investigative sites from 3 December 2021 to 09 November 2023.
| Milestone | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Started | 22 | 46 | 23 |
| Full analysis set (fas) | 22 | 45 | 23 |
| Completed | 0 | 1 | 3 |
| Not completed | 22 | 45 | 20 |
| Withdrew: Voluntary withdrawal | 2 | 1 | 0 |
| Withdrew: Pregnancy | 1 | 0 | 0 |
| Withdrew: Roll over to cs7 | 19 | 44 | 20 |
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, divided by the number of days the participant contributed to the 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).
| HAE attacks per month | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25 | 2.26 (1.657 to 3.085) | 0.44 (0.265 to 0.727) | 1.02 (0.651 to 1.594) |
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the 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).
| HAE attacks per month | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 2.25 (1.594 to 3.183) | 0.30 (0.151 to 0.581) | 0.90 (0.529 to 1.520) |
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). Percentages are rounded off to the nearest decimal.
| Percentage of participants | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25 | 9.1 | 53.3 | 34.8 |
The time-adjusted HAE attack rate was calculated as number of investigator-confirmed moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the 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).
| HAE attacks per month | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 1.15 (0.718 to 1.831) | 0.12 (0.044 to 0.351) | 0.68 (0.372 to 1.229) |
Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. The HAE attack rate between Week 5 and Week 25 for each participant is calculated as number of HAE attacks occurring from Week 5 to week 25 divided by the number of days the participant contributed to the 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). Baseline= Run-in period which is the period from screening to the last day prior to Study Day 1.
| Participants | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| ≥ 50% Reduction | 6 | 42 | 19 |
| ≥ 70% Reduction | 4 | 37 | 15 |
| ≥ 90% Reduction | 2 | 28 | 11 |
Time-adjusted HAE attack rate is calculated as number of IC HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days the participant contributed to 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). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist.
| HAE attacks per month | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25 | 1.80 (1.232 to 2.616) | 0.15 (0.057 to 0.391) | 0.59 (0.308 to 1.146) |
The AECT is a validated participant-reported outcome instrument to assess disease activity in participants with recurrent angioedema. The questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last 4 weeks. Each question has 5 response choices with total score ranging from 0 to 16. 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 well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal.
| Percentage of participants | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | 47.1 | 92.9 | 77.3 |
The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL impairment in participants suffering from recurrent angioedema. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0 = never, 1 = rarely, 2 = occasionally, 3 = often, 4 = very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. The calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline is defined as the score on Study Day 1.
| Score on a scale | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | -6.19 (-13.737 to 1.353) | -24.76 (-29.860 to -19.652) | -19.85 (-26.960 to -12.734) |
Collected over Up to Week 38. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Pooled Placebo | 0/22 (0%) | 1/22 (4.5%) | 15/22 (68.2%) |
| Cohort A: Donidalorsen 80 mg | 0/45 (0%) | 0/45 (0%) | 22/45 (48.9%) |
| Cohort B: Donidalorsen 80 mg | 0/23 (0%) | 0/23 (0%) | 13/23 (56.5%) |
| Event | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| Limb InjuryInjury, poisoning and procedural complications | 1/22 | 0/45 | 0/23 |
| Event | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg |
|---|---|---|---|
| NasopharyngitisInfections and infestations | 5/22 | 6/45 | 3/23 |
| InfluenzaInfections and infestations | 2/22 | 4/45 | 5/23 |
| HeadacheNervous system disorders | 4/22 | 7/45 | 2/23 |
| Covid-19Infections and infestations | 3/22 | 1/45 | 1/23 |
| Limb InjuryInjury, poisoning and procedural complications | 3/22 | 0/45 | 1/23 |
| Injection Site ErythemaGeneral disorders | 0/22 | 6/45 | 1/23 |
| Upper Respiratory Tract InfectionInfections and infestations | 1/22 | 4/45 | 3/23 |
| PyrexiaGeneral disorders | 1/22 | 0/45 | 3/23 |
| Abdominal PainGastrointestinal disorders | 2/22 | 1/45 | 0/23 |
| GastroenteritisInfections and infestations | 2/22 | 1/45 | 1/23 |
The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Age, Continuous(years) | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg | Total |
|---|---|---|---|---|
| Mean | 35.4 ± 11.03 | 39.6 ± 15.23 | 34.1 ± 13.22 | 37.2 ± 13.88 |
| Sex: Female, Male(Participants) | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg | Total |
|---|---|---|---|---|
| Female | 8 | 28 | 12 | 48 |
| Male | 14 | 17 | 11 | 42 |
| Ethnicity (NIH/OMB)(Participants) | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg | Total |
|---|---|---|---|---|
| Hispanic or Latino | 1 | 2 | 3 | 6 |
| Not Hispanic or Latino | 21 | 43 | 20 | 84 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized(Participants) | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg | Total |
|---|---|---|---|---|
| Race — American Indian or Alaskan Native | 2 | 0 | 1 | 3 |
| Race — Asian | 0 | 1 | 0 | 1 |
| Race — Black or African American | 1 | 1 | 0 | 2 |
| Race — White | 18 | 42 | 22 | 82 |
| Race — Multiple | 1 | 0 | 0 | 1 |
| Race — Other | 0 | 1 | 0 | 1 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: 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/.
Data sharing details ↗ · vivli.org
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Studies of the drug tested here: Donidalorsen