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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-002571-19 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pooled Placebo | Placebo Comparator | 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) |
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| Cohort A: Donidalorsen 80 mg | Experimental | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
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| Cohort B: Donidalorsen 80 mg | Experimental | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Donidalorsen | Drug | Donidalorsen was administered by SC injection. |
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| Measure | Description | Time Frame |
|---|---|---|
| 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). | Week 1 to Week 25 |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
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Key Inclusion Criteria
Participants, or their legally appointed and authorized representatives, must provide written and signed informed consent form (ICF)/assent
Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent
Participants must have a documented diagnosis of hereditary angioedema type 1 (HAE-1)/hereditary angioedema type 2 (HAE-2)
Participants must:
Participants must have access to, and the ability to use acute medication(s) to treat angioedema attacks
Key Exclusion Criteria
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)
Any clinically-significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion in the study
Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of Screening
Participated in a prior ISIS 721744 study
Exposure to any of the following medications:
Recent history (3 years) of, or current drug or alcohol abuse
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ionis Investigative Site | Scottsdale | Arizona | 85251 | United States | ||
| Ionis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38819395 | Result | Riedl MA, Tachdjian R, Lumry WR, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Gompels MM, Manning ME, Bordone L, Newman KB, Treadwell S, Wang S, Yarlas A, Cohn DM; OASIS-HAE Team. Efficacy and Safety of Donidalorsen for Hereditary Angioedema. N Engl J Med. 2024 Jul 4;391(1):21-31. doi: 10.1056/NEJMoa2402478. Epub 2024 May 31. |
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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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A total of 91 participants were enrolled and randomized in the study. Out of 91, 1 participant withdrew consent prior to receiving the study drug. 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.
Participants took part in the study at 39 investigative sites from 3 December 2021 to 09 November 2023.
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| ID | Title | Description |
|---|---|---|
| FG000 | Pooled Placebo | Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). |
| FG001 | Cohort A: Donidalorsen 80 mg |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 12, 2022 |
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| Placebo | Drug | Donidalorsen-matching placebo was administered by SC injection. |
|
| 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. | 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). | 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. | 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. | 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. | 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. | Week 25 |
| San Diego |
| California |
| 92122 |
| United States |
| Ionis Investigative Site | Santa Monica | California | 90404 | United States |
| Ionis Investigative Site | Walnut Creek | California | 94598 | United States |
| Ionis Investigative Site | Colorado Springs | Colorado | 80907 | United States |
| Ionis Investigative Site | Tampa | Florida | 33613 | United States |
| Ionis Investigative Site | Kansas City | Kansas | 66205 | United States |
| Ionis Investigative Site | Boston | Massachusetts | 02114 | United States |
| Ionis Investigative Site | Ann Arbor | Michigan | 48109 | United States |
| Ionis Investigative Site | St Louis | Missouri | 63110 | United States |
| Ionis Investigative Site | Columbus | Ohio | 43235 | United States |
| Ionis Investigative Site | Toledo | Ohio | 43617 | United States |
| Ionis Investigative Site | Hershey | Pennsylvania | 17033 | United States |
| Ionis Investigative Site | Dallas | Texas | 75231 | United States |
| Ionis Investigative Site | Murray | Utah | 84107 | United States |
| Ionis Investigative Site | Brussels | 1020 | Belgium |
| Ionis Investigative Site | Brussels | 1200 | Belgium |
| Ionis Investigative Site | Edegem | 2650 | Belgium |
| Ionis Investigative Site | Sofia | 1431 | Bulgaria |
| Ionis Investigative Site | Sofia | 1680 | Bulgaria |
| Ionis Investigative Site | Ottawa | Ontario | K1G6C6 | Canada |
| Ionis Investigative Site | Edmonton | T6G 2G3 | Canada |
| Ionis Investigative Site | Odense | 5000 | Denmark |
| Ionis Investigative Site | La Tronche | 38700 | France |
| Ionis Investigative Site | Marseille | 13385 | France |
| Ionis Investigative Site | Paris | 75012 | France |
| Ionis Investigative Site | Berlin | 12203 | Germany |
| Ionis Investigative Site | Frankfurt | 60590 | Germany |
| Ionis Investigative Site | Munich | 81675 | Germany |
| Ionis Investigative Site | Ashkelon | 78278 | Israel |
| Ionis Investigative Site | Haifa | 3104802 | Israel |
| Ionis Investigative Site | Tel Aviv | 6423906 | Israel |
| Ionis Investigative Site | Catania | 95124 | Italy |
| Ionis Investigative Site | Milan | 20138 | Italy |
| Ionis Investigative Site | Naples | 80131 | Italy |
| Ionis Investigative Site | Padova | 35128 | Italy |
| Ionis Investigative Site | Palermo | 90146 | Italy |
| Ionis Investigative Site | Amsterdam | 1105 AZ | Netherlands |
| Ionis Investigative Site | Groningen | 9713 GZ | Netherlands |
| Ionis Investigative Site | Krakow | 31-503 | Poland |
| Ionis Investigative Site | Barcelona | 08035 | Spain |
| Ionis Investigative Site | Barcelona | 8907 | Spain |
| Ionis Investigative Site | Madrid | 28046 | Spain |
| Ionis Investigative Site | Seville | 41013 | Spain |
| Ionis Investigative Site | Valencia | 46026 | Spain |
| Ionis Investigative Site | Ankara | 6230 | Turkey (Türkiye) |
| Ionis Investigative Site | Istanbul | 34093 | Turkey (Türkiye) |
| Ionis Investigative Site | Izmir | 35100 | Turkey (Türkiye) |
| Ionis Investigative Site | Birmingham | B9 5SS | United Kingdom |
| Ionis Investigative Site | Bristol | BS10 5NB | United Kingdom |
| Ionis Investigative Site | London | E1 1FR | United Kingdom |
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| FG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
| Full Analysis Set (FAS) | The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). |
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| COMPLETED |
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| NOT COMPLETED |
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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.
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| ID | Title | Description |
|---|---|---|
| BG000 | Pooled Placebo | Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). |
| BG001 | Cohort A: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| BG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | 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. | Posted | Least Squares Mean | 95% Confidence Interval | HAE attacks per month | Week 1 to Week 25 |
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| Secondary | 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). | 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. | Posted | Least Squares Mean | 95% Confidence Interval | HAE attacks per month | Week 5 to Week 25 |
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| Secondary | 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. | 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. | Posted | Number | Percentage of participants | Week 5 to Week 25 |
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| Secondary | 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). | 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. | Posted | Least Squares Mean | 95% Confidence Interval | HAE attacks per month | Week 5 to Week 25 |
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| Secondary | 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. | 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. | Posted | Count of Participants | Participants | Week 5 to Week 25 |
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| Secondary | 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | HAE attacks per month | Week 5 to Week 25 |
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| Secondary | 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. | The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). Overall number analyzed is the number of participants with data available for analysis at the specified timepoint. 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. | Posted | Number | Percentage of participants | Week 25 |
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| Secondary | 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. | The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). Overall number of participants analyzed is the number of participants with data available for analysis at the specified time point. 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. | Posted | Least Squares Mean | 95% Confidence Interval | Score on a scale | Week 25 |
|
Up to Week 38
The safety set 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.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pooled Placebo | Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). | 0 | 22 | 1 | 22 | 15 | 22 |
| EG001 | Cohort A: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. | 0 | 45 | 0 | 45 | 22 | 45 |
| EG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. | 0 | 23 | 0 | 23 | 13 | 23 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Limb Injury | Injury, poisoning and procedural complications | MedDRA26.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA26.1 | Systematic Assessment |
| |
| Injection Site Erythema | General disorders | MedDRA26.1 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Urinary Tract Infection | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Injection Site Discolouration | General disorders | MedDRA26.1 | Systematic Assessment |
| |
| Injection Site Pruritus | General disorders | MedDRA26.1 | Systematic Assessment |
| |
| Injection Site Pain | General disorders | MedDRA26.1 | Systematic Assessment |
| |
| Abdominal Discomfort | Gastrointestinal disorders | MedDRA26.1 | Systematic Assessment |
| |
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA26.1 | Systematic Assessment |
| |
| Abdominal Pain | Gastrointestinal disorders | MedDRA26.1 | Systematic Assessment |
| |
| Covid-19 | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | MedDRA26.1 | Systematic Assessment |
| |
| Limb Injury | Injury, poisoning and procedural complications | MedDRA26.1 | Systematic Assessment |
| |
| Oral Herpes | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA26.1 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA26.1 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA26.1 | Systematic Assessment |
|
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ionis Pharmaceuticals, Inc. | Ionis Pharmaceuticals, Inc. | 760-603-2346 | globalregulatoryaffairs@ionis.com |
| Feb 13, 2025 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D054179 | Angioedemas, Hereditary |
| ID | Term |
|---|---|
| D000799 | Angioedema |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000081208 | Hereditary Complement Deficiency Diseases |
| D000081207 | Primary Immunodeficiency Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D014581 | Urticaria |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D007153 | Immunologic Deficiency Syndromes |
Not provided
Not provided
| ID | Term |
|---|---|
| C000723381 | donidalorsen |
Not provided
Not provided
Not provided
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Black or African American |
|
| White |
|
| Multiple |
|
| Other |
|
| The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential overdispersion. | Poisson regression model | =0.004 | IC HAE attack rate ratio | 0.45 | 2-Sided | 95 | 0.261 | 0.777 | Model adjusted rate ratio from Poisson regression model. | Superiority |
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
|
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
|
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
|
| OG001 | Cohort A: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
|
| OG001 | Cohort A: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
|
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
| OG001 | Cohort A: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. |
| OG002 | Cohort B: Donidalorsen 80 mg | Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
|
|
|