OASIS-HAE: A Study to Evaluate the Safety and Efficacy of Donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in Participants With Hereditary Angioedema (HAE)

Phase 3

Completed

Conditions: Hereditary Angioedema

Interventions: Drug: Donidalorsen
Drug: Placebo

Registration Number: NCT05139810

Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary: 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).

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 91

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pooled Placebo	Donidalorsen	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)
Cohort A: Donidalorsen 80 mg	Donidalorsen	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.
Cohort B: Donidalorsen 80 mg	Placebo	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

Primary Outcome Measures

Name	Time	Method
Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25	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).

Secondary Outcome Measures

Name	Time	Method
Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25	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).
Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25	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-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25	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).
Number of Participants With a Clinical Response From Week 5 to Week 25	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.
IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25	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.
Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25	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.
Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25	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.