A Study to Assess the Clinical Efficacy of Donidalorsen (Also Known as IONIS-PKK-LRx and ISIS 721744) in Participants With Hereditary Angioedema

• ClinicalTrials.gov Identifier: NCT04030598
• Recruitment Status: Completed
• First Posted: July 24, 2019
• Results First Posted: September 28, 2022
• Last Update Posted: April 3, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hereditary Angioedema
• Interventions: Drug: Donidalorsen; Drug: Placebo
• Enrollment: 23

Participant Flow

Recruitment Details	Participants took part in the study at 7 investigative sites from 7 January 2020 to 1 March 2021.
Pre-assignment Details	Participants with hereditary angioedema were concurrently enrolled in Part A and B, respectively. In Part A, 20 participants with hereditary angioedema type I/type II (HAE-1/HAE-2) were randomized in 2:1 ratio to receive donidalorsen or placebo for 13 weeks. In Part B, 3 participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen for 13 weeks after Part A.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description	Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Period Title: Overall Study
Started	6	14	3
Completed [1]	6	13	3
Not Completed	0	1	0
Reason Not Completed
Voluntary Withdrawal	0	1	0
[1] Completed=Participants who completed study treatment

Baseline Characteristics

Arm/Group Title		Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg	Total
Arm/Group Description		Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Total of all reporting groups
Overall Number of Baseline Participants		6	14	3	23
Baseline Analysis Population Description		The safety population included all enrolled participants who received at least 1 dose of study drug (donidalorsen or placebo).
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	6 participants	14 participants	3 participants	23 participants
		40.0; (22 to 56)	37.8; (21 to 66)	34.0; (25 to 40)	37.26; (21 to 66)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants	14 participants	3 participants	23 participants
	Female	4 66.7%	9 64.3%	3 100.0%	16 69.6%
	Male	2 33.3%	5 35.7%	0 0.0%	7 30.4%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants	14 participants	3 participants	23 participants
	Hispanic or Latino	0 0.0%	1 7.1%	0 0.0%	1 4.3%
	Not Hispanic or Latino	6 100.0%	13 92.9%	3 100.0%	22 95.7%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants	14 participants	3 participants	23 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 16.7%	0 0.0%	0 0.0%	1 4.3%
	White	5 83.3%	14 100.0%	3 100.0%	22 95.7%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17
Description	The Week 1 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks occurring from Week 1 to 28 days after the last dose date 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 17

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population included all enrolled or randomized participants.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:	Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed	6	14	3
Mean (Standard Deviation); Unit of Measure: HAE attacks per month
	2.21 (1.558)	0.23 (0.268)	1.52 (2.221)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Wald Chi-Square
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-90.00
	Confidence Interval	(2-Sided) 95%; -96.00 to -76.00
	Estimation Comments	The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100 percentage (%) × (mean rate ratio -1).

2. Secondary Outcome

Title	Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
Description	The Week 5 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks occurring from Week 5 to 28 days after the last dose date 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 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:	Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed	6	14	3
Mean (Standard Deviation); Unit of Measure: HAE attacks per month
	2.06 (1.574)	0.07 (0.267)	1.78 (2.795)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Wald Chi-Square
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-89.00
	Confidence Interval	(2-Sided) 95%; -95.00 to -77.00
	Estimation Comments	The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100% × (mean rate ratio -1).

3. Secondary Outcome

Title	Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
Description	The Week 5 to end of on-treatment period HAE attack rate was calculated for each participant as number of moderate or severe HAE attacks occurring from Week 5 to 28 days after the last dose date 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 attack severity: Mild: transient or mild discomfort, Moderate: mild to moderate limitation in activity, some assistance needed, and Severe: marked limitation in activity, assistance required.
Time Frame	Week 5 to Week 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:	Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed	6	14	3
Mean (Standard Deviation); Unit of Measure: HAE attacks per month
	1.25 (1.208)	0.05 (0.178)	0.89 (1.540)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Wald Chi-Square
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-96.00
	Confidence Interval	(2-Sided) 95%; -100.00 to -65.00
	Estimation Comments	The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100% × (mean rate ratio -1).

4. Secondary Outcome

Title	Number of Participants With Clinical Response by Week 17
Description	Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 17. The HAE attack rate was calculated as number of investigator-confirmed HAE attacks occurring from Week 5 to 28 days after last dose administration, 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 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants. Overall number of participants analyzed is the number of participants with data available for analyses.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:	Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed	6	13	3
Measure Type: Count of Participants; Unit of Measure: Participants
≥ 50% Reduction	2 33.3%	13 100.0%	2 66.7%
≥ 70% Reduction	1 16.7%	12 92.3%	2 66.7%
≥ 90% Reduction	0 0.0%	12 92.3%	1 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	For ≥ 50% reduction from Baseline in the HAE attack rate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	66.7
	Confidence Interval	(2-Sided) 95%; 17.5 to 95.7
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	For ≥ 70% reduction from Baseline in the HAE attack rate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	75.6
	Confidence Interval	(2-Sided) 95%; 26.8 to 96.5
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	For ≥ 90% reduction from Baseline in the HAE attack rate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	92.3
	Confidence Interval	(2-Sided) 95%; 48.0 to 99.8
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17
Description	The Week 5 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks requiring acute therapy occurring from Week 5 to 28 days after the last dose date 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 requiring acute therapy included those attacks with medical intervention or hospitalization marked on the case report form (CRFs).
Time Frame	Week 5 to Week 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:	Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed	6	14	3
Mean (Standard Deviation); Unit of Measure: HAE attacks per month
	1.25 (1.208)	0.05 (0.178)	0.89 (1.540)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.009
	Comments	[Not Specified]
	Method	Wald Chi-Square
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-95.00
	Confidence Interval	(2-Sided) 95%; -99.00 to -52.00
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17
Description	High-molecular-weight kininogen (HMWK) is an abundant protein found in plasma and it has a critical role in acute attacks of HAE. During HAE attack plasma kallikrein cleaves HMWK producing cleaved HMWK (cHMWK) and bradykinin, the major biologic peptide that promotes the edema, one of the characteristic traits of HAE. Percentage of cHMWK levels were assessed to evaluate pharmacodynamics of donidalorsen.
Time Frame	Weeks 9 and 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants. Number analyzed is number of participants with data available for analysis at specified time point.

Arm/Group Title		Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:		Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed		6	14	3
Mean (Standard Deviation); Unit of Measure: percentage of cHMWK levels
Week 9	Number Analyzed	6 participants	14 participants	3 participants
		5.62 (3.255)	2.07 (1.241)	1.03 (0.115)
Week 17	Number Analyzed	6 participants	13 participants	3 participants
		7.00 (4.338)	2.35 (1.353)	2.13 (0.929)

7. Secondary Outcome

Title	Prekallikrein (PKK) Activity Levels at Weeks 9 and 17
Description	Prekallikrein (PKK) has a critical role in acute attacks of HAE. During HAE attack PKK is activated to form plasma kallikrein. Plasma kallikrein cleaves HMWK producing cleaved HMWK (cHMWK) and bradykinin, the major biologic peptide that promotes the edema, one of the characteristic traits of HAE. Prekallikrein levels were measured to assess pharmacodynamics of donidalorsen.
Time Frame	Weeks 9 and 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants. Number analyzed is number of participants with data available for analysis at specified timepoint.

Arm/Group Title		Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:		Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed		6	14	3
Mean (Standard Deviation); Unit of Measure: milligram per liter (mg/L)
Week 9	Number Analyzed	6 participants	14 participants	3 participants
		95.467 (23.7193)	37.676 (14.5639)	25.630 (19.2671)
Week 17	Number Analyzed	6 participants	13 participants	2 participants
		98.600 (34.5944)	37.795 (38.6618)	28.615 (22.8042)

8. Secondary Outcome

Title	Number of Participants Who Consumed On-demand Medication at Weeks 9 and 17
Description	Treatment options for HAE included on-demand treatment of attacks and prophylaxis. On-demand medication options included supplementation of C1-INH (either plasma-derived or recombinant C1-INH concentrate) and inhibition of BK2 receptor activation (BK2-receptor antagonist). The number of participants who used on-demand medication at Week 9 (Day 57) and at Week 17 (end of the on-treatment period) were reported.
Time Frame	Weeks 9 and 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants.

Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:	Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed	6	14	3
Measure Type: Count of Participants; Unit of Measure: Participants
Week 9	6 100.0%	12 85.7%	3 100.0%
Week 17	6 100.0%	11 78.6%	3 100.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	Week 9
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-14.3
	Confidence Interval	(2-Sided) 95%; -59.1 to 33.9
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.521
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-21.4
	Confidence Interval	(2-Sided) 95%; -64.9 to 27.1
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17
Description	The AE-QoL was developed to measure health-related quality of life (HRQoL) impairment in participants with recurrent angioedema. The AE-QoL is a self-administered questionnaire that can be completed in less than 5 minutes. It comprises 17 items across 4 domains: functioning, fatigue/mood, fears/shame, and food. Responses use a 5-point Likert scale ranging from '0 = never' to '4 = very often.' Per-participant scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-participant total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. The outputs from the scoring algorithm were normalized on a scale ranging from 0 (less adverse impact) to 100 (most adverse impact). Global total score ranges from 0 to 100, with higher scores indicating greater impairment. Mixed model for repeated measures (MMRM) was used for analyses.
Time Frame	Baseline, Weeks 9 and 17

Outcome Measure Data

Analysis Population Description

ITT population included all enrolled or randomized participants. Number analyzed is the number of participants with data available at specified timepoint.

Arm/Group Title		Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description:		Participants with HAE-1/HAE-2 received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Overall Number of Participants Analyzed		6	14	3
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Change from Baseline at Week 9	Number Analyzed	6 participants	14 participants	3 participants
		-1.50 (4.413)	-27.42 (2.854)	25.49 (17.421)
Change from Baseline at Week 17	Number Analyzed	6 participants	13 participants	3 participants
		-6.15 (4.671)	-26.85 (3.133)	26.96 (20.918)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	Week 9
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-25.92
	Confidence Interval	(2-Sided) 95%; -37.10 to -14.74
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: Donidalorsen 80 mg
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-20.69
	Confidence Interval	(2-Sided) 95%; -32.70 to -8.68
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug up to end of the study (Up to Week 26)
Adverse Event Reporting Description	The safety population included all enrolled participants who received at least 1 dose of study drug (donidalorsen or placebo).
Arm/Group Title	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Arm/Group Description	Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.	Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
All-Cause Mortality
	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/6 (0.00%)	0/14 (0.00%)	0/3 (0.00%)
Serious Adverse Events
	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/6 (0.00%)	0/14 (0.00%)	0/3 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	3/6 (50.00%)	2/14 (14.29%)	3/3 (100.00%)
Gastrointestinal disorders
Nausea † 1	1/6 (16.67%)	1/14 (7.14%)	0/3 (0.00%)
Vomiting † 1	0/6 (0.00%)	0/14 (0.00%)	1/3 (33.33%)
General disorders
Application site rash † 1	0/6 (0.00%)	0/14 (0.00%)	1/3 (33.33%)
Feeling hot † 1	0/6 (0.00%)	0/14 (0.00%)	1/3 (33.33%)
Hyperhidrosis † 1	0/6 (0.00%)	0/14 (0.00%)	1/3 (33.33%)
Nervous system disorders
Headache † 1	2/6 (33.33%)	2/14 (14.29%)	0/3 (0.00%)
1 Term from vocabulary, 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.

Results Point of Contact

• Name/Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.
• Phone: 800-679-4747
• EMail: patients@ionisph.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fijen LM, Riedl MA, Bordone L, Bernstein JA, Raasch J, Tachdjian R, Craig T, Lumry WR, Manning ME, Alexander VJ, Newman KB, Revenko A, Baker BF, Nanavati C, MacLeod AR, Schneider E, Cohn DM. Inhibition of Prekallikrein for Hereditary Angioedema. N Engl J Med. 2022 Mar 17;386(11):1026-1033. doi: 10.1056/NEJMoa2109329.

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04030598
• Other Study ID Numbers: ISIS 721744-CS2; 2019-001044-22 ( EudraCT Number )
• First Submitted: July 22, 2019
• First Posted: July 24, 2019
• Results First Submitted: July 26, 2022
• Results First Posted: September 28, 2022
• Last Update Posted: April 3, 2023