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

Primary Purpose

Hereditary Angioedema

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Donidalorsen
Placebo
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hereditary Angioedema focused on measuring IONIS PKK-LRx, Donidalorsen

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or HAE-nC1-INH (for inclusion in Part B)
  • Participants must have experienced a minimum of 2 HAE attacks (assessed by the Angioedema Activity Score [AAS] and confirmed by the investigator) during the screening period
  • Access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks

Exclusion Criteria:

  • Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the screening or study periods
  • Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema
  • Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
  • Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
  • Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of screening

  • Exposure to any of the following medications:

    • Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to screening
    • Chronic prophylaxis with Lanadelumab within 10 weeks prior to screening
    • Oligonucleotides (including small interfering ribonucleic acid [RNA]) within 4 months of screening (if single dose received) or within 12 months of screening (if multiple doses received)

Sites / Locations

  • Medical Research of Arizona
  • University of California San Diego (UCSD)
  • AIRE Medical of Los Angeles
  • Midwest Immunology Clinical
  • Bernstein Clinical Research Center, LLC
  • Penn State Hershey Medical Center
  • AARA Research Center
  • Amsterdam UMC, loc. AMC

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Experimental

Arm Label

Part A: Placebo

Part A: Donidalorsen 80 mg

Part B: Donidalorsen 80 mg

Arm 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.

Outcomes

Primary Outcome Measures

Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17
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).

Secondary Outcome Measures

Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
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-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
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.
Number of Participants With Clinical Response by Week 17
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).
Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17
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).
Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17
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.
Prekallikrein (PKK) Activity Levels at Weeks 9 and 17
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.
Number of Participants Who Consumed On-demand Medication at Weeks 9 and 17
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.
Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17
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.

Full Information

First Posted
July 22, 2019
Last Updated
March 30, 2023
Sponsor
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04030598
Brief Title
A Study to Assess the Clinical Efficacy of Donidalorsen (Also Known as IONIS-PKK-LRx and ISIS 721744) in Participants With Hereditary Angioedema
Official Title
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients With Hereditary Angioedema
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
January 7, 2020 (Actual)
Primary Completion Date
January 4, 2021 (Actual)
Study Completion Date
March 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study was to evaluate the clinical efficacy, safety, and tolerability of donidalorsen in participants with hereditary angioedema (HAE) type 1 (HAE-1), HAE type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH) and to evaluate the effect of donidalorsen on plasma prekallikrein (PKK) and other relevant biomarkers.
Detailed Description
This was a randomized, double-blind, placebo-controlled study in 23 participants conducted concurrently in 2 parts (Part A and Part B); participants were allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or HAE-nC1-INH in Part B). Part A was randomized, double-blind, and placebo-controlled; and Part B was open-label. The length of participation in the study was approximately 8 months, which included an up to 8-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Angioedema
Keywords
IONIS PKK-LRx, Donidalorsen

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Part A was randomized, double-blind; Part B was open-label.
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part A: Placebo
Arm Type
Placebo Comparator
Arm 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.
Arm Title
Part A: Donidalorsen 80 mg
Arm Type
Experimental
Arm Description
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
Arm Title
Part B: Donidalorsen 80 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Donidalorsen
Other Intervention Name(s)
ISIS 721744, IONIS-PKK-LRx
Intervention Description
Donidalorsen administered SC
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo matching solution administered SC
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
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
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
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or HAE-nC1-INH (for inclusion in Part B) Participants must have experienced a minimum of 2 HAE attacks (assessed by the Angioedema Activity Score [AAS] and confirmed by the investigator) during the screening period Access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks Exclusion Criteria: Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the screening or study periods Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of screening Exposure to any of the following medications: Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to screening Chronic prophylaxis with Lanadelumab within 10 weeks prior to screening Oligonucleotides (including small interfering ribonucleic acid [RNA]) within 4 months of screening (if single dose received) or within 12 months of screening (if multiple doses received)
Facility Information:
Facility Name
Medical Research of Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85251
Country
United States
Facility Name
University of California San Diego (UCSD)
City
San Diego
State/Province
California
ZIP/Postal Code
92122
Country
United States
Facility Name
AIRE Medical of Los Angeles
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Midwest Immunology Clinical
City
Plymouth
State/Province
Minnesota
ZIP/Postal Code
55446
Country
United States
Facility Name
Bernstein Clinical Research Center, LLC
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45231
Country
United States
Facility Name
Penn State Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
AARA Research Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75231
Country
United States
Facility Name
Amsterdam UMC, loc. AMC
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35294812
Citation
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.
Results Reference
derived

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

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