- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04030598
A Study to Assess the Clinical Efficacy of Donidalorsen (Also Known as IONIS-PKK-LRx and ISIS 721744) in Participants With Hereditary Angioedema
March 30, 2023 updated by: Ionis Pharmaceuticals, Inc.
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
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.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
23
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Amsterdam, Netherlands, 1105 AZ
- Amsterdam UMC, loc. AMC
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Arizona
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Scottsdale, Arizona, United States, 85251
- Medical Research of Arizona
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California
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San Diego, California, United States, 92122
- University of California San Diego (UCSD)
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Santa Monica, California, United States, 90404
- AIRE Medical of Los Angeles
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Minnesota
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Plymouth, Minnesota, United States, 55446
- Midwest Immunology Clinical
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Ohio
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Cincinnati, Ohio, United States, 45231
- Bernstein Clinical Research Center, LLC
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Pennsylvania
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Hershey, Pennsylvania, United States, 17033
- Penn State Hershey Medical Center
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Texas
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Dallas, Texas, United States, 75231
- AARA Research Center
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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)
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Placebo Comparator: Part A: Placebo
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.
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Placebo matching solution administered SC
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Experimental: Part A: Donidalorsen 80 mg
Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
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Donidalorsen administered SC
Other Names:
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Experimental: Part B: Donidalorsen 80 mg
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.
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Donidalorsen administered SC
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17
Time Frame: Week 1 to Week 17
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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).
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Week 1 to Week 17
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
Time Frame: Week 5 to Week 17
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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).
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Week 5 to Week 17
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Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
Time Frame: Week 5 to Week 17
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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.
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Week 5 to Week 17
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Number of Participants With Clinical Response by Week 17
Time Frame: Week 5 to Week 17
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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).
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Week 5 to Week 17
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Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17
Time Frame: Week 5 to Week 17
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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).
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Week 5 to Week 17
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Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17
Time Frame: Weeks 9 and 17
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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.
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Weeks 9 and 17
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Prekallikrein (PKK) Activity Levels at Weeks 9 and 17
Time Frame: Weeks 9 and 17
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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.
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Weeks 9 and 17
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Number of Participants Who Consumed On-demand Medication at Weeks 9 and 17
Time Frame: Weeks 9 and 17
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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.
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Weeks 9 and 17
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Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17
Time Frame: Baseline, Weeks 9 and 17
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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.
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Baseline, Weeks 9 and 17
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
January 7, 2020
Primary Completion (Actual)
January 4, 2021
Study Completion (Actual)
March 1, 2021
Study Registration Dates
First Submitted
July 22, 2019
First Submitted That Met QC Criteria
July 22, 2019
First Posted (Actual)
July 24, 2019
Study Record Updates
Last Update Posted (Actual)
April 3, 2023
Last Update Submitted That Met QC Criteria
March 30, 2023
Last Verified
March 1, 2023
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Skin Diseases
- Immunologic Deficiency Syndromes
- Immune System Diseases
- Hypersensitivity, Immediate
- Genetic Diseases, Inborn
- Skin Diseases, Vascular
- Hypersensitivity
- Urticaria
- Hereditary Complement Deficiency Diseases
- Primary Immunodeficiency Diseases
- Angioedema
- Angioedemas, Hereditary
Other Study ID Numbers
- ISIS 721744-CS2
- 2019-001044-22 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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