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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ClinicalTrials.gov Identifier: NCT04030598 |
Recruitment Status :
Completed
First Posted : July 24, 2019
Results First Posted : September 28, 2022
Last Update Posted : April 3, 2023
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Condition or disease | Intervention/treatment | Phase |
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Hereditary Angioedema | Drug: Donidalorsen Drug: Placebo | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 23 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Investigator, Outcomes Assessor) |
Masking Description: | Part A was randomized, double-blind; Part B was open-label. |
Primary Purpose: | Treatment |
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 |
Actual Study Start Date : | January 7, 2020 |
Actual Primary Completion Date : | January 4, 2021 |
Actual Study Completion Date : | March 1, 2021 |
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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Drug: Placebo
Placebo matching solution administered SC |
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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Drug: Donidalorsen
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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Drug: Donidalorsen
Donidalorsen administered SC
Other Names:
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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 ]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-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Week 5 to 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline, 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.
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
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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)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04030598
United States, Arizona | |
Medical Research of Arizona | |
Scottsdale, Arizona, United States, 85251 | |
United States, California | |
University of California San Diego (UCSD) | |
San Diego, California, United States, 92122 | |
AIRE Medical of Los Angeles | |
Santa Monica, California, United States, 90404 | |
United States, Minnesota | |
Midwest Immunology Clinical | |
Plymouth, Minnesota, United States, 55446 | |
United States, Ohio | |
Bernstein Clinical Research Center, LLC | |
Cincinnati, Ohio, United States, 45231 | |
United States, Pennsylvania | |
Penn State Hershey Medical Center | |
Hershey, Pennsylvania, United States, 17033 | |
United States, Texas | |
AARA Research Center | |
Dallas, Texas, United States, 75231 | |
Netherlands | |
Amsterdam UMC, loc. AMC | |
Amsterdam, Netherlands, 1105 AZ |
Documents provided by Ionis Pharmaceuticals, Inc.:
Responsible Party: | Ionis Pharmaceuticals, Inc. |
ClinicalTrials.gov Identifier: | NCT04030598 |
Other Study ID Numbers: |
ISIS 721744-CS2 2019-001044-22 ( EudraCT Number ) |
First Posted: | July 24, 2019 Key Record Dates |
Results First Posted: | September 28, 2022 |
Last Update Posted: | April 3, 2023 |
Last Verified: | March 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
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 |
IONIS PKK-LRx Donidalorsen |
Angioedema Angioedemas, Hereditary Vascular Diseases Cardiovascular Diseases Urticaria Skin Diseases, Vascular Skin Diseases |
Hypersensitivity, Immediate Hypersensitivity Immune System Diseases Hereditary Complement Deficiency Diseases Primary Immunodeficiency Diseases Genetic Diseases, Inborn Immunologic Deficiency Syndromes |