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
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hereditary Angioedema
Keywords: IONIS PKK-LRx
Donidalorsen
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-07-24
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17
timeFrame: Week 1 to Week 17
Secondary outcomes:
measure: Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
timeFrame: Week 5 to Week 17
measure: Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17
timeFrame: Week 5 to Week 17
measure: Number of Participants With Clinical Response by Week 17
timeFrame: Week 5 to Week 17
measure: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17
timeFrame: Week 5 to Week 17
measure: Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17
timeFrame: Weeks 9 and 17
measure: Prekallikrein (PKK) Activity Levels at Weeks 9 and 17
timeFrame: Weeks 9 and 17
measure: Number of Participants Who Consumed On-demand Medication at Weeks 9 and 17
timeFrame: Weeks 9 and 17
measure: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17
timeFrame: Baseline, Weeks 9 and 17
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Medical Research of Arizona
state: Arizona
city: San Diego
country: United States
facility: University of California San Diego (UCSD)
state: California
city: Santa Monica
country: United States
facility: AIRE Medical of Los Angeles
state: California
city: Plymouth
country: United States
facility: Midwest Immunology Clinical
state: Minnesota
city: Cincinnati
country: United States
facility: Bernstein Clinical Research Center, LLC
state: Ohio
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: AARA Research Center
state: Texas
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, loc. AMC
Study officials:
References:
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.