Primary objective: The primary objective of the study is to evaluate the clinical efficacy of ISIS 721744 in patients with hereditary angioedema (HAE).Secondary objective: Evaluate the effects of ISIS 721744 on the quality and pattern of HAE attacks…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
- Angioedema and urticaria
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the time-normalized number of Investigator-confirmed
HAE attacks (per month) from Week 1 to Week 25 compared to placebo.
Secondary outcome
Secondary endpoints:
• The time-normalized number of Investigator-confirmed HAE attacks (per month)
from Week 5 to Week 25 compared to placebo
• The percentage of Investigator-confirmed HAE attack-free patients from Week 5
to Week 25 compared to placebo
• The time normalized number of moderate or severe Investigator-confirmed HAE
attacks (per month) from Week 5 to Week 25 compared to placebo
• The number of patients with a clinical response defined as a >= 50%, >= 70%, or
>= 90% reduction from Baseline (i.e., screening rate) in Investigator-confirmed
HAE attack rate between Week 5 to Week 25 compared to placebo
• The number of Investigator-confirmed HAE attacks requiring acute HAE therapy
from Week 5 to Week 25 compared to placebo
• Percent of patients who are well controlled on the Angioedema Control Test
(AECT) at Week 25
• Change in Angioedema Quality of Life (AE QoL) questionnaire total score at
Week 25
Safety endpoints:
The number, type, severity, and dose-relationship of AEs; vital signs; ECGs;
and clinical laboratory parameters
Exploratory endpoints include change or percent change from Baseline compared
to placebo in the following:
• PKK level in plasma
• GAD-7 questionnaire score
• EQ-5D-5L
• PGIS
• Work Productivity and Impairment (WPAI) questionnaire score
Also:
• Incidence of all cause emergency room visits, hospitalization and total
inpatient days
• PGIC
• PK: Potential exposure response analysis using relevant exposure parameters
(such as ISIS 721744 plasma Ctrough) and biomarkers (plasma PKK) and/or
clinical endpoints, as appropriate
Background summary
Hereditary angioedema is a rare genetic disorder that is characterized by
disabling recurrent episodes of local skin swellings, painful abdominal
attacks, and, occasionally, laryngeal attacks that can be life-threatening. The
disorder is classified in 3 subtypes. Hereditary angioedema type 1 and HAE-2
are caused by an autosomal dominant mutation in the SERPING1 gene, resulting in
either decreased levels of C1-INH (HAE-1) or loss of-function of this protein
(HAE 2) (Bissler et al. 1997). The third form of HAE is associated with normal
levels and function of C1-INH (HAE-nC1-INH). This form is currently categorized
as 4 subtypes, with either specific genetic mutations in the factor XII gene,
the plasminogen gene, or the angiopoietin-1 gene, or due to an unknown cause
(Maurer et al. 2018). Extensive evidence from in vitro and in vivo studies
supports the key role of bradykinin (BK) in HAE attacks, although the data
linking HAE-nC1-INH with BK are less strong (Zuraw and Christiansen 2016).
Diagnosing HAE
nC1 INH can be challenging given the large heterogeneity of this patient
population, the lack of diagnostic tests, and the fact that specific genetic
mutations account only partially for the occurrence of this type of HAE.
Recently, a threshold-stimulated kallikrein activity assay was shown to
discriminate BK-mediated angioedema from histamine-mediated angioedema
(Lara*Marquez et al. 2018). This technique may, therefore, enhance the
identification of HAE nC1 INH patients that are likely to benefit from
inhibition of the contact activation pathway.
This study involves the use of the investigational medicinal product known as
ISIS 744721. When prekallikrein, a protein that is produced by the liver, is
released into the blood stream, it can lead to HAE attacks. The study drug is
designed to lower the amount of prekallikrein produced by the liver. The study
is to assess if reducing the amount of prekallikrein can reduce HAE attacks.
Study objective
Primary objective:
The primary objective of the study is to evaluate the clinical efficacy of ISIS
721744 in patients with hereditary angioedema (HAE).
Secondary objective:
Evaluate the effects of ISIS 721744 on the quality and pattern of HAE attacks
and their impact on Quality of Life.
Safety objective:
To evaluate safety and tolerability of ISIS 721744 in patients with HAE.
Exploratory objective:
Further characterize the effects of ISIS 721744 on health economic and
utilization parameters and additional Patient Reported Outcomes (PROs) and
biomarkers.
Study design
This study is a randomized (ISIS 721744:placebo), double-blind,
placebo-controlled trial conducted in multiple centers to evaluate the efficacy
and safety of ISIS 721744 in preventing angioedema attacks in patients with
HAE-1 (Type I) and HAE-2 (Type II). Patients will be randomized 2:1 to Cohort
A (3:1 ISIS 721744 80 mg or placebo every 4 weeks) or Cohort B (3:1 ISIS 721744
80 mg or placebo every 8 weeks).
Intervention
Patients will receive either 6 (Cohort A) or 3 (Cohort B) doses, of either
study drug (80 mg per dose) or placebo as injection under the skin in either
their abdomen (stomach area), thigh or upper arm. Doses will be given in 4
(Cohort A) or 8 (Cohort B) week interval periods during the 25-week treatment
period.
Patients who complete the study visit week 25 and meet the eligibility
requirements may enroll in the open-label extension study. All patients will
then receive the study drug for up to one year or longer.
Study burden and risks
Burden: during the study patients will be asked to come to the study center for
11 visits. Patients will be treated with ISIS 721744 every 4 or 8 weeks during
the 25 week treatment period. ISIS 721744 will be administered as a SC
injection in the abdomen, thigh, or outer area of the upper arm, 3 or 6 times
in total.
The patient will be asked questions about their health and medications they are
taking. A Quality of life questionnaire will be conducted. The HAE attack
history of the patients will be recorded and their HAE attacks will be tracked
daily by completing a questionnaire. Furthermore, patients need to inform their
doctor of any adverse events they experienced. A physical examination and heart
tracing (ECG) will be done and weight and vital signs will be measured. Also
urine and blood tests will be done to see if patients are able to participate
in the study and to check general health, pregnancy, pharmacodynamics,
pharmocokinetics, inflammatory markers and antibodies in the body.
Risk: Possible side effects of the study drug and study procedures.
Gazelle Court 2855
Carlsbad CA 92010
US
Gazelle Court 2855
Carlsbad CA 92010
US
Listed location countries
Age
Inclusion criteria
• Patients must be aged >= 12 years at the time of informed consent, and, as
applicable, assent
• Patients must have a documented diagnosis of HAE-1/HAE-2 based upon ALL of
the following:
a. Documented clinical history consistent with HAE (subcutaneous [SC] or
mucosal, non-pruritic swelling episodes without accompanying urticaria)
b. Diagnostic testing results that confirm HAE-1/HAE-2: C1-INH functional
level < 40% normal level. Patients with a functional level of 40% to 50% of
normal can be enrolled if their complement factor C4 level is below the lower
limit of normal (LLN) or if a known pathogenic mutation in the SERPING1 gene
has been demonstrated
c. At least 1 of the following: age at reported HAE onset <= 30 years; a family
history consistent with HAE-1/HAE-2; or complement component 1q within the
normal range
• Patients must:
a. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during
the Screening Period
b. Be willing to complete the PRO assessments throughout the study
• Patients must have access to, and the ability to use, >= 1 acute medication(s)
(e.g., plasma derived or recombinant C1-INH concentrate or a BK2-receptor
antagonist) to treat angioedema attacks
Exclusion criteria
• Anticipated use of short-term prophylaxis for angioedema attacks for a
pre-planned procedure during the Screening, Treatment or Post-Treatment Periods
• Concurrent diagnosis of any other type of recurrent angioedema, including
acquired, idiopathic angioedema or HAE with normal C1-INH (also known as HAE
Type III)
• Anticipated change in the use of concurrent androgen prophylaxis used to
treat angioedema attacks
• Participation in a prior ISIS 721744 study
• Exposure to any of the following medications:
a. 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
b. Chronic prophylaxis with Takhzyro (lanadelumab), Haegarda (C1-esterase
inhibitor SQ), Cinryze and Ruconest (C1 esterase inhibitor) or Orladeyo
(berotralstat) within 5 half lives prior to Screening (i.e., Takhzyro within 10
weeks prior to Screening, Haegarda/Cinryze/Ruconest within 2 weeks prior to
screening, Orladeyo within 3 weeks prior to Screening)
c. Oligonucleotides (including small interfering ribonucleic acid) within 4
months of Screening if single dose received, or within 12 months of Screening
if multiple doses received. This exclusion does not apply to vaccines
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-002571-19-NL |
| ClinicalTrials.gov | NCT05139810 |
| CCMO | NL79190.000.22 |