This study has been transitioned to CTIS with ID 2023-509201-77-00 check the CTIS register for the current data. Primary ObjectiveTo evaluate the safety of long-term dosing with donidalorsen in patients with HAE. Secondary ObjectivesTo evaluate the…
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 incidence and severity of treatment-emergent
adverse events (TEAEs)
Secondary outcome
Secondary Endpoints:
All the analyses will be performed on both roll-over (OLE) and non-roll-over
(*Switch*) patients:
• The time-normalized number of Investigator-confirmed HAE attacks (per month)
from Week 1 to Week 53
• The time-normalized number of Investigator-confirmed HAE attacks (per month)
from Week 5 to Week 53
• The percentage of Investigator-confirmed HAE attack-free patients from Week 5
to Week 53
• The time-normalized number of moderate or severe Investigator-confirmed HAE
attacks (per month) from Week 5 to Week 53
• The number of Investigator-confirmed HAE attacks requiring acute therapy from
Week 5 to Week 53
• Angioedema Quality of Life (AE-QoL) questionnaire total score over 53 weeks
Exploratory Endpoints:
The analyses will be performed on both roll-over (OLE) and non-roll-over
(*Switch*) patients as shown below:
All patients:
• The time-normalized number of Investigator-confirmed HAE attacks (per month)
from Week 1 to Week 157
• Angioedema Quality of Life (AE-QoL) questionnaire total score over 157 weeks
• Percentage of total days during the Treatment Period that patients are attack
free
• Percentage of total months during the Treatment Period that patients are
attack free
• Duration in days of the longest attack free interval
• Percent of patients that are attack free for 6 or 12 consecutive months
• Mean/median longest attack free interval
• Rate of HAE attacks that involves the larynx
• Plasma PKK levels over 53 weeks
• Angioedema Control Test (AECT) over 53 weeks
• Hereditary Angioedema Quality of Life (HAE-QoL) questionnaire total score
over 53 weeks
• Treatment Satisfaction Questionnaire for Medication (TSQM-II) score over 53
weeks
• Incidence of ER visits, all cause hospitalization and total inpatient days
over 53 weeks
• PK exposure over time and potential exposure-response analysis using relevant
exposure parameters and biomarkers
Open-Label Extension patients only:
• The time-normalized number of Investigator-confirmed HAE attack rate (per
month) compared to ISIS 721744-CS5 study from Week 1 to Week 53
Switch patients only:
• The time-normalized number of Investigator-confirmed attack rate (per month)
from Week 1 to Week 17
• The time-normalized number of Investigator-confirmed attack rate (per month)
from Week 5 to Week 17
• Angioedema Quality of Life (AE-QoL) questionnaire total score at Week 17
• Treatment Satisfaction Questionnaire for Medication (TSQM-II) from Week 1
(Day1) to Week 17
• Injection site pain (ISP) assessment during Screening and Treatment Periods
• Treatment preference questionnaire at Week 17
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 I (HAE-1) and
Type II (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). 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. 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. 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. 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
This study has been transitioned to CTIS with ID 2023-509201-77-00 check the CTIS register for the current data.
Primary Objective
To evaluate the safety of long-term dosing with donidalorsen in patients with
HAE.
Secondary Objectives
To evaluate the long-term efficacy and the effects of donidalorsen on the
number of HAE attacks and their impact on the quality of life (QoL) of patients
with HAE.
Exploratory Objectives
Further characterize the effects of donidalorsen on HAE attacks, additional
Patient Reported Outcomes (PROs) and biomarkers.
Study design
This study is an Open-Label global study with donidalorsen conducted in
multiple centers to evaluate the long-term safety and efficacy of donidalorsen
in preventing angioedema attacks in patients with HAE-1 (Type I) and HAE-2
(Type II). There are 2 arms to this study; 1) patients who roll-over from
another study of donidalorsen (OLE patients), and 2) patients who are not
rolling over from another study of donidalorsen and were previously maintained
on HAE prophylactic therapy (*Switch* patients) with lanadelumab, berotralstat
or C1-esterase inhibitor.
Following the Week 53 Treatment Period visit, patients will have the option of
receiving donidalorsen in an Extended Treatment Period for up to an additional
104 weeks.
Intervention
OLE Patients:
Patients continue on their dosing schedule from ISIS 721744-CS5:
• Patients who received drug or placebo Q4W in ISIS 721744-CS5 will receive 80
mg of donidalorsen Q4W
• Patients who received drug or placebo Q8W in ISIS 721744-CS5 will receive 80
mg of donidalorsen Q8W unless they are not attack free for >= 8 weeks (Weeks
17-25 in ISIS 721744-CS5), in that case they will receive 80 mg of donidalorsen
Q4W
Switch Patients:
All patients will receive 80 mg of donidalorsen Q4W.
Study burden and risks
Burden: during the study patients will be asked to come to the study center for
18 visits. Patients will be treated with donidalorsen every 4 or 8 weeks during
the treatment period of about one year. Donidalorsen will be administered as a
SC injection in the abdomen, thigh, or outer area of the upper arm.
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
1. Participants and, as applicable, legally authorized representatives (i.e.,
parent(s)/legal guardian), must provide written and signed informed consent
form (ICF).
2. Participants must have access to, and the ability to use, >= 1 acute
medication(s) (e.g., plasma-derived or recombinant C1-INH concentrate or a
bradykinin receptor (BK) 2-receptor antagonist) to treat angioedema attacks
Open-Label Extension Participants ONLY:
3. Satisfactory completion of ISIS 721744-CS5 (randomized placebo-controlled
index study) through Week 25 or participants who are allowed to exit ISIS
721744-CS5 study per protocol with an acceptable safety and tolerability profile
New (not previously on donidalorsen) Participants ONLY
4. Participants must be aged >= 12 years at the time of informed consent and, as
applicable, assent
5. Participants must have a documented diagnosis of HAE-1/HAE-2
6. Participants must be on a stable dose (>= 12 weeks) of prophylaxis treatment
with lanadelumab or berotralstat or C1-esterase inhibitor prior to the
Screening Period
Exclusion criteria
1. Have any new condition or worsening of an existing condition or change or
anticipated change in medication
De-novo Participants:
2. 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)
3. Anticipated change in the use of concurrent androgen or tranexamic acid
prophylaxis used to prevent angioedema attacks
4. Any clinically-significant abnormalities in screening laboratory values
5. Malignancy within 5 years of Screening, except for non-melanoma skin
cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage
1 prostate carcinoma that has been successfully treated.
6. Hypersensitivity to the active substance (donidalorsen) or to any of the
excipients
7. Treatment with another investigational drug (non-oligonucleotide) or
biological agent within 1 month of Screening or 5 half-lives of investigational
agent, whichever is longer
8. Recent history of, or current drug or alcohol abuse
9. Participated in a prior donidalorsen study
10. Exposure to any of the following medications:
Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing
medications with systemic absorption
Oligonucleotides (including small interfering ribonucleic acid [siRNA]) 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 |
|---|---|
| EU-CTR | CTIS2023-509201-77-00 |
| EudraCT | EUCTR2022-000757-93-NL |
| ClinicalTrials.gov | NCT05392114 |
| CCMO | NL81330.000.22 |