Hereditary Angioedema
Conditions
Keywords
Hereditary Angioedema, HAE
Brief summary
The purpose of this study was to evaluate the safety and efficacy of extended dosing of donidalorsen administered subcutaneously (SC), with alternative dosing and/or dose frequency with donidalorsen in participants with hereditary angioedema (HAE).
Detailed description
This was an open-label extension study of donidalorsen in 20 participants with HAE. The length of participation in the study was approximately 68 weeks, which included an up to 4-week qualification period, a 52-week treatment period, and a 12-week post-treatment period. Following the Week 53 treatment period visit, participants received donidalorsen in an extended treatment period for up to an additional 156 weeks. Participants taking part in the extended treatment period entered the 12-week post-treatment period after completion of, or early termination from, the extended treatment period.
Interventions
DRUGDonidalorsen
Donidalorsen administered SC
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Satisfactory completion of ISIS 721744-CS2 (index study) through Week 17 with an acceptable safety and tolerability profile, per Sponsor and Investigator judgement 2. Able and willing to participate in a 64-week study 3. Females must be non-pregnant, non-lactating and either surgically sterile or post-menopausal 4. Males must be surgically sterile or abstinent\* or if engaged in sexual relations with a female of child-bearing potential, participant is utilizing an acceptable contraceptive method 5. Participants must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1- inhibitor (C1-INH) concentrate or a bradykinin-2 \[BK-2\] antagonist) to treat angioedema attacks
Exclusion criteria
1\. Have any new condition or worsening of an existing condition or change or anticipated change in medication, which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | Up to Week 221 | An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. TEAEs were defined as those AEs that either started or worsened in severity on or after the date/time of first administration of study drug in this OLE Study. TEAEs included both serious and non-serious TEAEs. |
| Percentage of Participants With Clinically Meaningful Changes in Clinical Laboratory Assessments | Up to Week 221 | Clinical laboratory tests including clinical chemistry, hematology, coagulation, complement, inflammatory, urinalysis were performed. The percentage of participants with clinically meaningful changes were reported. Clinical meaningfulness was determined by the investigator. |
| Percentage of Participants With Clinically Meaningful Changes in Vital Signs | Up to Week 221 | Vital sign measurements including heart rate, respiratory rate, body temperature, systolic and diastolic blood pressure and pulse pressure were assessed. Percentage of participants with clinically meaningful changes in the vital signs were reported. Clinically meaningfulness was determined by the investigator. |
| Percentage of Participants With Clinically Meaningful Changes in Electrocardiograms (ECGs) Parameters | Up to Week 221 | The ECG parameters included ventricular rate, PR interval, QRS duration, QTc, QT corrected using the Fridericia's formula (QTcF), QT corrected using the Bazett's formula (QTcB), and overall interpretation. Percentage of participants with clinically meaningful changes in the ECG parameters were reported. Clinical meaningfulness was determined by the investigator. |
| Percentage of Participants Who Received At Least One Concomitant Medication | Up to Week 221 | Concomitant medications include medications that participants were exposed to on or after the first dose of ISIS 721744 in the OLE study. Percentage of participants who received at least one concomitant medication were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Time-normalized HAE Attack (Per 4 Weeks) Rate | Up to Week 221 | HAE attack rate was calculated for each participant as the number of HAE attacks occurring during the respective period divided by the number of days the participant contributed to this 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). A negative change from baseline in HAE attacks indicates an improvement in HAE attacks. |
| Percentage of Participants Who Used On-demand Medications | Up to Week 221 | The most commonly used on-demand medications during the On-Treatment Period were C1 esterase inhibitors (human) and icatibant, which were allowed per-protocol for treatment of acute attacks. |
Countries
Netherlands, United States
Participant flow
Recruitment details
Participants took part in the study from 31 March 2020 to 24 January 2025.
Pre-assignment details
A total of 20 subjects were enrolled to receive study drug ISIS 721744 in this study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 38.9 years STANDARD_DEVIATION 14.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 3 | 0 / 13 | 0 / 8 | 0 / 1 | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 12 / 17 | 2 / 3 | 11 / 13 | 5 / 8 | 1 / 1 | 1 / 1 | 2 / 2 |
| serious Total, serious adverse events | 0 / 17 | 0 / 3 | 0 / 13 | 0 / 8 | 0 / 1 | 1 / 1 | 0 / 2 |
Outcome results
None listed