Clinical trial NCT05127226: HALOS: A Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Multiple Ascending Doses of ION582 in Participants With Angelman Syndrome
Official title: HALOS: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION582 in Patients With Angelman Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Angelman Syndrome
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-11-19
Enrollment: 51
Sex: ALL
Minimum age (years): 2
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and tolerability of ascending doses of ION582 administered intrathecally in participants with Angelman syndrome.

Detailed description: This is a Phase 1-2a, open-label study consisting of 3 parts. Part 1 is a multiple ascending dose (MAD) study, consisting of a 13-week MAD Treatment Period and a minimum 12-week but up to 32-week Post-MAD Follow-Up Period. Part 2 is a multi-center 49-week study where participants who completed Part 1 will receive IT bolus doses of ION582 followed by a minimum 12-week Part 2 follow up period. Part 3 extends the treatment period for participants who completed Part 2 for up to an additional 3 years followed by a 32-week post-LTE follow up period. The study will enroll approximately 44, and up to 55, participants.

Eligibility criteria: Inclusion Criteria:

1. Participant has a documented and certified diagnosis of Angelman syndrome (AS) (ubiquitin-protein ligase E3A \[UBE3A\] deletion or UBE3A mutation)
2. Male or female between the ages of 2-50 years of age, with signed informed consent from parent(s) or legal guardian(s)
3. Currently receiving stable standard of care treatments such as, stable doses of anti-epileptic medication, behavioral management medications, sleep medications, gabapentin, cannabidiol, and including special diets, supplements or nutritional support for at least 3 months prior to first dose.
4. Follow good study practice and not participate in the sharing of personal or study information on social media platforms, such as any website or social media site (e.g., Facebook, Instagram, Twitter, YouTube, etc.) until notified that the study is completed.

Exclusion Criteria:

1. Has documented molecular AS confirmation of paternal uniparental disomy (UPD) or imprinting defect (ID).
2. Any clinically significant (CS) cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, will make the patient unsuitable for participation in, and/or unable to complete the study procedures. Has poorly controlled seizures as determined by the Investigator or has documented Status Epilepticus in the past 6 months that could pose a safety risk while on study.
3. Known bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid, antisense oligonucleotide \[ASOs\]). COVID-19 vaccinations are allowed.
4. Any prior use of gene therapy. Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the participant taking part in or completing the study.

Primary outcomes:
measure: To evaluate the safety and tolerability of single and multiple doses of ION582 (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters).
timeFrame: Part 1: Up to Week 45; Part 2: Up to Week 81
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of ION582
timeFrame: Part 1: Up to Week 45; Part 2: Up to Week 81
measure: Time to Reach Maximal Plasma Concentration (Tmax) of ION582
timeFrame: Part 1: Up to Week 45; Part 2: Up to Week 81
measure: Plasma Elimination Half-Life (t1/2λz) of ION582
timeFrame: Part 1: Up to Week 45; Part 2: Up to Week 81
measure: Concentration ION582 in CSF
timeFrame: Part 1: Up to Week 13; Part 2: Up to Week 49
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Aurora
country: United States
facility: Colorado Children's Hospital Research Institute
state: Colorado
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Carrboro
country: United States
facility: University of North Carolina at Chapel Hill School of Medicine
state: North Carolina
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Randwick
country: Australia
facility: Sydney Children's Hospital, Kids Cancer Centre
city: Paris
country: France
facility: Necker-Enfants Malades Hospital
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Pisa
country: Italy
facility: Azienda Ospedaliera Universitaria Pisana
city: Oxford
country: United Kingdom
facility: STRONG Group University of Oxford
state: Oxfordshire
Study officials:
References: