Clinical trial NCT01780246: An Open-label Safety and Tolerability Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy Who Previously Participated in ISIS 396443-CS1 (NCT01494701)
Official title: An Open-label Study to Assess the Safety and Tolerability of a Single Intrathecal Dose of ISIS 396443 in Patients With Spinal Muscular Atrophy Who Previously Participated in ISIS 396443-CS1
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS 396443
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2013-01-31
Enrollment: 18
Sex: ALL
Minimum age (years): 2
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to examine the safety and tolerability of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA) who previously participated in ISIS 396443-CS1 (NCT02865109). The secondary objective was to examine the plasma pharmacokinetics of a single dose of ISIS 396443 administered intrathecally to participants with SMA who previously participated in ISIS 396443-CS1.

Detailed description: This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc.

In August 2016, sponsorship of the trial was transferred to Biogen.

Eligibility criteria: Key Inclusion Criteria:

* Clinical signs attributable to Spinal Muscular Atrophy
* Satisfactory completion of dosing and all study visits in ISIS 396443-CS1 (NCT01494701) with an acceptable safety profile, per Investigator judgement.
* Able to complete all study procedures, measurements and visits and parent/participant has adequately supportive psychosocial circumstances, in the opinion of the investigator
* Estimated life expectancy \> 2 years from Screening
* Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key Exclusion Criteria:

* Have any new or worsening of existing condition 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.
* Dosing in ISIS 396443-CS1 (NCT01494701) within 270 days (9 months) of screening, or longer ago than 450 days (15 months)
* Dosing in ISIS 396443-CS2 (NCT01703988)
* Hospitalization for surgery (i.e. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy any time during the screening period
* Clinically significant abnormalities in hematology or clinical chemistry parameters
* Treatment with investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 1 months of screening. Any history of gene therapy or cell transplantation

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Number of participants that experience Adverse Events (AEs) and Serious Adverse Events
timeFrame: Up to 24 Weeks
measure: Number of participants with clinically significant neurological examination abnormalities
timeFrame: Up tp 24 Weeks
measure: Number of participants with clinically significant vital sign abnormalities
timeFrame: Up to 24 Weeks
measure: Number of participants with clinically significant physical examination abnormalities
timeFrame: Up to 24 Weeks
measure: Number of participants with clinically significant weight abnormalities
timeFrame: Up to 24 Weeks
measure: Number of participants with clinically significant laboratory parameters
timeFrame: Up to 24 Weeks
measure: Number of participants with clinically significant electrocardiograms (ECGs) abnormalities
timeFrame: Up to 24 Weeks
measure: Number of participants who use concomitant medications
timeFrame: Up to 24 Weeks
Secondary outcomes:
measure: PK parameters of nusinersen (ISIS 396443): Maximum observed plasma drug concentration (Cmax)
timeFrame: Plasma at 1, 2, 4 and 6 hours after dosing
measure: PK parameters of nusinersen: Time to reach maximum observed concentration (Tmax)
timeFrame: Plasma at 1, 2, 4 and 6 hours after dosing
measure: PK parameters of nusinersen: Area under the plasma concentrations time curve from the time of the intrathecal (IT) dose to the last collected sample (AUCinf)
timeFrame: Plasma at 1, 2, 4 and 6 hours after dosing
measure: PK parameters of nusinersen (ISIS 396443): Apparent terminal elimination half-life (t1/2), if possible
timeFrame: Plasma at 1, 2, 4 and 6 hours after dosing
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Dallas
country: United States
facility: UT Southwestern Medical Center - Children's Medical Center Dallas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
Study officials:
References:
citation: Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.
citation: Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. J Child Neurol. 2016 Jun;31(7):899-906. doi: 10.1177/0883073815627882. Epub 2016 Jan 27.