Clinical trial NCT01494701: An Open-label Safety, Tolerability, and Dose-range Finding Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA)
Official title: An Open-label, Escalating Dose Study to Assess the Safety, Tolerability and Dose-range Finding of a Single Intrathecal Dose of ISIS 396443 in Patients With Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS-SMN Rx
ISIS 396443
IONIS-SMNRx
IONIS-SMN Rx
Spinraza
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2011-12-19
Enrollment: 28
Sex: ALL
Minimum age (years): 2
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This objectives of this study are to evaluate the safety, tolerability, and pharmacokinetics of a single dose of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA).

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:

* Documented Survival Motor Neuron1 (SMN1) homozygous gene deletion
* Clinical signs attributable to Spinal Muscular Atrophy (SMA)
* 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:

* Respiratory insufficiency defined by the need for invasive or non-invasive ventilation during a 24 hour period
* Presence of a gastric feeding tube
* Previous scoliosis surgery or scoliosis surgery planned during the duration of the study that would interfere with the lumbar puncture (LP) injection procedure
* Hospitalization for surgery or pulmonary event within the last 2 months or planned during the study
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy
* History of brain or spinal cord disease that would interfere with LP procedures or cerebrospinal fluid (CSF) circulation
* Presence of an implanted shunt for the draining of CSF or an implanted Central Nervous System (CNS) catheter
* History of bacterial meningitis
* Clinically significant abnormalities in hematology or clinical chemistry parameters
* Treatment with another investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent whichever is longer. Any history of gene therapy or cell transplantation
* Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromised the ability of the participant to undergo study procedures

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 88 Days
measure: Number of participants with clinically significant neurological examination abnormalities
timeFrame: Up to 88 Days
measure: Number of participants with clinically significant vital sign abnormalities
timeFrame: Up to 88 Days
measure: Number of participants with clinically significant physical examination abnormalities
timeFrame: Up to 88 Days
measure: Number of participants with clinically significant weight abnormalities
timeFrame: Up to 88 Days
measure: Number of participants with clinically significant laboratory parameters
timeFrame: Up to 88 Days
measure: Number or participants with clinically significant cerbrospinal fluid (CSF) laboratory parameters
timeFrame: Up to 88 Days
measure: Number of participants with clinically significant electrocardiograms (ECGs) abnormalities
timeFrame: Up to 88 Days
measure: Number of participants who use concomitant medications
timeFrame: Up to 88 Days
measure: PK parameters of nusinersen (ISIS 396443): Maximum observed plasma drug concentration (Cmax)
timeFrame: Plasma at 1, 2, 4 and 20 hours after dosing
measure: PK parameters of nusinersen: Time to reach maximum observed concentration (Tmax)
timeFrame: Plasma at 1, 2, 4 and 20 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 20 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 20 hours after dosing
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Children's Hospital Boston
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:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
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.