Clinical trial NCT01839656: A Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)
Official title: A Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Infantile-Onset Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS 396443
IONIS-SMNRx
Spinraza
Nusinersen
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2013-04-25
Enrollment: 21
Sex: ALL
Minimum age (years): 21
Maximum age (years): 210
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective is to examine the clinical efficacy of multiple doses of nusinersen (ISIS 396443) administered intrathecally to participants with Infantile-Onset Spinal Muscular Atrophy (SMA). The secondary objectives are to examine the safety and tolerability of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA and to examine the cerebral spinal fluid (CSF) and plasma Pharmacokinetics (PK) of multiple doses of nusinersen administered intrathecally to participants with infantile-onset 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:

* Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
* Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and \<6 months (180 days) of age
* At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
* Body weight \>5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
* Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
* Gestational age of 35 to 42 weeks and gestation body weight ≥2 kg
* Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence \>2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
* Able to complete all study procedures, measurements and visits and parent or guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator

Exclusion Criteria:

* Hypoxemia (O2 saturation awake \<96% or O2 saturation asleep \<96%, without ventilation support)
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
* History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
* Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
* History of bacterial meningitis
* Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the participant unsuitable for inclusion
* Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea etc), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
* The participants parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
* Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures

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

Primary outcomes:
measure: Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit
timeFrame: Day 1352 or Early Termination
Secondary outcomes:
measure: Event-free Survival at the End of Study
timeFrame: Up to Day 1638
measure: Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale
timeFrame: Day 1352 or Early Termination
measure: Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude
timeFrame: Baseline, Day 1072
measure: Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
timeFrame: Up to Day 1352
measure: Concentration of Nusinersen in Cerebrospinal Fluid (CSF)
timeFrame: Day 1135 (Predose)
measure: PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax)
timeFrame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
measure: PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)
timeFrame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
measure: PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)
timeFrame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Toronto
country: Canada
facility: The Hospital for Sick Children (SickKids)
state: Ontario
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Bishop KM, Foster R, Liu Y, Ramirez-Schrempp D, Schneider E, Bennett CF, Wong J, Farwell W. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc Health. 2021 Jul;5(7):491-500. doi: 10.1016/S2352-4642(21)00100-0. Epub 2021 Jun 3.
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: Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. doi: 10.1016/S0140-6736(16)31408-8. Epub 2016 Dec 7.