Spinal Muscular AtrophyPhase 1/2NCT01703988
An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy
A Phase 1/2 study testing Nusinersen in people with Spinal Muscular Atrophy, run by Biogen at 4 sites in United States.
Trial summary
This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA). Four dose levels will be evaluated sequentially. Read more about this study
- Who is it for?
- Ages 2 to 15 years
- Conditions the study is for
- Spinal Muscular Atrophy
- What is being tested?
- Nusinersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 4 sitesUnited States
- Study dates
- 31 Oct 2012to 31 Jan 2015
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 15 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
- Clinical signs attributable to SMA
- Able to complete all study procedures, measurements, and visits and parent/patient 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
Who cannot join
- Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
- Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
- Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
- Hospitalization for surgery (e.g. 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 at any time during the screening period
- History of brain or spinal cord disease that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation
Show all 14Show fewer
- Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter
- History of bacterial meningitis
- Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
- Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
- Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG) at the Screening visit, as assessed by the Site Investigator that would render the subject unsuitable for inclusion
- 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 3-months of screening. 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) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures.
- NOTE: Other protocol defined inclusion/exclusion criteria may apply.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
Boston Children's Hospital
Boston, Massachusetts, 02115
UT Southwestern Medical Center - Children's Medical Center Dallas
Dallas, Texas, 75207
Columbia University Medical Center
New York, New York, 10032
University of Utah School of Medicine
Salt Lake City, Utah, 84132
About this study
Official title: An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Spinal Muscular Atrophy
This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA).
Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.
Read the 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.
- Conditions
- Spinal Muscular Atrophy
- Being tested
- Nusinersen
- Keywords
- Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443
- Medical subject headings
- Muscular Atrophy, Spinal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NusinersenDrug
Also called ISIS-SMNRx, ISIS 396443, BIIB058, Spinraza
Single IT injection for each dose
| Study group | Role | What they receive |
|---|---|---|
| Nusinersen 3 mg | Experimental | 3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection Receives: Drug: Nusinersen |
| Nusinersen 6 mg | Experimental | 6 mg nusinersen on Days 1, 29, 85, IT injection Receives: Drug: Nusinersen |
| Nusinersen 9 mg | Experimental | 9 mg nusinersen on Days 1 and 85, IT injection Receives: Drug: Nusinersen |
| Nusinersen 12 mg | Experimental | 12 mg nusinersen on Days 1, 29, 85, IT injection Receives: Drug: Nusinersen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.
Measured: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days
Secondary outcomes (5)
Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)
Measured: Day 1 and Day 85
Plasma Pharmacokinetics: Time to Reach Cmax in Plasma
Measured: Day 1 and Day 85
Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)
Measured: Day 1 and Day 85
Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations
Measured: Day 1, Day 29, and Day 85
Urine Pharmacokinetics: Renal Clearance, Cohort 4
Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.
Measured: Day 1 and Day 85
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2012 (estimated)
- Study start31 Oct 2012
- Primary completion31 Jan 2015
- Study completion31 Jan 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Spinal Muscular AtrophyStudies of the same condition, open and under way.
- More trials run by BiogenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Biogen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Biogen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01703988
- Sponsor's protocol ID
- ISIS 396443 - CS2
- Other IDs
- 2017-000327-27, 2017
- Status last verified
- Mar 2021
- First submitted
- 8 Oct 2012
- Last updated
- 13 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
- Expanded access
- Available
Publications
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.
PubMed 31420846
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Spinal Muscular Atrophy
- ClinicalTrials.gov ID
- NCT01703988
- Acronym / sponsor ID
- ISIS 396443 - CS2
- Conditions
- Spinal Muscular Atrophy
- Keywords
- Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- BiogenIndustry (pharma, biotech, devices)
- Study start
- 31 Oct 2012 (actual)
- Primary completion
- 31 Jan 2015 (actual)
- Study completion
- 31 Jan 2015 (actual)
- First posted
- 11 Oct 2012 (estimated)
- Results
- Posted 13 Mar 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA).
Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Nusinersen 3 mg | Experimental | Drug: Nusinersen3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection |
| Nusinersen 6 mg | Experimental | Drug: Nusinersen6 mg nusinersen on Days 1, 29, 85, IT injection |
| Nusinersen 9 mg | Experimental | Drug: Nusinersen9 mg nusinersen on Days 1 and 85, IT injection |
| Nusinersen 12 mg | Experimental | Drug: Nusinersen12 mg nusinersen on Days 1, 29, 85, IT injection |
Who may qualify
- Ages
- 2 to 15 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
- Clinical signs attributable to SMA
- Able to complete all study procedures, measurements, and visits and parent/patient 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 (14 listed)
- Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
- Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
- Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
- Hospitalization for surgery (e.g. 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 at any time during the screening period
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NusinersenAlso: ISIS-SMNRx, ISIS 396443, BIIB058, SpinrazaSingle IT injection for each dose | Drug | Nusinersen 12 mg, Nusinersen 3 mg, Nusinersen 6 mg, Nusinersen 9 mg |
Primary outcome
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs
Time frame: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.
5 secondary outcomes
Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)
Time frame: Day 1 and Day 85
Plasma Pharmacokinetics: Time to Reach Cmax in Plasma
Time frame: Day 1 and Day 85
Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)
Time frame: Day 1 and Day 85
Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations
Time frame: Day 1, Day 29, and Day 85
Urine Pharmacokinetics: Renal Clearance, Cohort 4
Time frame: Day 1 and Day 85
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31420846Darras 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.
- Clinical Study Report (CSR) Synopsis - a results summaryLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Biogen
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nusinersen in people with Spinal Muscular Atrophy, run by Biogen at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Mar 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs (time frame: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01703988, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2021.