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An Open-label Safety, Tolerability, and Dose-range Finding Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA) (SMNRx)

Primary Purpose

Spinal Muscular Atrophy

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

nusinersen

About this trial

This is an interventional treatment trial for Spinal Muscular Atrophy focused on measuring Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, IONIS-SMNRx, IONIS-SMN Rx, Spinraza

Eligibility Criteria

2 Years - 14 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Children's Hospital Boston
Columbia University Medical Center
UT Southwestern Medical Center - Children's Medical Center Dallas
University of Utah School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Cohort 1 (n=6)

Cohort 2 (n=6)

Cohort 3 (n=6)

Cohort 4 (n=10)

Arm Description

Outcomes

Primary Outcome Measures

Number of participants that experience Adverse Events (AEs) and Serious Adverse Events

Number of participants with clinically significant neurological examination abnormalities

Number of participants with clinically significant vital sign abnormalities

Number of participants with clinically significant physical examination abnormalities

Number of participants with clinically significant weight abnormalities

Number of participants with clinically significant laboratory parameters

Number or participants with clinically significant cerbrospinal fluid (CSF) laboratory parameters

Number of participants with clinically significant electrocardiograms (ECGs) abnormalities

Number of participants who use concomitant medications

PK parameters of nusinersen (ISIS 396443): Maximum observed plasma drug concentration (Cmax)

PK parameters of nusinersen: Time to reach maximum observed concentration (Tmax)

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)

PK parameters of nusinersen (ISIS 396443): Apparent terminal elimination half-life (t1/2), if possible

Secondary Outcome Measures

Full Information

NCT ID

NCT01494701

First Posted

December 13, 2011

Last Updated

February 17, 2021

Sponsor

Biogen

1. Study Identification

Unique Protocol Identification Number

NCT01494701

Brief Title

An Open-label Safety, Tolerability, and Dose-range Finding Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA)

Acronym

SMNRx

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

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

November 30, 2011 (Actual)

Primary Completion Date

January 31, 2013 (Actual)

Study Completion Date

January 31, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Biogen

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Spinal Muscular Atrophy

Keywords

Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, IONIS-SMNRx, IONIS-SMN Rx, Spinraza

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 (n=6)

Arm Type

Experimental

Arm Title

Cohort 2 (n=6)

Arm Type

Experimental

Arm Title

Cohort 3 (n=6)

Arm Type

Experimental

Arm Title

Cohort 4 (n=10)

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

nusinersen

Other Intervention Name(s)

ISIS 396443, BIIB058, Spinraza, IONIS-SMN Rx, ISIS SMNRx

Intervention Description

Administered by intrathecal (IT) injection

Primary Outcome Measure Information:

Title

Number of participants that experience Adverse Events (AEs) and Serious Adverse Events

Time Frame

Up to 88 Days

Title

Number of participants with clinically significant neurological examination abnormalities

Time Frame

Up to 88 Days

Title

Number of participants with clinically significant vital sign abnormalities

Time Frame

Up to 88 Days

Title

Number of participants with clinically significant physical examination abnormalities

Time Frame

Up to 88 Days

Title

Number of participants with clinically significant weight abnormalities

Time Frame

Up to 88 Days

Title

Number of participants with clinically significant laboratory parameters

Time Frame

Up to 88 Days

Title

Number or participants with clinically significant cerbrospinal fluid (CSF) laboratory parameters

Time Frame

Up to 88 Days

Title

Number of participants with clinically significant electrocardiograms (ECGs) abnormalities

Time Frame

Up to 88 Days

Title

Number of participants who use concomitant medications

Time Frame

Up to 88 Days

Title

PK parameters of nusinersen (ISIS 396443): Maximum observed plasma drug concentration (Cmax)

Time Frame

Plasma at 1, 2, 4 and 20 hours after dosing

Title

PK parameters of nusinersen: Time to reach maximum observed concentration (Tmax)

Time Frame

Plasma at 1, 2, 4 and 20 hours after dosing

Title

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)

Time Frame

Plasma at 1, 2, 4 and 20 hours after dosing

Title

PK parameters of nusinersen (ISIS 396443): Apparent terminal elimination half-life (t1/2), if possible

Time Frame

Plasma at 1, 2, 4 and 20 hours after dosing

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

14 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Biogen

Official's Role

Study Director

Facility Information:

Facility Name

Children's Hospital Boston

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Columbia University Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

UT Southwestern Medical Center - Children's Medical Center Dallas

City

Dallas

State/Province

Texas

ZIP/Postal Code

75207

Country

United States

Facility Name

University of Utah School of Medicine

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

31420846

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.

Results Reference

derived

PubMed Identifier

26823478

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.

Results Reference

derived

Links:

URL

http://www.curesma.org

Description

Cure SMA

URL

http://mda.org/disease/spinal-muscular-atrophy

Description

Muscular Dystrophy Association

URL

http://www.rarediseases.org

Description

National Organization for Rare Diseases

URL

http://clinicalresearch.biogen.com/Content/Studies/CS1%20Biogen.com%20Packet.pdf

Description

Clinical Study Report (CSR) Synopsis - a results summary

Learn more about this trial

An Open-label Safety, Tolerability, and Dose-range Finding Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA)

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