Status:Enrolling by invitation
The objectives of this study are to evaulate the safety, tolerability, and pharmacokinetics of multiple doses of ISIS 396443 administered intrathecally to patients with Spinal Muscular Atrophy (SMA).
1.1 Primary Objective
To examine the safety and tolerability of multiple doses of ISIS 396443 administered intrathecally to patients with SMA.
1.2 Secondary Objective
To examine the cerebral spinal fluid (CSF) and plasma pharmacokinetics of multiple doses of ISIS 396443 administered intrathecally to patients with SMA.
1.3 Exploratory Objective
To examine the effects of multiple doses of ISIS 396443 administered intrathecally to patients with SMA on biomarkers and clinical outcomes related to SMA.
This study will test the safety, tolerability, and dose-range finding of multiple doses of ISIS 396443 administered as IT injections by lumbar puncture (LP). Three dose levels (3 mg, 6 mg, 9 mg) will be evaluated sequentially. Each dose level will be studied in a cohort of 8 subjects where all subjects will receive ISIS 396443. Within each cohort, no more than 4 subjects >7 years of age at screening will be enrolled. Cohort 1: 3 mg ISIS 396443 on Day 1, 29, 85, IT injection, (n=8) Cohort 2: 6 mg ISIS 396443 on Day 1, 29, 85, IT injection, (n=8) Cohort 3: 9 mg ISIS 396443 on Day 1 and 85, IT injection, (n=8) After Informed consent/assent is obtained, subjects will undergo a Screening evaluation no greater than 28 days prior to first dose administration at which their eligibility for the study will be examined. Subjects who meet the eligibility criteria will be admitted to the study center on Study Day 1, undergo pre-dose evaluations, and then receive an LP injection of study drug (ISIS 396443). The subject will remain at the study center for at least 24 hours post-injection for safety monitoring and laboratory specimen collection. Subjects in Cohorts 1 and 2 will return to the study center on Days 29 and 85 for follow-up evaluations and subsequent injections. Subjects in Cohort 3 will return to the study center on Day 85 for follow-up evaluations and a subsequent injection. Following LP injections on study Days 29 and 85, subjects will not stay overnight in the hospital but will be monitored for at least 6 hours post-injection before leaving the study facility. The study center will monitor the subject’s condition through telephone contact on Study Days 15, 30 (Cohorts 1 and 2 only), 57, 86, 127 and 211. Safety monitoring visits will occur on Days 8, 36, 92, 169, and 253 (through 24 weeks after the last dose of ISIS 396443). A CSF sample will be taken pre-dose on each injection day for safety and PK analyses. If a subject terminates early from the study, they will be encouraged to complete safety assessments per the Day 92 visit. Subjects who participated in ISIS 396443-CS1 Cohort 1 (Single-dose of 1 mg ISIS 396443) may enroll. Subjects who are being re-enrolled must repeat all screening assessments, except the Brain and Spinal Cord MRI which does not have to be repeated if they have had a study-specific MRI at screening in ISIS 396443-CS1.
To be eligible to participate in this study candidates must meet the following eligibility criteria at screening.
1. Signed informed consent of parent or guardian. Signed informed assent of subject, if indicated per subject’s age and institutional guidelines.
2. Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
3. Clinical signs attributable to SMA
4. Males and females 2 to 15 years of age
5. Able to complete all study procedures, measurements and visits and parent or guardian/subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
6. Estimated life expectancy >2 years from screening
7. Meets age-appropriate institutional criteria for use of anesthesia/sedation at Screening, if use is planned for study procedures (as assessed by the Site Investigator and either anesthesiologist or pulmonologist)
8. For subjects who, in the opinion of the Investigator, have reached reproductive maturity, satisfy one of the following:
Females: have a negative pregnancy test at Screening and must not be able to become pregnant (e.g., be abstinent or use adequate birth control methods as defined in Section 6.3) for the duration of the study
Males: be abstinent for the duration of the study
Subjects meeting any of the following criteria are not eligible for the study:
1. Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24 hour period
2. Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
3. Previous scoliosis surgery that would interfere with the LP injection procedure
4. Hospitalization for surgery (i.e. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
5. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
6. History of brain or spinal cord disease, including tumors, or abnormalities by MRI or CT that would interfere with the LP procedures or CSF circulation
7. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
8. History of bacterial meningitis
9. Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
10. Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
11. Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG), as assessed by the Site Investigator, at the screening visit that would render the patient unsuitable for inclusion
12. Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, etc.), 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
13. Ongoing medical condition that according to the Site Investigator 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 compromise the ability of the subject to undergo study procedures.