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

Study ID
STU 082012-054

Cancer Related

Healthy Volunteers

Study Sites

  • Children's Medical Center (Dallas, Plano, Southlake)

Margaret Cowie

Principal Investigator
Susan Iannaccone


The proposed study will test the safety, tolerability, and pharmacokinetics of a single
dose of iSiS 396443 administered as an intrathecal (iT) injection. Four dose levels will be evaluated
sequentially, and each dose level will be studied in a cohort of 6 patients. The study will
be an open-label design in which all patients will receive iSiS 396443. The lowest
iSiS 396443 dose level will be at a dose that is at the low end of the predicted therapeutic
(pharmacologically active) dose range, escalating to a highest dose level that is not
intended to elicit dose-limiting toxicities. The use of a placebo control group would not
be ethically justified in this pediatric study, due to the inherent risks of a placebo iT
injection as well as the risk associated with anesthesia/sedation that will be required for
this procedure at most study sites. Furthermore, the benefits of a placebo injection group
are anticipated to be negligible, since the adverse events related to the intrathecal
injection procedure are well characterized and can be anticipated (Lee et al. 2007), as this
is a common clinical procedure in both pediatric and adult populations. Drug-related
safety and toxicity signals are anticipated to be detectable on the background of
procedure-related events and SMa disease-related events, given the study design
considerations of a single-dose study, the well documented expected adverse events from
the intrathecal delivery procedure, and the medically stable SMa patient population

Participant Eligibility

1. Signed informed consent of parent or guardian. Signed informed assent of subject, if indicated per subject[Single Quote]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