PPT Slide
SYGENÆ (GM-1 GANGLIOSIDE) ACUTE SPINAL CORD INJURY STUDY
Fred H. Geisler, M.D., Ph.D., F. C. Dorsey, Ph.D.,
F. Patarnello, Ph.D., G. Grieco, M.D.,
D. Poonian, and R. Fiorentini, M.D.
SygenÆ (monosialotetrahexosylganglioside GM-1)
SygenÆ (GM-1 Ganglioside)
- Natural cell membrane component abundant in CNS
- Acute neuroprotective and longer-term regenerative effect in experimental models of ischemia & injury
- Proposed mechanisms of action of SygenÆ include:
- Anti-excitotoxic
- Apoptosis prevention
- Neuro-reintegration enhancement
- Clinical trials in stroke, Parkinsonís disease, & other indications
Maryland GM-1 Acute SCI Trial
- Single-center, 37 patients
- MPSS dose 1/10 of NASCIS2 dose
- ASIA baseline grade affected the recovery pattern
- The distribution of motor recovery scores was highly non-normal
- Improvement based on proportion of patients with a large change in neurologic function (nonparametric statistics used)
- Significant drug effect reported (p=0.034)
SygenÆ (GM-1) Acute SCI Study Design
- Double-blind, randomization, multi-center
- Initially stratified by
- Level (Cervical vs Thoracic)
- Baseline (post-MPSS) ASIA Impairment Score A, B, C+D
- Initially block randomized 1:1:1 - three parallel groups
- High Dose SygenÆ
- 600 mg loading dose, then
- 200 mg/day for 56 days
- Low Dose SygenÆ
- 300 mg loading dose, then
- 100 mg/day for 56 days
- Placebo
- Placebo loading dose, then
- Placebo for 56 days
SygenÆ (GM-1) Acute SCI Study Design (contíd)
- Major spinal cord injury
- Neurologic deficit in 1 lower limb with total ASIA Motor score £ 15
- Pure spinal cord injury with potential of recovery
- No cord transection or penetration; no cauda damage; no significant plexus or peripheral nerve injury
- NASCIS2 MPSS regimen £ 8 hrs after SCI
- Study medication £ 72 hrs after SCI, but after MPSS
SygenÆ (GM-1) Acute SCI Study Operational Aspects
- Data in case report forms verified by study monitors at each site throughout the study.
- Adjudication committee reviewed data for consistency of medical information.
- Extramural Monitoring Committee (Chairman: Michael D. Walker, M.D.), after planned interim analysis of first 180 patients, recommended:
- Dropping high dose group
- Adding additional stratification by Age (ìYoungerî < 29 yrs., vs ìOlderî > 29 yrs.) to correct baseline imbalance
ASIA Impairment Scale (AIS) (Pre-Treatment Only)
ìAî-Complete: No motor or sensory function is preserved in
the sacral segments S4-S5.
ìBî-Incomplete: Sensory but not motor function is
preserved below the neurological level and extends through the sacral segments S4-S5.
ìCî-Incomplete: Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have a muscle grade less than 3/5.
ìDî-Incomplete: Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have a muscle grade greater than or equal to 3/5.
ìEî-Normal: Motor and sensory function is normal.
Modified Benzel Classification (Weeks 4, 8, 16, 26, and 52 F/U)
- I. Complete - No motor or sensory function is preserved in the sacral segments S4-S5. (=AIS A)
- II. Sensory Preservation - Sensory but no motor function is preserved in the sacral segments S4-S5. (=AIS B)
- III. Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have muscle grades less than 3/5. Unable to walk. (=AIS C)
- IV. Some functional motor control below the level of injury that is significantly useful (i.e., assist in transfers, etc.). Unable to walk independently. (=AIS D or high C)
Modified Benzel Classification (cont.) (Weeks 4, 8, 16, 26, and 52 F/U)
- V. Motor function allows walking with or without assistance, but significant problems secondary to lack of endurance or fear of falling limit patient mobility. Limited walking.
- VI. Independent ambulation ᡑ feet but may have one or both of the following: difficulties with micturition, dyscoordination.
- VII. Neurologically intact with the exception of minimal deficits that cause no functional difficulties.
Major Improvement Criterion: AIS/Benzel Neurologic Improvement
Six Month Modified Benzel Classification
Pre-planned Primary Outcome Measures
- The proportion of major improvers (2 grades) vs no major improvers in AIS/Benzel grade change between treatment groups at 26 weeks
- ASIA Motor Score Improvement at week 26
- ANCOVA model with center, stratum and treatment
- AIS/Benzel 26 week grade change adjusted for baseline AIS
Pre-planned Secondary Outcome Measures and Analyses
- Subgroup analysis
- strata, time to entry, surgery timing, traction timing, MPSS and study medication timing
SygenÆ (GM-1) Acute SCI Study Size and Duration
- This study is the largest prospective SCI drug trial ever conducted - 797 Patients randomized.
- 28 Neurotrauma Centers in North America
- All 12 month follow up data collection completed February 1998.
Enrollment in the SygenÆ (GM-1) Acute SCI Study
Patient Accounting
- 3130 patients screened in 28 centers
- 2333 not qualified by exclusion criteria of study
- 797 patients randomized in the study
- Unique database of acute SCI with more detail than any previous study - 8 Million data values
- 37 truly ineligible patients, in safety analysis only
- 760 patients for analysis
Analysis Group (n=760)
- 395 patients with cervical traction
- 600 patients with a spinal operation
Safety Data Summary
- The adverse events were consistent with the acute spinal cord injury population
- No noteworthy differences between treatment groups in frequency or severity of events
- There was an anticipated dose associated pattern of modest elevations in cholesterol and triglycerides in the SygenÆ groups during the treatment phase
- Further analysis in progress
Survival by Treatment Group (47 Deaths in 797 Patients)
Population Characteristics
- No unexpected observations of
- Mechanism of injury
- Neurologic level distribution
- Age or sex distribution
- Timing of medical/surgical treatment
- SCI to ER median < 20 minutes
- SCI to MPSS median < 2 hours
- SCI to cervical traction median < 6 hours if used
- SCI to surgery median < 4 days if operated
- No noteworthy differences between treatment groups
Week 26 Major AIS/Benzel Improvers by Baseline AIS Strata and Level
Week 26 Benzel Outcome Grade by Baseline AIS Strata
Week 26 Major AIS/Benzel Improvers by Baseline AIS Strata and MPSS Timing
Patient Enrollment by Treatment Group and Strata: Age, Level, Baseline AIS
Major (2 Grade AIS/Benzel) Improvers by Visit
Baseline A
Baseline B
Baseline C+D
Operated (n=521) vs. Non-Operated (n=140) Patients (Placebo and Sygen 100mg)
Operated vs. Non-Operated by Treatment Group
P=0.011, Principal Endpoint
Summary of Findings to Date
- SygenÆ 100mg and placebo comparable groups at baseline
- No noteworthy differences in medical/surgical management of groups
- No clinically relevant safety issues associated with SygenÆ identified
- Prespecified primary outcome measure of two grade change AIS/Benzel for all patients:
- pɘ.05 at 8 and 16 weeks: SygenÆ100mg favored over placebo
- not statistically significant at 26 weeks (primary endpoint)
Summary of Findings to Date (cont.)
- SygenÆ 100 mg-treated group had greater and earlier recovery than Placebo-treated group consistently across baseline severity groups
- Aís - Earlier modest effect, possibly constrained by general small recovery among Aís
- Bís - Earlier and greater effect observable
- C+Dís - Earlier effect, ceiling effect observed
- Large drug effect seen in the non-operated patients
- Pattern of positive drug effect response is consistent across primary and secondary efficacy measures
Conclusions
- At week 26 the largest treatment differences were observed among the Bís and patients with ìspinal cord contusionsî
- Sygen patients with major recovery at week 26 obtained it earlier than placebo patients
- Caution should be used in interpreting the positive findings reported today
- Principal efficacy analysis was not statistically significant at week 26
- Analyses not completed
SygenÆ (GM-1) Principal Investigators and Centers
Janet Alteveer, MD Cooper Hospital, Univ Medical Center, Camden, NJ
Lee V. Ansell, MD Univ of Texas Health Science Center, Houston, TX
Gregory J. Bennett, MD Univ of Buffalo, Buffalo, NY
Edward C. Benzel, MD Univ of New Mexico, Albuquerque, NM
Charles L. Branch, MD Bowman Gray School of Medicine, Winston-Salem, NC
Richard Bucholz, MD St. Louis University Hospital, St. Louis, MO
James E. Burgess, MD Fairfax Hospital, Falls Church, VA
George R. Cybulski, M.D. Northwestern Univ Medical School, Chicago, IL
Gail Delaney, MD Victoria Hospital, London, Ontario, Canada
Herbert H. Engelhard, MD, PhD Northwestern Univ Medical School, Chicago, IL
Mahmood Fazl, MD Sunnybrook Health Science Center, North York, Ontario, Canada
Kevin Foley, MD Semmes-Murphey Clinic, Memphis, TN
Gerard Fulda, MD Medical Center of Delaware, Newark, DE
M. Sean Grady, MD Univ of Washington, Seattle, WA
P. W. Hitchon, MD Univ of Iowa Hospitals & Clinics Iowa City, IA
Katharyn Holloway, MD Medical College of Virginia, Richmond, VA
SygenÆ (GM-1) Principal Investigators and Centers (cont.)
Amie Jackson, MD University of Alabama Hospital, Birmingham, AL
Nachshon Knollen, MD Maryland Institute for Emergency Medical Services Systems, Baltimore MD
Daniel P. Lammertse, MD Craig Hospital, Englewood, CO
Peter L. Lane, MD Victoria Hospital, London, Ontario, Canada
Dennis Maiman, MD, PhD Medical College of Wisconsin, Milwaukee, WI
Lawrence Marshall, MD UCSD Medical Center, San Diego, CA
Duncan McBride, MD Harbor/UCLA Medical Center, Torrance, CA
Michael Miner, MD, PhD Ohio State Univ Hospitals, Columbus, OH
Steven E. Murk, MD Univ of Texas Health Science Center San Antonio, TX
Kristjan T. Ragnarsson, MD Mt. Sinai Medical Center, New York, NY
Walker Robinson, MD Maryland Institute for Emergency Medical Services Systems, Baltimore, MD
Michael Rosner, MD Univ of Alabama Hospital, Birmingham, AL
Paula Stewart, MD Charlotte Rehabilitation Hospital Charlotte, NC
Dan R. Thompson, MD The Mercy Hospital of Pittsburgh, Pittsburgh, PA
Peter C. Werner, MD Santa Clara Valley Medical Center San Jose, CA
Jack E. Wilberger, Jr., MD Allegheny General Hospital, Pittsburgh, PA
C. Wilmot, MD Santa Clara Valley Medical Center, San Jose, CA