Most common questions

Q) How do I get enrolled into the study?

A) Most acute spinal cord injured patients throughout North America are potential candidates for the study. They are entered into the study after admission or transfer to one of the participating study centers (22 in the United States and 3 in Canada). If the patient is not admitted to one of the participating centers within 72 hours of the injury, then they cannot be entered into the study. Any patient can request to be transferred to a participating facility (see list below). If the patient is considering transferring to a study center, both the patient and family members should check with the physicians at the existing facility regarding the safety of a transfer. The physicians at the study center should also be consulted prior to transferring the patient to ensure that the patient meets all of the entrance criteria.

Q) When will the results of the current Sygen (GM-1) study be known?

A) Patient enrollment is expected to terminate in January 1997 and a 6-month follow up of all patients will be completed in July 1997. Initial results of this study should be available to the scientific community by late summer or fall of 1997.

Q) Is Sygen (GM-1) useful in the treatment of chronic spinal cord injury to restore neurologic function?

A) Currently there is no valid scientific information to support the efficacy of Sygen (GM-1) relative to chronic spinal cord injury. A large randomized study involving chronic spinal cord injury is planned in the future after completion of the acute spinal cord injury study. However, it will be several years before any results are known.

Sygen (GM-1) Protocol Synopsis

The Sygen (GM-1) Acute Spinal Cord Injury Study, sponsored by FIDIA Pharmaceutical Corporation, Washington, DC, is a randomized, stratified, double-blind, multicenter study involving the efficacy and safety of Sygen (GM-1) vs. placebo following standard methylprednisolone sodium succinate (MPSS) therapy in the treatment of acute spinal cord injury. The objectives of this study are to determine the efficacy and safety of Sygen in the treatment of patients with acute spinal cord injury following standard treatment with MPSS.

The study medication is administered intravenously for 29 days followed by intravenous or intramuscular administration for an additional 28 days. Follow-up neurologic evaluations are performed at 1 month, 2 months, 6 months and 12 months after initiation of treatment.

The study is being conducted in 25 neurotrauma centers throughout North America with a total planned enrollment of 720 patients completing the entire one-year follow up. The enrollment period is expected to terminate in January 1997. The first patient was admitted into the study on April 13, 1992, and as of May 10, 1996, 645 patients have been entered into this study. This is the largest acute spinal cord injury drug study conducted to date.

All patients initially receive the standard MPSS treatment per the recommendations of NASCIS 2(1). The study medication (Sygen or placebo) is administered after completing the 24-hour MPSS treatment. Patients were initially block randomized (1:1:1) to receive 1 of 3 regimens (placebo, low-dose Sygen or high-dose Sygen ). Following the Extramural Monitoring Committee recommendations of May 11, 1994, it was decided that patients would no longer be randomized into one of the two Sygen dose levels. Thus, all patients are currently block randomized (1:1) to receive 1 of 2 regimens (placebo and one dose of Sygen ).

Patients were initially stratified within each center on the basis of spinal cord injury level and severity of injury:

A. Spinal Level

a. Cervical Cl - C7 (including C7 - Tl disc space)

b. Thoracic Tl - T10 (starting at the top of the Tl body)

B. Severity (See Appendix I)

a. ASIA Impairment Scale A

b. ASIA Impairment Scale B

c. ASIA Impairment Scale C and D

At the onset of the study, patients were randomized into six strata: 1) cervical A; 2) cervical B; 3) cervical C and D; 4) thoracic A; 5) thoracic B; and 6) thoracic C and D. Consequent to recommendation of the Extramural Monitoring Committee (EMC) at its May 11, 1994 meeting, because of an age-related imbalance in randomization, patients were then also stratified by age: "younger" (age #29 years) versus "older" (age .29 years). Thus, the six initial strata were converted into twelve strata.

This study is conducted along strict scientific guidelines and in cooperation with the U.S. Food & Drug Administration (FDA). In order to be considered for entry into the study, the patient must meet the following inclusion criteria: 1) patient age 12 to 70 years; 2) restoration of blood pressure within 8 hours of injury; 3) standard MPSS therapy initiated within eight hours of the injury; 4) a motor deficit attributable to an acute spinal cord injury with the sum of motor strengths in the five ASIA motor groups of one leg #15 points; 5) study medication initiated within 72 hours of the injury and after the conclusion of MPSS therapy; 6) patient written informed consent obtained.

Additionally, if the patient meets any of the following exclusion criteria, then the patient is not entered: 1) direct spinal cord damage as a result of a gunshot wound or other penetrating trauma; 2) traumatic spinal cord anatomic transaction; 3) presence of cauda equina damage, major brachial or lumbar plexus injury; 4) significant head trauma or multitrauma; 5) significant systemic disease; 6) pre-existing polyneuropathy, focal or multifocal neuropathy, myelopathy or radiculopathy; 7) presence of any medical condition which can interfere with assessment of spinal cord function; 8) history of Guillain-Barré syndrome; 9) psychoactive substance use disorder six months prior to injury; 10) history of major depression, schizophrenia, paranoia or other psychotic disorder; 11) women who are pregnant or nursing; 12) history of life-threatening allergic reaction; l3) poor likelihood of patient being available for follow-up evaluation; 14) inability to communicate effectively with the neurological examiner.

The main statistical test of this study is to determine whether the percentage of large improvers is increased with the addition of Sygen . The two groups of patients (Sygen and placebo) are compared based on their improvement from baseline utilizing the ASIA Impairment Scale(2), (Appendix I) and at six months utilizing the Modified Benzel Classification Scale(3), (Appendix II). Patients will be considered to have attained marked recovery if they have obtained: 1) a two grade improvement, if the initial ASIA Impairment Scale grade is A or B; or 2) a three grade improvement, if the initial ASIA Impairment Scale grade is C or D. Clearly, changes as large as these increase both the patient function and quality of life significantly. The ASIA Motor Score(2) (Appendix III) is also collected at baseline and all follow up examinations to aid in secondary analysis.

Background and Rationale for the Sygen Acute Spinal Cord Injury Study

Spinal cord injury affects approximately 10,000 new victims per year often producing permanent disability; it is particularly devastating among the youth of America. Prompt triage to regional spinal cord injury centers has decreased morbidity and mortality, primarily by preventing secondary injury and complications. Although efficient and modern treatment is provided in these centers, the final morbidity is often life-long disability. Only a minority of patients experience major recovery, which are rarely complete(4).

Ideally, medical treatment would help to reverse the neurologic deficit, but acute spinal cord injury has been extraordinarily resistant to effective treatment. Recent animal models involving spinal cord injury suggest that pharmacologic intervention can improve neurologic outcome(5). Within the last five years, studies using animal models of spinal cord injury have shown enhanced neurologic recovery utilizing several drug therapies including gangliosides(6). These data may apply to humans. The pharmacologic agents tested may decrease cell death and enhance regeneration or recovery of the remaining injured cells.

In an effort to determine if these animal data could apply to humans, double-blind, controlled clinical trials have been conducted. These trials have provided new hope for pharmacologic management of spinal cord injury.

The First National Acute Spinal Cord Injury Study 1 (NASCIS 1)(7) showed that an intravenous infusion of 100 mg or 1000 mg of MPSS did not have a significant effect on recovery from spinal cord injury(8). A statistically significant recovery of neurologic function was shown when massive doses of MPSS administered within 8 hours of injury were used in NASCIS 2(1) (a 30 mg/kg bolus intravenously administered, 2100 mg in a 70 kg person, followed by 5.4 mg/kg/hr for 23 hours).

In a separate recently reported study(9), Sygen was compared with placebo in the treatment of acute spinal cord injury. Treatment was instituted within 72 hours of injury and administered daily for 18 to 32 days. Patients were followed for one year. Neurologic status was assessed by means of the American Spinal Injury Association (ASIA) Impairment Scale and the ASIA Motor Score(2). Analyses revealed that patients treated with Sygen recovered significantly as assessed by both scales and that the increased recovery in the Sygen treated group was attributable to initially paralyzed muscles regaining useful motor strength rather than to paretic muscles gaining more strength. This study provides evidence that Sygen enhances the recovery of neurologic function in human spinal cord injuries and provides the rationale for a larger study involving Sygen .

Gangliosides are complex acidic glycolipids that are particularly abundant in the nervous system. They form a major component of the cell membrane and are predominantly located in the outer leaflet of the cell's membrane bilayer(10-12).

In-vitro and in-vivo evidence from various experimental studies indicate that

Sygen may have both an acute and chronic beneficial effect on damaged CNS tissue(13). The acute effect has recently been attributed to the "Receptor Abuse Dependent Antagonist" (RADA), a property of GM-1. At the site of neural injury, excessive quantities of excitatory amino acid neurotransmitters are released which overstimulate associated amino acid receptors (i.e. receptor abuse) and neurons, leading to cell injury and death. The RADA property of GM-1 prevents these toxic consequences without interfering with the normal physiologic functions of amino acid neurotransmitters on undamaged neural tissue. The well-described chronic effect of GM-1, (the ability of gangliosides to stimulate the growth of nerve cells and the regeneration of damaged nervous tissues) is likely due to the ability of GM-1 to potentiate the effect of natural trophic factors including nerve growth factor(13).

The current study proposes to examine recovery of neurologic function after human spinal cord injury and confirm the Sygen results previously reported (9,11,14). Since most institutions now include high-dose MPSS treatment within 24 hours, patients in this study will also receive MPSS treatment per the NASCIS 2 recommendtions.

The initial clinical trial utilizing Sygen for spinal cord injury(9), consisted of 100 mg Sygen intravenously administered daily. This was the maximum safe dose according to data available at the time the initial human investigation was initiated. In order to enhance the potential chronic effect, treatment has been extended to approximately two months in the current study.

REFERENCES

1. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1411.

2. American Spinal Injury Association, International Medical Society of Paraplegia. International Standards for Neurologic and Functional Classification of Spinal Cord Injury. Chicago, Il: ASIA/IMSOP, 1992.

3. Benzel EC, Larson SJ. Functional recovery after decompressive spine operation for cervical spine fractures. Neurosurgery 1987;20:742-6.

4. Stover SL, Fine PR. Spinal Cord Injury: The Facts and Figures. Birmingham, Ala: The University of Alabama at Birmingham, 1986.

5. Braughler JM, Hall ED. Lactate and pyruvate metabolism in injured cat spinal cord before and after a single large intravenous dose of methylprednisolone. J Neurosurg 1998;59:261.

6. Gorio A, DiGuillo AM, Young W. GM1 effects on chemical, traumatic and peripheral nerve induce lesions to the spinal cord. In: Goldberger ME, Gorio A, Murray M, eds. Development and Plasticity of the Mammalian Spinal Cord. Fidia Research Series. Padova, Italy: Liviana Press, 1986:227-42.

7. Bracken MB, Shepard MJ, Hellenbrand KG, et al. Methylprednisone and neurological function 1 year after spinal cord injury. Results of the National Acute Spinal Cord Injury Study. J Neurosurg 1985;63:704-13.

8. Bracken MB, Collins WF, Freeman DF, et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA 1984;251:45-52.

9. Geisler FH, Dorsey FC, Coleman WP. Recovery of motor function after spinal cord injury. A randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 1991;324:1829-38.

10. Mahadik SP, Karpiak SK. Gangliosides in treatment of neural injury and disease. Drug Devel Res 1988;15:337-60.

11. Geisler FH. Gangliosides. In: Peterson PL, Phillis JW, eds. Traumatic and Ischemic Injuries to the Brain and Spinal Cord: Prevention and Repair. Boca Raton: CRC Press, 1995:291-310.

12. Rodden FA, Wiegandt H, Bauer BL. Gangliosides: the relevance of current research to neurosurgery. J Neurosurg 1991;74:606.

13. Samson JC. GM1 ganglioside treatment of central nervous system injury: Clinical evidence for improved recovery. Drug Devel Res 1990;19:209-24.

14. Geisler FH, Dorsey FC, Coleman WP. Corection: recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside. Letter. N Engl J Med 1991;325:1659-60.

Appendix I

Based on the International Standards for Neurologic and Functional Classification

by American Spinal Cord Injury Association (ASIA) and the

International Medical Society of Paraplegia (IMSOP) (2)

Grade A Complete - No motor or sensory function is preserved in the sacral segments S4-5.

Grade B Incomplete - Sensory but no motor function is preserved below the neurologic level and extends through the sacral segments S4-5.

Grade C Incomplete - Motor function is preserved below the neurologic level, and the majority of key muscles below the neurologic level have a muscle grade <3.

Grade D Incomplete - Motor function is preserved below the neurologic level, and the majority of key muscles below the neurologic level have a muscle grade 3.

Grade E Normal - Motor and sensory function is normal.

Appendix II

Assessment of Neurologic Function at Follow Up Examination

Using the Benzel Classification Scale (3)

This is a modification of the Benzel Classification of functional recovery which categorizes neurologic disability by the type and completeness of neurologic function that remains below the level of the spinal cord injury. There are 7 grades.

I. No motor or sensory function is preserved in the sacral segments S4-5.

II. Sensory but no motor function is preserved in the sacral segments S4-5.

III. Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have a muscle grade <3. Patient is unable to walk.

IV. Some functional motor control below the level of injury that is significantly useful (i.e., assist in transfers) Patient is unable to walk.

NOTE: Patient must be able to transfer from a wheelchair to a bed with one leg bearing weight and pivoting (assistance* is allowed but the patient must be able to independently perform the weight bearing on one leg).

V.* Motor function allows walking with assistance* or unassisted, but significant problems secondary to lack of endurance or fear of falling limit patient mobility. Patient has limited walking ability.

NOTE: Must be able to ambulate at least 25 feet.

VI.** Ambulatory without assistance and without significant limitations other than one or both of the following: Difficulties with micturition; slightly dyscoordinated gait. Patient has unlimited walking ability.

NOTE: Must be able to ambulate at least 150 feet without assistance.

VII.** Neurologically intact with the exception of minimal deficits that cause no functional difficulties.

NOTE: Patient must have a neurologically normal gait and be able to walk without assistance or assistive devices (highest possible score).

*Assistance is defined as an individual providing minimal contact assistance (i.e., maintain balance so that the patient is expending at least 75% of the effort in performing the task).

**No assistive devices (braces, prostheses, special adaptive shoes, canes, crutches or walkerettes) may be used to attain grades V, VI, or VII.

Appendix III

Assessment of Specific Motor Groups

Using the ASIA Motor Score (2)

This scale emphasizes evaluation of specific motor groups. The ASIA Motor Score has a range from 0 to 100. Zero represents complete quadriplegia and 100 represents normal motor function.

Key muscles in upper Extremities

Elbow flexion (biceps C5)

Wrist extension (wrist extensors C6)

Elbow extension (triceps C7)

Finger flexion (distal phalanx of middle finger) (flexor profundus C8)

Finger abduction (little finger) (hand intrinsics Tl)

Key muscles in lower Extremities

Hip flexion (iliopsoas Ll, L2, L3)

Knee extension (quadriceps femoris L2, L3, L4)

Ankle dorsiflexion (tibialis anterio L4, L5)

Great toe extension (ext hallucis longus L5, Sl)

Ankle plantar flexion (gastrocnemius Sl, S2)

Each key muscle is assessed on a 0 to 5 point scale of strength:

0 = Total paralysis

1 = Palpable or visible contraction

2 = Active movement, full range of motion with gravity eliminated

3 = Active movement, full range of motion against gravity

4 = Active movement, full range of motion against moderate resistance

5 = (Normal) Active movement, full range of motion against normally surmountable resistance.

An additional motor assessment is made of the voluntary anal contraction.

Sponsor:

Roberto Fiorentini, President

FIDIA Pharmaceutical Corporation

1401 Eye Street, NW, Suite 900

Washington, DC 20005

Coordinating Centers:

Fred H. Geisler, M.D., Ph.D.

Principal Investigator, Sygen Acute SCI Study

Director, Comprehensive Spinal Care Center

Chicago Institute of Neurosurgery and Neuroreasearch

Suite 800

2515 North Clark Street

Chicago, Illinois 60614

William P. Coleman, Ph.D.

Principal Investigator, Sygen Acute SCI Study

Department of Mathematics and Statistics

University of Maryland at Baltimore

Baltimore, MD 21228

Active patient enrollment sites/investigators:

J. Alteveer, M.D.

Division of Emergency Medical Services

Robert Wood Johnson Medical Center

One Cooper Plaza

Camden, NJ 08103

G. Bennett, M.D.

University of Buffalo

State University of New York

Department of Neurosurgery

School of Medicine and Biomedical Sciences

3 Gates Circle

Buffalo, NY 14209

E. Benzel, M.D.

Professor and Chief of Neurosurgery

University of New Mexico

School of Medicine

2211 Lomas Blvd., N.E.

Albuquerque, NM 87131

C. Branch, M.D.

Department of Neurosurgery

Bowman Gray School of Medicine

Medical Center Boulevard

Winston-Salem, NC 2

R. Bucholz, M.D.

Division of Neurosurgery

St. Louis University

3635 Vista Ave. at Grand Boulevard

PO Box 15250

St. Louis, MO 6

J. Burgess, M.D.

Institute of Research & Education

3300 Gallows Road

Falls Church, VA 22046

H. Engelhard, M.D., Ph.D.

Streeterville Center

Northwestern University Medical Center

233 East Erie Street, Suite 500

Chicago, IL 6

M. Fehlings, M.D.

The Toronto Hospital

Toronto Western Division

Suite 2-417

399 Bathurst Street

Toronto, Ontario M5T 288

M. Fazl, M.D.

Sunnybrook Health Science Centre

A-138

2075 Bayview Avenue

New York, Ontario M4N 3M5

K. Foley, M.D.

Semmes-Murphey Clinic

930 Madison Avenue

Memphis, TN 38103

M. Sean Grady, M.D.

Associate Professor of Neurologic Surgery

University of Washington School of Medicine

Harborview Medical Center

325 Ninth Avenue, ZA-86

Seattle, WA 98104

P. W. Hitchon, M.D.

Division of Neurosurgery

University of Iowa Hospital :& Clinics

200 Hawkins Drive

Iowa City, IA 52242

K. Holloway, M.D.

Division of Neurological Surgery

Medical College of Virginia

8th Floor West Hospital

South Wing

1200 East Broad Street

Richmond, VA 23298

D. Lammertse, M.D.

Director

Craig Hospital

3425 S. Clarkson

Englewood, CO 80110

P. Lane, M.D.

Director

Trauma Services

Victoria Hospital

375 South Street

London, Ontario N6A 4G5

Canada

D. Maiman, M.D., Ph.D.

Medical Director

The Spinal Cord Injury Center

Medical College of Wisconsin

Froedtert Memorial Lutheran Hospital

9200 W. Wisconsin Ave.

Milwaukee, WI 53226

L. Marshall, M.D.

UCSD Medical Center

Dept. of Neurosurgery

200 W. Arbor Drive

San Diego, CA 9

D. McBride, M.D.

Neurological Surgery

Harbor/UCLA Medical Center

Box 424

1000 West Carson Street

Torrance, CA 90509

M. Miner, M.D., Ph.D.

Chairman

Ohio State University Hospital

Division of Neurosurgery

473 West 12th Street, Upham Hall

Room N007

Columbus, OH 4

W. Robinson, M.D.

MIEMSS

University of Maryland Hospital

Room TBR #56

22 South Greene Street

Baltimore, MD 21201

M. Rosner, M.D.

Univ. of Alabama Hospital

UAB Station Division of

Neurosurgery

MEB 516

1813 Sixth Avenue South

Birmingham, AL 35294

P. Stewart, M.D.

Charlotte Rehabilitation Hospital

1100 Blythe Boulevard

Charlotte, NC 28203

D. Thompson, M.D.

The Mercy Hospital of Pittsburgh

1400 Locust Street

Pittsburgh, PA 1

P. Werner, M.D.

Spinal Cord Injury Project

Santa Clara Valley Medical Center

950 S. Bascom Avenue, Box A421

San Jose, CA 95128

J. Wilberger, M.D.

Dept. of Neurosurgery

Allegheny General Hospital

320 E. North Avenue

Pittsburgh, PA 1

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