Brief Title
Continuously Infused Recombinant-Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (GDNF) to Treat Progressive Supranuclear Palsy
Official Title
Dose-Escalation Trial of Continuously Infused Recombinant-Methionyl Human Glial Cell Line-Derived Neurotrophic Factor for the Treatment of PSP
Brief Summary
This study will examine the safety and effectiveness of an experimental drug called GDNF
delivered through an investigational device to treat progressive supranuclear palsy (PSP).
The drug will be administered directly into the brain through catheters attached to an
infusion pump implanted in the abdomen. The study will evaluate 1) if the drug is safe and
well tolerated when given by this method; 2) the performance of the catheters and pump
system, and 3) the effects of GDNF on PSP symptoms.
PSP is a rare neurological disease that causes eye movement dysfunction, muscle rigidity,
slowness of movement, swallowing, speech, emotional, cognitive and personality problems.
Patients 35 to 75 years old with PSP may be eligible for this study. Candidates will be
screened at the National Institutes of Health outpatient clinic in Bethesda, MD, with a
medical history, physical examination, neurological and neuropsychiatric evaluations, blood
tests, electrocardiogram, CT scan of the brain, and baseline studies including a special eye
examination, evaluation of symptoms, lumbar puncture (spinal tap) and psychiatric interview.
Patients enrolled in the study will undergo surgery to place two catheters into the brain and
two infusion pumps under the skin in the upper abdomen. The surgery will be performed at
Vanderbilt University Medical Center in Nashville, TN. It will be done under general
anesthesia and will require a 3 day hospitalization. Within 24 hours after the surgery, a CT
scan of the brain will be done to ensure the catheters are properly placed. Patients return
to NIH two weeks after surgery for post-surgery examination and treatment initiation.
All patients will receive continuous infusions of GNDF through one catheter and placebo (an
inactive salt solution) through the other for 6 months. Half of the patients will receive
placebo in the right side of the brain and GNDF in the left, and half will receive GNDF in
the right side of the brain and placebo in the left. All patients will also undergo the
following procedures:
Brief physical examination, and evaluation of symptoms and adverse side effects - every 2
weeks
Blood and urine tests - every 2 weeks for the first 2 months and then every 8 weeks until the
end of the study
CT scan to check catheter placement - weeks 9 and 27
Thorough evaluation of symptoms - before beginning treatment and weeks 1, 5, 9, 17 and 27
Neuropsychiatric evaluation - week 27
Special eye examination - weeks 1 and 27
Lumbar puncture - week 27
Additional blood tests to measure drug concentration and antibodies - 6 times during the
study
In addition, some patients may be asked to have positron emission tomography (PET) scans or a
single photon emission tomography (SPECT) scan, or both.
The potential benefit of GDNF is unknown. In studies with rats and monkeys, GNDF increased
the number and size of brain cells containing the chemical messenger dopamine and some
movement and balance problems were lessened. Earlier studies of GDNF infused into the
ventricles of patients with Parkinson's disease showed no benefit and no serious harm.
Detailed Description
The safety and initial efficacy of the unilateral intralenticular infusion of
recombinant-methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) will be
compared with the contralateral intralenticular infusion of a placebo solution, both
continuously administered using chronically implanted catheters and pumps in up to 10
patients with progressive supranuclear palsy. Safety will be evaluated by analyzing implant-,
post-implant-, and treatment-emergent adverse events, clinical laboratory test results, and
disease status. Efficacy will be studied by comparing left and right sided neurologic
function using validated clinical scales as well as by putative surrogate biochemical and
radiographic measures.
Study Phase
Phase 2
Study Type
Interventional
Condition
Progressive Supranuclear Palsy
Intervention
GDNF & Synchro Med Infusion System
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
15
Start Date
June 2000
Completion Date
May 2005
Eligibility Criteria
INCLUSION CRITERIA:
1. Diagnosis of PSP with bilateral symptoms based on medical history and neurologic
examination in accordance with NINDS criteria. Those evidencing ratable limb
dysfunction bilaterally as well as a past history levodopa responsivity will be
especially sought.
2. PSP will be considered clinically to be at a moderate to moderately advanced stage
(PSP Staging System grade BB - DD), associated with ratable parkinsonian signs in the
limbs bilaterally and a Hoehn and Yahr grade of 3 - 5.
3. Men or nonpregnant women age 35 to 75 years. Women of childbearing potential must have
a negative human chorionic gonadotropin (HCG) test result immediately before (within
48 hours) catheter and pump implantation and repeated again immediately before (within
48 hours) the start of drug infusion; men and women of childbearing potential must
practice adequate contraception during the course of the study.
4. Before any study-specific procedures are performed, the subject and their designated
representative must give signed informed consent for their participation. All patients
must sign a Durable Power of Attorney (DPA). Device implantation must occur within 60
days after a subject consents to participate in the study.
5. The subject is medically able to undergo the surgical procedures required to implant
bilateral pumps and intracranial catheters using stereotactic procedures.
EXCLUSION CRITERIA:
1. Treatment with levodopa, dopamine agonists or any other antiparkinsonian medications.
2. Presence of clinically significant psychosis or hallucinations.
3. Any disorder that precludes a surgical procedure (e.g., bleeding diathesis, signs of
sepsis or inadequately treated infection) alters wound healing or renders bilateral
catheter and infusion pump implants unsuitable.
4. Any history of clinically significant head trauma or cerebrovascular disease or recent
history (within previous 2 years) of drug or alcohol abuse.
5. A computed tomography (CT) scan or magnetic resonance image (MRI) of the brain within
3 months before the implantation procedure that indicates the presence of a central
nervous system abnormality that may interfere with the assessments of safety or
biologic effect in this protocol, or represent a surgical risk to the subject.
6. The presence of an intracranial shunt or catheter system other than the one used in
this protocol.
7. Any medical disability, condition or laboratory abnormality (e.g., severe degenerative
arthritis, compromised nutritional state, body weight less than 15% of ideal, Na less
than 130 (grade 3 or above), cardiovascular disease) that would be deemed likely to
increase risk of participation in the protocol or interfere with assessment of the
safety and biologic effect of study materials, the chronic implantation of catheters
and infusion pumps, or would compromise the ability of the subject to give informed
consent.
8. Known allergy to E coli-derived products or history of anaphylaxis.
9. Treatment with an investigational agent or used an investigational device within 60
days before the first dose of study material, other than those described in this
protocol.
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
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Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00005903
Organization ID
000145
Secondary IDs
00-N-0145
Study Sponsor
National Institute of Neurological Disorders and Stroke (NINDS)
Study Sponsor
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Verification Date
May 2005