A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy
Status: Open to Enrollment
Start Date: Sep 09 2010
End Date: OPEN
Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by early postural instability and falls; axial rigidity; dysarthria and dysphagia; gaze palsy; and frontal lobe-type cognitive and behavioral disturbances. Preclinical experiments indicate that davunetide has neuroprotective, cognitive protective, and neurotrophic properties. In this study, davunetide will be administered intranasally by a multidose metered nasal spray. Primary: The primary objectives are to evaluate davunetide 30 mg BlD relative to placebo, when both are administered intranasally (IN) for 52 weeks to subjects with progressive supranuclear palsy (PSP), with respect to:
- Efficacy, as measured by change from baseline scores of the Progressive Supranuclear Palsy Rating Scale (PSPRS) at 52 weeks.
- Safety, as measured by reported adverse events (AEs), electrocardiograms
Secondary: The secondary objectives are to evaluate davunetide 30 mg BlD relative to placebo, when both are administered IN to subjects with PSP, with respect to:
- Efficacy, as measured by the change from baseline of the Schwab and England Activities of Daily Living Scale (SEADL) at 52 weeks.
- Efficacy, as measured by the change from baseline of the Clinical Global Impression of Disease Severity (CGI-ds) at 52 weeks.
- Brain atrophy, as measured by change from baseline of ventricular volumes measured by volumetric brain magnetic resonance imaging (MRI) at 52 weeks.
Subjects may be included in the study only if they meet all of the following criteria:
1. Probable or possible progressive supranuclear palsy defined as:
1) at least a l2-month history of a) postural instability or falls during the first 3 years that symptoms are present; and b) decreased downward saccade velocity defined as observable eye movement (deviation from the "main sequence" linear relationship between saccade amplitude and saccade velocity), or supranuclear ophthalmoplegia defined as 50% reduction in upward gaze or 30% reduction in downward gaze.
2) age at symptom onset of 40 to 85 years by history; and
3) an akinetic-rigid syndrome with prominent axial rigidity.
2. Aged 41 to 85 years at the time of screening (Visit 1).
3. Judged by investigator to be able to comply with neuropsychological evaluation at baseline and throughout the study.
4. Must have reliable caregiver accompany subject to all study visits. Caregiver must read, understand, and speak local language fluently to ensure comprehension of informed consent form and informant-based assessments of subject. Caregiver must also have frequent contact with subject (at least 3 hours per week at one time or at different times) and be willing to monitor study medication compliance and the subject's health and concomitant medications throughout the study.
5. Modified Hachinski score < or= 3. This modified Hachinski will not include the focal neurological signs, symptoms or pseuodobulbar affect questions, given the prominence of all 3 in PSP.
6. Score < or = 15 on the Mini-Mental State Examination (MMSE) at screening (Visit 1).
7. Written informed consent provided by subject (or legally-appointed representative, as appropriate) and caregiver (if not the legally-appointed representative) who are both fluent local language speakers.
8. Subject resides outside a skilled nursing facility or dementia care facility at the time of screening (Visit 1), and admission to such a facility is not planned. Residence in an assisted living facility is allowed.
9. If subject is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, catechol-omethyltransferase (COMT) inhibitor, or other Parkinson's medication, the dose must have been stable for at least 90 days prior to the screening visit (Visit 1) and must remain stable for the duration of study. No such medication can be initiated during the study.
10. Able to tolerate the MRI scan during screening without the use of sedation.
11. Able to ambulate independently or with assistance defined as the ability to take at least 5 steps with a walker (guarding is allowed provided there is no contact) or the ability to take at least 5 steps with the assistance of another person who can only have contact with one upper extremity.
12. Presence of symptoms for less than 5 years or the presence of symptoms for more than 5 years with a PSPRS baseline score 2: 40.
13. Stable on other chronic medications for at least 30 days prior to screening.
Exclusion Criteria- Subjects will be excluded from the study for any of the following reasons:
1. Insufficient fluency in local language to complete neuropsychological and functional assessments.
2. A diagnosis of Amyotrophic Lateral Sclerosis (ALS) or other motor neuron disease.
3. Any of the following:
a. Abrupt onset of symptoms defined in inclusion criteria 1 associated with ictal events,
b. Head trauma related to onset of symptoms defined in inclusion criteria 1,
c. Severe amnesia within 6 months of the symptoms defined in inclusion criteria 1,
d. Cerebellar ataxia,
f. Early, symptomatic autonomic dysfunction, or
g. Tremor while at rest.
4. Presence of other significant neurological or psychiatric disorders including (but not limited to) Alzheimer's disease; dementia with Lewy bodies; prion disease; Parkinson's disease (which has not subsequently been revised to PSP), any psychotic disorder; severe bipolar or unipolar depression; seizure disorder; tumor or other space- occupying lesion; or history of stroke or head injury with loss of consciousness for at least 15 minutes within the past 20 years.
5. Within 4 weeks of screening (Visit 1) or during the course of the study, concurrent treatment with memantine; acetylcholinesterase inhibitors; antipsychotic agents (other than quetiapine) or mood stabilizers (e.g., valproate, lithium); or benzodiazepines (other than temazepam or zolpidem).
6. Treatment with lithium, methylene blue, tramiprosate, ketone bodies, latrepirdine, or any putative disease modifying agent directed at tau within 90 days of screening (Visit 1).
7. A history of alcohol or substance abuse within 1 year prior to screening (Visit 1) and deemed to be clinically significant by the site investigator.
8. Any malignancy (other than non-metastatic basal cell carcinoma of the skin) within 5 years of the screening visit (Visit 1) or current clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disease. For the non-cancer conditions, if the condition has been stable for at least the one year before the screening visit (Visit 1) and is judged by the site investigator not to interfere with the subject's participation in the study, the subject may be included.
9. Clinically significant laboratory abnormalities at screening(Visit 1), including creatinine ~ 2.5 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ~ 3 times the upper limit of the normal reference range, vitamin B 12 below the laboratory normal reference range, or thyroid stimulating hormone (TSH) above the laboratory normal reference range.
10. The systolic blood pressure measurement is > 190 or < S5 mm Hg. The diastolic blood pressure measurement is > 105 or < 50 mm Hg at screening (Visit 1).
11. Abnormal ECG tracing at screening (Visit 1) and judged to be clinically significant by the site investigator.
12. Treatment with any investigational drugs or device or participation in an investigational drug study within 90 days of screening (Visit 1).
13. Known history of serum or plasma progranulin level less than one standard deviation below the normal subject mean for the laboratory performing the assay.
14. Known presence of known disease-associated mutation in TDP-43, PGRN, CHMPB2 or VCP genes or any other frontotemporal lobar degeneration (FTLD) causative genes not associated with underlying tau pathology (e.g., Chromosome 9 associated FTD).
15. History of deep brain stimulator surgery other than sham surgery for deep brain stimulation (DBS) clinical trial.
16. History of early, prominent rapid eye movement (REM) sleep behavior disorder.
17. Women who are pregnant or lactating and women of childbearing potential who are not using at least 2 forms of medically recognized contraception.
18. Is an employee or relative of an employee of the Sponsor, a clinical site, or contract research organization (CRO) participating in the study.
19. Significant anatomical nasal abnormality (e.g., septal deviation obstructing airflow to at least one nostril or septal perforation) or history of nasal turbinate surgery.
20. History of a clinically significant medical condition that would interfere with the subject's ability to comply with study instructions, would place the subject at increased risk, or might confound the interpretation of the study results.
21. Contraindication to the MRl examination for any reason (e.g., severe claustrophobia, ferromagnetic metal in body).
22. Structural abnormality on the MR1 that precludes diagnosis of PSP, such as cortical infarct in brain region that might account for subject's symptoms.
23. In subjects receiving anti-Parkinson's Disease medication at the time of screening (Visit 1), in the opinion of the investigator substantial worsening of motor signs or symptoms compared with normal functioning following overnight withdrawal of the anti-Parkinson medication.
24. Known hypersensitivity to davunetide or any ingredient of the formulation.
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