Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy

Progressive Supranuclear Palsy Clinical Trial

Official title:

A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01110720
• Other study ID #: AL-108-231
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: April 23, 2010
• Last updated: January 15, 2013
• Start date: October 2010
• Est. completion date: December 2012

Study information

• Verified date: January 2013
• Source: Allon Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationCanada: Health CanadaFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to evaluate the safety and efficacy of davunetide for the treatment of Progressive Supranuclear Palsy.

Description:

A Phase 2/3,Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy

Recruitment information / eligibility

• Status: Completed
• Enrollment: 313
• Est. completion date: December 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 41 Years to 85 Years

Eligibility

Inclusion Criteria:

• Probable or possible PSP defined as:

• at least a 12-month history of postural instability or falls during the first 3 years that symptoms are present; and

• at screening, a 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; and

• age at symptom onset of 40 to 85 years by history; and

• an akinetic-rigid syndrome with prominent axial rigidity.

• Aged 41 to 85 years at the time of screening.

• Judged by investigator to be able to comply with neuropsychological evaluation at baseline and throughout the study.

• 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.

• Modified Hachinski score = 3 (Appendix 7). This modified Hachinski will not include the focal neurological signs, symptoms or pseudobulbar affect questions, given the prominence of all 3 in PSP.

• Score = 15 on the mini-mental state examination (MMSE) at screening (Visit 1).

• 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.

• Subject resides outside a skilled nursing facility or dementia care facility at the time of screening, and admission to such a facility is not planned. Residence in an assisted living facility is allowed.

• If the subject is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, catechol-o-methyltransferase (COMT) inhibitor, or other Parkinson's medication,with teh exception of Azilect(rasagiline), the dose must have been stable for at least 60 days prior to the screening visit (Visit 1) and must remain stable for the duration of the study. No such medication can be initiated during the study. Subjects receiving rasagiline or CoQ10 must be on a stable dose for at least 90 days prior to the screening visit.

• Able to tolerate the MRI scan during screening with either no sedation or low dose lorazepam.

• 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.

• Presence of symptoms for less than 5 years or the presence of symptoms for more than 5 years with a PSPRS baseline score = 40.

• Stable on all other chronic medications for at least 30 days prior to the screening visit (Visit 1).

Exclusion Criteria:

• Insufficient fluency in local language to complete neuropsychological and functional assessments.

• A diagnosis of Amyotrophic Lateral Sclerosis or other motor neuron disease.

• Any of the following:

• Abrupt onset of symptoms defined in inclusion criteria 1 associated with ictal events,

• Head trauma related to onset of symptoms defined in inclusion criteria 1,

• Severe amnesia within 6 months of the symptoms defined in inclusion criteria 1,

• Cerebellar ataxia,

• Choreoathetosis,

• Early, symptomatic autonomic dysfunction; or

• Tremor while at rest.

• 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.

• Within 4 weeks of screening 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 (except as below).

• Low dose lorazepam (not more than 2 mg) may be used for sedation prior to MRI scans for those subjects requiring sedation. Neuropsychological testing may not be performed after lorazepam administration.

• Subjects who take short acting benzodiazepines (only temazepam or zolpidem are allowed) for sleep may continue to do so if they have been on a stable dose for 30 days prior to screening.

• Clonazepam may be used for treatment of dystonia or painful rigidity associated with PSP if the dose has been stable for 90 days prior to screening and is not expected to change during the course of the study.

• Treatment with lithium, methylene blue, tramiprosate, ketone bodies, latrepirdine, or any putative disease-modifying agent directed at tau within 90 days of screening.

• A history of alcohol or substance abuse within 1 year prior to screening and deemed to be clinically significant by the site investigator.

• Any malignancy (other than non-metastatic dermatological conditions) 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 one year before the screening visit and is judged by the site investigator not to interfere with the subject's participation in the study, the subject may be included.

• Clinically significant laboratory abnormalities at screening, including creatinine = 2.5 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 3 times the upper limit of the normal reference range, vitamin B12 below the laboratory normal reference range, or thyroid stimulating hormone TSH above laboratory normal reference range.

• The systolic blood pressure measurement is > 190 or < 85 mm Hg. The diastolic blood pressure measurement is > 105 or < 50 mm Hg at screening.

• Abnormal ECG tracing at screening and judged to be clinically significant by the site investigator.

• Treatment with any investigational drugs or device within 90 days of screening.

• Known history of serum or plasma progranulin level less than one standard deviation below the normal subject mean for the laboratory performing the assay.

• 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).

• History of deep brain stimulator (DBS) surgery other than sham surgery for DBS clinical trial.

• History of early, prominent rapid eye movement (REM) sleep behavior disorder.

• Women who are pregnant or lactating and women of childbearing potential who are not using at least two different forms of medically recognized and highly effective methods of birth control, resulting in a low failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.

• An employee or relative of an employee of the Sponsor, a clinical site, or Contract Research Organization participating in the study.

• Significant anatomical nasal abnormality (e.g., septal deviation obstructing airflow to at least one nostril or septal perforation) or history of nasal turbinate surgery.

• 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.

• Contraindication to MRI examination for any reason (e.g., severe claustrophobia, ferromagnetic metal in body).

• Structural abnormality on MRI that precludes diagnosis of PSP, such as cortical infarct in brain region that might account for subject's symptoms.

• In subjects receiving anti-Parkinson's Disease medication at the time of screening, 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.

• Known hypersensitivity to davunetide or any ingredient of the formulation.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Progressive Supranuclear Palsy
• Supranuclear Palsy, Progressive

Intervention

Drug:
• Davunetide
Davunetide Nasal Spray 30 mg BID IN 52 weeks
• Placebo
Placebo Nasal Spray BID IN 52 weeks

Locations

Country	Name	City	State
Australia	The Alfred Hospital	Melbourne	Victoria
Canada	London Sciences Health Center University Hospital	London	Ontario
Canada	CHUM-Notre Dame Hospital Unité de Troubles du Mouvement	Montreal	Quebec
Canada	McGill University Health Centre - Montreal General Hospital	Montreal	Quebec
Canada	Parkinson's Disease & Movement Disorders Clinic	Ottawa	Ontario
Canada	Toronto Western Hospital University Health Network	Toronto	Ontario
France	Limoges University Hospital	Limoges
France	Hopital Timone	Marseille
France	Hôpitaux de Paris	Paris
Germany	Humboldt University Charité	Berlin
Germany	Neurologisch Klinik der Ruhr-Universität im St. Josef-Hospital	Bochum
Germany	Universitätsklinikum Carl Carus an der Technischen Universität	Dresden
Germany	Paracelsus-Elena Klinik	Kassel
Germany	Philipps Universität Marburg	Marburg
Germany	Klinikum Großhadern	München
Germany	Universität Rostock Zentrum für Nervenheilkunde und Poliklinik	Rostock
Germany	Universitäts- und Rehabilitationskliniken Ulm	Ulm
United Kingdom	Princess Royal Hospital	Haywards Heath
United Kingdom	Clinical Ageing Research Unit (CARU) Newcastle University	Newcastle
United Kingdom	Greater Manchester Neuroscience Centre	Salford
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	John Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Lahey Clinic	Burlington	Massachusetts
United States	Univeristy of North Carolina Department of Neurology	Chapel Hill	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Colorado Neurological Institute - Rocky Mountain Movement Disorders Ctr, PC	Englewood	Colorado
United States	Baylor College of Medicine	Houston	Texas
United States	Mayo Clinic, Florida	Jacksonville	Florida
United States	University of Kansas Medical Center Parkinson Disease & Movement Disorders Center	Kansas City	Kansas
United States	David Geffen School of Medicine - UCLA	Los Angeles	California
United States	USC Keck School of Medicine	Los Angeles	California
United States	University of Louisville Division of Movement Disorders	Louisville	Kentucky
United States	University of Minnesota Department of Neuology	Minneapolis	Minnesota
United States	UMDNJ - Robert Wood Johnson Medical Center	New Brunswick	New Jersey
United States	Columbia University	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Muhammed Ali Parkinson Center and Movement Disorders Clinic	Phoenix	Arizona
United States	Mayo Clinic, Rochester, MN	Rochester	Minnesota
United States	University of Utah Center for Alzheimer's Care, Imaging &Research	Salt Lake City	Utah
United States	UCSD/VA Neurology Service	San Diego	California
United States	UCSF Memory and Aging Center	San Francisco	California
United States	Mayo Clinic, AZ	Scottsdale	Arizona
United States	University Hospitals Case Medical CenterNI Movement Disorders Center	South Euclid	Ohio
United States	The Frances J. Zesiewicz Foundation for Parkinson's Disease at USF	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Allon Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy, as measured by change from baseline scores of the Progressive Supranuclear Palsy Rating Scale (PSPRS) at 52 weeks		52 weeks	No
Primary	Efficacy, as measured by the change from baseline of the Schwab and England Activities of Daily Living Scale (SEADL) at 52 weeks		52 weeks	No
Primary	Safety, as measured by reported AEs, electrocardiograms (ECG), nasal examinations and clinical laboratory measures		52 weeks	Yes
Secondary	Efficacy, as measured by the Clinical Global Impression of Change (CGI-C) at 52 weeks		52 weeks	No
Secondary	Brain atrophy, as measured by change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks.		52 weeks	No