Clinical trial NCT01110720: Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Progressive Supranuclear Palsy
Lead sponsor: Allon Therapeutics
Sponsor class: INDUSTRY
First posted: 2010-04-27
Enrollment: 313
Sex: ALL
Minimum age (years): 41
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Efficacy, as measured by change from baseline scores of the Progressive Supranuclear Palsy Rating Scale (PSPRS) at 52 weeks
timeFrame: 52 weeks
measure: Efficacy, as measured by the change from baseline of the Schwab and England Activities of Daily Living Scale (SEADL) at 52 weeks
timeFrame: 52 weeks
measure: Safety, as measured by reported AEs, electrocardiograms (ECG), nasal examinations and clinical laboratory measures
timeFrame: 52 weeks
Secondary outcomes:
measure: Efficacy, as measured by the Clinical Global Impression of Change (CGI-C) at 52 weeks
timeFrame: 52 weeks
measure: Brain atrophy, as measured by change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks.
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Muhammed Ali Parkinson Center and Movement Disorders Clinic
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic, AZ
state: Arizona
city: Los Angeles
country: United States
facility: USC Keck School of Medicine
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine - UCLA
state: California
city: San Diego
country: United States
facility: UCSD/VA Neurology Service
state: California
city: San Francisco
country: United States
facility: UCSF Memory and Aging Center
state: California
city: Englewood
country: United States
facility: Colorado Neurological Institute - Rocky Mountain Movement Disorders Ctr, PC
state: Colorado
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic, Florida
state: Florida
city: Tampa
country: United States
facility: The Frances J. Zesiewicz Foundation for Parkinson's Disease at USF
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center Parkinson Disease & Movement Disorders Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville Division of Movement Disorders
state: Kentucky
city: Baltimore
country: United States
facility: John Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Department of Neuology
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic, Rochester, MN
state: Minnesota
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: Univeristy of North Carolina Department of Neurology
state: North Carolina
city: South Euclid
country: United States
facility: University Hospitals Case Medical CenterNI Movement Disorders Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Center for Alzheimer's Care, Imaging &Research
state: Utah
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: London
country: Canada
facility: London Sciences Health Center University Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Parkinson's Disease & Movement Disorders Clinic
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital University Health Network
state: Ontario
city: Montreal
country: Canada
facility: CHUM-Notre Dame Hospital Unité de Troubles du Mouvement
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre - Montreal General Hospital
state: Quebec
city: Limoges
country: France
facility: Limoges University Hospital
city: Marseille
country: France
facility: Hopital Timone
city: Paris
country: France
facility: Hôpitaux de Paris
city: Berlin
country: Germany
facility: Humboldt University Charité
city: Bochum
country: Germany
facility: Neurologisch Klinik der Ruhr-Universität im St. Josef-Hospital
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Carus an der Technischen Universität
city: Kassel
country: Germany
facility: Paracelsus-Elena Klinik
city: Marburg
country: Germany
facility: Philipps Universität Marburg
city: München
country: Germany
facility: Klinikum Großhadern
city: Rostock
country: Germany
facility: Universität Rostock Zentrum für Nervenheilkunde und Poliklinik
city: Ulm
country: Germany
facility: Universitäts- und Rehabilitationskliniken Ulm
city: Haywards Heath
country: United Kingdom
facility: Princess Royal Hospital
city: Newcastle
country: United Kingdom
facility: Clinical Ageing Research Unit (CARU) Newcastle University
city: Salford
country: United Kingdom
facility: Greater Manchester Neuroscience Centre
Study officials:
affiliation: Memory and Aging Center, University of California, San Francisco
name: Adam Boxer, M.D., PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoglinger GU, Schope J, Stamelou M, Kassubek J, Del Ser T, Boxer AL, Wagenpfeil S, Huppertz HJ; AL-108-231 Investigators; Tauros MRI Investigators; Movement Disorder Society-Endorsed PSP Study Group. Longitudinal magnetic resonance imaging in progressive supranuclear palsy: A new combined score for clinical trials. Mov Disord. 2017 Jun;32(6):842-852. doi: 10.1002/mds.26973. Epub 2017 Apr 24.
citation: Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, Doody RS, Lees A, Golbe LI, Williams DR, Corvol JC, Ludolph A, Burn D, Lorenzl S, Litvan I, Roberson ED, Hoglinger GU, Koestler M, Jack CR Jr, Van Deerlin V, Randolph C, Lobach IV, Heuer HW, Gozes I, Parker L, Whitaker S, Hirman J, Stewart AJ, Gold M, Morimoto BH; AL-108-231 Investigators. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 2014 Jul;13(7):676-85. doi: 10.1016/S1474-4422(14)70088-2. Epub 2014 May 27.