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Safety, Tolerability, and Efficacy of Two Different Oral Doses of NP031112 Versus Placebo in the Treatment of Patients With Mild-to-Moderate Progressive Supranuclear Palsy (Tauros)

Primary Purpose

Progressive Supranuclear Palsy

Status
Completed
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
tideglusib
tideglusib
placebo
Sponsored by
Noscira SA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Progressive Supranuclear Palsy

Eligibility Criteria

40 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Men and women with diagnosis of possible or probable PSP according to clinical criteria of National Institute of Neurologic Diseases and Stroke - the Society for PSP (Appendix 1).
  2. Age of 40 to 85 years (patients over 85 years could be included after previous assessment by Investigator and approved by sponsor).
  3. Brain magnetic resonance imaging (MRI) study within 24 months before Baseline visit excluding other potential causes of parkinsonism, especially cerebrovascular lesions and space occupying lesions.
  4. Mild-to-moderate stage of disease severity according to score of 1 to 4 in Golbe Staging System.(Appendix 2)
  5. Female patients must be surgically sterilized; at least 1 year postmenopausal (confirmed by follicle-stimulating hormone [FSH] >20 international units [IUs]); using adequate birth control (implants, injectables, combined oral contraceptives, intrauterine contraceptive device, total sexual abstinence during the study or vasectomised partner). Male patients must be willing to use barrier contraception (condom) during the study and for 6 months after last treatment administration.

    In European arms of study female patients must be without childbearing potential.

  6. Caregiver (or dedicated nurse) living in same household or interacting with patient for >4 hours every day able to assure correct preparation and administration of study drug.
  7. Patients living at home or in retirement home not requiring continuous nursing care.
  8. General health status acceptable for participation in 64-week clinical trial.
  9. Ability to swallow 100 mL of water suspension.
  10. Any concomitant medication for PSP must be well-tolerated and unchanged for at least 1 month prior to Baseline visit and its dose and regimen should be maintained during study if there are no clinical reasons to modify it.
  11. Occupational, physical, respiratory, or speech therapy is allowed but it must be stable for at least 1 month prior to screening.
  12. Pharmacological treatment of any other chronic condition must be stable and well-tolerated for at least 1 month prior to screening. Analgesics, occasional per request nonsteroidal anti-inflammatory agents, and treatments for transient or emergent conditions are allowed.
  13. Signed informed consent by patient and permitted prior to initiation of any study-specific procedure.

Exclusion Criteria:

  1. Failure to perform screening or baseline examinations.
  2. Hospitalization or change of chronic concomitant medication 1 month prior to or during screening period (apart from pre-planned hospitalization for a condition, which did not deteriorate since 1 month prior to screening period).
  3. Clinical, laboratory or neuroimaging findings consistent with:

    • other primary degenerative diseases such as Parkinson's disease; dementia with Lewy bodies; corticobasal degeneration; frontotemporal dementia; multiple system atrophy; parkinsonism-dementia complex of Guam, Kii or Guadeloupe; Alzheimer's disease; amyotrophic lateral sclerosis; Creutzfeldt-Jakob Disease; Huntington's disease; Down's syndrome; etc.
    • cerebrovascular disease as major, strategic or multilacunar infarcts, or extensive white matter lesions scoring 3 in the Wahlund's scale [Wahlund et al., 2001].
    • other central nervous system diseases (hydrocephalus, severe head trauma, tumours, subdural haematoma or other relevant space occupying processes, etc.).
    • epilepsy.
    • other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, clinically significant serum electrolyte disturbances, juvenile onset diabetes mellitus, etc.).
  4. A current Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnosis of active major depression, schizophrenia or bipolar disorder.
  5. Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, may bias clinical or mental assessment or put patient at special risk, such as:

    • chronic liver disease, as indicated by liver function test abnormalities (ALAT, ASAT, bilirubin or GGT out of range) positive serology for Hepatitis C, or other manifestations of liver disease
    • respiratory insufficiency
    • renal insufficiency (serum creatinine >2 mg/dL (>150 micromol/L) and creatinine clearance <60 (according to Cockcroft-Gault formula)
    • heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within 6 months before screening).
    • bradycardia (heart beat <50/min) or tachycardia (heart beat >95/min)
    • episodes of unstable or uncontrolled hypertension (systolic pressure >160 mm Hg or diastolic pressure >100 mm Hg) or hypotension (systolic pressure <90 mm Hg or diastolic pressure <45 mm Hg) during 2 months prior to Baseline visit.
    • atrioventricular block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF interval (males >450 msec and females >470 msec using Fridericia's formula: QTc = QT/cube root of RR).
    • uncontrolled diabetes mellitus.
    • malignant tumors within last 5 years except skin malignancies (other than melanoma) or indolent prostate cancer.
    • metastases.
  6. Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, and severe language difficulty).
  7. Chronic daily drug intake of:

    • drugs metabolized by cytochrome P450 (CYP)3A4 with narrow therapeutic window (acenocoumarol, warfarin, and digitoxin)
    • anticonvulsants indicated for epileptic seizures
    • systemic anticholinergics with relevant action on central nervous system
    • acetylcholinesterase inhibitors
    • neuroleptics except quetiapine, clozapine or other atypical neuroleptics
    • nootropics such as piracetam, propentofylline, hydergine, vinpocetine, ginkgo biloba, coenzyme Q-10, idebenone and derivatives
    • centrally active anti-hypertensive drugs such as clonidine, alpha methyl dopa, guanidine, and guanfacine
    • systemic cortico-steroids or immunosuppressants
    • systemic nonsteroidal anti-inflammatory agents (except taken as occasional medication per request or acetylsalicylic acid up to 100 mg/day as an antiplatelet agent).
    • memantine, lithium, valproic acid or other GSK-3 inhibitors within 3 months prior to the Baseline visit.
  8. Suspected or known history of drug abuse or excessive alcohol intake*
  9. Suspected or known allergy to any components of study treatments.
  10. Enrollment in another investigational drug study within 3 months before Baseline visit.
  11. Any condition, which in the opinion of Investigator makes patient unsuitable for inclusion or likely to be non-compliant.

    • More than 21 units per week for men and 14 for women; or consumption of more than 8 units in a single episode. 1 unit equals approximately 1 glass of wine, 250 ml of beer or 1 shot (25 ml) of spirit.

Sites / Locations

  • The Parkinson's and Movement Disorder Institute
  • Department of Neurology, David Geffen School of Medicine at UCLA
  • Mayo Clinic Jacksonville
  • University of South Florida 5
  • Division of Movement Disorders, University of Louisville
  • University of Medicine and Dentistry, Robert Wood Johnson Medical School
  • Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson Beelitz
  • Humboldt Universitat Charite, Campus Virchow, Neurologisch
  • Universitatsklinikum Carl-Guslav-Carus, Technische Universitat Dresden, Klinik und Poliklinik fur Neurologie
  • Medizinische Hochschule Hannover, Neurologie 0E 7210
  • Zentrum fur Nervenheilkunde. Klinik fur Neurologie mit Poliklinik.
  • University Hospital Tuebingen,Eberhard-Karls-Universitat, Universitatsklinikum Neurologie
  • Hospital de Cruces
  • Fundació Ace
  • Dpto.neurologia. H. Clinic.
  • Dpt. Neurologia. Hospital Ramón y Cajal.
  • Hospital U. La Paz
  • Hospital Puerta del Hierro
  • Hospital de Donostia
  • Hospital Mutua Terrassa
  • Departement of Neurology, Hospital La Fe
  • The Walton Centre for Neurology and Neurosurgery NHS Trust
  • Reta Lila Weston Institute of Neurological Studies,Sara Koe PSP Research Centre
  • Clinical Ageing Research Unit

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Experimental

Arm Label

Placebo

NP031112 800 mg

NP031112 600 mg

Arm Description

once daily administration of powder for oral suspension.

Group dosed with 800 mg once daily for 52 weeks

Group treated with 600 mg once daily for 52 weeks

Outcomes

Primary Outcome Measures

The change from Baseline between the 2 active study medication groups compared with the placebo group in the Progressive Supranuclear Palsy Rating Scale of Golbe

Secondary Outcome Measures

Number of AEs and patients with an incidence rate of ≥ 5% AEs
Change from Baseline between 2 active study medication groups vs placebo group in Modified Schwab and England Scale
Change from Baseline between 2 active study medication groups vs placebo group in Timed Up and Go Test (quantitative motor function)
Change from Baseline between 2 active study medication groups vs placebo group in cognitive function(Dementia Rating Scale-2,Frontal Assessment Battery,category and letter verbal fluency)
Change from Baseline between 2 active study medication groups vs placebo group in Starkstein Apathy Scale (behavior)
Change from Baseline between 2 active study medication groups vs placebo group in functional assessments(Unified Parkinson Disease rating Scale part II and European Quality of Life questionnaire)
Change from Baseline between 2 active study medication groups vs placebo group in Clinical Global Impression of Change
Change from Baseline between 2 active study medication groups vs placebo group in Clinical Global Impression of Severity

Full Information

First Posted
January 13, 2010
Last Updated
January 2, 2012
Sponsor
Noscira SA
Collaborators
i3 Research
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1. Study Identification

Unique Protocol Identification Number
NCT01049399
Brief Title
Safety, Tolerability, and Efficacy of Two Different Oral Doses of NP031112 Versus Placebo in the Treatment of Patients With Mild-to-Moderate Progressive Supranuclear Palsy
Acronym
Tauros
Official Title
A Double-Blind, Placebo-Controlled, Randomized, Parallel-Group Study Evaluating the Safety, Tolerability, and Efficacy of Two Different Oral Doses of NP031112, a GSK-3 Inhibitor, Versus Placebo in the Treatment of Patients With Mild-to-Moderate Progressive Supranuclear Palsy
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Completed
Study Start Date
December 2009 (undefined)
Primary Completion Date
September 2011 (Actual)
Study Completion Date
November 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Noscira SA
Collaborators
i3 Research

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine wether NP031112 is safe and effective in the treatment of mild to moderate Progressive Supranuclear Palsy

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Progressive Supranuclear Palsy

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
146 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
once daily administration of powder for oral suspension.
Arm Title
NP031112 800 mg
Arm Type
Experimental
Arm Description
Group dosed with 800 mg once daily for 52 weeks
Arm Title
NP031112 600 mg
Arm Type
Experimental
Arm Description
Group treated with 600 mg once daily for 52 weeks
Intervention Type
Drug
Intervention Name(s)
tideglusib
Other Intervention Name(s)
NP031112
Intervention Description
800 mg of tideglusib as a powder for oral suspension once daily in fasting conditions for 52 weeks
Intervention Type
Drug
Intervention Name(s)
tideglusib
Other Intervention Name(s)
NP031112
Intervention Description
600 mg of tideglusib as a powder for oral suspension, administered once daily in fasting conditions for 52 weeks
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
powder for oral suspension administered once daily in fasting conditions for 52 weeks
Primary Outcome Measure Information:
Title
The change from Baseline between the 2 active study medication groups compared with the placebo group in the Progressive Supranuclear Palsy Rating Scale of Golbe
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
Number of AEs and patients with an incidence rate of ≥ 5% AEs
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in Modified Schwab and England Scale
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in Timed Up and Go Test (quantitative motor function)
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in cognitive function(Dementia Rating Scale-2,Frontal Assessment Battery,category and letter verbal fluency)
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in Starkstein Apathy Scale (behavior)
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in functional assessments(Unified Parkinson Disease rating Scale part II and European Quality of Life questionnaire)
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in Clinical Global Impression of Change
Time Frame
52 weeks
Title
Change from Baseline between 2 active study medication groups vs placebo group in Clinical Global Impression of Severity
Time Frame
52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women with diagnosis of possible or probable PSP according to clinical criteria of National Institute of Neurologic Diseases and Stroke - the Society for PSP (Appendix 1). Age of 40 to 85 years (patients over 85 years could be included after previous assessment by Investigator and approved by sponsor). Brain magnetic resonance imaging (MRI) study within 24 months before Baseline visit excluding other potential causes of parkinsonism, especially cerebrovascular lesions and space occupying lesions. Mild-to-moderate stage of disease severity according to score of 1 to 4 in Golbe Staging System.(Appendix 2) Female patients must be surgically sterilized; at least 1 year postmenopausal (confirmed by follicle-stimulating hormone [FSH] >20 international units [IUs]); using adequate birth control (implants, injectables, combined oral contraceptives, intrauterine contraceptive device, total sexual abstinence during the study or vasectomised partner). Male patients must be willing to use barrier contraception (condom) during the study and for 6 months after last treatment administration. In European arms of study female patients must be without childbearing potential. Caregiver (or dedicated nurse) living in same household or interacting with patient for >4 hours every day able to assure correct preparation and administration of study drug. Patients living at home or in retirement home not requiring continuous nursing care. General health status acceptable for participation in 64-week clinical trial. Ability to swallow 100 mL of water suspension. Any concomitant medication for PSP must be well-tolerated and unchanged for at least 1 month prior to Baseline visit and its dose and regimen should be maintained during study if there are no clinical reasons to modify it. Occupational, physical, respiratory, or speech therapy is allowed but it must be stable for at least 1 month prior to screening. Pharmacological treatment of any other chronic condition must be stable and well-tolerated for at least 1 month prior to screening. Analgesics, occasional per request nonsteroidal anti-inflammatory agents, and treatments for transient or emergent conditions are allowed. Signed informed consent by patient and permitted prior to initiation of any study-specific procedure. Exclusion Criteria: Failure to perform screening or baseline examinations. Hospitalization or change of chronic concomitant medication 1 month prior to or during screening period (apart from pre-planned hospitalization for a condition, which did not deteriorate since 1 month prior to screening period). Clinical, laboratory or neuroimaging findings consistent with: other primary degenerative diseases such as Parkinson's disease; dementia with Lewy bodies; corticobasal degeneration; frontotemporal dementia; multiple system atrophy; parkinsonism-dementia complex of Guam, Kii or Guadeloupe; Alzheimer's disease; amyotrophic lateral sclerosis; Creutzfeldt-Jakob Disease; Huntington's disease; Down's syndrome; etc. cerebrovascular disease as major, strategic or multilacunar infarcts, or extensive white matter lesions scoring 3 in the Wahlund's scale [Wahlund et al., 2001]. other central nervous system diseases (hydrocephalus, severe head trauma, tumours, subdural haematoma or other relevant space occupying processes, etc.). epilepsy. other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, clinically significant serum electrolyte disturbances, juvenile onset diabetes mellitus, etc.). A current Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnosis of active major depression, schizophrenia or bipolar disorder. Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, may bias clinical or mental assessment or put patient at special risk, such as: chronic liver disease, as indicated by liver function test abnormalities (ALAT, ASAT, bilirubin or GGT out of range) positive serology for Hepatitis C, or other manifestations of liver disease respiratory insufficiency renal insufficiency (serum creatinine >2 mg/dL (>150 micromol/L) and creatinine clearance <60 (according to Cockcroft-Gault formula) heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within 6 months before screening). bradycardia (heart beat <50/min) or tachycardia (heart beat >95/min) episodes of unstable or uncontrolled hypertension (systolic pressure >160 mm Hg or diastolic pressure >100 mm Hg) or hypotension (systolic pressure <90 mm Hg or diastolic pressure <45 mm Hg) during 2 months prior to Baseline visit. atrioventricular block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF interval (males >450 msec and females >470 msec using Fridericia's formula: QTc = QT/cube root of RR). uncontrolled diabetes mellitus. malignant tumors within last 5 years except skin malignancies (other than melanoma) or indolent prostate cancer. metastases. Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, and severe language difficulty). Chronic daily drug intake of: drugs metabolized by cytochrome P450 (CYP)3A4 with narrow therapeutic window (acenocoumarol, warfarin, and digitoxin) anticonvulsants indicated for epileptic seizures systemic anticholinergics with relevant action on central nervous system acetylcholinesterase inhibitors neuroleptics except quetiapine, clozapine or other atypical neuroleptics nootropics such as piracetam, propentofylline, hydergine, vinpocetine, ginkgo biloba, coenzyme Q-10, idebenone and derivatives centrally active anti-hypertensive drugs such as clonidine, alpha methyl dopa, guanidine, and guanfacine systemic cortico-steroids or immunosuppressants systemic nonsteroidal anti-inflammatory agents (except taken as occasional medication per request or acetylsalicylic acid up to 100 mg/day as an antiplatelet agent). memantine, lithium, valproic acid or other GSK-3 inhibitors within 3 months prior to the Baseline visit. Suspected or known history of drug abuse or excessive alcohol intake* Suspected or known allergy to any components of study treatments. Enrollment in another investigational drug study within 3 months before Baseline visit. Any condition, which in the opinion of Investigator makes patient unsuitable for inclusion or likely to be non-compliant. More than 21 units per week for men and 14 for women; or consumption of more than 8 units in a single episode. 1 unit equals approximately 1 glass of wine, 250 ml of beer or 1 shot (25 ml) of spirit.
Facility Information:
Facility Name
The Parkinson's and Movement Disorder Institute
City
Fountain Valley
State/Province
California
ZIP/Postal Code
92708
Country
United States
Facility Name
Department of Neurology, David Geffen School of Medicine at UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Mayo Clinic Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
University of South Florida 5
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Division of Movement Disorders, University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
University of Medicine and Dentistry, Robert Wood Johnson Medical School
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
Facility Name
Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson Beelitz
City
Beelitz-Heilstätten
ZIP/Postal Code
14547
Country
Germany
Facility Name
Humboldt Universitat Charite, Campus Virchow, Neurologisch
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Universitatsklinikum Carl-Guslav-Carus, Technische Universitat Dresden, Klinik und Poliklinik fur Neurologie
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Medizinische Hochschule Hannover, Neurologie 0E 7210
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Zentrum fur Nervenheilkunde. Klinik fur Neurologie mit Poliklinik.
City
Marburg
ZIP/Postal Code
35039
Country
Germany
Facility Name
University Hospital Tuebingen,Eberhard-Karls-Universitat, Universitatsklinikum Neurologie
City
Tubingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Hospital de Cruces
City
Barakaldo
ZIP/Postal Code
48902
Country
Spain
Facility Name
Fundació Ace
City
Barcelona
ZIP/Postal Code
08014
Country
Spain
Facility Name
Dpto.neurologia. H. Clinic.
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Dpt. Neurologia. Hospital Ramón y Cajal.
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital U. La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Puerta del Hierro
City
Madrid
ZIP/Postal Code
28222
Country
Spain
Facility Name
Hospital de Donostia
City
San Sebastian
ZIP/Postal Code
20014
Country
Spain
Facility Name
Hospital Mutua Terrassa
City
Terrasa
ZIP/Postal Code
8221
Country
Spain
Facility Name
Departement of Neurology, Hospital La Fe
City
Valencia
ZIP/Postal Code
460009
Country
Spain
Facility Name
The Walton Centre for Neurology and Neurosurgery NHS Trust
City
Liverpool
ZIP/Postal Code
L9 7LJ
Country
United Kingdom
Facility Name
Reta Lila Weston Institute of Neurological Studies,Sara Koe PSP Research Centre
City
London
ZIP/Postal Code
WC1N 1PJ
Country
United Kingdom
Facility Name
Clinical Ageing Research Unit
City
Newcastle upon Tyne
ZIP/Postal Code
NE4 5PL
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
28436538
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.
Results Reference
derived

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Safety, Tolerability, and Efficacy of Two Different Oral Doses of NP031112 Versus Placebo in the Treatment of Patients With Mild-to-Moderate Progressive Supranuclear Palsy

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