- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04253132
Evaluation of Tolfenamic Acid in Individuals With PSP at 12-Weeks
January 31, 2020 updated by: Zoltan Mari, MD, NeuroTau, Inc.
A Phase 2a Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Tolfenamic Acid for the Treatment of Progressive Supranuclear Palsy
This is a 12-week study of oral tolfenamic acid vs. placebo in Progressive Supranuclear Palsy (PSP)
Study Overview
Status
Unknown
Conditions
Intervention / Treatment
Detailed Description
This is a 12-week, Phase 2a randomized, double-blind, placebo-controlled, parallel group study evaluating the safety and efficacy of tolfenamic acid (50 mg, 300 mg, and 600 mg daily) compared with placebo administered to subjects with PSP.
The study will include 8 visits and a final telephone contact: screening (Week -6: Visit 1), randomization (7 to 10 days prior to Week 0: visit 2), treatment (Week 0 through Week 12: Visits 2 - 6), end of study Week 12: Visit 7), and telephone contact (Visit 8).
Lumbar puncture will be obtained from consenting subjects at screening (Week -6: visit 10 and End of Study (Week 12: Visit 7) to primary exploratory biomarkers.
Study Type
Interventional
Enrollment (Anticipated)
24
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Zoltan Mari, MD
- Phone Number: 702 483-6000
- Email: mariz@ccf.org
Study Locations
-
-
Nevada
-
Las Vegas, Nevada, United States, 89106
- Lou Ruvo Center for Brain Health - Cleveland Clinic Nevada
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
40 years to 85 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
Subjects may be included in the study only if they meet all of the following criteria:
- Probable or possible progressive supranuclear palsy 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 (Visit 1), 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 (Visit 1).
- 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. This modified Hachinski will not include the focal neurological signs, symptoms or pseuodobulbar 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 (Visit 1), 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 the 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 (Visit 1).
- 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 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:
- Insufficient fluency in local language to complete neuropsychological and functional assessments.
- A diagnosis of Amyotrophic Lateral Sclerosis (ALS) 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 (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 (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 (Visit 1).
- 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.
- 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 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.
- 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 B12 below the laboratory normal reference range, or thyroid stimulating hormone (TSH) above the 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 (Visit 1).
- Abnormal ECG tracing at screening (Visit 1) and judged to be clinically significant by the site investigator.
- Treatment with any investigational drugs or device within 90 days of screening (Visit 1).
- 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 surgery other than sham surgery for deep brain stimulation (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 (CRO) 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 the MRI examination for any reason (e.g., severe claustrophobia, ferromagnetic metal in body).
- Structural abnormality on the 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 (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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: 50 mg daily oral dose
50 mg daily, oral dose of tolfenamic acid
|
Tolfenamic acid is an NSAID closely resembling mefenamic and flufenamic acid.
Other Names:
|
Active Comparator: 300 mg daily oral dose
300 mg daily, oral dose of tolfenamic acid
|
Tolfenamic acid is an NSAID closely resembling mefenamic and flufenamic acid.
Other Names:
|
Active Comparator: 600 mg daily oral dose
50 mg daily, oral dose of tolfenamic acid
|
Tolfenamic acid is an NSAID closely resembling mefenamic and flufenamic acid.
Other Names:
|
Placebo Comparator: Placebo control - 50 mg daily oral dose
50 mg daily oral placebo control
|
oral placebo
Other Names:
|
Placebo Comparator: Placebo control - 300 mg daily oral dose
300 mg daily oral placebo control
|
oral placebo
Other Names:
|
Placebo Comparator: Placebo control - 600 mg daily oral dose
600 mg daily oral placebo control
|
oral placebo
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety and tolerance of tolfenamic acid in individuals with PSP
Time Frame: 12-weeks
|
Safety measures include: number of AEs, ECG changes, nasal examination and clinical laboratory tests
|
12-weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CSF biomarker change from baseline
Time Frame: 12-weeks
|
total tau, phosphporylated tau, amyloid beta peptide (1-42), NFL, ngrn, pNFH
|
12-weeks
|
Pharmacodynamic parameter of amyloid beta peptide
Time Frame: 12-weeks
|
To measure treatment effect of tolfenamic acid in amyloid beta peptide concentrations in CSF
|
12-weeks
|
Pharmacodynamic parameter of total tau
Time Frame: 12-weeks
|
To measure treatment effect of tolfenamic acid in total tau contcentrations in CSF
|
12-weeks
|
Pharmacodynamic parameter of phosphorylated tau
Time Frame: 12-weeks
|
To measure treatment effect of tolfenamic acid in phosphorylated tau concentrations in CSF
|
12-weeks
|
Pharmacodynamic parameter of NFL
Time Frame: 12-weeks
|
To measure treatment effect of tolfenamic acid in NFL concentrations in CSF
|
12-weeks
|
Pharmacodynamic parameter of ngrn
Time Frame: 12-weeks
|
To measure treatment effect of tolfenamic acid in ngrn concentrations in CSF
|
12-weeks
|
Pharmacodynamic parameter of pNFH
Time Frame: 12-weeks
|
To measure treatment effect of tolfenamic acid in pNFH concentrations in CSF concentrations
|
12-weeks
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinical global Impression of Change
Time Frame: 12-weeks
|
Impression of change - CGI-C
|
12-weeks
|
Progressive Supranuclear Pallsy Rating Scale (PSPRS)
Time Frame: 12-weeks
|
Change from baseline in disease severity.
Higher values represent an increase in severity
|
12-weeks
|
Schwab and England Activities of Daily Living Scale (SEADL)
Time Frame: 12-weeks
|
Change from baseline in ability to preform activities of daily living using a scale of 0 to 100 with 100 indicating total independance.
|
12-weeks
|
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Time Frame: 12-weeks
|
Change from baseline measurement of cognitive function.
Higher scores indicate better performance.
|
12-weeks
|
Phonemic Fluency
Time Frame: 12-weeks
|
Change from baseline in Phonemic Fluency with higher score indicating a better health state
|
12-weeks
|
Color Trails Test
Time Frame: 12-weeks
|
Change from baseline in Color Trails Test with lower score indicating a better.
health state
|
12-weeks
|
Letter-number sequencing
Time Frame: 12-weeks
|
Change from baseline in Letter-Number Sequencing with a higher score indicating a better health state
|
12-weeks
|
Clinical Global Impression of Disease Severity (CGI-ds)
Time Frame: 12-weeks
|
Change from baseline in disease severity.
Lower scores are associated with better health.
|
12-weeks
|
Geriatric Depression Scale (GDS)
Time Frame: 12-weeks
|
Depression measurement of change from baseline with a higher score indicating depressive symptoms.
|
12-weeks
|
Plasma biomarkers
Time Frame: 12-weeks
|
Tau, ngrn, NFL, pNFH, AB42
|
12-weeks
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Study Director: Nasser Zawia, PhD, NeuroTau, Inc.
- Study Director: Marwan Sabbagh, MD, NeuroTau, Inc.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Anticipated)
January 1, 2021
Primary Completion (Anticipated)
December 31, 2022
Study Completion (Anticipated)
December 31, 2022
Study Registration Dates
First Submitted
December 17, 2019
First Submitted That Met QC Criteria
January 31, 2020
First Posted (Actual)
February 5, 2020
Study Record Updates
Last Update Posted (Actual)
February 5, 2020
Last Update Submitted That Met QC Criteria
January 31, 2020
Last Verified
January 1, 2020
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Eye Diseases
- Neurologic Manifestations
- Basal Ganglia Diseases
- Movement Disorders
- Neurodegenerative Diseases
- Tauopathies
- Cranial Nerve Diseases
- Ocular Motility Disorders
- Paralysis
- Ophthalmoplegia
- Supranuclear Palsy, Progressive
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Membrane Transport Modulators
- Serotonin Agents
- Serotonin Antagonists
- Hormone Antagonists
- Calcium-Regulating Hormones and Agents
- Calcium Channel Blockers
- Prostaglandin Antagonists
- Tolfenamic acid
Other Study ID Numbers
- NT 101-201
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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