Evaluation of Tolfenamic Acid in Individuals With PSP at 12-Weeks

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Brief Title

Evaluation of Tolfenamic Acid in Individuals With PSP at 12-Weeks

Official Title

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

Brief Summary

      This is a 12-week study of oral tolfenamic acid vs. placebo in Progressive Supranuclear Palsy
      (PSP)
    

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 Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Safety and tolerance of tolfenamic acid in individuals with PSP

Secondary Outcome

 CSF biomarker change from baseline

Condition

Progressive Supranuclear Palsy

Intervention

Tolfenamic Acid

Study Arms / Comparison Groups

 50 mg daily oral dose
Description:  50 mg daily, oral dose of tolfenamic acid

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

January 1, 2021

Completion Date

December 31, 2022

Primary Completion Date

December 31, 2022

Eligibility Criteria

        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
      

Gender

All

Ages

40 Years - 85 Years

Accepts Healthy Volunteers

No

Contacts

Nasser Zawia, PhD, 702 483-6000, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04253132

Organization ID

NT 101-201


Responsible Party

Principal Investigator

Study Sponsor

NeuroTau, Inc.

Collaborators

 The Cleveland Clinic

Study Sponsor

Nasser Zawia, PhD, Study Director, NeuroTau, Inc.


Verification Date

January 2020