A 6 Month, Open-Label, Pilot Futility Clinical Trial of Oral Salsalate for Progressive Supranuclear Palsy

• ClinicalTrials.gov Identifier: NCT02422485
• Recruitment Status: Completed
• First Posted: April 21, 2015
• Last Update Posted: April 1, 2021
• Sponsor: Adam Boxer
• Information provided by (Responsible Party): Adam Boxer, University of California, San Francisco

Study Description

Brief Summary:

This is a multi-center, open label, pilot futility clinical trial of the safety, tolerability, pharmacodynamics and preliminary efficacy of oral salsalate in up to 10 patients with PSP.

Condition or disease	Intervention/treatment	Phase
Progressive Supranuclear Palsy	Drug: Salsalate	Phase 1

Detailed Description:

This is a multi-center, open label, pilot futility clinical trial of the safety, tolerability, pharmacodynamics and preliminary efficacy of oral salsalate in up to 10 patients with PSP. All participants will be administered 2,250 mg daily [1,500 mg every day before noon (every AM) and 750 mg every night at bedtime (every HS)] for 6 months.

If ≥3 patients experience drug limiting toxicity (DLT), as defined below, the study will be terminated.

A DLT is defined as: 1) any Grade 3 or higher adverse event (AE) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) for which there is reasonable possibility that salsalate caused the event, 2) any Grade 2 AE in the CTCAE system organ class of nervous system disorders that is considered clinically significant and for which there is reasonable possibility that salsalate caused the event, or 3) any Grade 2 or higher treatment-related adverse events during administration that do not resolve promptly with supportive treatment.

An interim futility analysis will be performed after five subjects have completed 6 months of study drug treatment. If the criteria listed in the Statistical Methods section of this synopsis are met, an additional 5 subjects will be enrolled in the trial. If not, the trial will be terminated.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 6 Month, Open-Label, Pilot Futility Clinical Trial of Oral Salsalate for Progressive Supranuclear Palsy
• Study Start Date: April 2015
• Actual Primary Completion Date: December 2019
• Actual Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Salsalate; All participants will be administered 2,250 mg daily [1,500 mg every day before noon (every AM) and 750 mg every night at bedtime (every HS)] for 6 months.	Drug: Salsalate; Salsalate is a non-acetylated dimer of salicylic acid, and is classified as a NSAID. The chemical name of salsalate is 2-hydroxy-benzoic acid, 2-carboxyphenyl ester. Salsalate has a molecular weight (MW) of 258.226 Da and a molecular formula of C14H10O5.

Outcome Measures

Primary Outcome Measures :

1. Number of patients experiencing drug limiting toxicity (DLT), [ Time Frame: 6 months ]
   defined as: 1) any Grade 3 or higher adverse event (AE) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) for which there is reasonable possibility that salsalate caused the event, 2) any Grade 2 AE in the CTCAE system organ class of nervous system disorders that is considered clinically significant and for which there is reasonable possibility that salsalate caused the event, or 3) any Grade 2 or higher treatment-related adverse events during administration that do not resolve promptly with supportive treatment.

Secondary Outcome Measures :

1. Changes in motor function [ Time Frame: 6 months ]
   Motor function as measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) comprising 28 items in six categories: daily activities (by history), behavior, bulbar, ocular motor, limb motor and gait/midline The available total score ranges from 0 to 100; lower scores reflect better outcome.
2. Changes in cognition [ Time Frame: 6 months ]
   Cognitive function as measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) comprising 28 items in six categories: daily activities (by history), behavior, bulbar, ocular motor, limb motor and gait/midline The available total score ranges from 0 to 100; lower scores reflect better outcome.
3. Changes in activities of daily living [ Time Frame: 6 months ]
   Activities of daily living as measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) comprising 28 items in six categories: daily activities (by history), behavior, bulbar, ocular motor, limb motor and gait/midline The available total score ranges from 0 to 100; lower scores reflect better outcome.
4. Changes in behavior [ Time Frame: 6 months ]
   Behavior as measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) comprising 28 items in six categories: daily activities (by history), behavior, bulbar, ocular motor, limb motor and gait/midline The available total score ranges from 0 to 100; lower scores reflect better outcome.

Other Outcome Measures:

1. Changes in concentration of cerebrospinal fluid (CSF) biomarkers [ Time Frame: 6 months ]
   Changes in the concentrations of cerebrospinal fluid (CSF) biomarkers
2. Changes in brain volume [ Time Frame: 6 months ]
   Changes in brain volume [T1-weighted volumetric magnetic resonance imaging (vMRI)], brain network functional and structural connectivity and perfusion [resting state functional magnetic resonance imaging (rsfMRI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI)]
3. Changes in motor function, cognition, activities of daily living, and behavior [ Time Frame: 6 months ]
   Motor function, cognition, activities of daily living, and behavior as measured by Schwab and England Activities of Daily Living scale (SEADL), PSP-Quality of Life. Scores range from one hundred percent, which indicates a completely independent individual, and zero percent, which indicates an individual in who is no longer functioning.
4. Changes in saccade eye movements [ Time Frame: 6 months ]
   To explore the effects of 2,250 mg daily salsalate on changes in saccade latency, velocity, and amplitude [infrared oculometry] from Screening to end of month 3 and end of month 6 compared to historical data;
5. Changes in sleep and activity levels [ Time Frame: 6 months ]
   Changes in actigraphic measures

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Meets National Institute of Neurological Disorders and Stroke - Society for Progressive Supranuclear Palsy (NINDS-SPSP) probable or possible PSP criteria,(Litvan 1996a) as modified from the AL-108-231 trial.(Boxer 2014)
2. Aged 50-85
3. Agrees to 3 magnetic resonance imaging (MRI) or subject to investigator's discretion
4. MRI at screening is consistent with PSP (≤4 microhemorrhages and no large strokes or severe white matter disease)
5. Mini-Mental State Examination (MMSE) score 14-30
6. Stable medications for 2 months prior to screening, including FDA approved Alzheimer's disease (AD) medications and Parkinson's disease medications
7. Availability of a study partner who knows the patient well and is willing to accompany the patient to all trial visits and to participate in questionnaires
8. Agrees to 2 lumbar punctures for cerebrospinal fluid (CSF) examination
9. Signed and dated written informed consent obtained from the subject and subject's caregiver in accordance with local IRB regulations

10. Males and all WCBP agree to abstain from sex or use an adequate method of contraception for the duration of the study and for 30 days after the last dose of study drug.

    • Adequate contraceptive methods include those with a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as complete abstinence from sexual intercourse with a potentially fertile partner, and some double barrier methods condom with spermicide) in conjunction with use by the partner of an intrauterine device (IUD), diaphragm with spermicide, oral contraceptives, birth control patch or vaginal ring, oral, or injectable or implanted contraceptives.
    • For this study, a woman who has been surgically sterilized or who has been in a state of amenorrhea for more than two years will be deemed not to be of childbearing potential;

Exclusion Criteria:

1. Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD (McKhann et al. 2011);
2. Any medical condition other than PSP that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);
3. A prominent and sustained response to levodopa therapy;
4. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);
5. History of hypertension (repeated elevations in blood pressure exceeding 180 mm Hg systolic or 100 mm Hg diastolic; medical intervention indicated);
6. History of severe gastrointestinal bleed, or gastric or peptic ulcers;
7. History of aspirin triad (i.e., aspirin allergy, nasal polyps and asthma) or asthma;
8. History of major psychiatric illness or untreated depression;
9. Neutrophil count <1,500/mm3, platelets <100,000/mm3, serum creatinine >1.5 x upper limit of normal (ULN), total bilirubin >1.5 x ULN, alanine aminotransferase (ALT) >3 x ULN, aspartate aminotransferase (AST) >3 x ULN, or INR >1.2 at Screening evaluations;
10. Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of study data;
11. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;
12. Current clinically significant viral infection. Subjects with chicken pox, influenza, or flu symptoms are not eligible;
13. Major surgery within four weeks prior to Screening;
14. Any contraindication to or unable to tolerate lumbar puncture at Screening, including use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to Screening;
15. Treatment with another investigational drug or participation in another interventional clinical trial within 3 months of Screening;
16. Chronic use of other NSAIDs or salicylates for any reason, except for daily baby aspirin (81 mg);
17. Concurrent treatment with thiazides or loop diuretics;
18. Concurrent use of oral corticosteroids or angiotensin-converting enzyme (ACE) inhibitors;
19. Treatment with any human blood product, including intravenous immunoglobulin, during the 6 months prior to Screening or during the trial;
20. Known hypersensitivity to the inactive ingredients in the study drug;
21. Pregnant or lactating;
22. Positive pregnancy test at Screening or Baseline (Day 1);
23. Cancer within 5 years of Screening, except for non-metastatic skin cancer or nonmetastatic prostate cancer not expected to cause significant morbidity or mortality within one year of Baseline.

Contacts and Locations

Locations

United States, California

University of California, San Francisco

San Francisco, California, United States, 94158

United States, Oregon

OHSU Parkinson Center & Movement Disorder Program

Portland, Oregon, United States, 97239

Sponsors and Collaborators

Adam Boxer

Investigators

• Principal Investigator: Adam Boxer, MD, PhD; University of California, San Francisco

More Information

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• Responsible Party: Adam Boxer, MD, PhD, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02422485
• Other Study ID Numbers: Salsalate PSP
• First Posted: April 21, 2015
• Last Update Posted: April 1, 2021
• Last Verified: March 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adam Boxer, University of California, San Francisco:

Salsalate

Additional relevant MeSH terms:

Supranuclear Palsy, Progressive; Paralysis; Neurologic Manifestations; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Ophthalmoplegia; Ocular Motility Disorders; Cranial Nerve Diseases; Tauopathies; Neurodegenerative Diseases; Eye Diseases; Salicylsalicylic acid; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents