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

Progressive Supranuclear Palsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02422485
• Other study ID #: Salsalate PSP
• Status: Completed
• Phase: Phase 1
• Start date: April 2015
• Est. completion date: December 2019

Study information

• Verified date: March 2021
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Progressive Supranuclear Palsy
• Supranuclear Palsy, Progressive

Intervention

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.

Locations

Country	Name	City	State
United States	OHSU Parkinson Center & Movement Disorder Program	Portland	Oregon
United States	University of California, San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Adam Boxer

Country where clinical trial is conducted

United States, 

References & Publications (27)

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in concentration of cerebrospinal fluid (CSF) biomarkers	Changes in the concentrations of cerebrospinal fluid (CSF) biomarkers	6 months
Other	Changes in brain volume	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)]	6 months
Other	Changes in motor function, cognition, activities of daily living, and behavior	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.	6 months
Other	Changes in saccade eye movements	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;	6 months
Other	Changes in sleep and activity levels	Changes in actigraphic measures	6 months
Primary	Number of patients experiencing drug limiting toxicity (DLT),	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.	6 months
Secondary	Changes in motor function	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.	6 months
Secondary	Changes in cognition	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.	6 months
Secondary	Changes in activities of daily living	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.	6 months
Secondary	Changes in behavior	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.	6 months