A 6 Month, Open-Label, Pilot Futility Clinical Trial of Oral Salsalate for Progressive Supranuclear Palsy
Primary Purpose
Progressive Supranuclear Palsy
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Salsalate
Sponsored by
About this trial
This is an interventional treatment trial for Progressive Supranuclear Palsy focused on measuring Salsalate
Eligibility Criteria
Inclusion Criteria:
- 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)
- Aged 50-85
- Agrees to 3 magnetic resonance imaging (MRI) or subject to investigator's discretion
- MRI at screening is consistent with PSP (≤4 microhemorrhages and no large strokes or severe white matter disease)
- Mini-Mental State Examination (MMSE) score 14-30
- Stable medications for 2 months prior to screening, including FDA approved Alzheimer's disease (AD) medications and Parkinson's disease medications
- 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
- Agrees to 2 lumbar punctures for cerebrospinal fluid (CSF) examination
- Signed and dated written informed consent obtained from the subject and subject's caregiver in accordance with local IRB regulations
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:
- Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD (McKhann et al. 2011);
- Any medical condition other than PSP that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);
- A prominent and sustained response to levodopa therapy;
- History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);
- History of hypertension (repeated elevations in blood pressure exceeding 180 mm Hg systolic or 100 mm Hg diastolic; medical intervention indicated);
- History of severe gastrointestinal bleed, or gastric or peptic ulcers;
- History of aspirin triad (i.e., aspirin allergy, nasal polyps and asthma) or asthma;
- History of major psychiatric illness or untreated depression;
- 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;
- 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;
- Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;
- Current clinically significant viral infection. Subjects with chicken pox, influenza, or flu symptoms are not eligible;
- Major surgery within four weeks prior to Screening;
- 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;
- Treatment with another investigational drug or participation in another interventional clinical trial within 3 months of Screening;
- Chronic use of other NSAIDs or salicylates for any reason, except for daily baby aspirin (81 mg);
- Concurrent treatment with thiazides or loop diuretics;
- Concurrent use of oral corticosteroids or angiotensin-converting enzyme (ACE) inhibitors;
- Treatment with any human blood product, including intravenous immunoglobulin, during the 6 months prior to Screening or during the trial;
- Known hypersensitivity to the inactive ingredients in the study drug;
- Pregnant or lactating;
- Positive pregnancy test at Screening or Baseline (Day 1);
- 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.
Sites / Locations
- University of California, San Francisco
- OHSU Parkinson Center & Movement Disorder Program
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Salsalate
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02422485
Brief Title
A 6 Month, Open-Label, Pilot Futility Clinical Trial of Oral Salsalate for Progressive Supranuclear Palsy
Official Title
A 6 Month, Open-Label, Pilot Futility Clinical Trial of Oral Salsalate for Progressive Supranuclear Palsy
Study Type
Interventional
2. Study Status
Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
April 2015 (undefined)
Primary Completion Date
December 2019 (Actual)
Study Completion Date
December 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Adam Boxer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Progressive Supranuclear Palsy
Keywords
Salsalate
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Salsalate
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Salsalate
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of patients experiencing drug limiting toxicity (DLT),
Description
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Changes in motor function
Description
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.
Time Frame
6 months
Title
Changes in cognition
Description
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.
Time Frame
6 months
Title
Changes in activities of daily living
Description
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.
Time Frame
6 months
Title
Changes in behavior
Description
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.
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Changes in concentration of cerebrospinal fluid (CSF) biomarkers
Description
Changes in the concentrations of cerebrospinal fluid (CSF) biomarkers
Time Frame
6 months
Title
Changes in brain volume
Description
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)]
Time Frame
6 months
Title
Changes in motor function, cognition, activities of daily living, and behavior
Description
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.
Time Frame
6 months
Title
Changes in saccade eye movements
Description
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;
Time Frame
6 months
Title
Changes in sleep and activity levels
Description
Changes in actigraphic measures
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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)
Aged 50-85
Agrees to 3 magnetic resonance imaging (MRI) or subject to investigator's discretion
MRI at screening is consistent with PSP (≤4 microhemorrhages and no large strokes or severe white matter disease)
Mini-Mental State Examination (MMSE) score 14-30
Stable medications for 2 months prior to screening, including FDA approved Alzheimer's disease (AD) medications and Parkinson's disease medications
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
Agrees to 2 lumbar punctures for cerebrospinal fluid (CSF) examination
Signed and dated written informed consent obtained from the subject and subject's caregiver in accordance with local IRB regulations
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:
Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD (McKhann et al. 2011);
Any medical condition other than PSP that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);
A prominent and sustained response to levodopa therapy;
History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);
History of hypertension (repeated elevations in blood pressure exceeding 180 mm Hg systolic or 100 mm Hg diastolic; medical intervention indicated);
History of severe gastrointestinal bleed, or gastric or peptic ulcers;
History of aspirin triad (i.e., aspirin allergy, nasal polyps and asthma) or asthma;
History of major psychiatric illness or untreated depression;
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;
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;
Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;
Current clinically significant viral infection. Subjects with chicken pox, influenza, or flu symptoms are not eligible;
Major surgery within four weeks prior to Screening;
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;
Treatment with another investigational drug or participation in another interventional clinical trial within 3 months of Screening;
Chronic use of other NSAIDs or salicylates for any reason, except for daily baby aspirin (81 mg);
Concurrent treatment with thiazides or loop diuretics;
Concurrent use of oral corticosteroids or angiotensin-converting enzyme (ACE) inhibitors;
Treatment with any human blood product, including intravenous immunoglobulin, during the 6 months prior to Screening or during the trial;
Known hypersensitivity to the inactive ingredients in the study drug;
Pregnant or lactating;
Positive pregnancy test at Screening or Baseline (Day 1);
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adam Boxer, MD, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
OHSU Parkinson Center & Movement Disorder Program
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
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A 6 Month, Open-Label, Pilot Futility Clinical Trial of Oral Salsalate for Progressive Supranuclear Palsy
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