Riluzole in Mild Alzheimer's Disease

• Sponsor: Icahn School of Medicine at Mount Sinai (Other)
• Overall Status: Completed
• CT.gov ID: NCT01703117
• Collaborator: Rockefeller University (Other)
• Enrollment: 50
• Locations: 2
• Arms: 2
• Actual Duration (Months): 78.8
• Patients Per Site: 25
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Cognitive aging is a major source of disability in an increasingly aging population. The paucity of effective treatments for cognitive aging disorders, and most importantly in Alzheimer's disease instigates a need for further research into novel therapeutic possibilities. Alzheimer's disease is the most common neurodegenerative disorder and its prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders and in particular in Alzheimer's disease has been shown to cause significant cerebral damage. Early effective therapeutic intervention in Alzheimer's disease is critical in order to prevent or at least slow down neuropathological progression that will lead to widespread irreversible neuronal loss and significant cognitive dysfunction. Riluzole, a glutamate modulator agent, will be tested in mild Alzheimer's disease patients. Cognitive functional changes along with two established in vivo biomarkers, namely, Magnetic Resonance Spectroscopy (MRS) and Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) will be evaluated.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Riluzole; Drug: Placebo	Phase 2

Detailed Description

A double-blinded, randomized, placebo-controlled study will be performed. Forty-two individuals with a diagnosis of mild Alzheimer's disease between 50-95 years old will complete the study. All forty-two individuals will have been on an acetylcholinesterase inhibitor, which is FDA approved for the treatment of Alzheimer's disease, for at least 2 months prior to initiating the study, unless the medication was not previously tolerated. Twenty to twenty-two mild Alzheimer's disease patients will receive riluzole and another 20-22 will receive a placebo. All patients will have a neurological evaluation and neuropsychological tests performed to confirm that they meet criteria for probable Alzheimer's disease set out by the National Institute on Aging - Alzheimer's disease Association that recently revisited the NINCDS-ADRDA criteria along with FDG-PET biomarker consistent with Alzheimer's disease.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimer's Disease
• Actual Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: May 26, 2020
• Actual Study Completion Date: May 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: age matched cohort 50-95 years old 20-22 subjects between the ages of 50-95 will receive riluzole	Drug: Riluzole; 20-22 subjects between the ages of 60-85 will receive study drug.; Other Names: no other names
Placebo Comparator: 24 subjects between 50-95 years old 20-22 subjects between 50-95 will receive placebo	Drug: Placebo; 20-22 subjects between the ages of 60-85 will receive placebo; Other Names: no other names

Outcome Measures

Primary Outcome Measures

1. Imaging Biomarkers FDG-PET SUVR in Regions of Interest [Change from baseline to 6 months]

   Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.

2. Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS [Changes from baseline to 6 months]

   N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.

Secondary Outcome Measures

1. Glutamate Levels Measured Through 1H MRS [Change from baseline to 6 months]

   In vivo measurement of glutamate with 1H magnetic resonance spectroscopy (MRS) (a neuroimaging study) in posterior cingulate as a marker of target engagement at three and six months compared to baseline.In vivo brain levels of glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of glutamate and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.

2. Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog) [baseline to 6 months]

   The ADAS comprises two subscales, cognitive and non-cognitive. The Cognitive Subscale (ADAScog) is a psychometric instrument that includes 11 tasks and evaluates memory, attention, reasoning, language, orientation, and praxis, scored from 0 to 70. The full ADAS total is scored by summing the number of errors made on each task on a range from 0 to 150 so that higher scores indicate worse performance.The non-cognitive component was not used in this study. Obtained for correlation with neuroimaging biomarkers.

3. Neuropsychiatry Inventory - NPI [baseline to 6 months]

   NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 0 to 144; Higher scores indicate greater disease severity. Obtained for correlation with neuroimaging

4. ADCS Activities of Daily Living [baseline to 6 months]

   ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Obtained for correlation with neuroimaging

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 95 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female; 50 - 95 years old with mild Alzheimer's disease determined after neurological and neuropsychological evaluation following the National Institute on Aging - Alzheimer's disease Association criteria that recently revisited the NINCDS-ADRDA criteria. For mild Alzheimer's disease, Clinical Dementia Ratings Scale (CDR) should be 0.5 or 1 and Mini Mental State Examination (MMSS) between 19 and 27.

• Must be on donepezil (Aricept®) or rivastigmine (Exelon®) or galantamine (Razadyne®) at a consistent dose for at least 2 months. Patients will be considered for inclusion if they were previously unable to tolerate acetylcholinesterase inhibitors and as a result, are no longer on the medication for at least 2 months.

• Must be fluent in English

• The subject will appoint or have previously appointed a health care proxy specifically designated for research consent and that this be documented.

Exclusion Criteria:

• Severe Alzheimer's disease and other dementias as determined by neuropsychological testing and neurological evaluation.

• Previous riluzole treatment.

• MRI contraindication (severe claustrophobia, metal implants, shunts, pacemaker, joint implants, metal valves).

• Currently taking medications that either have evidence of glutamatergic activity or has previous MRS evidence of effects on brain glutamate levels at the discretion of the PI such as memantine, lamotrigine, lithium, opiates, bupropion, psychostimulants such as amphetamines and methylphenidate, tricyclic antidepressants, benzodiazepines and any other drug that the investigators judge might interfere with the study. (subjects on those medications may still be included in the study however only the values of NAA from MRS will be utilized and not the glutamate measurements).

• Currently a user of the following illicit drugs: cocaine, methylenedioxymethamphetamine (MDMA) ("ecstasy"), heroin and other opioids or has a history of drug or alcohol abuse within the past 5 years.

• Serum creatinine >1.5 times the upper limit of normal.

• Abnormal liver function test (greater than 2 times the upper limit of normal for alanine aminotransferase (ALT) or aspartate aminotransferase (AST); or bilirubin >1.5 times the upper limit of normal.

• History of brain disease including Parkinson's Disease, severe brain trauma, seizures, history of stroke, clinically significant lacunar infarct in a region important for cognition or multiple lacunes or a cortical infarct or focal lesions of clinical significance, multiple sclerosis, mental retardation, normal pressure hydrocephalus, central nervous system (CNS) tumor, Huntington's disease, subdural hematoma or other serious neurological disorder.

• Uncontrolled diabetes mellitus (Hba1c higher than 7) or chronically uncontrolled hypertension.

• Subject must not be taking Namenda® (memantine) for 6-weeks prior to study entrance.

• Currently taking any concomitant hepatotoxic drugs such as allopurinol, methyldopa and sulfasalazine.

• Any unstable serious co-existing medical condition(s) including but not limited to myocardial infarction, coronary artery disease requiring coronary bypass surgery, unstable angina, clinically evident congestive heart failure within 6 months prior to the screening visit.

• Current smoker or user of nicotine-containing products, such as chewing tobacco, nicotine patch or gum for the past 2 months.

• Current untreated major depression defined by Geriatric Depression Scale > 20.

• Participation in any investigational or marketed drug or device trial within 30 days prior to the screening visit.

• Significant neuropsychiatric illnesses such as bipolar disorder, schizophrenia, moderate-severe anxiety, vascular dementia, Creutzfeldt-Jakob dementia, HIV dementia, and dementia in other specified diseases.

• Subjects who have been on donepezil for longer than 5 years.

• Weight> 300 pounds.

• Lactose intolerance.

• Any medical or social condition that, in the opinion of the Investigator, might pose additional risk to the participant or confound the results of the study.

• Positive Hepatitis Serology (Hep. B antigen+ or Hep. C antibody+)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
2	The Rockefeller University	New York	New York	United States	10065

Sponsors and Collaborators

• Icahn School of Medicine at Mount Sinai
• Rockefeller University

Investigators

• Principal Investigator: Ana Pereira, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 18, 2020

More Information

Publications

None provided.

• Responsible Party: Ana Pereira, Principal Investigator; Assistant Professor of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01703117
• Other Study ID Numbers: GCO 18-0623; APE-0792
• First Posted: Oct 10, 2012
• Last Update Posted: Sep 22, 2021
• Last Verified: Jul 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Ana Pereira, Principal Investigator; Assistant Professor of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai: Alzheimer's Disease; Dementia
• Additional relevant MeSH terms: Alzheimer Disease; Riluzole

Study Results

Participant Flow

Arm/Group Title	Riluzole	Placebo
Arm/Group Description	Riluzole 50mg twice a day	Matching placebo twice a day
Period Title: Overall Study
STARTED	26	24
COMPLETED	22	20
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Placebo	Riluzole	Total
Arm/Group Description	Matching placebo twice a day	Riluzole 50mg twice a day	Total of all reporting groups
Overall Participants	20	22	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.6 (7.7)	75.3 (5.8)	74.98 (6.7)
Sex: Female, Male (Count of Participants)
Female	14 70%	12 54.5%	26 61.9%
Male	6 30%	10 45.5%	16 38.1%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	0 0%	1 4.5%	1 2.4%
Black/non-Hispanic	1 5%	0 0%	1 2.4%
Latino/Hispanic	0 0%	1 4.5%	1 2.4%
White/non-Hispanic	19 95%	20 90.9%	39 92.9%
Education (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.1 (3.1)	15.9 (3.0)	15.5 (3.0)

Outcome Measures

1. Primary Outcome

Title	Imaging Biomarkers FDG-PET SUVR in Regions of Interest
Description	Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.
Time Frame	Change from baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Riluzole
Arm/Group Description	Matching placebo twice a day	Riluzole 50mg twice a day
Measure Participants	20	22
Posterior cingulate	-0.048 (0.035)	-0.005 (0.035)
Precuneus	-0.032 (0.028)	-0.007 (0.032)
Temporal	-0.023 (0.033)	0.002 (0.029)
Frontal	-0.129 (0.066)	-0.077 (0.072)
Parietal	-0.020 (0.027)	-0.005 (0.024)
Hippocampus	-0.018 (0.034)	-0.002 (0.029)
Right Hippocampus	-0.021 (0.036)	0.002 (0.027)
AD Progression score	0.579 (0.607)	0.245 (0.558)
Post Cing - Precuneus	-0.041 (0.042)	-0.006 (0.038)
Orbitofrontal	-0.019 (0.044)	0.014 (0.036)

2. Primary Outcome

Title	Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS
Description	N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.
Time Frame	Changes from baseline to 6 months

Outcome Measure Data

Analysis Population Description

Some participants could not complete MRS study due to multiple reasons (eg could not tolerate lengthy exam, did not return to visit etc) or did complete it but quality control of the MRS spectra did not pass screening criteria for analysis.

Arm/Group Title	Riluzole	Placebo
Arm/Group Description	Riluzole 50mg twice a day	Matching placebo twice a day
Measure Participants	19	19
BASELINE (NAA/W)	0.3843874 (0.0815156)	0.4274546 (0.0684472)
3 MONTHS (NAA/W)	0.3996655 (0.0927727)	0.4248429 (0.0774599)
6 MONTHS (NAA/W)	0.3784181 (0.0758756)	0.4415926 (0.1039630)
BASELINE (NAA/tCr)	1.4488809 (0.1731644)	1.4802620 (0.1412636)
3 MONTHS (NAA/tCr)	1.4271889 (0.1140340)	1.4766125 (0.1304353)
6 MONTHS (NAA/tCr)	1.4594796 (0.1458860)	1.4811814 (0.1474927)

3. Secondary Outcome

Title	Glutamate Levels Measured Through 1H MRS
Description	In vivo measurement of glutamate with 1H magnetic resonance spectroscopy (MRS) (a neuroimaging study) in posterior cingulate as a marker of target engagement at three and six months compared to baseline.In vivo brain levels of glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of glutamate and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.
Time Frame	Change from baseline to 6 months

Outcome Measure Data

Analysis Population Description

Some participants could not complete MRS study due to multiple reasons (eg could not tolerate lengthy exam, did not return to visit etc) or did complete it but quality control of the MRS spectra did not pass screening criteria for analysis.

Arm/Group Title	Riluzole	Placebo
Arm/Group Description	Riluzole 50mg twice a day	Matching placebo twice a day
Measure Participants	19	19
BASELINE (Glu/W)	0.0598059 (0.0164069)	0.0677906 (0.0133271)
3 MONTHS (Glu/W)	0.0579899 (0.0181040)	0.0646162 (0.0107094)
6 MONTHS (Glu/W)	0.0609985 (0.0156960)	0.0633453 (0.0147764)
BASELINE (Glu/tCr)	0.2280186 (0.0543718)	0.2367567 (0.0484442)
3 MONTHS (Glu/tCr)	0.2080647 (0.0515160)	0.2285644 (0.0441709)
6 MONTHS (Glu/tCr)	0.2339366 (0.0370164)	0.2162526 (0.0426140)

4. Secondary Outcome

Title	Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)
Description	The ADAS comprises two subscales, cognitive and non-cognitive. The Cognitive Subscale (ADAScog) is a psychometric instrument that includes 11 tasks and evaluates memory, attention, reasoning, language, orientation, and praxis, scored from 0 to 70. The full ADAS total is scored by summing the number of errors made on each task on a range from 0 to 150 so that higher scores indicate worse performance.The non-cognitive component was not used in this study. Obtained for correlation with neuroimaging biomarkers.
Time Frame	baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riluzole	Placebo
Arm/Group Description	Riluzole 50mg twice a day	Matching placebo twice a day
Measure Participants	22	20
BASELINE	22.4981818 (7.8875264)	17.9005000 (7.4614719)
6 MONTHS	21.8022727 (9.7334313)	18.8495000 (9.2608983)

5. Secondary Outcome

Title	Neuropsychiatry Inventory - NPI
Description	NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 0 to 144; Higher scores indicate greater disease severity. Obtained for correlation with neuroimaging
Time Frame	baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riluzole	Placebo
Arm/Group Description	Riluzole 50mg twice a day	Matching placebo twice a day
Measure Participants	22	20
BASELINE	9.6363636 (9.1627894)	10.2000000 (11.1383642)
6 MONTHS	9.0909091 (6.6254135)	14.0500000 (12.8082005)

6. Secondary Outcome

Title	ADCS Activities of Daily Living
Description	ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Obtained for correlation with neuroimaging
Time Frame	baseline to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riluzole	Placebo
Arm/Group Description	Riluzole 50mg twice a day	Matching placebo twice a day
Measure Participants	22	20
BASELINE	68.3636364 (9.5096215)	68.0500000 (9.3215935)
6 MONTHS	65.5000000 (11.5377228)	64.3000000 (10.7757037)

Adverse Events

Time Frame	6 months
Arm/Group Title	Riluzole		Placebo
Arm/Group Description	Riluzole 50mg twice a day		Matching placebo twice a day
All Cause Mortality
	Riluzole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/24 (0%)
Serious Adverse Events
	Riluzole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/26 (7.7%)		1/24 (4.2%)
Blood and lymphatic system disorders
Blood disorder	1/26 (3.8%)	1	0/24 (0%)	0
Cardiac disorders
Cardiac	0/26 (0%)	0	1/24 (4.2%)	1
Gastrointestinal disorders
GI	1/26 (3.8%)	1	0/24 (0%)	0
Other (Not Including Serious) Adverse Events
	Riluzole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/26 (80.8%)		21/24 (87.5%)
Gastrointestinal disorders
Abdominal discomfort	4/26 (15.4%)		0/24 (0%)
Diarrhea	4/26 (15.4%)		2/24 (8.3%)
Nausea	2/26 (7.7%)		0/24 (0%)
General disorders
Dizziness	4/26 (15.4%)		1/24 (4.2%)
Fatigue	1/26 (3.8%)		2/24 (8.3%)
Somnolence	0/26 (0%)		3/24 (12.5%)
Hepatobiliary disorders
Elevated liver enzymes	2/26 (7.7%)		1/24 (4.2%)
Musculoskeletal and connective tissue disorders
Back Pain	2/26 (7.7%)		2/24 (8.3%)
Psychiatric disorders
Anxiety	2/26 (7.7%)		4/24 (16.7%)
Paranoia	1/26 (3.8%)		3/24 (12.5%)
Renal and urinary disorders
Urinary frequency	3/26 (11.5%)		0/24 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	5/26 (19.2%)		3/24 (12.5%)
Skin and subcutaneous tissue disorders
Rash	1/26 (3.8%)		2/24 (8.3%)

Limitations/Caveats

1.Sample size was relatively small, and results require replication in larger-sample studies. 2.lack of amyloid characterization. 3.MRS is unable to differentiate neurotransmitter or vesicular and metabolic pools of glutamate. Longitudinal MRS measurements can be subject to technical variability and head motion. 4. the study was not powered for neuropsychological outcome and clinical changes must be viewed only as directional/exploratory.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.