Anti-Inflammatory Treatment of Schizophrenia

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT01514682
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 2
• Actual Duration (Months): 58.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Despite current antipsychotic treatment, the majority of people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. An alternative approach to the use of psychotropic agents for the treatment of persistent symptoms is the use of anti-inflammatory agents to reverse the pro-inflammatory state hypothesized to underlie the symptom and sign manifestations of the illness.

The investigators primary hypothesis is that add-on anti-inflammatory combination therapy will have significant beneficial effects on persistent positive symptoms and cognitive impairments.

The investigators secondary hypotheses are:

1. add-on anti-inflammatory combination therapy will be associated with improvements in depressive and negative symptoms and a reduction in pro-inflammatory cytokines

2. add-on anti-inflammatory combination therapy compared to placebo will not be associated with elevated adverse risk.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Anti-inflammatory Combination Therapy; Drug: Placebo	N/A

Detailed Description

Schizophrenia has been hypothesized to be due, in part, to disruptions of normal immune system and inflammatory responses to viral or bacterial infections or other stimuli of these systems. Epidemiological and clinical studies have provided extensive evidence that perinatal exposure to infection contributes to the etiology of schizophrenia. The recent reports of associations between markers of single nucleotide polymorphisms located within the major histocompatibility complex on chromosome 6p22.1 and schizophrenia provide further support for etiological hypotheses of immune system dysfunction in schizophrenia.

There are a large number of reports that suggest that people with schizophrenia have altered cytokine levels, with one or more studies reporting elevated levels of the pro-inflammatory cytokines: IL-1β, IL-6, IL-12, CRP, IFN-γ, and TNF-α; and reduced levels of the anti-inflammatory cytokine: IL-10. In this study we examine the use of combination anti-inflammatory therapy as an intervention in patients with schizophrenia. We will use

1. Salsalate, 4 gm/day. Salsalate is a potent inhibitor of nuclear transcription factor NF-κB activation. NF-κB is activated by pro-inflammatory cytokines;

2. Omega-3-fatty acids eicosapentaenoic (EPA; 2 gm/day) and docosahexaenoic (DHA; 2 gm/day). Omega-3-fatty acids exert their anti-inflammatory effects through their oxygenation into resolvins or protectins, which are potent anti-inflammatory agents;

3. Fluvastatin, 40 mgs/day. Fluvastatin is a lipid-lowering drugs, which acts through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA). Fluvastatin may also exert anti-inflammatory effects independent of its lipid-lowering effects via a mechanism involving HMG-CoA inhibition and decreased NF-κB activation.

We have chosen to use combination therapy with three different classes of anti-inflammatory agents to address the potential benefit of this therapeutic approach for persistent positive symptoms and cognitive impairments. The three agents have unique anti-inflammatory mechanisms of action, which we believe offers the most robust evaluation of this therapeutic approach and maximizes the likelihood of eliciting pronounced therapeutic effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia
• Actual Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Apr 17, 2017
• Actual Study Completion Date: Apr 17, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo pills to be assigned using a permuted randomization system	Drug: Placebo; Non-medication pills; To be taken in morning and evening intervals.
Experimental: Anti-inflammatory Combination Therapy Salsalate, statin and omega-3-fatty acid combination therapy	Drug: Anti-inflammatory Combination Therapy; salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening fluvastatin: target dose 40 mg/day, administered in a single evening dose combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose

Outcome Measures

Primary Outcome Measures

1. Change in Persistent Positive Symptoms [The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.]

   The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating.

2. Change in Neuropsychological Test Performance [The MCCB was administered at baseline and end-of-study (Week 12).]

   The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome.

Secondary Outcome Measures

1. Change in Depressive Symptoms [The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.]

   The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. Total score calculated by adding scores for scales #1-#9. Each scale ranges from "0=Absent" to "3=Severe". The minimum total CDS score is 0 and the maximum total CDS score is 27. A higher score indicates a more severe depression rating.

2. Change in Negative Symptoms [Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.]

   The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Median SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms.

3. Change in Pro-inflammatory Cytokines [A cytokine profile will be collected at baseline and at week 12 (end-of-study).]

   Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.

4. Change in C-Reactive Protein (CRP) [A cytokine profile will be collected at baseline and at week 12 (end-of-study).]

   Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants will meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder.

• Participants will be required to meet the following symptom criteria:

1. BPRS total score of 45 or greater on the 18 item version (scale: 1-7) or a Clinical Global Impression (CGI) severity of illness item score of 4 (moderate) or greater.

2. BPRS positive symptom item total score of 8 or greater and a score of 4 or more on at least one individual item.

• Participants will be clinically stable, be treated with the same antipsychotic for at least 60 days and a constant therapeutic dose for at least 30 days prior to study entry.

• Participants must be judged competent to participate in the informed consent process and provide voluntary informed consent

Exclusion Criteria:

• Participants who meet DSM-IV-TR criteria for alcohol or substance dependence (except nicotine) within the last 6 months or DSM-IV-TR criteria for alcohol or substance abuse (except nicotine) within the last month will be excluded

• Participants with a current infection or an organic brain disorder or medical condition, whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol will be excluded.

• Participants with a history of: aspirin allergy, pre-existing tinnitus, tuberculosis, HIV, or hepatitis C; or autoimmune disease.

• Participants who are currently treated with a statin, warfarin, dipyridamole, or other anti-coagulants.

• Participant is currently treated with an omega-3-fatty acid preparation and cannot discontinue their use of the preparation for the duration of the study.

• Female participant who is sexually active and not using any form of birth control such as oral contraceptives or IUDs.

• Female participant who is pregnant or breastfeeding.

• Participant with current/active peptic ulcer disease or gastritis; anemia or thrombocytopenia (platelet count ≤120).

• Participant who is currently treated with a medication that can increase the risk of myopathy and rhabdomyolysis such as Fluconazole, Ketoconazole, Colchicine, Daptomycin, Erythromycin, or immunosuppressants that alter statin levels.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Maryland Psychiatric Research Center	Baltimore	Maryland	United States	21228

Sponsors and Collaborators

• University of Maryland, Baltimore

Investigators

• Principal Investigator: Robert W Buchanan, MD, Maryland Psychiatric Research Center, University of Maryland School of Medicine
• Principal Investigator: William T Carpenter, MD, Maryland Psychiatric Research Center, University of Maryland School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 1, 2016

More Information

Publications

None provided.

• Responsible Party: Robert Buchanan, Chief, Maryland Psychiatric Research Center, Outpatient Research Program, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT01514682
• Other Study ID Numbers: HP-00051603; 11T-002
• First Posted: Jan 23, 2012
• Last Update Posted: Mar 3, 2022
• Last Verified: Mar 1, 2022

• Keywords provided by Robert Buchanan, Chief, Maryland Psychiatric Research Center, Outpatient Research Program, University of Maryland, Baltimore: schizophrenia; anti-inflammatory; salsalate; statins; omega-3-fatty acids
• Additional relevant MeSH terms: Schizophrenia; Anti-Inflammatory Agents

Study Results

Participant Flow

Pre-assignment Detail	Signed a consent form: 52 (50 unique subjects: 2 withdrew then later re-enrolled, not counted in analysis); Ineligible prior to Evaluation Phase: 1 subject (1=clinically unstable); Entered Evaluation Phase: 49 subjects; Withdrawn prior to randomization: 10 (8=Did not meet BPRS criteria; 1=Did not meet age criteria; 1=On an excluded medication)

Arm/Group Title	Anti-inflammatory Combination Therapy	Placebo
Arm/Group Description	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.
Period Title: Overall Study
STARTED	19	20
COMPLETED	13	14
NOT COMPLETED	6	6

Baseline Characteristics

Arm/Group Title	Anti-inflammatory Combination Therapy	Placebo	Total
Arm/Group Description	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Total of all reporting groups
Overall Participants	19	20	39
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	19 100%	20 100%	39 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	6 31.6%	6 30%	12 30.8%
Male	13 68.4%	14 70%	27 69.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	18 90%	18 46.2%
Not Hispanic or Latino	19 100%	1 5%	20 51.3%
Unknown or Not Reported	0 0%	1 5%	1 2.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 5.3%	1 5%	2 5.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 31.6%	9 45%	15 38.5%
White	10 52.6%	9 45%	19 48.7%
More than one race	2 10.5%	1 5%	3 7.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	19 100%	20 100%	39 100%

Outcome Measures

1. Primary Outcome

Title	Change in Persistent Positive Symptoms
Description	The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating.
Time Frame	The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.

Outcome Measure Data

Analysis Population Description

Participants completing the BPRS assessment rating.

Arm/Group Title	Placebo	Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Measure Participants	19	18
Baseline Week 0	13	14
Treatment Week 2	14	14
Treatment Week 4	14	15
Treatment Week 6	14	14
Treatment Week 8	12	14
Treatment Week 10	14	14
Treatment Week 12	14	12

2. Primary Outcome

Title	Change in Neuropsychological Test Performance
Description	The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome.
Time Frame	The MCCB was administered at baseline and end-of-study (Week 12).

Outcome Measure Data

Analysis Population Description

Participants completing the MCCB testing.

Arm/Group Title	Placebo	Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Measure Participants	19	19
Baseline Week 0	25	36
Treatment Week 12	24	26

3. Secondary Outcome

Title	Change in Depressive Symptoms
Description	The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. Total score calculated by adding scores for scales #1-#9. Each scale ranges from "0=Absent" to "3=Severe". The minimum total CDS score is 0 and the maximum total CDS score is 27. A higher score indicates a more severe depression rating.
Time Frame	The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.

Outcome Measure Data

Analysis Population Description

Participants completing the CDS assessment rating.

Arm/Group Title	Placebo	Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Measure Participants	19	19
Baseline Week 0	2	0
Treatment Week 2	2	1
Treatment Week 4	1	1
Treatment Week 6	2	1
Treatment Week 8	2	1
Treatment Week 10	2	0
Treatment Week 12	1	0

4. Secondary Outcome

Title	Change in Negative Symptoms
Description	The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Median SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms.
Time Frame	Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.

Outcome Measure Data

Analysis Population Description

Participants completing the SANS rating assessment.

Arm/Group Title	Placebo	Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Measure Participants	19	19
Baseline Week 0	27	26
Treatment Week 2	28	24
Treatment Week 4	32	30
Treatment Week 6	28	27
Treatment Week 8	30	24
Treatment Week 10	30	30
Treatment Week 12	28	28

5. Secondary Outcome

Title	Change in Pro-inflammatory Cytokines
Description	Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.
Time Frame	A cytokine profile will be collected at baseline and at week 12 (end-of-study).

Outcome Measure Data

Analysis Population Description

Participants who had a cytokine profile collected.

Arm/Group Title	Placebo	Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Measure Participants	19	19
Baseline IL-2 levels	59.16 (88.38)	34.94 (77.01)
End of study IL-2 levels	88.4 (146.0)	47.5 (86.0)
Baseline IL-8 levels	9.16 (5.59)	8.35 (4.59)
End of study IL-8 levels	8.91 (7.24)	19.78 (46.91)

6. Secondary Outcome

Title	Change in C-Reactive Protein (CRP)
Description	Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.
Time Frame	A cytokine profile will be collected at baseline and at week 12 (end-of-study).

Outcome Measure Data

Analysis Population Description

Participants who had a cytokine profile collected.

Arm/Group Title	Placebo	Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.	Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Measure Participants	19	19
Baseline CRP levels	38953 (27218)	42950 (32468)
End of study CRP levels	38759 (21753)	31849 (23176)

Adverse Events

Time Frame	12-week Treatment Phase.
Adverse Event Reporting Description	Participants are systematically monitored for any increases on the Side Effects Checklist (SEC). An SEC AE includes any symptom/side effect rated with a score of 4 (severe) or for which there was a 2 point change in severity from baseline. Psychotic symptoms are also systematically monitored with the Brief Psychiatric Rating Scale (BPRS) rating. A BPRS AE includes an increase of 3 points or more relative to baseline or an increase from a score of 5 (moderately severe) to a 7 (very severe).
Arm/Group Title	Placebo		Anti-inflammatory Combination Therapy
Arm/Group Description	Placebo pills to be assigned using a permuted randomization system Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose Placebo: Non-medication pills; To be taken in morning and evening intervals.		Salsalate, statin and omega-3-fatty acid combination therapy Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
All Cause Mortality
	Placebo		Anti-inflammatory Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)
Serious Adverse Events
	Placebo		Anti-inflammatory Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		1/19 (5.3%)
General disorders
Hospitalization	0/20 (0%)	0	1/19 (5.3%)	1
Psychiatric disorders
Hospitalization	1/20 (5%)	1	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Anti-inflammatory Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/20 (50%)		14/19 (73.7%)
Blood and lymphatic system disorders
High triglyceride levels	1/20 (5%)	1	0/19 (0%)	0
Cardiac disorders
Abnormal EKG	0/20 (0%)	0	1/19 (5.3%)	1
Ear and labyrinth disorders
Tinnitus	0/20 (0%)	0	1/19 (5.3%)	1
Gastrointestinal disorders
Eructation	2/20 (10%)	2	0/19 (0%)	0
Flatulence	1/20 (5%)	1	0/19 (0%)	0
Diarrhea	2/20 (10%)	2	1/19 (5.3%)	1
Nausea	1/20 (5%)	1	0/19 (0%)	0
Vomiting	0/20 (0%)	0	3/19 (15.8%)	4
Upset stomach	0/20 (0%)	0	1/19 (5.3%)	1
General disorders
Abdominal pain	1/20 (5%)	1	0/19 (0%)	0
Hypersalivation	0/20 (0%)	0	3/19 (15.8%)	3
Fever	0/20 (0%)	0	2/19 (10.5%)	2
Memory loss	0/20 (0%)	0	1/19 (5.3%)	1
Dysgeusia	0/20 (0%)	0	2/19 (10.5%)	2
Gait instability	0/20 (0%)	0	1/19 (5.3%)	1
Insomnia	0/20 (0%)	0	1/19 (5.3%)	1
Dry mouth	0/20 (0%)	0	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Myoclonus	0/20 (0%)	0	1/19 (5.3%)	1
Myalgia	0/20 (0%)	0	1/19 (5.3%)	1
Stiffness	0/20 (0%)	0	2/19 (10.5%)	2
Nervous system disorders
Generalized pain	0/20 (0%)	0	1/19 (5.3%)	1
Psychiatric disorders
Psychiatric symptom increase	4/20 (20%)	6	4/19 (21.1%)	8
Suicidal ideation	0/20 (0%)	0	2/19 (10.5%)	2
Renal and urinary disorders
Enuresis	1/20 (5%)	1	0/19 (0%)	0
Dark urine	0/20 (0%)	0	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Tachypnea	0/20 (0%)	0	1/19 (5.3%)	1
Bronchitis	0/20 (0%)	0	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
Pruritus	0/20 (0%)	0	1/19 (5.3%)	1
Rash	1/20 (5%)	1	1/19 (5.3%)	1
Urticaria	1/20 (5%)	2	1/19 (5.3%)	1
Vascular disorders
Hypertension	1/20 (5%)	1	0/19 (0%)	0

Limitations/Caveats

[Not Specified]

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.