Schizoaffective Disorder, Schizophrenia
Conditions
Keywords
Schizophrenia, Cognition, Metabolism, Antipsychotics, Psychopathology
Brief summary
This is a 12-week, randomized, double-blinded, placebo-controlled trial of telmisartan 80 mg/day as an adjunctive to clozapine or olanzapine therapy, in 70 schizophrenia subjects to examine telmisartan's effect on glucose metabolism, weight, food intake, resting energy expenditure, and body composition. In addition, the study will examine insulin's effects on psychopathology and cognition. Potential subjects will be identified by their clinicians at the Freedom Trail Clinic, or Massachusetts General Hospital. Approximately 70 subjects will be enrolled.
Detailed description
The specific aims include: Primary Aims: 1. Examine the efficacy of telmisartan added to regular doses of clozapine or olanzapine in improving insulin resistance. 2. Examine the efficacy of telmisartan in reducing fasting triglycerides. Secondary Aims: 1. Examine the effects of telmisartan on negative symptoms, positive symptoms, and cognitive function. 2. Examine telmisartan's effects on lipids, body composition, and waist/hip ratio. 3. Examine telmisartan's effects on inflammatory biomarkers including C-reactive protein (CRP) and interleukin 6 (IL-6).
Interventions
DRUGTelmisartan
Telmisartan 40mg/day for the first 2 weeks. Telmisartan 80mg/day for the next 10 weeks.
DRUGPlacebo
Placebo (plus existing clozapine or olanzapine treatment) for 12 weeks.
DRUGClozapine
Clozapine (plus telmisartan or placebo) for 12 weeks.
DRUGOlanzapine
Olanzapine (plus telmisartan or placebo) for 12 weeks.
Sponsors
National Institutes of Health (NIH)
University of Massachusetts, Worcester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-65 years 2. Diagnosis of schizophrenia, any subtype or schizoaffective disorder, any subtype 3. Treatment with clozapine or olanzapine for at least 6 months 4. Stable dose of antipsychotic agent for at least one month 5. Well establish compliance with out-patient medications 6. Females subjects will be eligible to participate in the study if they are of non-childbearing potential or of child-bearing potential and willing to practice appropriate birth control methods (complete abstinence from sexual intercourse, female sterilization, sterilization of male partner, implants of levonorgestrel, injectable progestogen, oral contraceptives, intrauterine devices, or double barrier methods of contraception using spermicide with either a condom or diaphragm) during the study.
Exclusion criteria
1. Inability to provide informed consent 2. Current substance abuse 3. Psychiatrically unstable 4. Significant medical illness including severe cardiovascular, hepatic, renal disease 5. Current insulin treatment of diabetes 6. History of immunosuppression 7. Current or recent radiation or chemotherapy treatment for cancer 8. Chronic use of steroids 9. Pregnancy or breast feeding 10. Use of diuretics, digoxin, warfarin because the possible drug-drug interaction of telmisartan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Resistance | 12 weeks | Insulin resistance as estimated by homeostasis model of assessment of insulin resistance (HOMA-IR) at week 12 in both the experimental and placebo arm. Insulin resistance is a condition in which cells fail to respond to the normal action of the hormone in the body. The HOMA-IR is calculated using a subject's fasting plasma insulin and glucose levels. The higher the score, the higher the level of insulin resistance. |
| Triglycerides | 12 weeks | Fasting triglycerides assessed in both experimental and placebo arm at week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lipid Metabolism - LDL-cholesterol and HDL-cholesterol | 12 weeks | Lipid metabolism - fasting low density lipoprotein (LDL) and high density lipoprotein (HDL) are estimated in both experimental and placebo arms at 12 weeks. |
| Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | 12 weeks | The Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) were used to assess the positive and negative symptoms in experimental and placebo arms at 12 weeks. The PANSS total scale includes positive and negative subscales. For both subscales, the score ranges from 7-49 and total PANSS score ranges from 30-210. The total scale is a summation of all the subscales. The SANS score ranges from 0-100. For all scales, a greater score represents a worse outcome. |
| Body Composition: Waist to Hip Ratio | 12 weeks | Body composition as estimated by waist to hip ratio in both experimental and placebo arms at 12 weeks. |
| Body Composition: Percent Total Body Fat | 12 weeks | Body composition estimated by percent total body fat as measured by a dual energy absorptiometry (DXA) scan in both experimental and placebo arms at 12 weeks. |
Countries
United States
Participant flow
Pre-assignment details
A total of 66 subjects were screened, 4 of which were screen fails. 62 subjects were then enrolled. Prior to randomization, 8 subjects withdrew consent. 54 subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| A: Telmisartan Telmisartan 80mg/day | 26 |
| B: Placebo Placebo Group | 28 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 4 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | A: Telmisartan | B: Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 28 Participants | 54 Participants |
| Age, Continuous | 41.65 years STANDARD_DEVIATION 12.14 | 44.68 years STANDARD_DEVIATION 11.02 | 43.22 years STANDARD_DEVIATION 11.56 |
| Sex: Female, Male Female | 4 Participants | 23 Participants | 27 Participants |
| Sex: Female, Male Male | 22 Participants | 5 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 22 | 2 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 |
Outcome results
Primary
Insulin Resistance
Insulin resistance as estimated by homeostasis model of assessment of insulin resistance (HOMA-IR) at week 12 in both the experimental and placebo arm. Insulin resistance is a condition in which cells fail to respond to the normal action of the hormone in the body. The HOMA-IR is calculated using a subject's fasting plasma insulin and glucose levels. The higher the score, the higher the level of insulin resistance.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Telmisartan | Insulin Resistance | 1.9997 HOMA-IR scores | Standard Deviation 1.4262 |
| B: Placebo | Insulin Resistance | 2.5824 HOMA-IR scores | Standard Deviation 2.469 |
Primary
Triglycerides
Fasting triglycerides assessed in both experimental and placebo arm at week 12.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Telmisartan | Triglycerides | 154.15 mg/dl | Standard Deviation 156.02 |
| B: Placebo | Triglycerides | 176.72 mg/dl | Standard Deviation 96.65 |
Secondary
Body Composition: Percent Total Body Fat
Body composition estimated by percent total body fat as measured by a dual energy absorptiometry (DXA) scan in both experimental and placebo arms at 12 weeks.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Telmisartan | Body Composition: Percent Total Body Fat | 31.9 percentage of body fat | Standard Deviation 9.88 |
| B: Placebo | Body Composition: Percent Total Body Fat | 31.28 percentage of body fat | Standard Deviation 9.02 |
Secondary
Body Composition: Waist to Hip Ratio
Body composition as estimated by waist to hip ratio in both experimental and placebo arms at 12 weeks.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Telmisartan | Body Composition: Waist to Hip Ratio | 0.99 Ratio | Standard Deviation 0.08 |
| B: Placebo | Body Composition: Waist to Hip Ratio | 0.95 Ratio | Standard Deviation 0.23 |
Secondary
Lipid Metabolism - LDL-cholesterol and HDL-cholesterol
Lipid metabolism - fasting low density lipoprotein (LDL) and high density lipoprotein (HDL) are estimated in both experimental and placebo arms at 12 weeks.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A: Telmisartan | Lipid Metabolism - LDL-cholesterol and HDL-cholesterol | LDL-cholesterol | 107 mg/dl | Standard Deviation 35.71 |
| A: Telmisartan | Lipid Metabolism - LDL-cholesterol and HDL-cholesterol | HDL-cholesterol | 41.05 mg/dl | Standard Deviation 9.59 |
| B: Placebo | Lipid Metabolism - LDL-cholesterol and HDL-cholesterol | LDL-cholesterol | 107.85 mg/dl | Standard Deviation 31.57 |
| B: Placebo | Lipid Metabolism - LDL-cholesterol and HDL-cholesterol | HDL-cholesterol | 43.18 mg/dl | Standard Deviation 11.71 |
Secondary
Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores.
The Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) were used to assess the positive and negative symptoms in experimental and placebo arms at 12 weeks. The PANSS total scale includes positive and negative subscales. For both subscales, the score ranges from 7-49 and total PANSS score ranges from 30-210. The total scale is a summation of all the subscales. The SANS score ranges from 0-100. For all scales, a greater score represents a worse outcome.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A: Telmisartan | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | PANSS total score | 67.41 units on a scale | Standard Deviation 13.36 |
| A: Telmisartan | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | PANSS negative score | 19.55 units on a scale | Standard Deviation 5.8 |
| A: Telmisartan | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | PANSS positive score | 15.50 units on a scale | Standard Deviation 5.55 |
| A: Telmisartan | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | SANS total score | 27.82 units on a scale | Standard Deviation 11.27 |
| B: Placebo | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | SANS total score | 29.28 units on a scale | Standard Deviation 10.96 |
| B: Placebo | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | PANSS total score | 71.05 units on a scale | Standard Deviation 20.32 |
| B: Placebo | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | PANSS positive score | 16.68 units on a scale | Standard Deviation 7.64 |
| B: Placebo | Psychopathology - PANSS Total, PANSS - Negative Score, PANNS - Positive Score and SANS - Total Scores. | PANSS negative score | 19.95 units on a scale | Standard Deviation 5.09 |