Trial Outcomes & Findings for Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk (NCT NCT00330733)
NCT ID: NCT00330733
Last Updated: 2020-01-21
Results Overview
Participants were admitted to the Clinical Research Units at 06:00-08:00 hours after an overnight fast. Euglycaemic-hyperinsulinaemic clamps were conducted at baseline and at the end of the study. Because salsalate therapy appears to decrease insulin clearance leading to higher circulating insulin levels during the clamp, we reduced the infusion rate of insulin in the active treatment arm by 20% (from 100 to 80 mUm-2 min-1) at the study end. Insulin solutions were prepared by the site pharmacist so that study staff remained blinded to drug assignment. Whole-body insulin sensitivity was estimated from glucose infusion rate (GIR) during last 30 min of insulin infusions.
COMPLETED
PHASE2/PHASE3
71 participants
3 months
2020-01-21
Participant Flow
Participants were veterans aged 21-75 years with impaired fasting glucose (i.e. ≥5.6 but \<7 mmol/l) or impaired glucose tolerance (2 h glucose values ≥7.8 but \<11.1 mmol/l) during a standard 2 h 75 g OGTT. Study participants were recruited from clinics and hospitals throughout the Phoenix and Boston VA Health Care systems.
After enrolment there were 1 week screening, 3 week single-masked placebo run-in (to assess compliance) and 12 week randomised, double-masked treatment periods, with participants randomised 1:1 to receive salsalate or placebo. 78 individuals entered the run-in phase.
Participant milestones
| Measure |
Placebo
Matching placebo
|
Salsalate
Salsalate therapy (Caraco Pharmaceutical Labs, Detroit, MI, USA) was initiated at 3.0 g/day and increased at weeks 2 and 4 of the treatment period to 3.5 and 4.0 g/day, respectively, in divided doses twice daily, as tolerated.
|
|---|---|---|
|
Overall Study
STARTED
|
37
|
34
|
|
Overall Study
Received Study Medication
|
36
|
34
|
|
Overall Study
COMPLETED
|
30
|
29
|
|
Overall Study
NOT COMPLETED
|
7
|
5
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk
Baseline characteristics by cohort
| Measure |
Placebo
n=36 Participants
Matching placebo
|
Salsalate Therapy
n=34 Participants
Salsalate therapy, double-masked. Salsalate (Caraco Pharmaceutical Labs, Detroit, MI, USA) was initiated at 3.0 g/day and increased at weeks 2 and 4 of the treatment period to 3.5 and 4.0 g/day, respectively, in divided doses twice daily, as tolerated for 12 weeks total.
|
Total
n=70 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
57 years
STANDARD_DEVIATION 9 • n=5 Participants
|
60 years
STANDARD_DEVIATION 6 • n=7 Participants
|
58 years
STANDARD_DEVIATION 8 • n=5 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
35 Participants
n=5 Participants
|
32 Participants
n=7 Participants
|
67 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
36 Participants
n=5 Participants
|
34 Participants
n=7 Participants
|
70 Participants
n=5 Participants
|
|
Insulin sensitivity
|
4.08 mg/ kg . min
STANDARD_DEVIATION 1.46 • n=5 Participants
|
3.8 mg/ kg . min
STANDARD_DEVIATION 1.0 • n=7 Participants
|
3.93 mg/ kg . min
STANDARD_DEVIATION 1.27 • n=5 Participants
|
|
Oral Glucose Tolerance Test
|
167 mg/dl. min
STANDARD_DEVIATION 21 • n=5 Participants
|
165 mg/dl. min
STANDARD_DEVIATION 17 • n=7 Participants
|
166 mg/dl. min
STANDARD_DEVIATION 19 • n=5 Participants
|
|
Fasting glucose
|
105 mg/dl
STANDARD_DEVIATION 12 • n=5 Participants
|
103 mg/dl
STANDARD_DEVIATION 10 • n=7 Participants
|
104 mg/dl
STANDARD_DEVIATION 11 • n=5 Participants
|
PRIMARY outcome
Timeframe: 3 monthsPopulation: analysis was performed on all participants with available baseline and final clamp studies
Participants were admitted to the Clinical Research Units at 06:00-08:00 hours after an overnight fast. Euglycaemic-hyperinsulinaemic clamps were conducted at baseline and at the end of the study. Because salsalate therapy appears to decrease insulin clearance leading to higher circulating insulin levels during the clamp, we reduced the infusion rate of insulin in the active treatment arm by 20% (from 100 to 80 mUm-2 min-1) at the study end. Insulin solutions were prepared by the site pharmacist so that study staff remained blinded to drug assignment. Whole-body insulin sensitivity was estimated from glucose infusion rate (GIR) during last 30 min of insulin infusions.
Outcome measures
| Measure |
Placebo
n=29 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=29 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Change in Systemic Glucose Disposal- Glucose Infusion Rates
|
1 percent change from baseline
Interval -39.0 to 56.0
|
6 percent change from baseline
Interval -20.0 to 61.0
|
SECONDARY outcome
Timeframe: 3 monthsPopulation: analysis was performed on all participants with available baseline and final clamp studies
Outcome measures
| Measure |
Placebo
n=30 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=28 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Glucose Area Under the Curve in These Subjects
|
8.98 mmol/l/hr
Standard Deviation 1.19
|
8.74 mmol/l/hr
Standard Deviation 1.33
|
SECONDARY outcome
Timeframe: 8 and 12 weeksPopulation: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
Plasma C-reactive protein was measured by PVAHS clinical laboratory. Data are reported as change from baseline at 8 and 12 weeks.
Outcome measures
| Measure |
Placebo
n=36 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=34 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Plasma CRP
Change in CRP at 12 weeks
|
-0.1 mg/l
Interval -2.6 to 3.6
|
-.3 mg/l
Interval -5.6 to 4.5
|
|
Plasma CRP
Change in CRP at 8 weeks
|
0 mg/l
Interval -2.3 to 4.1
|
-0.8 mg/l
Interval -8.0 to 4.5
|
SECONDARY outcome
Timeframe: Baseline and 12 weeksPopulation: Analysis was performed on all participants with available baseline and final clamp studies
Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel).
Outcome measures
| Measure |
Placebo
n=26 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=27 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Endothelial Function
Pat Index baseline
|
1.8 index
Standard Error .5
|
1.9 index
Standard Error .5
|
|
Endothelial Function
Pat Index 12 week
|
1.7 index
Standard Error .5
|
1.7 index
Standard Error .6
|
SECONDARY outcome
Timeframe: 8 and 12 weeksPopulation: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
Plasma IL-6 was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
Outcome measures
| Measure |
Placebo
n=36 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=34 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Plasma Interleukin 6
Change in IL-6 at 8 weeks
|
0.1 pg/ml
Interval -0.5 to 0.9
|
0 pg/ml
Interval -0.2 to 0.4
|
|
Plasma Interleukin 6
Change in IL-6 at 12 weeks
|
0.2 pg/ml
Interval -0.3 to 0.7
|
0 pg/ml
Interval -0.2 to 0.7
|
SECONDARY outcome
Timeframe: 8 and 12 weeksPopulation: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
Plasma soluble VCAM was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
Outcome measures
| Measure |
Placebo
n=36 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=34 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Plasma sVCAM
Change in sVCAM at 8 weeks
|
-12 ng/ml
Interval -162.0 to 75.0
|
-5 ng/ml
Interval -105.0 to 272.0
|
|
Plasma sVCAM
Change in sVCAM at 12 weeks
|
9 ng/ml
Interval -145.0 to 166.0
|
171 ng/ml
Interval 7.0 to 320.0
|
SECONDARY outcome
Timeframe: 8 and 12 weeksPopulation: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
Plasma soluble Adiponectin was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
Outcome measures
| Measure |
Placebo
n=36 Participants
Placebo: Matching placebo
|
Salsalate Therapy
n=34 Participants
Salsalate: Salsalate therapy
|
|---|---|---|
|
Plasma Adiponectin
Change in adiponectin at 8 weeks
|
-0.5 μg/ml
Interval -1.1 to 0.3
|
1.3 μg/ml
Interval -0.1 to 2.1
|
|
Plasma Adiponectin
Change in adiponectin at 12 weeks
|
-0.1 μg/ml
Interval -1.0 to 1.7
|
1.2 μg/ml
Interval -0.4 to 2.8
|
Adverse Events
Placebo
Salsalate Therapy
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Placebo
n=36 participants at risk
Placebo: Matching placebo The frequency of tinnitus was relatively low (n=4 for salsalate, n= 2 for placebo), only one instance was graded \> mild. Gastrointestinal complaints did not differ between groups (n= 8 for salsalate, n=5 for placebo). No hypoglycaemia occurred.
|
Salsalate Therapy
n=34 participants at risk
Salsalate: Salsalate therapy The frequency of tinnitus was relatively low (n=4 for salsalate, n= 2 for placebo), only one instance was graded \> mild. Gastrointestinal complaints did not differ between groups (n= 8 for salsalate, n=5 for placebo). No hypoglycaemia occurred.
|
|---|---|---|
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Ear and labyrinth disorders
tinnitus
|
5.6%
2/36 • Number of events 2 • 14 weeks (12 weeks active treatment + 2-week follow-up).
|
11.8%
4/34 • Number of events 4 • 14 weeks (12 weeks active treatment + 2-week follow-up).
|
|
Gastrointestinal disorders
nausea
|
13.9%
5/36 • Number of events 5 • 14 weeks (12 weeks active treatment + 2-week follow-up).
|
23.5%
8/34 • Number of events 8 • 14 weeks (12 weeks active treatment + 2-week follow-up).
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place