Trial Outcomes & Findings for Saxagliptin + Metformin Compared to Saxagliptin or Metformin Monotherapy in PCOS Women With Impaired Glucose Homeostasis (NCT NCT02022007)

NCT ID: NCT02022007

Last Updated: 2017-06-28

Results Overview

Glucose metabolic secretory status after drug treatment (normal, impaired or diabetic). We used the American Diabetes Association (ADA) definition of impairment which is fasting glucose greater than 100 mg/dL and/or 2 hour glucose greater than 140 mg/dL.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 38 participants
• Primary outcome timeframe: 16 weeks
• Results posted on: 2017-06-28

Participant Flow

PCOS women age 18 and 42 years and impaired glucose regulation were enrolled in the study from March 2014 to January 2016. PCOS was defined according to modified National Institutes of Health [NIH] 1990 criteria. ). Prediabetic hyperglycemia was determined by a 75-gram OGTT and included impaired fasting glucose (IFG), IGT, or both (IFG/IGT).

Exclusion criteria included diabetic subjects, smokers, suspected pregnancy, desiring pregnancy or injectable hormonal contraceptive use within 6 months; and use of oral contraceptives, other steroid hormones, drugs that affect gastrointestinal motility or carbohydrate metabolism and/or anti-obesity drugs within 3 months prior to study entry.

Participant milestones

Measure	Metformin XR Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Overall Study STARTED	13	12	13
Overall Study COMPLETED	12	11	11
Overall Study NOT COMPLETED	1	1	2

Reasons for withdrawal

Measure	Metformin XR Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Overall Study Withdrawal by Subject	1	1	1
Overall Study Noncompliant	0	0	1

Baseline Characteristics

Saxagliptin + Metformin Compared to Saxagliptin or Metformin Monotherapy in PCOS Women With Impaired Glucose Homeostasis

Baseline characteristics by cohort

Measure	Metformin XR n=13 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=12 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=13 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study	Total n=38 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	13 Participants n=5 Participants	12 Participants n=7 Participants	13 Participants n=5 Participants	38 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	12 Participants n=7 Participants	13 Participants n=5 Participants	38 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	10 Participants n=4 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	9 Participants n=7 Participants	9 Participants n=5 Participants	28 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	13 Participants n=5 Participants	12 Participants n=7 Participants	13 Participants n=5 Participants	38 Participants n=4 Participants

PRIMARY outcome

Timeframe: 16 weeks

Population: Change from impaired to normal was evaluated. No patients were diabetic at the start or completion of the study

Glucose metabolic secretory status after drug treatment (normal, impaired or diabetic). We used the American Diabetes Association (ADA) definition of impairment which is fasting glucose greater than 100 mg/dL and/or 2 hour glucose greater than 140 mg/dL.

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Glucose Metabolism	3 Participants	6 Participants	10 Participants

PRIMARY outcome

Timeframe: 16 weeks

Post-treatment in insulin-sensitivity-secretion index . The insulin secretion-sensitivity index (IS-SI) provides an estimate of β-cell compensation relative to the prevailing insulin resistance, not absolute insulin secretion. It is derived by applying the concept of the disposition index (DI) to measurements obtained during the 2-h OGTT. The IS-SI, a surrogate measure of the DI derived from the OGTT (IGI multiplied by the SIOGTT], was calculated as the product of acute β-cell response [IGI] and Matsuda index (SIOGTT) based on the existence of the predicted hyperbolic relationship between these two measures

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Oral Disposition Index	208 index Standard Deviation 126	359 index Standard Deviation 295	532 index Standard Deviation 347

SECONDARY outcome

Timeframe: 16 weeks

Post-treatment fasting glucose levels

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Fasting Glucose	5.4 mmol/L Standard Deviation 0.7	5.3 mmol/L Standard Deviation .51	5.0 mmol/L Standard Deviation .36

SECONDARY outcome

Timeframe: 16 weeks

Post-treatment mean blood glucose levels. Mean blood glucose (MBG) concentrations were calculated by summing glucose values obtained at 0,30,60 and 120 minutes during the OGTT and dividing by 4.

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Mean Blood Glucose During the OGTT	7.9 mmol/L Standard Deviation 1.4	7.1 mmol/L Standard Deviation 1.64	6.2 mmol/L Standard Deviation 1.2

SECONDARY outcome

Timeframe: 16 weeks

Post-treatment insulin sensitivity index. The Matsuda index of whole-body insulin sensitivity is calculated from an oral glucose tolerance test (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), and is highly correlated with the rate of whole-body glucose disposal during the euglycemic insulin clamp

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Matsuda Index of Insulin-Sensitivity (SI OGTT)	2.5 Index Standard Deviation 1.6	3.5 Index Standard Deviation 3.4	4.1 Index Standard Deviation 2.6

SECONDARY outcome

Timeframe: 16 weeks

Post-treatment corrected early phase insulin secretion index (IGI/HOMA-IR). . Early pancreatic β-cell response is estimated as the insulinogenic index (IGI) derived from the ratio of the increment of insulin to that of glucose 30 minutes after a glucose load (insulin 30 min - insulin 0 min/glucose 30 min - glucose 0 min) corrected for by the relative level of insulin resistance (IGI/HOMA-IR which is estimated by homeostasis model assessment of insulin resistance using fasting insulin and glucose levels).

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Pancreatic ß-cell Compensatory Function	0.46 Ratio Standard Deviation 0.3	1.4 Ratio Standard Deviation 1.7	1.03 Ratio Standard Deviation 0.7

SECONDARY outcome

Timeframe: 16 weeks

Height and weight measurements were used to calculate body mass index (BMI), defined as kg/m2.

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Body Mass Index at 16 Weeks	42 kg/mg2 Standard Deviation 7.7	36.7 kg/mg2 Standard Deviation 7.4	42 kg/mg2 Standard Deviation 10.2

SECONDARY outcome

Timeframe: 16 weeks

The circumference measurement was taken in the upright position using a 15-mm width flexible metric tape held close to the body but not tight enough to indent the skin. Waist circumference (WC) was measured in centimeters at the narrowest level midway between the lowest ribs and the iliac crest.

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Waist Circumference at 16 Weeks	109 centimeters Standard Deviation 13	99.6 centimeters Standard Deviation 17	106 centimeters Standard Deviation 16

SECONDARY outcome

Timeframe: 16 weeks

The number of menstrual cycles during the previous year was recorded and the average menstrual interval calculated by dividing 365 by the number of menstrual cycles in the previous year . During the study period, the patients in a menstrual diary recorded vaginal bleeding over 16 weeks. The effects of treatment intervention on menstrual cycle interval was calculated evaluated by dividing 112 days by the number of menstrual cycles recorded in each patient's menstrual cycle diary.

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Menstrual Cycle Interval at 16 Weeks	81 days between menstrual cycles Standard Deviation 44	58 days between menstrual cycles Standard Deviation 29	36 days between menstrual cycles Standard Deviation 11

SECONDARY outcome

Timeframe: 16 weeks

The measure of TRG levels and HDL- cholesterol levels are used as an estimate of insulin sensitivity. A TRG/HDL-C ratio of greater than 3.0 is used as an indirect measure of insulin resistance

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Triglyceride (TRG) /HDL-cholesterol Ratio	4.2 Ratio Standard Deviation 2.4	2.9 Ratio Standard Deviation 1.3	3.0 Ratio Standard Deviation 0.9

SECONDARY outcome

Timeframe: 16 weeks

Hyperandrogenism is measured by a combination of total testosterone (T) and sex hormone binding globulin (SHBG). The FAI was calculated as the quotient 100 x T/SHBG; hyperandrogenism was defined by a FAI value >3.85.

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Free Androgen Index (FAI)	6.3 index Standard Deviation 2.8	5.5 index Standard Deviation 3.4	4.3 index Standard Deviation 3.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 16 weeks

The safety criteria will include laboratory values for liver enzymes and document the absence of pregnancy in all participants during the trial

Outcome measures

Measure	Metformin XR n=12 Participants Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=11 Participants Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=11 Participants Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Number of Participants With No Clinically Significant Changes in Liver Enzyme Levels or Positive Pregnancy Tests	0 Participants	0 Participants	0 Participants

Adverse Events

Metformin XR

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Saxagliptin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Saxagliptin-Metformin XR

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Metformin XR n=13 participants at risk Metformin 2000 mg QD for 16 weeks Metformin XR: Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study	Saxagliptin n=12 participants at risk Saxagliptin 5 mg QD for 16 weeks Saxagliptin: Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study	Saxagliptin-Metformin XR n=13 participants at risk Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks Saxagliptin-Metformin XR: Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study
Gastrointestinal disorders Diarrhea	7.7% 1/13 • Number of events 1 • 22 months	0.00% 0/12 • 22 months	15.4% 2/13 • Number of events 2 • 22 months

Additional Information

Dr Karen Elkind-Hirsch

Woman''s Hospital

Phone: 225-231-5275

Email: karen.elkind-hirsch@womans.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place