Trial Outcomes & Findings for Effects of 5 Weeks Treatment With Dapagliflozin in Type 2 Diabetes Patients on How the Hormone Insulin Acts on Sugar Uptake in Muscles. (NCT NCT03338855)
NCT ID: NCT03338855
Last Updated: 2021-01-15
Results Overview
Skeletal muscle insulin sensitivity was measured as cGDR (referred to as delta RD \[basal vs high insulin\]) using a 2-step 5.5 hour euglycemic hyperinsulinemic clamp (EHC) procedure in combination with infusion of D-glucose (6,6-D2) glucose. Delta RD (basal vs high insulin) was corrected for urinary glucose excretion and measured at the end of Treatment Periods 1 and 2.
COMPLETED
PHASE4
26 participants
At end (Week 5) of Treatment Periods 1 and 2
2021-01-15
Participant Flow
This was a double-blind, randomized, placebo-controlled, cross-over Phase IV mechanistic study which was conducted in 1 study center in the Netherlands between 05 March 2018 and 04 November 2019.
Eligible patients with Type 2 diabetes mellitus were randomized to a specific double-blind treatment sequence (either dapagliflozin then placebo or placebo then dapagliflozin). Each of the 2 treatment periods had a maximum duration of 40 days, separated by a wash-out period of 6 to 8 weeks.
Participant milestones
| Measure |
Dapagliflozin 10 mg Then Placebo
Patients received an oral dose of 10 milligrams (mg) dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks.
|
Placebo Then Dapagliflozin 10 mg
Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks.
|
|---|---|---|
|
Overall Study
STARTED
|
12
|
14
|
|
Overall Study
Received Treatment in Period 1
|
12
|
14
|
|
Overall Study
Received Treatment in Period 2
|
11
|
14
|
|
Overall Study
COMPLETED
|
11
|
14
|
|
Overall Study
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
Dapagliflozin 10 mg Then Placebo
Patients received an oral dose of 10 milligrams (mg) dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks.
|
Placebo Then Dapagliflozin 10 mg
Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks.
|
|---|---|---|
|
Overall Study
Withdrawn as birth control pill stopped
|
1
|
0
|
Baseline Characteristics
Effects of 5 Weeks Treatment With Dapagliflozin in Type 2 Diabetes Patients on How the Hormone Insulin Acts on Sugar Uptake in Muscles.
Baseline characteristics by cohort
| Measure |
Dapagliflozin 10 mg Then Placebo
n=12 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks.
|
Placebo Then Dapagliflozin 10 mg
n=14 Participants
Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks.
|
Total
n=26 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
63.0 years
STANDARD_DEVIATION 4.7 • n=5 Participants
|
64.4 years
STANDARD_DEVIATION 4.7 • n=7 Participants
|
63.8 years
STANDARD_DEVIATION 4.7 • n=5 Participants
|
|
Sex: Female, Male
Female
|
5 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
7 Participants
n=5 Participants
|
13 Participants
n=7 Participants
|
20 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
12 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
26 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 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
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
12 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
26 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (clamp) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the clamp method were excluded.
Skeletal muscle insulin sensitivity was measured as cGDR (referred to as delta RD \[basal vs high insulin\]) using a 2-step 5.5 hour euglycemic hyperinsulinemic clamp (EHC) procedure in combination with infusion of D-glucose (6,6-D2) glucose. Delta RD (basal vs high insulin) was corrected for urinary glucose excretion and measured at the end of Treatment Periods 1 and 2.
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=22 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=22 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment
|
8.523 micromole/kilogram body weight/minute
Interval 5.566 to 11.481
|
9.592 micromole/kilogram body weight/minute
Interval 6.634 to 12.549
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (clamp) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the clamp method were excluded.
A 2-step 5.5 hour EHC in combination with infusion of 6,6-D2 glucose was used to determine rates of EGP at the end of Treatment Periods 1 and 2. Results of the change in EGP are presented as delta EGP (basal vs low insulin and basal vs high insulin).
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=22 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=22 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment
Delta EGP (basal vs low insulin)
|
-4.656 micromole/kilogram body weight/minute
Interval -5.494 to -3.817
|
-2.591 micromole/kilogram body weight/minute
Interval -3.79 to -2.112
|
|
Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment
Delta EGP (basal vs high insulin)
|
-10.803 micromole/kilogram body weight/minute
Interval -11.726 to -9.88
|
-8.512 micromole/kilogram body weight/minute
Interval -9.435 to -7.589
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (indirect calorimetry) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the indirect calorimetry method were excluded.
During the indirect calorimetry of the EHC test, respiratory gas exchange was measured using open air circuit respirometry with an automated ventilated hood system. Metabolic flexibility was determined by the change in RER from fasted state to insulin stimulated state at the end of Treatment Periods 1 and 2 and results are presented as delta RER (basal vs high insulin).
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=21 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=21 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
Change in Respiratory Exchange Ratio (RER) From Fasted State to Insulin Stimulated State After 5 Weeks of Treatment
|
0.101 ratio
Interval 0.08 to 0.122
|
0.089 ratio
Interval 0.068 to 0.11
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
RER was measured before and after meals over a 24-hour period.
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=24 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=24 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
24-Hour RER After 5 Weeks of Treatment
|
0.812 ratio
Interval 0.803 to 0.821
|
0.835 ratio
Interval 0.826 to 0.844
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
Whole body energy expenditure was measured over a 24-hour period.
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=24 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=24 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
24-Hour Energy Expenditure After 5 Weeks of Treatment
|
9.519 megajoules/day
Interval 9.017 to 10.02
|
9.628 megajoules/day
Interval 9.126 to 10.13
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (DEXA) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with procedure specific protocol deviations regarding the DEXA method were excluded.
On Day 6, 7 or 8 of the end of treatment visit in both treatment periods, a Dual-energy X-ray absorptiometry (DEXA) scan was used to determine body composition.
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=24 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=24 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment
Fat Mass
|
25318.3 grams
Interval 22978.4 to 27658.1
|
25564.9 grams
Interval 23225.0 to 27904.8
|
|
Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment
Lean Mass
|
59929.0 grams
Interval 56762.1 to 63095.8
|
60595.4 grams
Interval 57428.5 to 63762.3
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (DEXA) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the DEXA method were excluded.
On Day 6, 7 or 8 of the end of treatment visit in both treatment periods a DEXA scan was used to determine body composition.
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=24 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=24 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
Body Composition (Total Mass) After 5 Weeks of Treatment
|
85.248 kilograms
Interval 81.608 to 88.888
|
86.504 kilograms
Interval 82.864 to 90.143
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At end (Week 5) of Treatment Periods 1 and 2Population: The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
From the end of Day 1 until the morning of Day 3 of the end of each treatment visit, the patients stayed in the metabolic chamber (36 hours). During this stay FGF21 was measured in plasma before and after meals and before bed-time to determine the AUC (last 24 hours).
Outcome measures
| Measure |
Dapagliflozin 10 mg
n=21 Participants
Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
Placebo
n=21 Participants
Patients received an oral dose of placebo, once daily for 5 weeks in either Treatment Period 1 or Treatment Period 2.
|
|---|---|---|
|
Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment
|
3310.415 nanograms/liter/hour
Interval 2626.919 to 3993.911
|
3554.716 nanograms/liter/hour
Interval 2871.27 to 4238.212
|
Adverse Events
Dapagliflozin 10mg
Placebo
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place