Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Obesity
Conditions
Brief summary
This is a randomized, double-blind, double-dummy, placebo-controlled, cross over design trial with empagliflozin compared to placebo that is added to open-label ramipril.
Interventions
DRUGEmpagliflozin
Empagliflozin will be taken once daily
DRUGPlacebo (matching empagliflozin)
Placebo will be taken once daily
DRUGramipril
Ramipril will be taken once or twice daily
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated written informed consent. * Male or female patients diagnosed with type 1 diabetes (T1D) at least 6 months prior to informed consent or type 2 diabetes (T2D) or non-diabetic obese patients. * T1D patients must use and be willing of and be willing to continue throughout the duration of the trial either: * multiple daily injections of insulin OR * continuous sub-cutaneous insulin infusion of any insulin type, with at least 3 months experience * For patients with T1D or T2D,HbA1c of 6.5 - 11% * Age at least 18 years of age * Body mass index of \>=18.5 kg/m\^2 * Estimated glomerular filtration rate greater than or equal to 60 ml/min/1.73m2 * Blood pressure greater than 90 /60 mmHg and less than or equal to 140 / 90 mmHg * Use of a highly effective method of contraception. * Further inclusion criteria apply
Exclusion criteria
* For patients with T1D, treatment with an antihyperglycaemic agent within 3 months prior to visit 1 * occurrence of severe hypoglycaemia within 3 months prior to visit 1 * hypoglycaemic unawareness within 3 months prior to visit 1 * occurrence of diabetic ketoacidosis within 3 months of visit 1 and until visit 3 Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril. | At week 4 and at week 12 | Glomerular filtration rate (GFR) under euglycaemic conditions after 4 weeks of treatment with either empagliflozin added to ramipril or placebo added to ramipril. The pre-specified statistical analysis was not conducted, because data are too sparse in the subgroup of hyperfilterers. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril | At week 4 and at week 12. | Filtration status (Glomerular Filtration Rate (GFR) \< 120 mL/min/1.73m²) after 4 weeks of treatment with either empagliflozin added to ramipril or placebo added to ramipril. Filtration status is defined as whether a patient has normal Filtration status (GFR \< mL/min/1.73m², yes) or not (GFR ≥ mL/min/1.73m², no). The pre-specified statistical analysis was not conducted, because data are too sparse in the subgroup of hyperfilterers. |
Countries
Canada
Participant flow
Recruitment details
A randomized, double-blinded, placebo-controlled, crossover trial to compare the effect of empagliflozin versus placebo when added to ramipril on reducing glomerular hyperfiltration in patients with type 1 Diabetes mellitus (T1D), Type 2 Diabetes (T2D), or obesity.
Pre-assignment details
Participants who successfully completed the 4 weeks open-label ramipril run-in period and meet all of the inclusion, and non of the exclusion criteria were randomized into the trial, with no stratification to one of two sequences.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A: 25 mg Empagliflozin / Placebo During dosing Period 1, participants were administered 1 tablet of 25 milligram (mg) empagliflozin once daily as single oral dose for 4 weeks added to open-label Ramipril, where participants had been dose escalated from 1.25, 5, 7.5, or 10 mg, up to 10 mg ramipril or to their maximum tolerated dose. This was followed by a 4-week wash-out period with background treatment of open-label ramipril administered orally as capsule once or twice daily as prescribed by the investigator,and then followed by 4 weeks of dosing period 2 of 1 tablet matching placebo administered once daily as single oral dose added to open-label Ramipril. | 16 |
| Sequence B: Placebo / 25 mg Empagliflozin During dosing Period 1, participants were administered 1 tablet of matching placebo once daily as single oral dose for 4 weeks added to open-label Ramipril, where participants had been dose escalated from 1.25, 5, 7.5, or 10 mg, up to 10 mg ramipril or to their maximum tolerated dose. This was followed by a 4-week wash-out period with background treatment of open-label ramipril administered orally as capsule once or twice daily as prescribed by the investigator,and then followed by 4 weeks of dosing period 2 of 1 tablet of 25 mg empagliflozin administered once daily as single oral dose added to open-label Ramipril. | 14 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Wash-out Period | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence A: 25 mg Empagliflozin / Placebo | Sequence B: Placebo / 25 mg Empagliflozin | Total |
|---|---|---|---|
| Age, Continuous | 26.5 Years STANDARD_DEVIATION 4.2 | 27.0 Years STANDARD_DEVIATION 5 | 26.7 Years STANDARD_DEVIATION 4.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 14 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Glomerular filtration rate (GFR) at baseline | 113.6 milliliter (mL) /minutes (min) /1.73m² STANDARD_DEVIATION 9.4 | 115.7 milliliter (mL) /minutes (min) /1.73m² STANDARD_DEVIATION 14 | 114.6 milliliter (mL) /minutes (min) /1.73m² STANDARD_DEVIATION 11.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 11 Participants | 25 Participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 15 / 31 | 13 / 30 |
| serious Total, serious adverse events | 0 / 31 | 2 / 30 |
Outcome results
Primary
Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril.
Glomerular filtration rate (GFR) under euglycaemic conditions after 4 weeks of treatment with either empagliflozin added to ramipril or placebo added to ramipril. The pre-specified statistical analysis was not conducted, because data are too sparse in the subgroup of hyperfilterers.
Time frame: At week 4 and at week 12
Population: Hyperfilterers: Patients before ramipril monotherapy with GFR ≥ 135 mL/min/1.73m², as measured at screening (visit 4).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 25 mg Empagliflozin | Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril. | 124.0 milliliter (mL) /minutes (min) /1.73m² | Standard Deviation 10.61 |
| Placebo | Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril. | 132.5 milliliter (mL) /minutes (min) /1.73m² | Standard Deviation 7.78 |
Secondary
Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril
Filtration status (Glomerular Filtration Rate (GFR) \< 120 mL/min/1.73m²) after 4 weeks of treatment with either empagliflozin added to ramipril or placebo added to ramipril. Filtration status is defined as whether a patient has normal Filtration status (GFR \< mL/min/1.73m², yes) or not (GFR ≥ mL/min/1.73m², no). The pre-specified statistical analysis was not conducted, because data are too sparse in the subgroup of hyperfilterers.
Time frame: At week 4 and at week 12.
Population: Hyperfilterers: Patients before ramipril monotherapy with GFR ≥ 135 mL/min/1.73m², as measured at screening (visit 4).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 25 mg Empagliflozin | Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril | Yes | 1 Participants |
| 25 mg Empagliflozin | Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril | No | 1 Participants |
| Placebo | Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril | Yes | 0 Participants |
| Placebo | Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril | No | 2 Participants |