Safety and Efficacy of Ertugliflozin in the Treatment of Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin and Sitagliptin (MK-8835-006; VERTIS SITA2)

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial to Evaluate the Safety and Efficacy of Ertugliflozin (MK-8835/PF-04971729) in the Treatment of Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin and Sitagliptin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02036515
• Other study ID #: 8835-006
• Secondary ID: 2013-003697-26B1
• Status: Completed
• Phase: Phase 3
• Start date: March 12, 2014
• Est. completion date: June 6, 2016

Study information

• Verified date: August 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a safety and efficacy study of ertugliflozin (MK-8835/PF-04971729) in the treatment of participants with type 2 diabetes mellitus who have inadequate glycemic control on metformin and sitagliptin. The primary objective of the trial is to assess the hemoglobin A1C (A1C)-lowering efficacy of the addition of ertugliflozin compared to the addition of placebo with an underlying hypothesis that addition of treatment with ertugliflozin provides greater reduction in A1C compared with the addition of placebo; the primary objective will be tested for both 5-mg and 15-mg doses of ertugliflozin.

Description:

The duration of the trial will be approximately 69 weeks. This will include a 1-week Screening Period, an up to 12-week wash-off/titration /dose-stabilization period, a 2-week single-blind, placebo run-in period, a 52-week double-blind, placebo-controlled treatment period (including a 26-week Phase A and 26-week Phase B), and a post-treatment telephone contact 14 days after the last dose of blinded investigational product.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 464
• Est. completion date: June 6, 2016
• Est. primary completion date: June 6, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of type 2 diabetes mellitus (T2DM)

• On stable diabetes therapy of metformin with either sitagliptin or another dipeptidyl peptidase-4 (DPP-4) inhibitor or a sulfonylurea (SU) prior to study participation and is willing to wash-off/switch from another DPP-4 inhibitor/SU to sitagliptin

• Body Mass Index (BMI) greater than or equal to 18.0 kg/m^2

• Male, postmenopausal female or surgically sterile female

• If a female of reproductive potential, agrees to remain abstinent or to use (or have their partner use) 2 acceptable combinations of birth control while participating in the trial and for 14 days after the last use of study drug

Exclusion Criteria:

• History of type 1 diabetes mellitus or a history of ketoacidosis

• History of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrine disorders, drug- or chemical-induced, and post-organ transplant)

• A known hypersensitivity or intolerance to any sodium-glucose co-transporter 2 (SGLT2) or DPP-4 inhibitor

• On a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable

• Has undergone bariatric surgery within the past 12 months or >12 months and is not weight stable

• Has been treated with insulin (except for short-term use [<= 7 days]), injectable antihyperglycemic agents (AHAs) (e.g., pramlintide, exenatide, liraglutide), pioglitazone or rosiglitazone, other sodium-glucose co-transporter 2 (SGLT2) inhibitors, alpha glucosidase inhibitors or meglitinides, bromocriptine (Cycloset™), colesevelam (Welchol™), or any other non-protocol approved AHAs within 12 weeks of study participation

• Has active, obstructive uropathy or indwelling urinary catheter

• History of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart Association (NYHA) functional class III-IV heart failure within 3 months of study participation

• A history of malignancy =5 years prior to study participation, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer

• Known history of Human Immunodeficiency Virus (HIV)

• Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells or any other clinically significant hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)

• A medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or active symptomatic gallbladder disease

• Has any clinically significant malabsorption condition

• If taking thyroid replacement therapy, has not been on a stable dose for at least 6 weeks prior to study participation

• Has been previously randomized in a study with ertugliflozin

• Has participated in other studies involving an investigational drug within 30 days prior or during study participation

• Has undergone a surgical procedure within 6 weeks prior to or planned major surgery during study participation

• Has a positive urine pregnancy test

• Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of study medication

• Planning to undergo hormonal therapy in preparation to donate eggs during the trial, including 14 days following the last dose of study medication

• Excessive consumption of alcoholic beverages or binge drinking

• Has donated blood or blood products within 6 weeks of study participation or plans to donate blood or blood products at any time during the trial

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Ertugliflozin 5 mg
Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks
• Ertugliflozin 15 mg
Ertugliflozin, oral, 5 mg and 10 mg tablet once daily for 52 weeks
• Placebo for ertugliflozin 5 mg
Matching placebo for ertugliflozin 5 mg, oral, once daily for 52 weeks
• Metformin
Participants are to remain on their stable doses of metformin (oral, >=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period.
• Sitagliptin
Participants are to remain on their stable doses of sitagliptin (oral, 100 mg once daily) while receiving blinded investigational product during the double-blind treatment period.
• Glimepiride
Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion

Biological:
• Insulin
Insulin glargine rescue medication, injectable, as required. In the event that an investigator considers use of glimepiride to not be appropriate for a participant meeting protocol specified glycemic rescue criteria, insulin glargine can be initiated as the rescue medication, and managed by the investigator according to clinical practice guidelines of the local country.

Drug:
• Placebo for ertugliflozin 10 mg
Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.	Pfizer

References & Publications (1)

Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, Liao Y, Huyck S, Golm G, Terra SG, Mancuso JP, Engel SS, Lauring B. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with me — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Hemoglobin A1C at Week 26	A1C is measured as percent. Thus this change from baseline reflects the Week 26 A1C percent minus the Week 0 A1C percent. Laboratory measurements were performed after an overnight fast =10 hours in duration. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Primary	Percentage of Participants Experiencing An Adverse Event (AE)	An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy.	Up to Week 54
Primary	Percentage of Participants Discontinuing Study Treatment Due to an AE	An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy.	Up to Week 52
Secondary	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26	The change from baseline is the Week 26 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast =10 hours in duration. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Secondary	Change From Baseline in Body Weight at Week 26	The change from baseline is the Week 26 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Secondary	Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 26	A1C is measured as percent. Laboratory measurements were performed after an overnight fast =10 hours in duration. Data presented exclude data following the initiation of rescue therapy.	Week 26
Secondary	Change From Baseline in Sitting Systolic Blood Pressure at Week 26	The change from baseline is the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Secondary	Change From Baseline in Hemoglobin A1C at Week 52	A1C is measured as percent. Thus this change from baseline reflects the Week 52 A1C percent minus the Week 0 A1C percent. Laboratory measurements were performed after an overnight fast =10 hours in duration. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52
Secondary	Change From Baseline in FPG at Week 52	The change from baseline is the Week 52 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast =10 hours in duration. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52
Secondary	Change From Baseline in Body Weight at Week 52	The change from baseline is the Week 52 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52
Secondary	Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52	A1C is measured as percent. Laboratory measurements were performed after an overnight fast =10 hours in duration. Data presented exclude data following the initiation of rescue therapy.	Week 52
Secondary	Change From Baseline in Sitting Systolic Blood Pressure at Week 52	The change from baseline is the Week 52 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52
Secondary	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26	The change from baseline is the Week 26 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Secondary	Change From Baseline in Sitting Diastolic Blood Pressure at Week 52	The change from baseline is the Week 52 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52
Secondary	Percentage of Participants Receiving Glycemic Rescue Medication by Week 26	Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant).	Week 26
Secondary	Percentage of Participants Receiving Glycemic Rescue Medication by Week 52	Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant).	Week 52
Secondary	Time to Initiation of Glycemic Rescue by Week 26	Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days. Below data include data from 1 participant in the Placebo arm who continued Phase A treatment for an additional 30 days.	Up to Week 26 (plus 30 days for 1 placebo participant)
Secondary	Time to Initiation of Glycemic Rescue by Week 52	Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days.	Up to week 52
Secondary	Baseline Homeostasis Model Assessment of ß-cell Function (HOMA-%ß) Value	HOMA-%ß is a well-accepted means of assessing fasting ß-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%ß = [20 x fasting insulin (µU/mL)] / [fasting plasma glucose (mmol/L) - 3.5]	Baseline
Secondary	Change From Baseline in HOMA-%ß at Week 26	HOMA-%ß is a well-accepted means of assessing fasting ß-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%ß = [20 x fasting insulin (µU/mL)] / [fasting plasma glucose (mmol/L) - 3.5]. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Secondary	Change From Baseline in HOMA-%ß at Week 52	HOMA-%ß is a well-accepted means of assessing fasting ß-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%ß = [20 x fasting insulin (µU/mL)] / [fasting plasma glucose (mmol/L) - 3.5]. Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52
Secondary	Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score	The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 1-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ visual analogue score (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best).	Baseline
Secondary	Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26	The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 26
Secondary	Change From Baseline in EQ-5D-3L Score at Week 52	The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy.	Baseline and Week 52