Approaches To Therapy Escalation In T2D (ATTACC)

Approaches To Therapy Escalation In T2D: A Cluster Randomized Control Trial (ATTACC)

Type 2 diabetes mellitus (T2D) is a serious public health challenge which affects more than 9% of Canadians older than 20 years, an estimated prevalence that is anticipated to increase by over 40% in the next decade. The microvascular and macrovascular complications of T2D markedly increase the risks of hospitalization, heart disease, amputation, blindness, end stage renal disease and death, with profound socio-economic consequences for patients, families and society.

Optimal glycemic control is fundamental to the management of T2D, as glycated hemoglobin (A1C) levels > 7.0% are associated with a significantly increased risk of both microvascular and cardiovascular complications. But despite detailed clinical practice guidelines for management of hyperglycemia, glycemic control remains sub-optimal in a large proportion of patients. For example, in over 5000 Canadian diabetic patients managed by primary care physicians (PCPs), more than 50% had an A1C > 7% and more than 20% an A1C > 8%.

For patients not achieving glycemic target on metformin monotherapy and without clinical CVD, Diabetes Canada 2018 Guidelines suggest that the preferred oral antihyperglycemic agents as add-on therapy be either DPP-4 inhibitors or SGLT2 inhibitors if avoidance of hypoglycemia and/or weight gain is a priority. Since most patients with type 2 diabetes would benefit from avoidance of hypoglycemia and/or weight gain, there is clinical rationale for adding DPP-4 inhibitors or SGLT2 inhibitors as oral therapy before considering other oral agents like sulfonylureas or thiazolidinediones. This study is designed to explore the possibility of improving care by providing more precise management guidance to primary care physicians when utilizing DPP-4 inhibitors or SGLT2 inhibitors as add-on therapy to metformin.

Study Overview

• Status: Withdrawn
• Conditions: Type2 Diabetes
• Intervention / Treatment: Drug: DPP-4 inhibitor; Drug: SGLT2 inhibitor; Drug: SGLT2 inhibitor and DPP-4 inhibitor

Detailed Description

This cluster-based study will be conducted in a Primary Care clinical practice setting in Canada. A total of approximately 60 physician practices will be stratified into single (1 PCP) or group (>1 PCP) practices and randomized 1:1 into two arms each consisting of approximately 30 Primary Care practices forming the Interventional arm and the Control arm. The study population will include approximately 600 male and female adult participants living in Canada; who have been diagnosed with T2D; who are being treated for this condition by their PCP; who do not have clinical cardiovascular disease (CVD) and whose eGFR is ≥ 60ml/min; who are receiving metformin at a dose of ≥1500 mg/day as monotherapy for T2D; who are not at the target for glycemic control and whose most recent A1C level is between 7.1 % and 9.0 %. Participant enrollment may be adjusted to ensure balanced distribution of glycemic values at entry across this range between study arms.

All physicians in both arms will receive training on the most current Diabetes Canada 2018 Guidelines for pharmacologic management of type 2 diabetes and the role of DPP-4 inhibitors or SGLT2 inhibitors as add-on therapy to metformin. Physicians in the Interventional arm will receive additional training on specific individualized management for adding DPP-4 inhibitors or SGLT2 inhibitors to metformin. The nature of the additional training will be described separately in a physician training manual. To avoid contamination, only physicians who have been randomized to the Interventional arm will be given access to the physician training manual during the operation of the study, while those physicians randomized into the Control arm will continue to follow their routine clinical practice for utilizing DPP-4 inhibitors or SGLT2 inhibitors as add-on to metformin according to the current Diabetes Canada Practice Guidelines.

• Study Type: Interventional
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged 18 years of age or older
4. Previously diagnosed with T2D
5. Have a glycated hemoglobin (A1C) result at Baseline between 7.1% and 9%
6. Have an eGFR value at Baseline ≥60 ml/min/1.73m2
7. Receiving stable (≥ 8 weeks) metformin at a dose of ≥1500 mg/day as monotherapy for T2D
8. Ability to take oral medication and be willing to adhere to the study intervention regimen
9. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration
10. No reason for investigator to suspect they will not tolerate the study medication

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Treated with antihyperglycemic agents other than metformin monotherapy.
2. Known allergies or contraindications to the use of either DPP-4 inhibitors or SGLT2 inhibitors
3. Presence of clinical evidence of cardiovascular disease including a history of heart failure, myocardial infarction, unstable angina, severe atherosclerotic cardiovascular disease on angiography, peripheral arterial disease and/or prior low extremity amputation, revascularization or stroke.
4. Known pregnancy or current lactation
5. Women of child bearing age not willing to use a method of contraception.
6. Febrile illness within 30 days of signing informed consent
7. Treatment with another investigational drug or other intervention within 90 days of signing informed consent
8. Any physical or psychological condition(s) or diagnoses that in the opinion of the treating physician may preclude participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional Arm; Adding a DPP-4i (sitagliptin) and/or an SGLT2i (ertugliflozin) to metformin after receiving extra training on individualized care.	Drug: DPP-4 inhibitor; Adding sitagliptin (DPP-4i) add-on using a fixed-dose combination with metformin (Janumet® 50/1000 mg BID).; Other Names: Sitagliptin; Drug: SGLT2 inhibitor; Adding ertugliflozin (SGLT2i) add-on using a fixed-dose combination with metformin(Segluromet® 2.5/1000 mg BID); Other Names: Ertugliflozin; Drug: SGLT2 inhibitor and DPP-4 inhibitor; Adding both a DPP-4i as Fixed dose combination (Janumet) plus SGLT2i ertugliflozin (steglatro) as add-on to metformin.; Other Names: Ertugliflozin and Sitagliptin
Experimental: Control Arm; Adding a DPP-4i (sitagliptin) and/or an SGLT2i (ertugliflozin) to metformin as per standard care/Diabetes Canada guidelines.	Drug: DPP-4 inhibitor; Adding sitagliptin (DPP-4i) add-on using a fixed-dose combination with metformin (Janumet® 50/1000 mg BID).; Other Names: Sitagliptin; Drug: SGLT2 inhibitor; Adding ertugliflozin (SGLT2i) add-on using a fixed-dose combination with metformin(Segluromet® 2.5/1000 mg BID); Other Names: Ertugliflozin; Drug: SGLT2 inhibitor and DPP-4 inhibitor; Adding both a DPP-4i as Fixed dose combination (Janumet) plus SGLT2i ertugliflozin (steglatro) as add-on to metformin.; Other Names: Ertugliflozin and Sitagliptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of participants achieving an A1C value of ≤ 7% at 24 weeks	This study is designed to test the hypothesis that the provision of physician guidance and specialized training on utilizing DPP-4 inhibitors or SGLT2 inhibitors as add-on to metformin will result in more participants achieving glycemic target at Week 24 when compared to a usual care approach.	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of participants achieving an A1C value ≤ 7% at 12 weeks	This secondary endpoint will be the proportion of participants who achieve an A1C value of ≤7%	12 weeks
The absolute reduction in A1C from Baseline at 24 weeks	This secondary endpoint will be the absolute reduction in A1C values between Baseline and Week 12 / Week 24.	Week 12 and Week 24.
The percentage of participants requiring a change of therapy or rescue therapy at 12 weeks	Change in therapy will be defined as a change from baseline in the medications or doses of these medications used for glycemic control during the 26 weeks of observation for each participant. Rescue therapy will be allowable at any time during the study for urgent clinical need, this should be delayed, if possible, for at least 12 weeks following the administration of the study drugs. At 12 weeks, if A1C is > 9.0%, rescue therapy can be initiated.	At 12 weeks
Drug tolerability including percentage of participants with hypoglycemic events, and percentage with adverse events.events.	Hypoglycemic events will be diagnosed based on symptoms (confirmed by self-monitored blood glucose ≤ 3.9 mmol/L where available) and will be categorized into 4 groups of: (a) severe, ie requiring the assistance of another person, (b) non-severe, ie those that could be self-managed, (c) nocturnal, (d) daytime.	24 weeks
The absolute reduction in FPG from Baseline at 24 weeks	This secondary endpoint will be the absolute reduction in FPG values between Baseline and Week 24.	24 weeks
The absolute change in body weight from Baseline at 24 weeks	This secondary endpoint will be the absolute change in body weight between Baseline and Week 24.	24 weeks
The absolute change in systolic blood pressure from Baseline at 24 weeks	This secondary endpoint will be the absolute change in systolic blood pressure from Baseline to Week 24.	24 weeks
The percentage of participants achieving the composite outcome of A1C ≤ 7.0%, no weight gain and no hypoglycemia at Week 24.	This secondary endpoint will be the percentage of participants achieving the composite outcome of A1C ≤ 7.0%, no weight gain and no hypoglycemia at Week 24.	24 weeks
The percentage of participants on statin therapy at 24 weeks	This secondary endpoint will be the percentage of participants on statin therapy at Week 24.	24 weeks
The percentage of participants on antihypertensive therapy at Week 24.	This secondary endpoint will be the percentage of participants on antihypertensive therapy at Week 24.	24 weeks

Collaborators and Investigators

• Sponsor: LMC Diabetes & Endocrinology Ltd.
• Collaborators: Merck Sharp & Dohme LLC; Syreon Corporation
• Investigators: Principal Investigator: Ronald M. Goldenberg, MD, LMC Clinical Research Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): September 18, 2019
• Study Completion (Actual): September 18, 2019

Study Registration Dates

• First Submitted: December 24, 2018
• First Submitted That Met QC Criteria: January 21, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): September 27, 2019
• Last Update Submitted That Met QC Criteria: September 25, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Diabetes; Type 2; T2D
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sitagliptin Phosphate; Ertugliflozin; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors
• Other Study ID Numbers: 58214

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No