Objective
Thirty six adults with T1D and albuminuria between 50 to 3500 mg/g will be randomly assigned to 4 weeks treatment periods in random order with ambrisentan 5 mg/d and/or sotagliflozin 200 mg/d, with 4 weeks wash-out periods in between the active treatment periods. Participants will thus receive ambrisentan and sotagliflozin individually and in combination. At the start and end of each active treatment period, we will collect first morning void to assess albuminuria (primary trial endpoint), measure GFR (mGFR) by iohexol clearance, assess fluid status by body weight and bioimpedance spectroscopy, estimate insulin sensitivity by an equation validated in T1D, assess metabolites of mitochondrial function, tubular injury markers and ketone bodies. Allowing for 10% drop out, the sample size provides 80% power to detect a 30% reduction in albuminuria with ambrisentan and sotagliflozin versus ambrisentan alone.
Background Rationale
In summary, the innovative ASPIRE trial, combining for the first time ambrisentan and sotagliflozin in a human mechanistic study, has the potential to provide new insight into a new and safe treatment paradigm that could impede the progression of DKD in people with T1D. The study will be conducted by a multidisciplinary research team collectively skilled in mechanistic multi-national clinical trials in DKD. The investigative team has ample experience in quantifying GFR by iohexol clearance, bio-impedance spectroscopy assessments, insulin sensitivity estimation as well as biomarker discovery and validation. The applicants will leverage these experiences and their longstanding successful collaboration in the proposed clinical trial.
Description of Project
Kidney disease is a common problem in type 1 diabetes with limited treatment options. This research proposal is a clinical trial to see if combining two new drugs, a sodium-glucose cotransporter-1/2 (SGLT1/2) inhibitor called sotagliflozin, and an endothelin receptor antagonist (ERA) called ambrisentan will delay development of kidney disease in adults with type 1 diabetes. We believe the combination of sotagliflozin and ambrisentan will protect the kidneys against disease to a greater degree than either medication alone. Additionally, we believe the combination therapy can improve the safety profile of both drugs. All 36 participants who take part in the trial will receive sotagliflozin alone, ambrisentan alone, or combination therapy for part of the study duration, and participants will have a series of tests to assess their kidney health, including urine and blood collections. Our proposed study is an important step to develop new treatments to halt or prevent diabetic kidney disease in type 1 diabetes.
Anticipated Outcome
The goals of this research are first, to find out if sotagliflozin and ambrisentan slow the progression of kidney disease in people with type 1 diabetes, and second, to determine how these two agents influence the fluid balance in the body as well as markers of metabolism, including insulin sensitivity and mitochondrial function. The overarching hypothesis of this proposal is that sotagliflozin and ambrisentan combination therapy lowers the amount of protein that is passed from the blood into the urine and is an early sign of kidney disease.
In the proposed study, we anticipate finding lower amounts of protein in the urine of participants on sotagliflozin and ambrisentan combination therapy compared with either agent alone. In addition, we expect to see less body fluid buildup in participants on combination therapy than those on ambrisentan alone.
Relevance to T1D
Despite advances in blood sugar monitoring, insulin therapy, and technology, a significant proportion of people with type 1 diabetes still develop diabetic kidney disease. Diabetic kidney disease is a common in in type 1 diabetes and increases the likelihood for heart disease and early death. It is therefore important to find new ways to protect against kidney disease. The purposes of this study are to find out if sotagliflozin and ambrisentan, new promising diabetes drugs, can safely stop progression of kidney disease in people with type 1 diabetes and elevated protein in their urine.