Clinical trial NCT01975935
Conditions: Diabetes Mellitus Type 2 Non-alcoholic Fatty Liver Disease Obesity
Keywords: diabetes mellitus type 2 non-alcoholic fatt liver disease obesity
Sponsor: University of Michigan
Start date: 2014-01-01; Completion date: 2017-08-18
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study involves research about an investigational medicine called Amlexanox. The reason for this study is to find out how Amlexanox can improve type 2 diabetes, insulin resistance, obesity and non-alcoholic fatty liver disease (NAFLD). In this study, Amlexanox is considered to be investigational (not approved by the Food and Drug Administration \[FDA\]) for type 2 diabetes, insulin resistance, obesity and non-alcoholic fatty liver disease (NAFLD). This is a placebo controlled study. There is a 50-50 chance that the patient may either receive the study drug, Amlexanox, or a placebo (sugar pill). Neither the patient or the study doctors will know if the patient is receiving the study drug or placebo.

Detailed description:
This proposal focuses on a clinical proof of concept study to evaluate a novel hypothesis. We propose that overnutrition, leading to obesity, represents a state of excessive energy storage promoted by insulin. The stress of excessive energy storage initiates a set of homeostatic responses that includes the generation of adipose tissue and liver inflammation, which involves the secretion of proinflammatory cytokines that block energy storage in fat and liver by inducing insulin resistance, thus relieving stress on the adipocyte and hepatocyte. However, our recent data suggest that inflammation itself is countered by a secondary feedback loop, which we have termed "counter-inflammation". We propose that this process keeps inflammation in check, ensuring that it is maintained at low levels. At the same time counter-inflammation also promotes energy conservation via increased energy storage and decreased utilization in a manner that is insulin-independent. We hypothesize that the noncanonical IkB kinases Ikke and TBK1 are "counterinflammatory" kinases that feedback inhibit inflammatory pathways while helping to support a positive energy balance.

How can this hypothesis be addressed in human subjects? A number of clinical trials have already been initiated with the intention of improving insulin resistance by attenuating inflammation. Many of these have focused on the blockade of single cytokines or their receptors such as TNFa, IL1 and MCP1 (CCR2 antagonist). While the record on these trials is mixed, the complexity of inflammatory pathways elicited during obesity suggests that inhibition of only a single cytokine is not likely to be sufficient. Additionally, because numerous studies have implicated the NFkB pathway in obesity-induced inflammation, NFkB inhibitors have been contemplated. Salsalate was originally resuscitated due to its perceived activity to block NFkB and hence to block inflammation. However, although clinical studies on this drug have been promising, precisely how salsalate works, what its target is, and whether it actually functions an NFkB inhibitor remains controversial (recent data indicate that it may act via activation of AMPK).

We describe here a new potential therapeutic agent that is the result of an academic collaborative drug discovery effort carried out at the University of Michigan. Our studies on elucidating the role of NFkB in insulin resistance and macrophage activation led to the identification of Ikke and TBK1 as potential targets for therapeutic intervention in obesity and type 2 diabetes. We performed a high throughput screen searching for inhibitors of these kinases, evaluating a group of 175,000 compounds that included a collection of approved drugs. Interestingly, the most potent and specific inhibitor discovered was amlexanox; an older drug originally developed in Japan for the treatment of asthma and allergic rhinitis, and later in the US for aphthous ulcers, but without a well understood mechanism of action. It has been in use since 1987, and has a favorable side effect profile.

This protocol is the first proof of concept study to evaluate the possible repurposing of Amlexanox for the treatment of type 2 diabetes and obesity. At the same time, we hope to test the hypothesis that IKKe and TBK1 may be important players in maintaining a positive energy balance, and also in supporting insulin resistance, during prolonged over-nutrition. Finally, these studies will also provide valuable insight into the validity of these two protein kinases as drug targets for the future development of new chemical entities useful in the treatment of type 2 diabetes. Therefore our specific aims are

1. Does amlexanox treatment improve measures of type 2 diabetes, insulin resistance and obesity? To address this question, we intend to treat patients with clinical Type 2 diabetes and Grade 1/2 obesity (BMI 27 to 45 kg/m2) for a period of 3 months in a double-blinded placebo controlled proof-of concept study. We will enroll 40 patients without evidence of severe end-organ damage from chronic complications of Type 2 diabetes who also are on metformin and/or DPPIV inhibitors or no medications, who also have clear-cut evidence of hyperglycemia (HbA1c\>6.5% and \<10.0%). These patients will be treated with either placebo or Amlexanox oral tablets at a starting dose of 25 mg PO tid for 2 weeks and then titrated up to a dose of 50 mg PO tid (doses used to treat asthma in humans and leading to serum concentrations comparable to metabolically effective doses in rodent studies) for the remainder of the therapy period. HbA1c is targeted as primary end-point in this study. Fasting lipid profiles, plasma insulin, HOMA-IR, clinical markers of inflammation and adipocytokine profiles will be measured as other parameters of interest at baseline, 6 weeks and 12 weeks. Insulin secretion as well as insulin sensitivity will be probed using a mixed meal test. Weight is also an important but secondary end-point in this study. We will determine resting energy expenditure with indirect calorimetry and total body composition using DEXA at baseline and 12 weeks. Safety monitoring with CBC, comprehensive metabolic biochemistry, CPK and urine analyses will be undertaken at 1, 2, 4, 6, and 12 weeks, and urinary albumin at baseline and 12 weeks. Measures of safety and efficacy will be repeated 4 weeks after the drug has been discontinued as well.
2. Does amlexanox treatment improve measures of NAFLD in obese patients? All participants in the clinical proof-of-concept study outlined in the aim above will be studied for the degree of steatosis in the liver with the use of MRI and MR spectroscopy at baseline and at 3 months of the study.
3. Development of biomarkers for treatment of patients with type 2 diabetes by amlexanox. We will evaluate the phosphorylation of proteins known to be targets of IKKe and TBK1 in blood, and adipose tissue samples. We will use phospho-specific antibodies to evaluate the regulation of targets that play a role in energy metabolism, and also in feedback inhibition of NFkB. These studies will pave the way for future evaluations probing the metabolic relevance of IKKe and TBK1 in humans using the same agent or more potent ones to be discovered or designed.

Arms: arm 1: Placebo tablet (TID) 2 weeks Placebo tablets (2 x TID) 10 weeks arm 2: Solfa tablets (Amlexanox 25mg) TID for 2 weeks Solfa tablets (Amlexanox 25mg x 2) TID for 10 weeks
Interventions: intervention 1: Amlexanox intervention 2: Placebo
Intervention descriptions: intervention 1: 25 mg amlexanox tablets blinded by encapsulation intervention 2: placebo sham blinded by encapsulation in the same capsules as the study drug arm

Protocol documents: