Ketohexokinase Inhibition in NAFLD
Condition: NAFLD
MeSH terms: Non-alcoholic Fatty Liver Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Fructose is a big contributor to the development of non-alcoholic fatty liver disease
      (NAFLD). Inhibiting ketohexokinase (KHK), the enzyme catalyzing the first committed step in
      fructose metabolism, is thought to reduced intrahepatic lipid (IHL) content. Pharmacological
      inhibition of KHK resulted in a decrease in IHL content in NAFLD patients, but additional
      health effects are still unknown. In this study the investigators aim to look at additional
      health effects following KHK inhibition (KHKi).
    

Detailed description: 
      Rationale: NAFLD is a highly prevalent (~30%) disease that is histologically characterized by
      simple steatosis, steatohepatitis and/or fibrosis in the absence of alcohol abuse. Liver
      fibrosis can progress to cirrhosis, which is a risk factor for endstage liver disease and
      hepatocellular carcinoma. Of interest, recent studies have shown that NAFLD is also a risk
      factor for systemic diseases, such as type 2 diabetes, which is probably mediated by hepatic
      insulin resistance. Previous research showed that inhibition of KHK, the first step in
      fructose metabolism, reduces IHL content in individuals with NAFLD. KHK is predominantly
      expressed in the gut, kidney, and liver where it facilitates the phosphorylation of fructose
      to fructose-1P, and thereby entrapment and subsequent metabolism within the cell. KHKi in the
      liver, therefore, impairs entrapment of ingested fructose and, consequently, conversion into
      fat which might lead to improvements in hepatic insulin sensitivity. However, studies
      investigating the effect of KHKi on hepatic insulin sensitivity are lacking. Objective: The
      primary objective of this study is to assess the effect of KHKi on hepatic insulin
      sensitivity in overweight/obese individuals with non-alcoholic fatty liver disease. The
      secondary objective includes the assessment of KHKi on fat distribution, adipose tissue
      insulin sensitivity, and fat oxidation in overweight/obese individuals with non-alcoholic
      fatty liver disease.

      Explorative objectives are the assessment of in vivo KHK activity, gut microbiota composition
      and alternative metabolic pathways upon KHK inhibition. Study design: The present study is a
      randomized, double-blinded, placebo-controlled cross over trial (RCT).

      Study population: 14 overweight/obese (BMI: 27-35 kg/m2

      ), male and (postmenopausal) female participants, aged 45 - 70 years with non-alcoholic fatty
      liver disease (IHL ≥ 5.56%) will participate in this study. From experience with similar
      studies, the investigators estimate a drop-out rate of 20% and a screening failure of 50%
      (due to the strict inclusion criteria), resulting in maximally 17 subjects that have to be
      included and 36 subjects that have to be screened (maximally).

      Intervention (if applicable): Participants receive once daily (in the morning) 300 mg in
      tablet form.

      of the KHK inhibitor PF-06835919 or a placebo for 42 days. Main study parameters/endpoints:
      The primary study endpoint is hepatic insulin sensitivity measured during a
      hyperinsulinemic-euglycemic clamp. Secondary outcome parameters are fat distribution, adipose
      tissue insulin sensitivity and fat oxidation. Explorative objectives are in vivo KHK
      activity, gut microbiota composition, and alternative metabolic pathways.

      Nature and extent of the burden and risks associated with participation, benefit, and group
      relatedness: PF-06835919 is well-tolerated and has not been associated with major
      side-effects. The main burden of this study is the large time investment. During the
      intervention

      periods, subjects will receive once daily (in the morning) 300 mg of the KHK inhibitor During
      the last three days of each intervention period, participants visit to the research facility
      for a 2-day stay (with overnight stay) for the test measurements (total time investment per
      intervention period is 34 hours). Moreover, the test days comprise several non-invasive and
      invasive measurements. The used techniques are safe, but the muscle biopsies can cause some
      discomfort and may result in a local bruise or hematoma. Likewise, blood sampling can cause a
      local hematoma. The risk of infection and/or prolonged bleeding is very low due to
      state-of-the-art techniques and sterility measures. During the hyperinsulinemic-euglycemic
      clamp, a very small risk of hypoglycaemia exists. In summary, we will draw approximately
      184ml blood during the entire study period. Measurements performed during the time course of
      the study can potentially lead to unexpected medical findings. Subjects will be informed
      about such a finding and possible advised to contact a doctor about this. If a subject does
      not want to be informed about incidental findings, participation in this study is not
      possible.
    

Intervention name(s): Ketohexokinase inhibition; Placebo
Intervention type(s): Drug; Other
Intervention description(s): participants will be asked to take 300 mg of the KHKi in tablet form daily for 6 weeks in either period 1 or 2.; participants will be asked to take 300 mg of the placebo in tablet form daily for 6 weeks in either period 1 or period 2.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment