Ketohexokinase Inhibition in NAFLD (KHKi)
Primary Purpose
NAFLD
Status
Recruiting
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Ketohexokinase inhibition
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for NAFLD
Eligibility Criteria
Inclusion Criteria:
- Participants are able to provide signed and dated written informed consent prior to any study specific procedures
- Men and (postmenopausal) woman
- Aged ≥ 45 and ≤ 70 years
- Body mass index (BMI) 27 - 35 kg/m2
- Hepatic steatosis (i.e. IHL ≥ 5.56%)
- Stable dietary habits (no weight loss or gain > 3 kg in the past 3 months)
Exclusion Criteria:
- Type 2 diabetes
- Patients with congestive heart failure and and/or severe renal and or liver insufficiency
- Uncontrolled hypertension
- Any contra-indication for MRI scanning
- Alcohol consumption of >3 servings per day for man and >2 servings per day for woman
- Smoking
- Unstable body weight (weight gain or loss > 3kg in the last 3 months)
- Engagement in structured exercise activities > 2 hours a week
- Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the investigator which would possibly hamper our study results
- Use of drugs that inhibit organic anion transporting polypeptide (OATP) transporters (e.g. rifampicin, gemfibrozil, cyclosporine, erythromycin and clarithromycin)
- Subjects who do not want to be informed about unexpected medical findings
Sites / Locations
- Maastricht University Medical centreRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
PF-06835919
Placebo
Arm Description
KHKi
Placebo
Outcomes
Primary Outcome Measures
Hepatic insulin sensitivity
insulin-mediated suppression of endogenous glucose production (EGP) in µmol/kg/min measured during the 2- step hyperinsulinemic-euglycemic clamp
Secondary Outcome Measures
Intrahepatic lipid content
1H-MRS in percent
Liver lipid content composition
1H-MRS in percent
Subcutaneous adipose tissue
MRI in cm^3
Visceral adipose tissue
MRI in cm^3
Insulin-mediated suppression of free fatty acids
Plasma in mmol/L
Inflammatory markers like adiponectin, interleukin-6, hsCRP, TNF-α
in blood serum in µg/mL
Resting energy expenditure (REE)
kcal/kg/min
Sleeping metabolic rate
kcal/kg/min
Body composition
fat mass (kg and percent)
Body composition
fat-free mass (kg and percent)
Full Information
NCT ID
NCT05463575
First Posted
July 1, 2022
Last Updated
March 30, 2023
Sponsor
Maastricht University Medical Center
Collaborators
Pfizer
1. Study Identification
Unique Protocol Identification Number
NCT05463575
Brief Title
Ketohexokinase Inhibition in NAFLD
Acronym
KHKi
Official Title
Metabolic Effects of Ketohexokinase Inhibition on Individuals With Non-alcoholic Fatty Liver Disease
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2022 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center
Collaborators
Pfizer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
NAFLD
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
17 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
PF-06835919
Arm Type
Experimental
Arm Description
KHKi
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Ketohexokinase inhibition
Intervention Description
participants will be asked to take 300 mg of the KHKi in tablet form daily for 6 weeks in either period 1 or 2.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Hepatic insulin sensitivity
Description
insulin-mediated suppression of endogenous glucose production (EGP) in µmol/kg/min measured during the 2- step hyperinsulinemic-euglycemic clamp
Time Frame
42 days
Secondary Outcome Measure Information:
Title
Intrahepatic lipid content
Description
1H-MRS in percent
Time Frame
41 days
Title
Liver lipid content composition
Description
1H-MRS in percent
Time Frame
41 days
Title
Subcutaneous adipose tissue
Description
MRI in cm^3
Time Frame
41 days
Title
Visceral adipose tissue
Description
MRI in cm^3
Time Frame
41 days
Title
Insulin-mediated suppression of free fatty acids
Description
Plasma in mmol/L
Time Frame
42 days
Title
Inflammatory markers like adiponectin, interleukin-6, hsCRP, TNF-α
Description
in blood serum in µg/mL
Time Frame
42 days
Title
Resting energy expenditure (REE)
Description
kcal/kg/min
Time Frame
42 days
Title
Sleeping metabolic rate
Description
kcal/kg/min
Time Frame
42 days
Title
Body composition
Description
fat mass (kg and percent)
Time Frame
42 days
Title
Body composition
Description
fat-free mass (kg and percent)
Time Frame
42 days
Other Pre-specified Outcome Measures:
Title
Liver phosphomonoester levels
Description
31P-MRS in mg/kg bw after an oral fructose load as a measure of KHK activity
Time Frame
41 days
Title
Peripheral insulin sensitivity
Description
Rd during the clamp in µmol/kg/min
Time Frame
42 days
Title
Metabolic flexibility
Description
delta REE between basal and insulin stimulated state
Time Frame
42 days
Title
Intramyocellular lipid content
Description
measured in muscle biopsies in arbitrary units
Time Frame
42 days
Title
Fecal short-chain fatty acids including acetate, propionate, and butyrate
Description
concentration in fecal samples in μmol/g
Time Frame
41 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Participants are able to provide signed and dated written informed consent prior to any study specific procedures
Men and (postmenopausal) woman
Aged ≥ 45 and ≤ 70 years
Body mass index (BMI) 27 - 35 kg/m2
Hepatic steatosis (i.e. IHL ≥ 5.56%)
Stable dietary habits (no weight loss or gain > 3 kg in the past 3 months)
Exclusion Criteria:
Type 2 diabetes
Patients with congestive heart failure and and/or severe renal and or liver insufficiency
Uncontrolled hypertension
Any contra-indication for MRI scanning
Alcohol consumption of >3 servings per day for man and >2 servings per day for woman
Smoking
Unstable body weight (weight gain or loss > 3kg in the last 3 months)
Engagement in structured exercise activities > 2 hours a week
Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the investigator which would possibly hamper our study results
Use of drugs that inhibit organic anion transporting polypeptide (OATP) transporters (e.g. rifampicin, gemfibrozil, cyclosporine, erythromycin and clarithromycin)
Subjects who do not want to be informed about unexpected medical findings
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Evi Koene
Phone
0031 43 3884596
Email
e.koene@maastrichtuniversity.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Patrick Schrauwen, PhD
Phone
0031 43 3881502
Email
p.schrauwen@maastrichtuniversity.nl
Facility Information:
Facility Name
Maastricht University Medical centre
City
Maastricht
State/Province
Limburg
ZIP/Postal Code
6202AZ
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patrick Schrauwen, PhD
Phone
043 3881502
Email
p.schrauwen@maastrichtuniversity.nl
First Name & Middle Initial & Last Name & Degree
Evi koene
Phone
043 3884596
Email
e.koene@maastrichtuniversity.nl
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
Data can be obtained with the PI on request
Learn more about this trial
Ketohexokinase Inhibition in NAFLD
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