Ketohexokinase Inhibition in NAFLD (KHKi)

January 23, 2024 updated by: Maastricht University Medical Center

Metabolic Effects of Ketohexokinase Inhibition on Individuals With Non-alcoholic Fatty Liver Disease

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).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Limburg
      • Maastricht, Limburg, Netherlands, 6202AZ
        • Maastricht University Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

45 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Placebo Comparator: Placebo
Other: Placebo
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.
Experimental: PF-06835919
KHKi
Drug: Ketohexokinase inhibition
participants will be asked to take 300 mg of the KHKi in tablet form daily for 6 weeks in either period 1 or 2.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Hepatic insulin sensitivity
Time Frame: 42 days
insulin-mediated suppression of endogenous glucose production (EGP) in µmol/kg/min measured during the 2- step hyperinsulinemic-euglycemic clamp
42 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Intrahepatic lipid content
Time Frame: 41 days
1H-MRS in percent
41 days
Liver lipid content composition
Time Frame: 41 days
1H-MRS in percent
41 days
Subcutaneous adipose tissue
Time Frame: 41 days
MRI in cm^3
41 days
Visceral adipose tissue
Time Frame: 41 days
MRI in cm^3
41 days
Insulin-mediated suppression of free fatty acids
Time Frame: 42 days
Plasma in mmol/L
42 days
Inflammatory markers like adiponectin, interleukin-6, hsCRP, TNF-α
Time Frame: 42 days
in blood serum in µg/mL
42 days
Resting energy expenditure (REE)
Time Frame: 42 days
kcal/kg/min
42 days
Sleeping metabolic rate
Time Frame: 42 days
kcal/kg/min
42 days
Body composition
Time Frame: 42 days
fat mass (kg and percent)
42 days
Body composition
Time Frame: 42 days
fat-free mass (kg and percent)
42 days

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Liver phosphomonoester levels
Time Frame: 41 days
31P-MRS in mg/kg bw after an oral fructose load as a measure of KHK activity
41 days
Peripheral insulin sensitivity
Time Frame: 42 days
Rd during the clamp in µmol/kg/min
42 days
Metabolic flexibility
Time Frame: 42 days
delta REE between basal and insulin stimulated state
42 days
Intramyocellular lipid content
Time Frame: 42 days
measured in muscle biopsies in arbitrary units
42 days
Fecal short-chain fatty acids including acetate, propionate, and butyrate
Time Frame: 41 days
concentration in fecal samples in μmol/g
41 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Maastricht University Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Pfizer

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 24, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 24, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 1, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 14, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 19, 2022

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 24, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 23, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL80131.068.22 / METC 22-006

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Data can be obtained with the PI on request

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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