Ketohexokinase Inhibition in Hereditary Fructose Intolerance

NCT ID: NCT06089265

Last Updated: 2024-01-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-15
• Study Completion Date: 2023-11-30

Brief Summary

Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism. Patients with HFI develop acute abdominal pain, nausea, vomiting, hypoglycemia and proximal tubular dysfunction upon consumption of a fructose containing food product. In rare cases, (prolonged) fructose consumption can even lead to liver and kidney failure. Patients with HFI are therefore treated with a lifelong fructose-restricted diet. Animal studies have shown that the clinical manifestations of HFI are abrogated upon inhibition of ketohexokinase (KHK), the enzyme that catalyses the first step in fructose metabolism.

Recently, PF-06835919, a KHK inhibitor (KHKi), was developed as a new treatment for non-alcoholic fatty liver disease. The compound was well tolerated in several phase II clinical trials.

It is hypothesized that PF-06835919 is also effective in patients with HFI.

Detailed Description

Rationale: Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism. Patients with HFI develop acute abdominal pain, nausea, vomiting, hypoglycemia and proximal tubular dysfunction upon consumption of a fructose containing food product. In rare cases, (prolonged) fructose consumption can even lead to liver and kidney failure. Patients with HFI are therefore treated with a lifelong fructose-restricted diet. Animal studies have shown that the clinical manifestations of HFI are abrogated upon inhibition of ketohexokinase (KHK), the enzyme that catalyses the first step in fructose metabolism.

Recently, PF-06835919, a KHK inhibitor (KHKi), was developed as a new treatment for non-alcoholic fatty liver disease. The compound was well tolerated in several phase II clinical trials.

It is hypothesized that PF-06835919 is also effective in patients with HFI. Objective: To study the effects of PF-06835919 on fructose tolerance and intrahepatic lipid content in patients with HFI. Study design: open-label, pilot study Study population: three adult patients with HFI will be treated with PF-06835919. Five adult healthy individuals will be included (but not be treated) as a reference. Intervention (if applicable): Patients receive once daily (in the morning) three tablets of 100 mg PF-06835919 for 9 days. They will subsequently be gradually exposed to increasing doses of either oral fructose or glucose (in a blinded fashion). Healthy individuals will only undergo oral fructose exposure, as a reference. Main study parameters/endpoints: Intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (at baseline and completion), intestinal fructose tolerance (after oral fructose in comparison to oral glucose), hepatic fructose tolerance (serum glucose and phosphate after oral fructose in comparison to healthy individuals) and renal fructose tolerance (urinary glucose, phosphate, pH and amino acids after oral fructose in comparison to healthy individuals). Nature and extent

Conditions

HFI

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HFI patients

HFI participants will receive PF-06835919 for 9 days. Dosage; once daily 300 mg PF-06835919 in the form of 3 tablets, oral.

Group Type: EXPERIMENTAL

PF-06801591

Intervention Type: DRUG

Active ketohexokinase inhibitor

Healthy controls

Healthy controls will receive no intervention, but a single fructose tolerance test.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

PF-06801591

Active ketohexokinase inhibitor

Intervention Type: DRUG

Other Intervention Names

KHKi

Eligibility Criteria

Inclusion Criteria

• Participants are able to provide signed and dated written informed consent prior to any study specific procedures
• Use of effective contraception (only applicable to premenopausal women; a pregnancy test will be performed in these women at baseline)
• Aged ≥ 18 years

Exclusion Criteria

• Diabetes mellitus
• Pregnancy
• Patients with congestive heart failure and/or severe renal and or liver insufficiency
• Uncontrolled hypertension
• 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 B1 (OATPB1) transporters (e.g. rifampicin, gemfibrozil, ciclosporine, erythromcyin and clarithromycin)*
• Treatment with irinotecan* Any contra-indications for MRI scanning*
• Subjects who do not want to be informed about unexpected medical findings

• Exclusion criterion for HFI patients only.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Maastricht University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patrick Schrauwen, PhD

Role: PRINCIPAL_INVESTIGATOR

Maastricht University

Locations

Maastricht University Medical centre

Maastricht, Limburg, Netherlands

Countries

Netherlands

Other Identifiers

NL83631.068.23 / METC23-006

Identifier Type: -

Identifier Source: org_study_id