Safety and Tolerability of PBI-4050 and Its Effects on the Biomarkers in Subjects With Alström Syndrome

A Phase 2, Single-Arm, Open-Label Study to Evaluate the Safety and Tolerability of PBI-4050 and of Its Effects on the Inflammatory, Fibrosis, Diabetes and Obesity Biomarkers in Subjects With Alström Syndrome

This is a Phase 2, single-centre, single-arm, open-label study of the safety, tolerability, and effects on biomarkers of PBI-4050 in subjects with Alström syndrome for a treatment duration of 24 weeks.

Subjects who complete the initial 24 weeks of treatment may continue treatment for an additional 36 or 48 weeks, provided the subject signs informed consent.

Study Overview

• Status: Completed
• Conditions: Diabetes; Inflammation and Fibrosis
• Intervention / Treatment: Drug: PBI-4050

Detailed Description

This is a Phase 2, single-centre, single-arm, open-label study of the safety, tolerability, and effects on biomarkers of PBI-4050 in subjects with Alström syndrome. Approximately 18 subjects will be enrolled. The duration of study participation is approximately 35 weeks for each subject and comprises of 9 on site visits and telephone contacts in between visits.

Subjects who complete the initial 24 weeks of treatment may continue treatment for an additional 36 or 48 weeks (Extension Period [EP]), provided the subject signs informed consent. The extension period includes a further 3 on site visits and telephone contacts in between visits. The total duration of the study participation is extended to approximately 71 or 83 weeks. The Data Safety Monitoring Board (DSMB) will determine if the safety data continue to support treatment for an additional 36 or 48 weeks.

At the completion of the EP End of Treatment, subjects will be allowed to enrol in the Alström Rollover Study PBI-4050-CT-9-10 and continue ongoing study medication without any break in treatment.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B15 2PR
    • University Hospitals Birmingham NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria :

• Subject is 16 years of age or older at screening.
• Subject has signed informed consent.
• Subject has a documented diagnosis of Alström syndrome
• Subject on diabetes treatment has been receiving the same antidiabetic agent(s) for a minimum of 1 month before screening.
• Subject is able and willing to self-monitor blood glucose level at home or can obtain adequate assistance from care givers.
• Female subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use adequate birth control from screening throughout the study and for 30 days after the last Investigational Medicinal Product (IMP) administration. If a male subject has not been vasectomized at least 6 months before screening and partners with a woman of childbearing potential, he must be willing to use an acceptable contraceptive method throughout the study and for 30 days after the last IMP administration.

Exclusion Criteria:

• Subject has recent or on-going infection requiring systemic treatment with an anti-infective agent within 30 days before screening.
• Subject has had at least two documented episodes of severe hypoglycaemia within 12 months before screening
• Subject has uncontrolled hypertension with BP > 170/100 mmHg as determined at screening.
• Subject has alanine transaminase (ALT) or aspartate transaminase (AST) level ≥ 5 × upper limit of normal (ULN) at screening.
• Subject is currently using weight loss medications at screening. Subjects may be re-screened after stopping the weight loss medication for a period of at least 5 half-lives.
• Subject has used any moderate/potent inducer or inhibitor of CYP2C9 isozyme or strong inducer or inhibitor of cytochrome P450 (CYP) 3A isozyme within 30 days prior to the first study drug administration.
• Subject has a history of chronic alcohol or other substance abuse as determined at screening.
• Woman who is pregnant, breast-feeding, or planning a pregnancy during the course of the study as determined at screening.
• Subject has any condition that, in the investigator's opinion, is likely to interfere with study conduct and compliance
• Subject has a history of an allergic reaction to PBI-4050 or any of its excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PBI-4050; Four 200 mg capsules (total 800 mg) administered orally, once daily.	Drug: PBI-4050; Four 200 mg capsules (800 mg total) administered orally, once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Description and number of abnormal laboratory values and adverse events that are related to treatment.	Primary on 24 weeks; Final on all data (including Extension Period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in metabolic syndrome parameters over time.	Change from baseline in fasting plasma glucose over time. Change from baseline in fasting plasma insulin over time. Change from baseline in glycated hemoglobin (HbA1c) over time. Change from baseline in Homeostasis Model Assessment for steady state beta cell function (HOMA-B) and insulin sensitivity (HOMA-S) over time.	24 weeks and end of Extension Period
Change from baseline in biomarkers in blood and urine over time	Percentage of reduction and/or increase of level of biomarkers	24 weeks and end of Extension Phase
Change from baseline in cardiac function parameter: NT-proBNP		24 weeks and end of Extension Phase
Change from baseline of antidiabetic treatment	Dosing change, new medication added or treatment discontinuation	24 weeks and end of Extension Phase

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline in histological appearances in fat biopsies	Measuring the degree of fibrosis	24 weeks and end of Extension Phase
Changes from baseline in global metabolome and microdialysate fractions		24 weeks and end of Extension Phase
Change from baseline in the liver stiffness	Measured in kilopascal (kPa) correlated to fibrosis by using a FibroScan	24 weeks and end of Extension Phase
Change from baseline in fat content and fibrosis burden in liver MRI		24 weeks and end of Extension Phase
Change from baseline in left ventricular ejection fraction in cardiac MRI		24 weeks and end of Extension Phase
Change from baseline in blood glucose as measured by weekly 4 point profile		24 weeks and end of Extension Phase
Change from baseline in hyperinsulinaemic-euglycaemic clamp measurements.		24 weeks and end of Extension Phase

Collaborators and Investigators

• Sponsor: Liminal BioSciences Ltd.
• Investigators: Principal Investigator: Tarekegn Hiwot, MD, The Queen Elizabeth Hospital

Publications and helpful links

General Publications

• Baig S, Veeranna V, Bolton S, Edwards N, Tomlinson JW, Manolopoulos K, Moran J, Steeds RP, Geberhiwot T. Treatment with PBI-4050 in patients with Alstrom syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial. BMC Endocr Disord. 2018 Nov 26;18(1):88. doi: 10.1186/s12902-018-0315-6.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2016
• Primary Completion (Actual): September 26, 2017
• Study Completion (Actual): June 4, 2018

Study Registration Dates

• First Submitted: February 25, 2016
• First Submitted That Met QC Criteria: April 11, 2016
• First Posted (Estimate): April 15, 2016

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 28, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Eye Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Eye Diseases, Hereditary; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Abnormalities, Multiple; Ciliopathies; Polyneuropathies; Retinitis Pigmentosa; Hereditary Sensory and Motor Neuropathy; Fibrosis; Inflammation; Alstrom Syndrome
• Other Study ID Numbers: PBI-4050-ATX-9-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No