A Single and Repeat Dose Trial in Participants With Hepatic Impairment

Study Overview
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Brief Summary
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This study is a a single (open-label) and repeat dose (randomised, placebo controlled) trial to assess the safety, tolerability and pharmacokinetics of GB1211 (Gal-3 inhibitor) in participants with hepatic impairment (Child Pugh B and Child Pugh C)

Detailed Description
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PART 1 A single dose, open-label safety and PK study of GB1211 administered to participants with moderate hepatic impairment (Child Pugh B) and to matched healthy participants (controls). PART 2 A randomised, double-blind, placebo-controlled study in participants with moderate hepatic impairment (Child Pugh B). GB1211 or placebo will be administered daily for 12 weeks. PART 3 A single dose, open-label safety and PK study of GB1211 administered to participants with severe hepatic impairment (Child Pugh C) and to healthy participants (controls).

Official Title
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GULLIVER-2 - A Single (Open-label) and Repeat Dose (Randomised, Placebo-controlled) Trial to Assess the Safety, Tolerability and Pharmacokinetics of GB1211 in Participants With Hepatic Impairment (Child Pugh B & C)

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: GB1211
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Main Inclusion Criteria: Males or females, of any race, ≥ 18 and ≤ 75 years of age at enrolment Body mass index (BMI) of ≥ 18-40 kg/m2 Participants with hepatic impairment: PART 1 and PART 2: Moderate hepatic impairment, as defined by the Child-Pugh score (Child-Pugh B) [1] who exhibit physical signs consistent with stable hepatic impairment and free of significant medical disorders unrelated to their hepatic disorder and are on stable concomitant medication for 2 weeks prior to and for the duration of this study PART 3: Severe hepatic impairment as defined by the Child-Pugh score (Child Pugh C) who exhibit physical signs consistent with stable hepatic impairment and free of significant medical disorders unrelated to their hepatic disorder and are on stable concomitant medication for 2 weeks prior to and for the duration of this study Healthy participants (controls) in PART 1 and PART 3: Healthy as determined by the investigator, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac assessment Match at least one of the participants with moderate or severe hepatic impairment with respect to gender, age (±10 years), and body mass index (BMI) ± 15% (ensure every participant with hepatic impairment has at least 1 matched control) Women of non-childbearing potential defined as permanently sterile or postmenopausal Males will agree to use contraception throughout the study and until 90-days after the Follow-up visit Male participants must agree to refrain from sperm donation from the date of Randomisation (Day 1) until 90 days after the Follow up visit Able to comprehend and willing to sign an ICF and to abide by the study restrictions Exclusion Criteria: All parts and all groups (control healthy volunteers and hepatic impairment) History of an organ transplant, including a remote history of bone marrow transplant History of febrile illness within 7 days prior to the first dose of study drug or participants with evidence of active infection Use of any oral glucocorticoids at any dose within 30 days prior to Screening and until study completion Have previously completed or withdrawn from a study investigating GB1211 and have previously received the investigational product Participant who, in the opinion of the Investigator (or Designee), should not participate in this study Vulnerable/institutionalised patients Patients related to Principal Investigator (PI)/site staff If female, the participant is of child-bearing potential Participation in a clinical study involving administration of an investigational agent e.g. new chemical entity or a biological product in the past 90 days (or 5 multiples of half-life, whichever is longer) prior to dosing. Medical history of cardiac disease and/or clinically significant ECG abnormalities. An abnormal ECG is defined as PR > 220 msec, QRS complex >120 msec, QTcF > 450 msec (males) and > 470msec (females), or any other morphological changes, other than nonspecific T-wave changes Donation or loss of ≥ 400 mL blood or plasma less than 4 weeks prior to screening, or longer if required by local regulations Positive HIV test Have received live vaccine(s) within 30 days prior to Screening or who will require a vaccine(s) and until study completion Use of any medications/products that may inhibit biliary excretion, e.g. bile salt chelators, mycophenolic acid, warfarin, and digoxin, within 30 days prior to Screening and until study completion Use of any medications/products that may inhibit renal excretion; e.g. cimetidine, pyrimethamine, dolutegravir, probenecid, within 30 days prior to Screening and until study completion Use of any medications/products that are known inhibitors of P-gp (e.g. clarithromycin, fostamatinib, quinidine, quinine) and inducers of P-gp (e.g. carbmazepine, rifampin, St. John's wort) within 30 days prior to Screening and until study completion Additional exclusion criteria for matched healthy control subjects: Use of any prescription or non-prescription medication (OTC), herbal medication, dietary supplements or vitamins during 30 days prior to dosing. Acetaminophen is acceptable History or presence of liver disease or liver injury as indicated by an abnormal liver function profile such as AST, ALT, alkaline phosphatase, or serum bilirubin A positive Hepatitis C test or a positive Hepatitis B surface antigen (HBsAg) Estimated glomerular filtration rate (eGFR) < 80 mL/[min*1.73 m²] (estimated using the Modification of Diet in Renal Disease [MDRD] equation) at Screening Additional exclusion criteria for hepatic impaired subjects: Participants meeting any of the following exclusion criteria are not to be enrolled in the study/randomised to treatment: History of any known serious disease (such as cancer, except skin basal cell carcinomas, major infection, clinically significant gastrointestinal disorder, major autoimmune disease) or other disease which in the Investigator's opinion would exclude the patient from the study Estimated glomerular filtration rate (eGFR) < 40 mL/[min*1.73 m²] (estimated using the [MDRD] equation) at Screening Use of any hepatotoxic drug (e.g. methotrexate, isoniazid, amiodarone) within 30 days of Screening and until study completion Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort, or other putatively hepatoprotective herbal remedies such as milk thistle derivatives, within 30 days prior to dosing, unless deemed acceptable by the Investigator (or Designee). Milk thistle derivates or other hepatoprotective herbal remedies are allowed if stable dose is administered 30 days before dosing Use or intend to use slow release medications/products considered to still be active within 14 days prior to Randomisation, unless deemed acceptable by the Investigator (or Designee)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parts 1 & 3 Open Label, Single Dose Part 2 Randomised to either GB1211 or Placebo
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 GB1211, Single Dose (Child Pugh B)<br>GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day. | Drug: GB1211<br>* GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day<br>|
| Experimental: Part 1 GB1211 Healthy Matched Participants, Single Dose<br>GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day. | Drug: GB1211<br>* GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day<br>|
| Experimental: Part 2 GB1211 Multiple Dose, Twice a day (Child Pugh B)<br>GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day. | Drug: GB1211<br>* GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day<br>|
| Placebo Comparator: Part 2 Placebo, Twice a day (Child Pugh B)<br>Placebo is administered twice daily | Drug: Placebo<br>* Placebo is administered orally twice a day<br>|
| Experimental: Part 1 GB1211, Single Dose (Child Pugh C)<br>Part 1 GB1211 Healthy Matched Participants, Single Dose | Drug: GB1211<br>* GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day<br>|
| Experimental: Part 3 GB1211 Healthy Matched Participants, Single Dose<br>Part 1 GB1211 Healthy Matched Participants, Single Dose | Drug: GB1211<br>* GB1211 is a galectin-3 inhibitor an orally available small molecule anti-fibrotic. It is administered orally twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 Safety and Tolerability of GB1211 | Incidence and severity of adverse events as reported by investigators | 11 Days | 
| Parts 2 Safety and Tolerability of GB1211 | Incidence and severity of adverse events as reported by investigators | 12 Weeks | 
| Parts 3 Safety and Tolerability of GB1211 | Incidence and severity of adverse events as reported by investigators | 11 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 Collagen Production and Breakdown Biomarkers | Assessment of liver fibrosis using pro-C3, CK18 and PAI-1 Biomarkers | 12 Weeks | 
| Part 2 Changes on liver and spleen stiffness | Assessment of liver and spleen stiffness measured by vibration control transient elastography | 12 Weeks | 
| Part 2 Changes in Liver Functional Capacity | Assessment of Liver functional Capacity measured by 13C methacetin breath test | 12 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Child Pugh B, Child Pugh C, Liver Cirrhosis, Galectin 3 Inhibitor