Single and Multiple Dose Escalation of PHIN-214 in Child-Pugh A and B Liver Cirrhotics

Study Overview
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Brief Summary
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This single and multiple ascending dose (SAD and MAD) study evaluates PHIN-214, being studied to determine the safety, tolerability, and pharmacokinetics, and establish the maximum tolerated dose of this compound in patients with Child Pugh A and B Cirrhosis.

Detailed Description
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Terlipressin has been shown to reduce portal hypertension, improve renal function, and induce natriuresis in cirrhotic patients with ascites without hepatorenal syndrome (HRS). It is approved in Europe for the treatment of bleeding esophageal varices and HRS type 1 and is usually administered as an IV bolus. This study is an open label, First in Human study of PHIN-214. PHIN-214 is a terlipressin derivative administered subcutaneously. It is a partial V1a agonist which is designed to reduce splanchnic blood pooling and portal hypertension. A resultant increase in systemic pressure and renal arterial pressure may increase kidney perfusion and creatinine clearance. As a partial V1a agonist that traffics into the bloodstream from a subcutaneous depot, this derivative is designed to be gentler than terlipressin and has been well tolerated at the injection site, to date. This study will evaluate the use of PHIN-214 administered at various dosing levels to establish the maximum tolerated dose in patients with Child Pugh A and B Cirrhosis.

Official Title
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A Phase 1 Open Label Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PHIN-214 in Adults With Child Pugh A and B Cirrhosis

Conditions
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Cirrhosis, Liver, Liver Fibrosis, Ascites Hepatic

Intervention / Treatment
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* Drug: PHIN-214 Subcutaneous injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index within the range 18 to 40 kg/m2 (inclusive) at screening. Females must be non-pregnant, non-lactating or of non-childbearing potential or using highly efficient contraception for the full duration of the study. Cirrhosis based on histology or a combination of clinical, radiological, or biochemical and classified as Child-Pugh A or B. Exclusion Criteria: Significant abnormalities in medical history or on physical examination, including: respiratory disease requiring therapy or history of respiratory failure, cardiovascular disease or hypertension, electrocardiogram abnormalities or history of significant EKG abnormalities. History of diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, or any other disorder associated with fluid or sodium imbalance. Significant kidney disease Estimated glomerular filtration rate (eGFR by CKD-Epi) <60 ml/min/1.73 m2 or Cr >2.0 mg/dL. Hepatic encephalopathy > grade 2 in the previous 3 months. Stable drug treatment for HE is not exclusionary. Recipient of a transjugular intrahepatic portosystemic shunt (TIPS). Known positive HIV serology confirmed by HIV viral load. Subjects with acute infections, including acute viral hepatitis are to be excluded. Subjects with chronic hepatitis B are eligible if treatment regimen is stable ≥ 3 months prior to study inclusion.

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single dose of PHIN-214<br>single ascending dose of PHIN-214 | Drug: PHIN-214 Subcutaneous injection<br>* Single or multiple subcutaneous injection(s) with PHIN-214 terlipressin derivative, single ascending dose or multiple ascending dose<br>* Other names: Terlipressin derivative;|
| Experimental: multiple daily dosing of PHIN-214<br>multiple doses of PHIN-214, daily for 28 days | Drug: PHIN-214 Subcutaneous injection<br>* Single or multiple subcutaneous injection(s) with PHIN-214 terlipressin derivative, single ascending dose or multiple ascending dose<br>* Other names: Terlipressin derivative;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities | Incidence of dose limiting toxicities | up to sixweeks | 
| incidence of stopping criteria | incidence of stopping criteria | up to six weeks | 
| incidence of AEs | incidence of AEs | up to six weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK of PHIN-214 | plasma concentration of PHIN-214 | up to six weeks | 
| AUC of PHIN-214 | AUC of PHIN-214 | up to six weeks | 
| PK of PHIN-214 metabolite | plasma concentration of PHIN-214 metabolite | up to six weeks | 
| AUC of PHIN-214 metabolite | AUC of PHIN-214 metabolite | up to six weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Terlipressin, Cirrhosis, Vasoconstrictor, Refractory Ascites