Pharmacokinetics of Lanraplenib in Adults With Impaired Renal Function

• ClinicalTrials.gov Identifier: NCT02959138
• Recruitment Status: Completed
• First Posted: November 8, 2016
• Results First Posted: October 25, 2019
• Last Update Posted: October 25, 2019
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

The primary objective of this study is to evaluate the pharmacokinetics (PK) of lanraplenib in participants with impaired renal function relative to matched healthy controls. Participants in this study will be enrolled using an adaptive design that includes up to 3 enrolled cohorts. Based on safety and/or PK data in Cohort 1, participants will be enrolled in adaptive Cohorts 2 and/or 3.

Condition or disease	Intervention/treatment	Phase
Inflammatory Disease	Drug: Lanraplenib.	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of GS-9876 in Subjects With Impaired Renal Function
• Actual Study Start Date: November 21, 2016
• Actual Primary Completion Date: October 5, 2018
• Actual Study Completion Date: October 5, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Moderate Renal Impairment (Cohort 1); Participants with moderate renal impairment and matched healthy controls will receive a single dose of lanraplenib	Drug: Lanraplenib.; 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1; Other Name: GS-9876
Experimental: Severe Renal Impairment (Adaptive Cohort 2); Participants with severe renal impairment and matched healthy controls will receive a single dose of lanraplenib	Drug: Lanraplenib.; 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1; Other Name: GS-9876
Experimental: Mild Renal Impairment (Adaptive Cohort 3); Participants with mild renal impairment and matched healthy controls will receive a single dose of lanraplenib	Drug: Lanraplenib.; 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1; Other Name: GS-9876

Outcome Measures

Primary Outcome Measures :

1. Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr [ Time Frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1 ]

   AUClast is defined as the concentration of drug from time zero to the last observable concentration. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation:

   For men: CLcr (mL/min) = ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL)

   For women: CLcr (mL/min) = 0.85 × ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL)

   Participants were classified based on estimated CLcr as:

   Moderate renal impairment: CLcr 30-59 mL/min

   Severe renal impairment: CLcr 15-29 mL/min

   Healthy control: CLcr ≥ 90 mL/min

2. PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr [ Time Frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1 ]

   AUCinf is defined as the concentration of drug extrapolated to infinite time. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation:

   For men: CLcr (mL/min) = ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL)

   For women: CLcr (mL/min) = 0.85 × ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL)

   Participants were classified based on estimated CLcr as:

   Moderate renal impairment: CLcr 30-59 mL/min

   Severe renal impairment: CLcr 15-29 mL/min

   Healthy control: CLcr ≥ 90 mL/min

3. PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr [ Time Frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1 ]

   Cmax is defined as the maximum concentration of drug. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation:

   For men: CLcr (mL/min) = ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL)

   For women: CLcr (mL/min) = 0.85 × ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL)

   Participants were classified based on estimated CLcr as:

   Moderate renal impairment: CLcr 30-59 mL/min

   Severe renal impairment: CLcr 15-29 mL/min

   Healthy control: CLcr ≥ 90 mL/min

Secondary Outcome Measures :

1. Percentage of Participants Who Experienced Treatment-Emergent Adverse Events [ Time Frame: Day 1 up to Day 31 ]
2. Percentage of Participants Who Experienced Graded Laboratory Abnormalities [ Time Frame: Day 1 up to Day 31 ]
   Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. The criteria used for grading was Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Key Inclusion Criteria:

All Individuals

• Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
• Have a calculated body mass index (BMI) of ≥ 18 kg/m^2 and ≤ 36 kg/m^2 at screening
• Females of childbearing potential must have a negative pregnancy test at screening and clinic admission (Day -1).
• Individuals have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug.
• Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the sponsor
• Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs

For Individuals with Renal Impairment

• Must have diagnosis of chronic (> 6 months), stable renal impairment with no clinically significant change in renal function status within 90 days prior to study drug administration (Day 1).
• Have a creatinine clearance (CLcr) < 90 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening.

For Healthy Matched Controlled Individuals (Individuals with Normal Renal Function)

• Have a CLcr ≥ 90 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening
• Match in age (± 10 years), gender, and body mass index (± 20%, 18 kg/m^2 ≤ BMI ≤ 36 kg/m^2).

Key Exclusion Criteria:

• Be a lactating female
• Have received any investigational compound within 30 days prior to study dosing
• Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance or individual's safety as judged by the investigator
• Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody
• Have poor venous access that limits phlebotomy

For Individuals with Renal Impairment

• Require or are anticipated to require dialysis within 90 days of study dosing
• Require during the study or have received moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A within 2 weeks prior to study drug administration.

For Healthy Matched Controlled Individuals (Individuals with Normal Renal Function)

• Have taken any prescription medications or over-the-counter medications, including herbal products and antacids, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications and/or stable hormone replacement therapy in peri- /post-menopausal female

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

United States, Florida

Clinical Pharmacology of Miami, Inc. (CPMI)

Miami, Florida, United States

Omega Research Consultants, LLC

Orlando, Florida, United States

Orlando Clinical Research Center

Orlando, Florida, United States

Germany

APEX GmBH

Munich, Germany

New Zealand

Auckland Clinical Studies

Grafton, Auckland, New Zealand

Christchurch Clinical Studies Trust

Christchurch, New Zealand

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

  Study Documents (Full-Text)

Documents provided by Gilead Sciences:

Study Protocol: Amendment 1  [PDF] January 9, 2017

Statistical Analysis Plan  [PDF] February 13, 2019

More Information

Publications:

Hsueh CH, Zheng H, Matzkies F, Mozaffarian A, Medzihradsky O, Tarnowski T, Curry N, and Mathias A. Pharmacokinetics and Short-Term Safety of GS-9876, an Oral Spleen Tyrosine Kinase Inhibitor in Subjects with Renal Impairment. American Society for Clinical Pharmacology and Therapeutics 2019; Washington D.C.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02959138
• Other Study ID Numbers: GS-US-379-1932; 2016-003823-47 ( EudraCT Number )
• First Posted: November 8, 2016
• Results First Posted: October 25, 2019
• Last Update Posted: October 25, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Renal Insufficiency; Kidney Diseases; Urologic Diseases