Pharmacokinetics of Single-dose Dolutegravir in HIV-seronegative Subjects With Severe Hepatic Impairment Compared to Matched Controls. (POLO)

This is an open-label, parallel-group, nonrandomized, multi-centre, phase-IV, single dose trial in 8 HIV-seronegative subjects with severe hepatic impairment and 8 matched controls to assess the pharmacokinetics of a single dose of 50mg of dolutegravir in subjects with severe hepatic impairment.

Study Overview

• Status: Withdrawn
• Conditions: Hepatic Impairment; HIV-1-infection
• Intervention / Treatment: Drug: Dolutegravir

Detailed Description

This is an open-label, parallel-group, nonrandomized, multi-centre, phase-IV, single dose trial. The primary aim of this study is to assess the pharmacokinetics of a single dose of 50mg of dolutegravir in HIV-seronegative subjects with severe hepatic impairment (n=8) and compare these with a single dose of 50mg of dolutegravir in matched controls (n=8). In both groups a pharmacokinetic (PK) curve will be recorded for determination of dolutegravir (and dolutegravir-glucuronide).

• Study Type: Interventional
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject is at least 18 and not older than 90 years at screening.
2. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
3. Child-Pugh score 10 or greater (Appendix A). Expected to be in clinical stable condition for at least 4 weeks as assessed by the subject's own hepatologist. This assessment takes into account the following aspects: MELD score, fibroscan results (if available), life expectancy, recent history of decompensation events and the rate of progression of hepatic insufficiency.

For healthy volunteers

1. Subject is at least 18 and not older than 90 years at screening.
2. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
3. Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges. If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
4. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement.

Exclusion Criteria:

1. Inability to understand the nature and extent of the study and the procedures required.
2. Gilbert's syndrome or other underlying disease (other than hepatic impairment) that causes alterations in the Child-Pugh class components (bilirubin, albumin, prothrombin, encephalopathy and ascites).
3. Therapy with strong inducers or inhibitors of UGT1A1 or drugs that are contra-indicated with concomitant use of dolutegravir (see appendix B). (NB. there are restrictions for intake of magnesium/aluminium-containing antacids, iron and calcium supplements, multivitamins and other cation-containing supplements (see appendix B and section 5.2)).
4. Positive HIV test.
5. Participation in a drug study within 60 days prior to Day 1.
6. Febrile illness within 3 days before Day 1.

For healthy volunteers

1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
2. Positive HIV test.
3. Positive hepatitis B or C test.
4. Pregnant female (as confirmed by an hCG test performed less than 4 weeks before Day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception.
5. Therapy with strong inducers or inhibitors of UGT1A1 or drugs that are contra-indicated with concomitant use of dolutegravir (see appendix B). (NB. there are restrictions for intake of magnesium/aluminium-containing antacids, iron and calcium supplements, multivitamins and other cation-containing supplements (see appendix B and section 5.2)).
6. Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders, hormonal disorders (especially diabetes mellitus), coagulation disorders.
7. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
8. History of or current abuse of drugs, alcohol or solvents.
9. Inability to understand the nature and extent of the study and the procedures required.
10. Participation in a drug study within 60 days prior to Day 1.
11. Donation of blood within 60 days prior to Day 1.
12. Febrile illness within 3 days before Day 1
13. UGT1A1 polymorphism (at least one *28, *37 or *6 allele) -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hepatic impairment group; Dolutegravir in HIV-seronegative subjects with severe hepatic impairment (child-Pugh score 10 or greater)	Drug: Dolutegravir; Intake of a single-dose dolutegravir 50 mg tablet on an empty stomach
Active Comparator: Matched controls; Dolutegravir in control group matched for gender, age and BMI with subjects in hepatic impairment group	Drug: Dolutegravir; Intake of a single-dose dolutegravir 50 mg tablet on an empty stomach

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
area under the curve	dolutegravir area under the curve	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse events	number and severity of adverse events	7 days

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: University Medical Center Groningen; Erasmus Medical Center; Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Anticipated): November 15, 2020
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: January 21, 2019
• First Submitted That Met QC Criteria: January 21, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): June 10, 2021
• Last Update Submitted That Met QC Criteria: June 7, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: pharmacokinetics; dolutegravir
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: UMCN-AKF-16.03

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No