PK of JULUCA in Hemodialysis

The Steady-State Pharmacokinetics of Dolutegravir/Rilpivirine Fixed Dose Combination (FDC) in Patients With End Stage Renal Disease (ESRD) Requiring Hemodialysis

This study will compare the pharmacokinetics of the component drugs in JULUCA, and HIV combination treatment pill, in HIV-negative patients who require hemodialysis with those with normal renal function.

Study Overview

• Status: Completed
• Conditions: HIV/AIDS; ESRD
• Intervention / Treatment: Drug: JULUCA 50Mg-25Mg Tablet

Detailed Description

The pharmacokinetics of dolutegravir and rilpivirine, the components of JULUCA, in patients with end stage renal disease requiring hemodialysis have not previously been adequately studied. It is possible that the PK of these drugs are affected by renal failure which may then compromise effectiveness and safety. This trial will rigorously assess the plasma PK and protein-binding of these two drugs in 10 HIV-negative patients requiring hemodialysis with 10 matched persons with normal renal function. All participants will receive JULUCA for up to 14 days and then undergo a 24 hour intensive PK evaluation.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Samir K Gupta, MD; Phone Number: 317-274-7926; Email: sgupta1@iu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Samir Gupta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Negative HIV antibody testing at screening.

2. For the ESRD requiring HD study group: ESRD requiring chronic hemodialysis for at least 6 months at an established center (not home dialysis).

   NOTE: The approximate date that hemodialysis was initiated should be reported, if known.

   For the normal renal function group: Estimated CrCl (using the Cockcroft-Gault equation) at screening ≥75mL/min.

3. Availability of alternative venous access (not used for dialysis) for the purpose of PK sampling.

4. The following laboratory values obtained within 30 days prior to study entry (obtained either at screening or done as part of routine clinical care):

   • AST (SGOT) and ALT (SGPT) less than or equal to ULN
   • Total bilirubin less than or equal to 1.5 x ULN
   • Hemoglobin greater than or equal to 8.0 mg/dL
5. A negative serum pregnancy test result at screening for all women of reproductive potential who have not reached menopause or undergone hysterectomy, bilateral oophorectomy, or tubal ligation.
6. Males and females, age 18-65 years.
7. Ability and willingness of participant or legal guardian/representative to provide written informed consent.

Exclusion Criteria:

1. Known allergy or hypersensitivity to either dolutegravir or rilpivirine
2. Use of peritoneal dialysis.
3. Serious illnesses, other than ESRD, requiring systemic treatment and/or hospitalization within 30 days prior to the Screening Visit.
4. Known liver cirrhosis, unstable liver disease (presence of ascites, encephalopathy, coagulopathy, esophageal/gastric varices), Child-Pugh Class A, B, or C, or known biliary abnormalities (except for known Gilbert's syndrome or asymptomatic gallstones).
5. Hepatitis B surface antigen or hepatitis C antibody with detectable RNA at screening.
6. Known gastrointestinal disease that may lead to poor absorption of the study drugs.
7. Known hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

8. Any of the following gastrointestinal signs or symptoms of Grade ≥ 2 within 7 days prior to the Screening Visit or during study drug administration prior to the Intensive PK Study Visit:

   • nausea
   • vomiting
   • diarrhea
   • abdominal pain

9. Use of any of the following within 30 days of initiating study drug:

   • Medications known to appreciably inhibit or induce CYP3A enzymes, P-glycoprotein, or UGT1A1 or UGT1A4 enzymes (e.g., anticonvulsants such as carbamazepine, phenytoin, oxacarbamazepine; antimycobacterials such as rifampin, rifabutin and rifapentine; antifungal agents such as ketoconazole, fluconazole and itraconazole; verapamil, clarithromycin, erythromycin)
   • St. John's Wort, echinacea, grapefruits or grapefruit juice, garlic supplements, ginseng, golden seal, and milk thistle
   • Cancer chemotherapeutic agents
   • Investigational agents
   • Immunomodulators, including systemic steroids greater than or equal to 100 mg/day of prednisone (Note: Topical and inhaled corticosteroids are allowed.)
   • Dofetilide
   • Positive pre-study drug screen. Drugs that will be screened for include amphetamines, barbiturates, cocaine and phencyclidine (PCP). Active injected drug users will be excluded from this study.
10. Use of proton pump inhibitors within 7 days of initiating study drug (H2 blockers are permitted).
11. Pregnancy and/or breast-feeding.
12. Moderate to severe depression, defined as a PHQ-9 ≥ 10 at Screening.
13. Significant change (i.e., more than a 50% change) in tobacco smoking habit within 6 weeks prior to the Screening Visit. Participants who have recently stopped smoking should have stopped smoking more than 6 weeks prior to the Screening Visit. Participants who have recently started smoking should have started more than 6 weeks prior to the Screening Visit.
14. QTc interval greater than 500 msec at Screening.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hemodialysis Group; Receipt of JULUCA one pill per day up to 14 days	Drug: JULUCA 50Mg-25Mg Tablet; One dose of JULUCA will be taken daily for up to 14 days
Active Comparator: Normal Renal Function Group; Receipt of JULUCA one pill per day up to 14 days	Drug: JULUCA 50Mg-25Mg Tablet; One dose of JULUCA will be taken daily for up to 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DTG Ctau	Steady-state plasma Ctau for dolutegravir	11-14 days
RPV Ctau	Steady-state plasma Ctau for rilpivirine	11-14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of DTG and RPV	The attributable adverse events associated with use of DTG and RPV will be assessed during the study.	26-30 days
DTG and RPV AUC	Steady-state plasma AUC for dolutegravir and rilpivirine	11-14 days
DTG and RPV Cmax	Steady-stage plasma Cmax for dolutegravir and rilpivirine	11-14 days

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Samir K Gupta, MD, Indiana University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2021
• Primary Completion (Actual): July 31, 2023
• Study Completion (Actual): July 31, 2023

Study Registration Dates

• First Submitted: June 9, 2020
• First Submitted That Met QC Criteria: June 11, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; ESRD; Hemodialysis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Dolutegravir, rilpivirine drug combination
• Other Study ID Numbers: ViiV Healthcare IIS 1837

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD will provided upon request and approval by the investigators or through online data repositories such as Figshare.
• IPD Sharing Time Frame: IPD will become available after publication of the data, anticipated to be by July 2022.
• IPD Sharing Access Criteria: Fully available when posted to online repositories. Additional data upon request and approval by the study investigators. The financial sponsor will not have a role in this process.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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