PK of JULUCA in Hemodialysis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV/AIDS, ESRD

Intervention / Treatment
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* Drug: JULUCA 50Mg-25Mg Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Negative HIV antibody testing at screening. 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. Availability of alternative venous access (not used for dialysis) for the purpose of PK sampling. 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 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. Males and females, age 18-65 years. Ability and willingness of participant or legal guardian/representative to provide written informed consent. Exclusion Criteria: Known allergy or hypersensitivity to either dolutegravir or rilpivirine Use of peritoneal dialysis. Serious illnesses, other than ESRD, requiring systemic treatment and/or hospitalization within 30 days prior to the Screening Visit. 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). Hepatitis B surface antigen or hepatitis C antibody with detectable RNA at screening. Known gastrointestinal disease that may lead to poor absorption of the study drugs. Known hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption. 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 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. Use of proton pump inhibitors within 7 days of initiating study drug (H2 blockers are permitted). Pregnancy and/or breast-feeding. Moderate to severe depression, defined as a PHQ-9 ≥ 10 at Screening. 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. QTc interval greater than 500 msec at Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Matched case-control
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, ESRD, Hemodialysis, Pharmacokinetics