ESRD, HIV/AIDS
Conditions
Keywords
HIV, ESRD, Hemodialysis, Pharmacokinetics
Brief summary
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
The pharmacokinetics (PK) of dolutegravir (DTG) and rilpivirine (RPV), the components of JULUCA, in patients with end stage renal disease (ESRD) requiring hemodialysis (HD) 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.
Interventions
DRUGJULUCA 50Mg-25Mg Tablet
One dose of JULUCA will be taken daily for up to 14 days
Sponsors
Indiana University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Matched case-control
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dolutegravir (DTG) Ctau | 0 to 24 hours post-dose on the intensive study visit | Steady-state plasma Ctau for dolutegravir at the intensive study visit, which occurred between days 11 and 14 |
| Rilpivirine (RPV) Ctau | 0 to 24 hours post-dose on the intensive study visit | Steady-state plasma Ctau for rilpivirine at the intensive study visit, which occurred between days 11 and 14 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of DTG | 30 days | The attributable grade 3 or 4 adverse events associated with use of DTG will be assessed during the study. Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. Grade 3 indicates a severe event, and Grade 4 indicates a potentially life-threatening event. |
| DTG AUC | 0 to 24 hours post-dose on the intensive study visit | Steady-state plasma AUC for dolutegravir at the intensive study visit, which occurred between days 11 and 14 |
| DTG Cmax | 0 to 24 hours post-dose on the intensive study visit | Steady-state plasma Cmax for dolutegravir at the intensive study visit, which occurred between days 11 and 14 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hemodialysis Group Receipt of JULUCA one pill per day up to 14 days
JULUCA 50Mg-25Mg Tablet: One dose of JULUCA will be taken daily for up to 14 days | 4 |
| Normal Renal Function Group Receipt of JULUCA one pill per day up to 14 days
JULUCA 50Mg-25Mg Tablet: One dose of JULUCA will be taken daily for up to 14 days | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Normal Renal Function Group | Total | Hemodialysis Group |
|---|---|---|---|
| Age, Continuous | 57.25 years | 57.375 years | 57.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 2 / 4 | 1 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Dolutegravir (DTG) Ctau
Steady-state plasma Ctau for dolutegravir at the intensive study visit, which occurred between days 11 and 14
Time frame: 0 to 24 hours post-dose on the intensive study visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hemodialysis Group | Dolutegravir (DTG) Ctau | 1259 ng/mL | Standard Deviation 447 |
| Normal Renal Function Group | Dolutegravir (DTG) Ctau | 1666 ng/mL | Standard Deviation 415 |
Primary
Rilpivirine (RPV) Ctau
Steady-state plasma Ctau for rilpivirine at the intensive study visit, which occurred between days 11 and 14
Time frame: 0 to 24 hours post-dose on the intensive study visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hemodialysis Group | Rilpivirine (RPV) Ctau | 50 ng/mL | Standard Deviation 17 |
| Normal Renal Function Group | Rilpivirine (RPV) Ctau | 77 ng/mL | Standard Deviation 47 |
Secondary
DTG AUC
Steady-state plasma AUC for dolutegravir at the intensive study visit, which occurred between days 11 and 14
Time frame: 0 to 24 hours post-dose on the intensive study visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hemodialysis Group | DTG AUC | 78095 h*ng/mL | Standard Deviation 28979 |
| Normal Renal Function Group | DTG AUC | 75301 h*ng/mL | Standard Deviation 23090 |
Secondary
DTG Cmax
Steady-state plasma Cmax for dolutegravir at the intensive study visit, which occurred between days 11 and 14
Time frame: 0 to 24 hours post-dose on the intensive study visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hemodialysis Group | DTG Cmax | 6346 ng/mL | Standard Deviation 2593 |
| Normal Renal Function Group | DTG Cmax | 5984 ng/mL | Standard Deviation 2804 |
Secondary
Safety of DTG
The attributable grade 3 or 4 adverse events associated with use of DTG will be assessed during the study. Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. Grade 3 indicates a severe event, and Grade 4 indicates a potentially life-threatening event.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hemodialysis Group | Safety of DTG | 0 Adverse Events |
| Normal Renal Function Group | Safety of DTG | 0 Adverse Events |