TMC114HIV2030: Darunavir/Cobicistat and Dolutegravir to Maintain Virologic Suppression and Reduce NRTI-associated Toxicity

Sponsor

Stanford University (Other)

Overall Status

Withdrawn

CT.gov ID

NCT02499978

Collaborator

Janssen Scientific Affairs, LLC (Industry), University of Colorado, Denver (Other)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a clinical research study to see if switching to Darunavir/Cobicistat ((PREZCOBIX™, DRV/COBI ) and Dolutegrivir (Tivicay®, DTG) in HIV-infected individuals with undetectable HIV viral load on nucleos(t)ide reverse transcriptase inhibitor (NRTI)-containing therapy will be effective in maintaining virologic suppression at 48 weeks of treatment.

Condition or Disease	Intervention/Treatment	Phase
HIV/AIDS	Drug: Darunavir/Cobicistat Drug: Dolutegravir	Phase 2/Phase 3

Detailed Description

NRTIs have been a stalwart for treatment in both the pre- and post-ART eras. However, NRTIs have numerous toxicities partly due to the fact that they are analogs of naturally occurring nucleotides and interfere with the activity of numerous cellular functions. In highly treatment-experienced individuals with more than two active drugs in their salvage regimens, an NRTI-sparing regimen has been shown to be non-inferior to an NRTI-containing regimen [33]. However, studies with NRTI-sparing regimens not consisting of more than two active medications have generally been disappointing.

One limitation of earlier NRTI-sparing regimens has been a higher pill burden than more standard regimens. However, the approvals of DTG and the co-formulated DRV/COBI, both with well-established antiviral activities, may allow for a compact, effective, NRTI-sparing regimen. A switch to DTG/DRV/COBI in virologically suppressed HIV-infected individuals has the potential to avoid NRTI-associated toxicity while maintaining virologic suppression.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Darunavir/Cobicistat and Dolutegravir to Maintain Virologic Suppression and Reduce NRTI-associated Toxicity (The 'deNUC' Study; TMC114HIV2030)

Study Start Date :

May 1, 2016

Actual Primary Completion Date :

Jun 1, 2016

Actual Study Completion Date :

Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DRV/COBI, DTG Immediate switch DARUNAVIR/COBICISTAT (800mg/150MG), DOLUTEGRAVIR 50MG DAILY at randomization and follow through week 48.	Drug: Darunavir/Cobicistat Fixed dose combination medication Other Names: Prezcobix, DRV/COBI Drug: Dolutegravir single tablet medication Other Names: Tivicay, DTG
Active Comparator: DRV/COBI, DTG Delayed Switch DARUNAVIR/COBICISTAT (800MG150MG), DOLUTEGRAVIR 50MG DAILY at week 24 and follow through week 48.	Drug: Darunavir/Cobicistat Fixed dose combination medication Other Names: Prezcobix, DRV/COBI Drug: Dolutegravir single tablet medication Other Names: Tivicay, DTG

Arm

Intervention/Treatment

Experimental: DRV/COBI, DTG Immediate switch

DARUNAVIR/COBICISTAT (800mg/150MG), DOLUTEGRAVIR 50MG DAILY at randomization and follow through week 48.

Drug: Darunavir/Cobicistat

Fixed dose combination medication

Other Names:

Prezcobix, DRV/COBI

Drug: Dolutegravir

single tablet medication

Other Names:

Tivicay, DTG

Active Comparator: DRV/COBI, DTG Delayed Switch

DARUNAVIR/COBICISTAT (800MG150MG), DOLUTEGRAVIR 50MG DAILY at week 24 and follow through week 48.

Drug: Darunavir/Cobicistat

Fixed dose combination medication

Other Names:

Prezcobix, DRV/COBI

Drug: Dolutegravir

single tablet medication

Other Names:

Tivicay, DTG

Outcome Measures

Primary Outcome Measures

Virologic suppression (24 weeks) [24 weeks]
Compare between arms the proportion of patients maintaining virologic suppression (i.e., no confirmed HIV RNA levels ≥200 copies/mL) at Week 24

Secondary Outcome Measures

Virologic Suppression (48 weeks) [48 weeks]
Evaluate the proportion of participants who maintain virologic suppression 24 weeks post-switch (i.e. at 24 weeks in the immediate switch arm and at 48 weeks in the delayed switch arm)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. A second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test or a previous detectable HIV RNA level.

2 .Age ≥ 18 years

HIV-1 RNA <50 copies/mL while on a stable antiretroviral regimen for at least 6 months prior to study entry excluding blips (i.e., a single measurement <200 copies/mL preceded and followed by measurements <50 copies/mL)
At screening, patient on a stable antiretroviral regimen containing at least one NRTI and a PI, NNRTI, or INSTI
No changes in antiretroviral regimen in the six months prior to screening (except for a switch to a coformulated tablet from the component tablets)
A desire to switch off current antiretroviral therapy due to: a) Renal dysfunction (microalbuminuria/proteinuria or CrCl<70 mL/min/1.73 m2) on tenofovir disoproxil fumarate (TDF) of tenofovir al; b) Osteopenia or osteoporosis on a TDF-containing regimen (i.e., lowest T-score ≥1.0 standard deviation below the young adult mean measured by dual-energy x-ray absorptiometry); c) Peripheral neuropathy or lipoatrophy at least partially attributable to ongoing NRTI use; d) Intermediate or high Framingham risk (i.e., ≥10% 10-year risk) on an abacavir-containing regimen; e) Patient preference.
Laboratory values within six months of screening visit

Hemoglobin ≥8.0 g/dL
Platelet count ≥40,000/mm3
AST, ALT, and alkaline phosphatase ≤5 × ULN
Total bilirubin ≤2.5 x ULN (except for those on atazanavir-containing regimens)
Calculated creatinine clearance (CrCl) ≥45 mL/min as estimated by the Cockcroft-Gault equation:

For men, (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) = CrCl (mL/min)*

*For women, multiply the result by 0.85 = CrCl (mL/min)

For women of reproductive potential, negative serum or urine pregnancy test at screening and a negative urine pregnancy test at the entry visit prior to randomization and also agreeable to using a contraceptive of choice during the study period.

"Women of reproductive potential" are defined as women who have not been post-menopausal for at least 24 consecutive months (i.e., who have had menses within the preceding 24 months) and have not undergone surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or tubal ligation)

Exclusion Criteria:

Current CD4+ T-cell count <200 cells/µL
Current antiretroviral regimen consisting of three of more antiretroviral classes
History of genotypic resistance, phenotypic resistance or intolerance to either DRV or DTG.

Prohibited protease mutations: V11I, V32I, L33F, I47V/A/L, I50V, I54T/S/L/M, T74P, L76V, V82F, I84V, or L89V

Prohibited INSTI mutations: E92Q, E92K/A, G140S/A/C, Q148H/R/K or Q148 substitution plus any of the following: L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R.

History of virologic failure while on an INSTI prior to study enrollment
Severe hepatic impairment (Child Pugh Class C)
Hepatitis B Surface Antigen Positive
Breastfeeding, pregnancy, or plans to become pregnant during the study
Known allergy/sensitivity to any study drug or their formulations.
Receipt or planned receipt of prohibited concomitant medications (See section 5.2.1)
Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study procedures and treatment.
Serious medical illness that, in the opinion of the site investigator, precludes safe participation in the study.