Clinical trial NCT02351908: Renal Integrase Study
Official title: A Phase IV, Open-label Three-arm Study Investigating the Impact of a Combination of Tenofovir Disoproxil Fumarate/Emtricitabine With Raltegravir or Dolutegravir or Elvitegravir/Cobicistat on Renal Tubular Function and Renal Transporters in HIV-1 Antiretroviral naïve Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Lead sponsor: St Stephens Aids Trust
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-01-30
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: The purpose of this study is to observe the safety of Truvada® (TDF/FTC) in relation to its impact on kidney function combined with different Integrase Inhibitors (Dolutegravir, or Elvitegravir/Cobicistat or Raltegravir), when given to patients who are commencing treatment for HIV infection for the first time.

All three combinations (Raltegravir + Truvada®, Dolutegravir + Truvada® and Stribild®, a single pill which contains Elvitegravir/Cobicistat/Truvada®) are currently recommended by the national guide-lines and used in standard clinical practice.

Detailed description: The study will monitor kidney function, and compare the safety and effectiveness of Truvada® when taken with Dolutegravir, or Elvitegravir/Cobicistat or Raltegravir, over the first 48 weeks of treatment in HIV-1 antiretrovirals naïve patients.

The safety and how well these drug combinations are tolerated will be determined based on physical examinations, laboratory tests, and questions about any problems the participant might experience during the study. As part of this trial, levels of HIV-1 in the blood and urinary markers of kidney function and inflammatory markers will be measured at various times during the study.

The total duration of participant involvement in the trial will be up to 48 weeks, with up to 45 days between the screening and baseline visits. Participants will need to visit the clinic 6 times within the 48 weeks.

Once participants have been confirmed to be eligible to participate in the study, participants will attend for a baseline visit (day 1) where they will be randomly assigned to receive one of the three treatments listed below:

* Treatment Arm 1: Stribild® (EVG/COBI/FTC/TDF) 1 tablet once a day
* Treatment Arm 2: Isentress® (Raltegravir 400 mg) 1 tablet twice a day + Truvada® 1 tablet once a day
* Treatment Arm 3: Tivicay® (Dolutegravir 50 mg) 1 tablet once a day + Truvada® 1 tablet once a day

Eligibility criteria: Inclusion Criteria:

1. Is male or female aged 18 years or above
2. Has documented HIV-1 infection
3. Has signed the Informed Consent Form voluntarily
4. Is willing to comply with the protocol requirements, including dosing schedules of each regimen
5. Has a HIV-plasma viral load at screening \>1000 copies/mL
6. Has any CD4 cell count
7. Has never been exposed to ART (other than via PEP or PREP, not associated with acquisition of HIV)
8. Has an estimated glomerular filtration rate (MDRD method) \>60 ml/min
9. Has no known resistance to TDF and FTC or to Integrase Inhibitors. HIV resistance test has to be dated no more than 1 year prior screening date. Only a RT/Pr gene resistance test is re-quired.
10. If female and of childbearing potential, she is using effective birth control methods (as agreed by the investigator) and is willing to continue practising these birth control methods during the trial and for at least 30 days after the end of the trial (or after last intake of investigational ARVs); Dosing of the OCP may need to be adjusted if randomized to the Stribild® arm.

    Note: Women who are postmenopausal for least 2 years, women with total hysterectomy, and women who have a tubal ligation are considered of non-childbearing potential
11. If a heterosexually active male, he is using effective birth control methods and is willing to con-tinue practising these birth control methods during the trial and until follow-up visit

Exclusion Criteria:

1. Is infected with HIV-2
2. Is using any concomitant therapy disallowed as per SPC for the study drugs
3. Has a currently active AIDS defining illness (Category C conditions according to the CDC Classification System for HIV Infection-1993) with the following exceptions (must be discussed with the sponsor prior to enrolment):

   * Stable cutaneous Kaposi's Sarcoma (no pulmonary or gastrointestinal involvement other than oral lesions) unlikely to require systemic therapy during the trial period
   * CD4 count less than 200 cells/mm3 Note: Primary and secondary prophylaxis for an AIDS defining illness is allowed
4. Has diabetes or any known or established renal disease or abnormality regardless of if stable
5. Has presence at screening of proteinurea and or a urinary protein/creatinine ratio \>30
6. Has untreated / not well controlled hypertension
7. Has acute viral hepatitis including, but not limited to, A, B, or C
8. Has chronic hepatitis B or chronic hepatitis C with AST and/or ALT \>5 x ULN Note: Subjects co-infected with chronic HCV (but not B) can enter the trial if clinically stable and not expected to require treatment during the trial period.
9. Has received any investigational drug within 30 days prior to the trial drug administration
10. No baseline resistance test to reverse transcriptase inhibitors available
11. Clinically significant allergy or hypersensitivity or other contraindication to any trial medication or excipients
12. If female, she is pregnant or breastfeeding
13. Screening blood results with any grade 3 / 4 toxicity according to Division of AIDS (DAIDS) grading scale, except: asymptomatic grade 3 glucose, amylase or lipid elevation or asymptomatic grade 4 triglyceride elevation (re-test allowed).
14. Clinical or laboratory evidence of significantly decreased hepatic function or decompensation: INR \> 1.5 or albumin \< 30g/L
15. Any condition (including drug/alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the trial.
16. Is not using high protein training supplements such as creatinine or intermittently following exclusionary or high protein diets
17. Is not receiving medication with known relevant drug interactions or contraindications to any of the trial medications

Primary outcomes:
measure: Change in retinol-binding protein/creatinine ratio (PCR) with each regimen over 24 weeks.
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in retinol-binding protein/creatinine ratio with each regimen over 12 and 48 weeks.
timeFrame: 48 weeks
measure: eGFR
timeFrame: 48 weeks
measure: Virologic response
timeFrame: 48 weeks
measure: Immunologic markers
timeFrame: 48 weeks
measure: Inflammatory markers
timeFrame: 48 weeks
measure: Metabolic markers
timeFrame: 48 weeks
measure: Tenofovir concentration
timeFrame: 4 weeks
measure: Genetic polymorphisms
timeFrame: 48 weeks
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: SSAT Clinical Research Facility
Study officials:
affiliation: Chelsea and Westminster NHS Foundation Trust
name: Graeme Moyle, MD, MBBS, Dip GUN
role: PRINCIPAL_INVESTIGATOR
References: