Switching From Tenofovir Disoproxil Fumarate to Abacavir or Tenofovir Alafenamide

NCT ID: NCT02957864

Last Updated: 2020-01-28

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-31
• Study Completion Date: 2020-09-30

Brief Summary

Tenofovir disoproxil fumarate (TDF) is one of the most frequently used drugs to treat HIV. Long term use of TDF can induce renal toxicity. Tenofovir alafenamide (TAF) is a new pro-drug of Tenofovir which has not been associated with renal toxicity and may therefore be a good substitute for TDF in patients with TDF induced renal toxicity. Abacavir (ABC) is another drug that can be used for the treatment of HIV and is not associated with renal toxicity.

In this study the investigators will compare the effect on renal function of a switch from TDF to TAF with a switch from TDF to ABC in patients with TDF induced renal insufficiency.

Detailed Description

The majority of HIV-1 infected patients in resource rich countries receive the tenofovir prodrug tenofovir disoproxil fumarate (TDF) as part of their combination antiretroviral therapy (cART). Long-term exposure to TDF can be associated with an accelerated estimated glomerular filtration rate (eGFR) decline and proximal renal tubular dysfunction (PTD, see definition below). The current practice in patients in which TDF related renal toxicity becomes apparent is to substitute abacavir (ABC) for TDF. However, ABC is contraindicated in patients with HLAB57*01 and has been associated with an increased risk of cardiovascular disease in large HIV cohort studies, but not in randomized clinical trials. Recently, a new tenofovir prodrug, tenofovir alafenamide (TAF) was developed by Gilead Sciences and is available in a coformulation with emtricitabine (FTC). Due to the targeted delivery of tenofovir inside the CD4 positive cell by this prodrug, only 25 mg TAF is needed for the same antiviral effect observed in patients taking 250 mg of TDF and this lower TAF dose leads to 90% lower serum levels of tenofovir. In recently completed phase III studies in which patients with a normal kidney function where included, this lower tenofovir exposure in patients on TAF was shown to prevent off-target renal and bone toxicity in comparison with patients taking TDF. However, whether an already established TDF related renal toxicity in a HIV patient can be reversed after a switch to TAF, remains to be shown.

Objective:

To study the renal safety when HIV patients with TDF related renal toxicity switch to TAF compared to the current practice of switching to ABC.

Study design:

96 week open label multicenter randomized non-inferiority clinical trial.

Study population:

HIV-1 infected adults, suppressed HIV-RNA <50c/mL on a TDF containing antiretroviral regimen, with signs of TDF related renal toxicity as indicated by an accelerated eGFR decline.

Intervention:

Replace TDF with TAF (intervention arm) or ABC (control arm).

Main study parameters/endpoints:

Primary endpoint:

Recovery of renal dysfunction in the TAF arm versus the ABC arm at 48 weeks after the switch from TDF to TAF or ABC using the time to the first eGFR within 75% of the eGFR at the time of TDF initiation.

Secondary endpoints:

See below

Conditions

Renal Insufficiency,Chronic; Hiv; Therapeutic Agent Toxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Switch to tenofovir alafenamide

Switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide

Group Type: EXPERIMENTAL

tenofovir alafenamide

Intervention Type: DRUG

Switch to abacavir

Switch from tenofovir disoproxil fumarate (TDF) to abacavir

Group Type: ACTIVE_COMPARATOR

abacavir

Intervention Type: DRUG

Interventions

tenofovir alafenamide

Intervention Type: DRUG

abacavir

Intervention Type: DRUG

Other Intervention Names

Descovy; TAF; ABC

Eligibility Criteria

Inclusion Criteria

HIV-positive documented by ELISA or Western Blot or plasma HIV-RNA > 1000 copies/mL.

18 years or older. Stable on TDF/FTC or TDF/3TC for ≥12 months (365 days) in combination with a third antiretroviral agent (NNRTI, INI, or PI) and with an unchanged third agent for at least 1 month.

HIV-1 RNA <50 copies/mL for ≥ 6 months. Patient is negative for the HLA B5701 allele.

Confirmed/probable TDF-related accelerated eGFR decline (one of the following):

1. Accelerated eGFR decline: mean of > 3 mL/min/year since start TDF after ≥5 years of TDF exposure.

2. Confirmed eGFR < 70 mL/min in patients with baseline eGFR > 90 mL/min at start of TDF.

3. eGFR decrease > 25% compared to baseline eGFR at TDF-initiation.

Absence of other causes of eGFR decline:

Diabetic patients with diabetic nephropathy (defined as an eGFR decline and uACR>30mg/mmol with uAPR >/=0.4, or biopsy proven).

Hypertensive patients (defined as the use of antihypertensives or untreated systolic (>=160mmHg) or diastolic (>=95mmHg) hypertension) in combination with hypertensive nephropathy (defined as eGFR decline with uACR>30mg/mmol with uAPR>/=0.4, or biopsy proven).

Nephrotic syndromes/nephrotic range proteinuria (uACR >300mg/mmol and uAPR ≥ 0.4, or total 24hrs proteinuria >3.5g/24hr, or biopsy proven) Nephrotic syndromes including rapid progressive glomerulonephritis and tubular interstitial nephritis (defined as active urine sediment with erythrocyturia and leucocyturia and proteinuria with eGFR decline, with or without the presence of systemic disease, or biopsy proven).

Obvious other renal toxic effects related to lifestyle or medication (e.g. creatin use) suspected by the investigators or biopsy proven.

Concomittantly used medication does not interfere with trial procedures (on investigators' discretion).

Exclusion Criteria

Likely other cause (as defined above) of the accelerated GFR decline. HLA-B5701 positivity. Active hepatitis C or B. Documented intermediate or high level resistance to ABC. eGFR <30ml/min. Any other disease or medical condition that, in the opinion of the investigators, would interfere with the safety of the participant or the conduct of the trial.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: collaborator

Erasmus Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Bart Rijnders

principle investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bart Rijnders, MD PhD

Role: STUDY_DIRECTOR

Erasmus Medical Center

Locations

Ziekenhuis Rijnstate

Arnhem, Gelderland, Netherlands

Site Status: RECRUITING

MC Slotervaart

Amsterdam, , Netherlands

Site Status: RECRUITING

OLVG

Amsterdam, , Netherlands

Site Status: NOT_YET_RECRUITING

Erasmus MC

Rotterdam, , Netherlands

Site Status: RECRUITING

Maasstad ziekenhuis

Rotterdam, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Ingeborg Wijting, MD

Role: CONTACT

i.wijting@erasmusmc.nl

0031107040704

bart rijnders, MD PhD

Role: CONTACT

b.rijnders@erasmusmc.nl

0031107033510

Facility Contacts

Marc Claassen, PhD

Role: primary

Saskia Vrouenraets, MD, PhD

Role: primary

saskia.vrouenraets@slz.nl

0205129333

Guido van den Berk, MD, PhD

Role: primary

g.e.l.vandenberk@olvg.nl

0205999111

ingeborg wijting, MD

Role: primary

i.wijting@erasmusmc.nl

0031107040704

bart rijnders, MD PhD

Role: backup

b.rijnders@erasmusmc.nl

0031107033510

Anna Roukens, MD, PhD

Role: primary

roukensa@maasstadziekenhuis.nl

0102911911

Other Identifiers

NL55668.078.16

Identifier Type: -

Identifier Source: org_study_id