Safety of Sofosbuvir in People With Advanced Kidney Failure
Condition: Kidney Failure, Chronic; Hepatitis C
MeSH terms: Hepatitis C; Hepatitis; Renal Insufficiency; Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 3

Summary: 
      Infection with hepatitis C virus (HCV), a hepatotropic RNA virus, is often chronic, and
      causes liver cirrhosis and liver cancer. The virus is transmitted through parenteral
      exposure. This infection is particularly common in those on maintenance hemodialysis.

      Sofosbuvir, an inhibitor of HCV RNA-dependent RNA polymerase, forms the backbone of DAA-based
      anti-HCV treatment regimens. In pre-clinical pharmacokinetic studies, administration of the
      usual 400 mg daily dose to in presence of advanced kidney failure (estimated glomerular
      filtration rate [eGFR] of <30 ml/min) showed that serum levels of the sofosbuvir and
      GS-331007, the primary metabolite of sofosbuvir, were elevated by several folds. Hence,
      sofosbuvir is not approved for use in people on maintenance hemodialysis.

      The newer DAAs (e.g. grazoprevir/elbasvir combination), which have been approved for use in
      people with eGFR <30 ml/min, are very costly and are not available in Asian countries
      including India. Hence, as a rescue measures, several physicians, including our group, have
      tried half-daily dose (i.e, 200 mg daily or 400mg on alternate days) of sofosbuvir and 60 mg
      daclatasvir in dialysis-dependent people, with good results in terms of both safety and
      efficacy. In fact, the use of this empirical 200 mg daily dose schedule has become common in
      clinical practice. However, this use is not based on any pharmacokinetic data.

      Hence, it is proposed to study the pharmacokinetics of low-dose (200 mg daily or 400 mg
      alternate day) of sofosbuvir and GS-331007 metabolite in people with eGFR <30/min and active
      HCV infection.
    

Detailed description: 
      Study design Three arms, observational, pharmacokinetic study

      Study duration Two years (March 2019-February 2020)

      Study participants Two groups of participants will be included (i) People without chronic
      kidney disease, i.e, normal eGFR and infected with HCV infection (ii) People with chronic
      kidney disease and eGFR <30 ml/min and infected with HCV infection

      We will include a total of thirty participants with ten in each of the three groups: Group A
      (ESRD, alternate day dose), Group B (ESRD, daily dose) and Group C (normal eGFR)

      Drug schedule Participants with eGFR <30 ml/min: will be given daclatasvir 60 mg once daily
      along with either sofosbuvir (200 mg) daily once or sofosbuvir 400mg once every alternate day
      Participants with normal renal function will be treated with sofosbuvir 400mg and daclatasvir
      60 mg once daily.

      The treatment duration will be 12 weeks for alll there three study groups.

      Dialysis schedule A four to five hour hemodialysis sessions will be provided twice in a week

      Plan for pharmacokinetic study (i) Molecules: Sofosbuvir and GS331007 (ii) Method: Liquid
      chromatography-tandem mass spectrometry (iii) Specimen collection (~2 ml each time) will be
      done as follows: Hour '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 [Day 1]; hour 36 [Day 2]; hour
      84 [Day 4], and hour 156 [Day 7].

      Sample Collection, Transport and Storage Soon after sample collection, serum will be
      separated by centrifugation at 4000×g for 10 min at 4°C and separated serum will stored at
      -80°C till analysis. Analysis will be done using validated bioanalytical method at CSIR-CDRI,
      Lucknow.

      Inactivation of hepatitis C virus in the stored sample HCV inactivation will be done by heat
      treatment. Before heat treatment, water bath chamber will be cleaned, filled with fresh RO
      water and temperature calibration will be checked for accuracy. The specimens will be heated
      at 60 C for 10 minutes or 65 C for 5 minutes to inactivate the virus. Immediately after heat
      treatment, the specimens will be put in crushed ice to stop the heat effect. The specimens
      will be transported in frozen condition for analysis.

      Sample preparation:

      The sample preparation consists of the simple liquid-liquid extraction and/or protein
      precipitation.

      Liquid chromatography-mass spectroscopy HPLC system consisting of Shimadzu UFLC system
      consisting of LC-20AD binary pumps and SIL-HTc autosampler (Shimadzu Corporation, Kyoto,
      Japan) will be used to inject 10 µL aliquots of the processed samples on a C18 column (4.6 mm
      × 50 mm, 5.0 µm). The separation will be achieved by running the mobile phase in isocratic
      mode containing acetonitrile and 10mM ammonium acetate buffer in suitable ratio (%v/v) at a
      flow rate capable of sufficient resolution to be optimized during method development and
      validation. The mobile phase will be duly filtered through 0.22 µm filter and degassed
      ultrasonically before use. Mass spectrometric detection will be performed on an API 5500 Q
      Trap mass spectrometer (Applied Biosystems, MDS Sciex Toronto, Canada) equipped with an API
      electron spray ionization (ESI) source. The ion spray voltage will be set at 5500 V. The
      instrument related parameters viz., nebulizer gas, curtain gas, auxiliary gas and collision
      gas and coompound related parameters viz., declustering potential (DP), collision energy
      (CE), entrance potential (EP) and collision cell exit potential (CXP) respectively will be
      optimized before validating the method . Zero air will be used as source gas while nitrogen
      will be used as both curtain and collision gas. The mass spectrometer will be operated at ESI
      positive as well as ESI negative ion mode and detection of the ions will be performed in the
      multiple reaction monitoring (MRM) mode monitering the transitions of the analytes.
      Quadrupole 1 and quadrupole 3 will be maintained at unit resolution and dwell time will be
      set at 200 ms. Analyst 1.6 software (version 1.6, Built 3773; AB Sciex, Toronto, Canada) will
      be used for data acquisition and quantitation.

      Pharmacokinetic parameters estimation The pharmacokinetic parameters will be estimated using
      WinNonlin software either through compartment/non-compartment modeling.
    

Intervention name(s): Sofosbuvir; Daclatasvir 60 mg
Intervention type(s): Drug; Drug
Intervention description(s): Sofosbuvir is the backbone of the most of the currently used anti-HCV treatment regimens; Daclatasvir, in combination with sofosbuvir, is approved for the treatment of hepatitis C virus infection in absence of liver cirrhosis
Intervention MeSH terms: Sofosbuvir
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a three arm, case control study aimed at studying the pharmacokinetics of sofosbuvir and its major metabolite (GS-331007) in people with estimated GFR (eGFR) <30 ml/min. Two arms will include participants with advanced renal failure with eGFR below 30 ml/min and third arm will include participants with normal eGFR. Participants with eGFR <30 ml/min will receive sofosbuvir in doses of either 400mg on alternate days or 200mg daily. The participants with normal eGFR will receive the standard of care, i.e, 400mg of sofosbuvir daily
Masking: None (Open Label)
Primary purpose: Basic Science