Bioequivalence study of CRUshed Sofosbuvir/velpAtasvir compareD to the wholE tablet (CRUSADE-1)/Hep-NED004

Epclusa® is a pan-genotypic, once-daily tablet for the treatment of chronic
hepatitis C virus (HCV) infection containing the NS5B- polymerase inhibitor
sofosbuvir (SOF, nucleotide analogue) 400 mg and the NS5A inhibitor velpatasvir
(VEL) 100 mg.

For patients with swallowing difficulties, administration of whole tablets can
be problematic. In addition, HCV patients that are hospitalized (at intensive
care units) due to severe illness (co-infections/ liver failure) might not be
able to swallow medication. Therefore it is useful to know whether it is
possible to administer SOF/VEL through a different route, like a feeding tube.

In daily practice, information about the safety and efficacy of crushed tablets
is lacking which might result in interruption or discontinuation of expensive
HCV therapy. However, it is not recommended to interrupt treatment because
there is no evidence about the efficacy of the therapy after discontinuation.
Currently, patients and healthcare professionals are crushing SOF/VEL tablets
without information about efficacy and safety. Depending on the
biopharmaceutical characteristics of a drug formulation, crushing tablets can
lead to altered pharmacokinetics of drugs.
It is important to know whether pharmacokinetic parameters are influenced by
crushing of tablets; both a decrease and an increase in exposure may occur. A
decrease of the plasma concentrations of SOF and/or VEL potentially reduces the
therapeutic effect of the drugs. Higher doses or switching to other HCV-drugs
might be needed. In contrast, in case a higher Cmax,ss and/or exposure occurs
there might be an increased risk of toxicity.

As a result, crushing the drug is a contra-indication based on the available
data.
Therefore this study will be conducted to investigate whether a crushed SOF/VEL
tablet is bioequivalent to SOF/VEL as a whole tablet.

Primary objective:
To assess the bioequivalence of SOF/VEL as a crushed (test) tablet compared to
a whole (reference) tablet in patients treated with SOF/VEL

Secondary objective:
To evaluate the safety and tolerability of crushed SOF/VEL tablets in patients.

Open-label, 2-period, randomised, cross-over, multiple-centre, phase-IV, multi
dose trial in 14 HCV infected patients.

Administration of a crushed tablet

For a number of reasons, administration of the large Epclusa® tablet can lead
to administration difficulties. Pharmacokinetic properties and information
about safety and efficacy of SOF/VEL after crushing are unknown. This also
accounts for other DAAs. Because no data are available on bioavailability of
SOF/VEL after crushing, crushing the drug is a contra-indication. The efficacy
after interruption or discontinuation of the expensive HCV therapy is unknown.

There are currently no treatment options with DAAs for patients with
administration difficulties like swallowing disorders. Therefore, potential
value of this research is to provide information about whether it is possible
to crush the tablets and/or administer SOF/VEL through a different route, like
a feeding tube.
Because SOF/VEL is the first DAA regimen with potent pan-genotypic activity it
is useful to determine whether a crushed SOF/VEL tablet is bioequivalent to
SOF/VEL as a whole tablet for this specific DAA.

Due to ethical considerations, this study will be performed in adult patients
who are currently treated with SOF/VEL instead of healthy patients. Patients
who are included have tolerated SOF/VEL for at least eleven weeks. Therefore
the risk for adverse events with the administration of one additional dose in
this population is very low. Using this study design, healthy patients are not
unnecessarily exposed to SOF/VEL.
Based on the list of excipients no large differences in bioavailability will be
expected. Although no large differences will be expected the crushed tablet
will be administrated during the last week of treatment in order to ensure the
efficacy.

The study participants are patients >= 18 years.

Patients will visit the clinical research centre for 1 short visit (15 minutes)
and 2 full days (9 hours).
Study duration will be between 3 and 8 days, depending study treatment days
(window day 78 - day 84).
Note: There will be an additional short visit (15 minutes) for patients who
prefer not to have the PK days on two consecutive days.

For pharmacokinetic purposes 15 blood samples will be taken for the standard
protocol. For safety assessment (haematology and clinical chemistry), a total
of six blood samples will be collected. The total blood volume taken will be
approximately 123 ml maximum. During the days that blood samples will be
collected for a PK-curve, an intravenous cannula will be inserted to facilitate
blood sampling and limit the amount of venous punctures.
Note: During the first short visit three additional blood samples (one PK
sample and two samples for safety assessment) will be taken for patients who
prefer not to have the PK days on two consecutive days. The total blood volume
taken will be approximately 136 ml maximum instead of 123 ml.

The patients will not benefit from the participation in this clinical trial.

Epclusa® is a registered product and is well tolerated in healthy and
HCV-infected subjects. As decribed previously the risk for included patients is
very low. See chapter 10.1.4 for information on the risks assessment.
A potential issue of concern might be the administration of the crushed tablet.
Crushing tablets can lead to altered pharmacokinetics of drugs, both a decrease
or an increase of exposure may occur.
In this study, only a single crushed dose will be administered during the last
week of the treatment. A decrease in exposure is assessed as not clinically
relevant.

A higher maximum concentration and/or exposure may result in an increased risk
of toxicity.
No dose- or exposure-response relationship for safety was explored for VEL and
SOF. The phase 3 studies only tested one single dose of SOF/VEL (400 mg/100
mg), and the FDA Office of Clinical Pharmacology (OCP) team did not identify
any prominent adverse events or adverse events of special interest for further
investigation. Thorough QT studies have been conducted for SOF and VEL. VEL
(500 mg) and SOF (1200 mg) do not prolong QTc interval to any clinically
relevant extent. (8)

Although no exposure-response relationship for safety was explored changes in
pharmacokinetic parameters for SOF and VEL have been investigated in drug-drug
interaction studies.
Recommendations concerning co-administration of a single drug with SOF or VEL
as a victim suggest no dose adjustment of Epclusa when the drug-drug
interaction leads to a higher Cmax or AUC.(8)
For example, a 60% increase in Cmax and 100% increase in AUC were observed when
VEL (100 mg) was coadministered with cyclosporine (600 mg). When SOF (400mg)
was coadministered with cyclosporine (600 mg) a 150% increase in Cmax and 350%
increase in AUC were observed. The magnitude of increase in VEL and SOF Cmax
and AUC when coadministered with cyclosporine was not considered clinically
significant since no dose adjustment is required. (8)

In addition, previously bioequivalence studies on crushing medication show
differences in maximum concentration and exposure. However, in comparable study
designs in HIV medication (without a gastro-resistant coating or slow-release
profile), no large increases in maximum concentration and exposure were found
relative to the range of bioequivalence (0.8-1.25)(6, 7).

The risk for adverse events with the administration of one additional dose in
this population is very low.