Bioequivalence Study of Crushed Sofosbuvir/Velpatasvir Compared to the Whole Tablet (CRUSADE-1)

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 (and restart).

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.

Study Overview

• Status: Withdrawn
• Conditions: HCV
• Intervention / Treatment: Drug: sofosbuvir/velpatasvir tablet; Drug: sofosbuvir/velpatasvir crushed

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany
    • University of Bonn, Germany
• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Hospital
  • Nijmegen, Netherlands
    • Radboud university medical center Department of GI tract

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with SOF/VEL treatment for the treatment of chronic HCV genotype 1 through 6.
2. Patient is at least 18 at the day of screening.
3. Patient is able and willing to sign the Informed Consent Form.
4. Patient is able and willing to follow protocol requirements.

Exclusion Criteria:

1. Pregnant female (as confirmed by an hCG urine test performed at screening) or breast-feeding female.
2. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
3. Inability to understand the nature and extent of the study and the procedures required.
4. Clinically relevant low hemoglobin concentration at screening judged by the patient's own hepatologist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: sofosbuvir/velpatasvir tablet; Single-dose sofosbuvir/velpatasvir as a whole tablet in a fasted state.	Drug: sofosbuvir/velpatasvir tablet; Single-dose SOF/VEL as a whole tablet in a fasted state.
Experimental: sofosbuvir/velpatasvir crushed; Single-dose crushed sofosbuvir/velpatasvir in a fasted state.	Drug: sofosbuvir/velpatasvir crushed; Single-dose crushed SOF/VEL in a fasted state.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
AUC	Up to 24 hours after administration
Cmax	one dosing interval after administration of SOF/VEL (up to 24 hours)

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events	During the entire conduct of the study, maximum of two weeks

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Publications and helpful links

General Publications

• van Seyen M, Samson AD, Cullen L, Eastick K, Knol H, Colbers A, Burger DM. Crushed application of sofosbuvir and velpatasvir in a patient with swallowing disorder. Int J Antimicrob Agents. 2020 Jun;55(6):105934. doi: 10.1016/j.ijantimicag.2020.105934. Epub 2020 Mar 7. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2018
• Primary Completion (Actual): March 22, 2019
• Study Completion (Actual): March 22, 2019

Study Registration Dates

• First Submitted: September 25, 2017
• First Submitted That Met QC Criteria: January 2, 2018
• First Posted (Actual): January 3, 2018

Study Record Updates

• Last Update Posted (Actual): December 7, 2020
• Last Update Submitted That Met QC Criteria: December 4, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Epclusa; Crushing
• Additional Relevant MeSH Terms: Wounds and Injuries; Crush Injuries; Anti-Infective Agents; Antiviral Agents; Sofosbuvir; Sofosbuvir-velpatasvir drug combination; Velpatasvir
• Other Study ID Numbers: UMCN-AKF 16.06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No