Hepatitis CPhase 1CRUSADE-2NCT03817619
Bioequivalence Study of Crushed Elbasvir/Grazoprevir Compared to the Whole Tablet
A Phase 1 study testing Zepatier whole tablet and Zepatier crushed tablet in people with Hepatitis C and Deglutition Disorders, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
Elbasvir/grazoprevir (Zepatier®) is a once-daily tablet for the treatment of chronic hepatitis C virus (HCV) GT1a, 1b or 4 infection containing the NS5A inhibitor elbasvir (ELB) 50 mg and the NS3/4A protease inhibitor grazoprevir (GZR) 100 mg. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatitis C, Deglutition Disorders
- What is being tested?
- Zepatier whole tablet and Zepatier crushed tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteNetherlands
- Study dates
- 28 Mar 2019to 30 Jul 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Subject is at least 18 and not older than 55 years at screening.
- Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1.
- Subject weighs at least 40 kg.
- Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
- Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
- Subject is in good age-appropriate health condition as established by medical history, physical examination, and electrocardiography, results of biochemistry, hematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, hematology and urinalysis testing should be within the laboratory's reference ranges. If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
- Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment.
Who cannot join
- Creatinine clearance below 60 mL/min.
- Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
- Positive hepatitis B or C test
- Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contra-ception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study.
- Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (max 2 gram/day).
- Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders (clinically relevant increased ALAT/ASAT or hyperbilirubinemia), hormonal disorders (especially diabetes mellitus), coagulation disorders.
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- Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
- History of or current abuse of drugs, alcohol or solvents (positive drugs of abuse test).
- Inability to understand the nature and extent of the study and the procedures required.
- Participation in a drug study within 60 days prior to Day 1.
- Donation of blood within 60 days prior to Day 1.
- Febrile illness within 3 days before Day 1.
- Co-worker of Radboud university medical center.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Bioequivalence Study of CRUshed ElbaSvir/GrAzoprevir compareD to the wholE Tablet (CRUSADE-2)/Hep-NED005
Elbasvir/grazoprevir (Zepatier®) is a once-daily tablet for the treatment of chronic hepatitis C virus (HCV) GT1a, 1b or 4 infection containing the NS5A inhibitor elbasvir (ELB) 50 mg and the NS3/4A protease inhibitor grazoprevir (GZR) 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 ELB/GZR through a different route, like a feeding tube.
Read more
In daily practice, information about the safety and efficacy of crushed tablets is lacking which might result in noncompliance, 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 restarting).
Currently, patients and healthcare professionals are crushing 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 ELB and/or GZR 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 and/or AUC 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 ELB/GZR tablet is bioequivalent to ELB/GZR as a whole tablet.
- Conditions
- Hepatitis C, Deglutition Disorders
- Being tested
- Zepatier whole tablet, Zepatier crushed tablet
- Medical subject headings
- Hepatitis C, Deglutition Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Zepatier whole tabletDrug
Single-dose ELB/GZR as a whole tablet in a fasted state.
Zepatier crushed tabletDrug
Single-dose crushed ELB/GZR in a fasted state.
| Study group | Role | What they receive |
|---|---|---|
| Treatment R (reference) | Active comparator | Single-dose ELB/GZR as a whole tablet in a fasted state. Receives: Drug: Zepatier whole tablet |
| Treatment T (test) | Experimental | Single-dose crushed ELB/GZR in a fasted state. Receives: Drug: Zepatier crushed tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Bioequivalence AUC0-72h
Determination of elbasvir/grazoprevir AUC0-72h by noncompartmental analysis. Descriptive statistics for the plasma concentrations of elbasvir/grazoprevir at each sampling time. Descriptive statistics for each PK parameter per treatment (geometric mean + CV%).
Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of treatment T (Test) vs. treatment R (Reference). AUC0-72h geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.
Measured: 72 hours
Secondary outcomes (2)
Bioequivalence (Cmax)
Determination of grazoprevir Cmax by noncompartmental analysis. Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of T (Test) vs. R (Reference).
Cmax geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.
Measured: 18 days
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
Adverse events after intake of elbasvir/grazoprevir tablets in healthy adult volunteers.
Measured: 18 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jan 2019
- Study start28 Mar 2019
- Primary completion30 Jul 2019
- Study completion30 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hepatitis CStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Open-label, 2-period, randomised, cross-over, single-centre, phase I, single-dose trial in 14 healthy adult subjects. Intrasubject comparison of PK parameters after different administrations of Zepatier
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03817619
- Sponsor's protocol ID
- UMCN-AKF 17.01
- Acronym
- CRUSADE-2
- Status last verified
- Aug 2019
- First submitted
- 21 Jan 2019
- Last updated
- 19 Oct 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Pijnenburg DWM, van Seyen M, Abbink EJ, Colbers A, Drenth JPH, Burger DM. Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection. J Antimicrob Chemother. 2020 Sep 1;75(9):2661-2665. doi: 10.1093/jac/dkaa230.
PubMed 32544221
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Bioequivalence Study of CRUshed ElbaSvir/GrAzoprevir compareD to the wholE Tablet (CRUSADE-2)/Hep-NED005
- ClinicalTrials.gov ID
- NCT03817619
- Acronym / sponsor ID
- CRUSADE-2 / UMCN-AKF 17.01
- Conditions
- Hepatitis C, Deglutition Disorders
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- 28 Mar 2019 (actual)
- Primary completion
- 30 Jul 2019 (actual)
- Study completion
- 30 Jul 2019 (actual)
- First posted
- 25 Jan 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Elbasvir/grazoprevir (Zepatier®) is a once-daily tablet for the treatment of chronic hepatitis C virus (HCV) GT1a, 1b or 4 infection containing the NS5A inhibitor elbasvir (ELB) 50 mg and the NS3/4A protease inhibitor grazoprevir (GZR) 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 ELB/GZR 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 noncompliance, 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 restarting).
Currently, patients and healthcare professionals are crushing 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 ELB and/or GZR 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 and/or AUC 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 ELB/GZR tablet is bioequivalent to ELB/GZR as a whole tablet.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Open-label, 2-period, randomised, cross-over, single-centre, phase I, single-dose trial in 14 healthy adult subjects. Intrasubject comparison of PK parameters after different administrations of Zepatier
| Arm | Type | Receives |
|---|---|---|
| Treatment R (reference) | Active comparator | Drug: Zepatier whole tabletSingle-dose ELB/GZR as a whole tablet in a fasted state. |
| Treatment T (test) | Experimental | Drug: Zepatier crushed tabletSingle-dose crushed ELB/GZR in a fasted state. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Subject is at least 18 and not older than 55 years at screening.
- Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1.
- Subject weighs at least 40 kg.
- Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
- Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
Key exclusion criteria (13 listed)
- Creatinine clearance below 60 mL/min.
- Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
- Positive hepatitis B or C test
- Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contra-ception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study.
- Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (max 2 gram/day).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zepatier whole tabletSingle-dose ELB/GZR as a whole tablet in a fasted state. | Drug | Treatment R (reference) |
| Zepatier crushed tabletSingle-dose crushed ELB/GZR in a fasted state. | Drug | Treatment T (test) |
Primary outcome
Bioequivalence AUC0-72h
Time frame: 72 hours
Determination of elbasvir/grazoprevir AUC0-72h by noncompartmental analysis. Descriptive statistics for the plasma concentrations of elbasvir/grazoprevir at each sampling time. Descriptive statistics for each PK parameter per treatment (geometric mean + CV%). Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of treatment T (Test) vs. treatment R (Reference). AUC0-72h geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.
2 secondary outcomes
Bioequivalence (Cmax)
Time frame: 18 days
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
Time frame: 18 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2020.
- Background: PubMed 32544221Pijnenburg DWM, van Seyen M, Abbink EJ, Colbers A, Drenth JPH, Burger DM. Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection. J Antimicrob Chemother. 2020 Sep 1;75(9):2661-2665. doi: 10.1093/jac/dkaa230.
- paperLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Zepatier whole tablet and Zepatier crushed tablet in people with Hepatitis C and Deglutition Disorders, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Bioequivalence AUC0-72h (time frame: 72 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03817619, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2020.