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Influence of Cola on the Absorption of the HCV Agent Velpatasvir in Combination With PPI Omeprazole. (COPA)

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ClinicalTrials.gov Identifier: NCT03513393
Recruitment Status : Not yet recruiting
First Posted : May 1, 2018
Last Update Posted : May 7, 2018
Sponsor:
Information provided by (Responsible Party):
Radboud University

Brief Summary:

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.

Velpatasvir has pH dependent absorption. At higher pH the solubility of velpatasvir decreases. It has been shown that in subjects treated with proton pump inhibitors (PPIs) such as omeprazole, the absorption of velpatasvir is reduced by 26-56%, depending on the dose of omeprazole, concomitant food intake, and timing/sequence of velpatasvir vs. omeprazole intake. As a result, concomitant intake of PPIs with velpatasvir is not recommended.

For a number of reasons, the prohibition of PPI use with velpatasvir is a clinically relevant problem. First, PPI use is highly frequent in the HCV-infected subject population with prevalences reported up to 40%. Second, PPIs are available as over-the-counter medications and thus can be used by subjects without informing their physician. Third, although HCV therapy is generally well tolerated, gastro-intestinal symptoms such as abdominal pain and nausea are frequently reported, which my lead to PPI use.

One solution of this problem could be the use of other acid-reducing agents such as H2-receptor antagonists or antacids. In general, they have a less pronounced effect on intragastric pH, and are considered less effective than PPIs by many patients and physicians.

A second solution would be the choice of another HCV agent or combination that is not dependent on low gastric pH for its absorption such as daclatasvir. Daclatasvir, however, is not a pan-genotypic HCV agent and may be less effective against GT 2 and 3 infections than velpatasvir. Second, not all subjects have access to daclatasvir, depending on health insurance company or region where they live.

A third solution, and the focus of this COPA study, is to add a glass of the acidic beverage cola at the time of velpatasvir administration in subjects concurrently treated with PPIs. This intervention has been shown to be effective for a number of drugs from other therapeutic classes who all have in common a reduced solubility (and thus reduced absorption) at higher intragastric pH, namely erlotinib, itraconazole, ketoconazole.

The advantages of this approach are: (1) only a temporary decrease in gastric pH at the time of cola intake; the rest of the day the PPI will have its therapeutic effect (2) cola is available worldwide (3) the administration of cola can be done irrespective to the timing of PPI use.


Condition or disease Intervention/treatment Phase
Hepatitis C Swallowing Disorder Drug: velpatasvir Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: An open-label, 3-period, single-centre, phase-I, multi PPI dose, single velpatasvir dose trial in 12 healthy volunteers.
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Influence of the Acidic Beverage Cola on the Absorption of the HCV Agent Velpatasvir in Healthy Volunteers Being Treated With the Proton Pump Inhibitor Omeprazole.
Estimated Study Start Date : August 1, 2018
Estimated Primary Completion Date : December 1, 2018
Estimated Study Completion Date : December 1, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: A: Epclusa + omeprazole + Coca Cola (test 1)
Day 1 - 6 40mg omeprazole QD; on Day 5 a single-dose of SOF/VEL with 250 mL of Coca Cola Classic is administered (test 1).
Drug: velpatasvir
Test 1
Other Names:
  • Omeprazole
  • Coca Cola Classic 250ml

Experimental: B: Epclusa + omeprazole + water (test 2)
Day 8 - 13: 40mg omeprazole QD; on Day 12 a single-dose of SOF/VEL is administered (test 2).
Drug: velpatasvir
Test 2
Other Names:
  • Omeprazole
  • water 250ml

Active Comparator: C: Epclusa + water (Reference)
Day 15 - 21: no treatment with omeprazole; on Day 19 a single-dose of SOF/VEL is administered (reference).
Drug: velpatasvir
Reference




Primary Outcome Measures :
  1. Bioequivalence AUC0-inf [ Time Frame: 21 days ]

    Determination of velpatasvir AUC0-inf by noncompartmental analysis.

    Descriptive statistics for the plasma concentrations of velpatasvir 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 A (Test 1) vs. C (Reference) and of B (Test 2) vs. C (Reference).

    AUC0-inf geometric mean ratios with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.



Secondary Outcome Measures :
  1. Safety and tolerability of Epclusa in healthy volunteers [ Time Frame: 21 days ]

    To evaluate the safety and tolerability of SOFA/EL tablets in healthy volunteers.

    Adverse events after administration of SOFA/EL in the three interventions will be described and compared (including clinically relevant laboratory abnormalities).


  2. Bioequivalence (Cmax) [ Time Frame: 21 days ]
    Determination of velpatasvir Cmax by noncompartmental analysis.

  3. Bioequivalence AUC0-48h [ Time Frame: 21 days ]
    Determination of velpatasvir AUC0-48h by noncompartmental analysis.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 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 (see Appendix A). 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.

Exclusion Criteria:

  • 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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03513393


Contacts
Contact: Minou van Seyen, MSc +31 (0) 24 361 77 44 minou.vanseyen@radboudumc.nl
Contact: David Burger +31 (0) 24 361 77 44 david.burger@radoudumc.nl

Locations
Netherlands
Radboud university medical Center Not yet recruiting
Nijmegen, Gelderland, Netherlands, 6525 GA
Contact: David M Burger, prof. dr.    +31243617744    david.burger@radboudumc.nl   
Principal Investigator: David M Burger, prof. dr.         
Sponsors and Collaborators
Radboud University

Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03513393     History of Changes
Other Study ID Numbers: UMCN-AKF 17.02
First Posted: May 1, 2018    Key Record Dates
Last Update Posted: May 7, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Radboud University:
velpatasvir
cola
omeprazole
proton pump inhibitors

Additional relevant MeSH terms:
Omeprazole
Hepatitis C
Deglutition Disorders
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Hepatitis
Liver Diseases
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Pharyngeal Diseases
Otorhinolaryngologic Diseases
Proton Pump Inhibitors
Anti-Ulcer Agents
Gastrointestinal Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action