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

Primary Purpose

Hepatitis C, Swallowing Disorder

Status

Completed

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

velpatasvir

About this trial

This is an interventional other trial for Hepatitis C focused on measuring velpatasvir, cola, omeprazole, proton pump inhibitors

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

Radboud university medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

A: Epclusa + omeprazole + Coca Cola (test 1)

B: Epclusa + omeprazole + water (test 2)

C: Epclusa + water (Reference)

Arm Description

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).

Day 8 - 13: 40mg omeprazole QD; on Day 12 a single-dose of SOF/VEL is administered (test 2).

Day 15 - 21: no treatment with omeprazole; on Day 19 a single-dose of SOF/VEL is administered (reference).

Outcomes

Primary Outcome Measures

Bioequivalence AUC0-inf

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

Safety and tolerability of Epclusa in healthy volunteers

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).

Bioequivalence (Cmax)

Determination of velpatasvir Cmax by noncompartmental analysis.

Bioequivalence AUC0-48h

Determination of velpatasvir AUC0-48h by noncompartmental analysis.

Full Information

NCT ID

NCT03513393

First Posted

April 18, 2018

Last Updated

October 16, 2020

Sponsor

Radboud University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT03513393

Brief Title

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

Acronym

COPA

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.

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Completed

Study Start Date

August 1, 2018 (Actual)

Primary Completion Date

December 1, 2018 (Actual)

Study Completion Date

December 1, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Radboud University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatitis C, Swallowing Disorder

Keywords

velpatasvir, cola, omeprazole, proton pump inhibitors

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

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)

Allocation

Randomized

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

A: Epclusa + omeprazole + Coca Cola (test 1)

Arm Type

Experimental

Arm Description

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).

Arm Title

B: Epclusa + omeprazole + water (test 2)

Arm Type

Experimental

Arm Description

Day 8 - 13: 40mg omeprazole QD; on Day 12 a single-dose of SOF/VEL is administered (test 2).

Arm Title

C: Epclusa + water (Reference)

Arm Type

Active Comparator

Arm Description

Day 15 - 21: no treatment with omeprazole; on Day 19 a single-dose of SOF/VEL is administered (reference).

Intervention Type

Drug

Intervention Name(s)

velpatasvir

Other Intervention Name(s)

Omeprazole, Coca Cola Classic 250ml

Intervention Description

Test 1

Intervention Type

Drug

Intervention Name(s)

velpatasvir

Other Intervention Name(s)

Omeprazole, water 250ml

Intervention Description

Test 2

Intervention Type

Drug

Intervention Name(s)

velpatasvir

Intervention Description

Reference

Primary Outcome Measure Information:

Title

Bioequivalence AUC0-inf

Description

Time Frame

21 days

Secondary Outcome Measure Information:

Title

Safety and tolerability of Epclusa in healthy volunteers

Description

Time Frame

21 days

Title

Bioequivalence (Cmax)

Description

Determination of velpatasvir Cmax by noncompartmental analysis.

Time Frame

21 days

Title

Bioequivalence AUC0-48h

Description

Determination of velpatasvir AUC0-48h by noncompartmental analysis.

Time Frame

21 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility 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.

Facility Information:

Facility Name

Radboud university medical Center

City

Nijmegen

State/Province

Gelderland

ZIP/Postal Code

6525 GA

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

31313296

Citation

van Seyen M, Colbers A, Abbink EJ, Drenth JPH, Burger DM. Concomitant Intake of Coca-Cola to Manage the Drug-Drug Interaction Between Velpatasvir and Omeprazole Studied in Healthy Volunteers. Clin Pharmacol Ther. 2019 Nov;106(5):1093-1098. doi: 10.1002/cpt.1569. Epub 2019 Aug 18.

Results Reference

result

Links:

URL

https://pubmed.ncbi.nlm.nih.gov/31313296/

Description

paper

Learn more about this trial

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

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