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Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): A structured summary of a study protocol for a randomised controlled trial
Trials volume 21, Article number: 584 (2020)
Abstract
Objectives
Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ).
Secondary objectives:
• Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells - peripheral blood mononuclear cells (PBMCs).
• Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes).
Trial design
Single centre, open-label, parallel group, two-arm, phase I drug-drug interaction trial.
Participants
Healthy volunteers (18-60 years old) are treated in the Clinical Pharmacological Trial Center of Heidelberg University Hospital, Germany.
Intervention and comparator
• Participants are randomized in a group to either receive a nine-day course of pantoprazole, or to a control group without pantoprazole. All participants receive a single dose of HCQ 400 mg.
• Additionally, CYP3A4 and CYP2D6 phenotyping with microdosed probe drugs is performed using midazolam and yohimbine as enzyme activity markers, respectively.
Main outcomes
Primary endpoint:
Area under the curve (AUC)0-72 h and maximum concentration (Cmax) of a single oral dose of 400 mg HCQ with and without pantoprazole (changes in these two values describe relevant aspects of exposure to HCQ with and without administration of pantoprazole).
Secondary endpoints:
• AUC2-4 h, AUC0-6 h and Cmax of midazolam and yohimbine.
• Correlation of HCQ concentrations in whole blood with concentrations in plasma and peripheral blood mononuclear cells (PBMC).
Randomisation
Participants are assigned to treatment groups by using a randomisation list (1:1, block size = 4) and consecutive enrolment.
Blinding (masking)
The trial is an open-label trial, participants and investigators are not blinded.
Numbers to be randomised (sample size)
A total number of 24 participants (12 per group) are planned to be randomised.
Trial Status
Protocol version 2.1 dated 24/04/2020, first patient first visit. April 30th, 2020, recruitment ongoing, anticipated end of study June 30th, 2020.
Trial registration
EudraCT Number: 2020-001470-30, registered on 31 March 2020 German Clinical trials register number / International Clinical Trials Registry Platform: DRKS00021573, registered on 27 April 2020
Full protocol
The full trial protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full trial protocol. The trial protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Availability of data and materials
Data will be available from the author on reasonable request.
Acknowledgements
We express our sincere gratitude to the study nurses of the Clinical Pharmacological Trial Center, Katharina Hilse, Florian Michel, Sophie Sherman, Marlies Stützle-Schnetz, and Brigitte Tayrouz for their excellent technical support during trial implementation and conduct. We also thank the clinical monitors Viktoria Jungreithmayr and Robert Möcker for their thorough supervision throughout the trial.
Funding
The study is funded by the Department of Clinical Pharmacology and Pharmacoepidemiology of Heidelberg University Hospital, Germany. The legal sponsor of the trial is the Ruprecht-Karls-University Heidelberg, Medical Faculty, represented in law by Heidelberg University Hospital, Germany, and its commercial director Katrin Erk. The trial is investigator-initiated, therefore, the main investigator has obtained all rights and duties from the legal sponsor except contract management. The legal sponsor itself does not have a role in collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.
Author information
Authors and Affiliations
Contributions
FS and AB: writing of trial protocol and manuscript, deputy investigators, conduct of the trial. WEH: conception of the trial, writing of trial protocol, principal investigator, conduct of the trial. GM: conception of the trial, writing of trial protocol, biostatistician. DC: conception of the trial, writing of trial protocol. AMu, KSH, SH, SHu: sub- investigators conducting the trial. KIF, JB, JW: laboratory methods and evaluation. The author(s) read and approved the final manuscript.
Authors’ information
WEH, AB, FS, GM and DC are experts in the field of clinical pharmacology and focus on optimization of drug therapy and safety of drug treatments.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The study was approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University on 17/04/2020 (AFmo-265/2020) and by the competent authority (Federal Institute for Drugs and Medical Devices, BfArM, Bonn, Germany) on 23/04/2020. All volunteers are fully informed about the trial, are free to participate, and are asked to give their written consent prior to any trial-related procedures. We certify that this trial has received ethical approval from the appropriate Ethics Committee as described above.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
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Supplementary information
Additional file 1.
Full Study Protocol.
Additional file 2.
SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.
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Stoll, F., Blank, A., Mikus, G. et al. Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): A structured summary of a study protocol for a randomised controlled trial. Trials 21, 584 (2020). https://doi.org/10.1186/s13063-020-04476-y
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DOI: https://doi.org/10.1186/s13063-020-04476-y