- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04525235
Phenotyping of High Dose Rifampicin (PHENORIF)
August 16, 2021 updated by: Radboud University Medical Center
The Effect of High Dose Rifampicin on the Activity of Cytochrome P450 Enzymes and P-glycoprotein in Patients With Pulmonary Tuberculosis: a Cocktail Phenotyping Study
Higher doses of rifampicin as a means of more efficient use of this pivotal TB drug has shown promising results and might become standard in future.
This means that higher doses of rifampicin will be co-administered with many other drugs taken by TB patients, including anti-retroviral, anti-diabetic, cardiovascular and other drugs.
Therefore, in this study the aim is to quantitatively assess the drug interaction potential of high dose rifampicin (~40 mg/kg daily dose, the currently available maximum tolerated dose) with respect to five major human drug-metabolizing CYP enzymes and P-gp in comparison to the conventional dose of 10 mg/kg daily in pulmonary TB patients.
A phenotyping approach with single administration of several selective substrates for multiple enzymes will be used, in order to prevent multiple drug-drug interaction studies.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
25
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Cape Town, South Africa
- TASK
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Cape Town, South Africa
- UCT Lung institute
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years to 63 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- The participant is able and willing to provide written, informed consent prior to all trial-related procedures.
- The participant is aged between 18 and 65 years, inclusive.
- The participant is a diagnosed pulmonary TB patient.
- The participant is currently being treated with a daily dose of 10 mg/kg rifampicin, i.e. 450 mg daily for patients with a body weight below 55 kg and 600 mg daily for participants with a body weight above 55 kg. This is in correspondence with the local South African TB treatment programme. Furthermore, the participant has to be in the continuation phase of the treatment regimen (i.e. month 3 to 6), has demonstrated reasonable treatment compliance (≥80% of doses) and tolerates treatment well.
- The participant has a body weight (in light clothing and with no shoes) between 40 and 85 kg, inclusive.
- The participant is and stays non-pregnant (based on a negative serum pregnancy test,) and non-lactating (female participants of childbearing potential only).
Exclusion Criteria:
- The patient is in poor general condition where any change in treatment cannot be accepted per discretion of the Investigator.
- The participant has active Hepatitis B.
- The participant has active Hepatitis C.
- The participant is receiving antiretroviral therapy (ART).
- There is evidence showing the participant has clinically significant metabolic, gastrointestinal, or other abnormalities than could possibly alter the PK of rifampicin and/or the probe drugs.
- The participant has a history of or current clinically relevant cardiovascular disorder such as:
- heart failure, atrioventricular (AV) block, arrhythmia, tachyarrhythmia or status after myocardial infarction.
- family history of sudden death of unknown or cardiac-related cause, or of prolonged QTc interval.
- The participant has clinically relevant abnormalities in the ECG such as atrioventricular (AV) block, prolongation of the QRS complex over 100 milliseconds, or of a QTc interval over 450 milliseconds on the screening ECG.
- The participant has abnormal alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels > 3 times the upper limit of the laboratory reference range at screening.
- The participant has a known or suspected, current drug or amphetamine abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the patient.
- The participant used any drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes and/or P-glycoprotein (P-gp) within 2 weeks prior to day 1 (i.e. 1 month before administration of the phenotyping probes on day 15) of the study (including carbamazepine, barbiturates, St. John's Wort, clarithromycin, itraconazole, fluconazole, quinidine, ketoconazole, erythromycin). Exceptions may be made for participants who have received 3 days or less of one of these drugs or substances, if there has been a wash-out period equivalent to at least 5 half-lives of that drug or substance before day 1 of the study.
- The participant uses any of the phenotyping probe drugs (i.e. midazolam, caffeine, dextromethorphan, tolbutamide, omeprazole and digoxin) as part of standard medical treatment.
- The participant has as history of allergy to any of the phenotyping probe drugs (i.e. midazolam, caffeine, dextromethorphan, tolbutamide, omeprazole and digoxin).
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Rifampicin standard dose
rifampicin standard dose + phenotyping cocktail
|
A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively.
Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters.
The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach
Other Names:
A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively.
Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters.
The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach
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Experimental: Rifampicin high dose
rifampicin high dose + phenotyping cocktail
|
A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively.
Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters.
The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach
Other Names:
A single dose of a cocktail of phenotyping probe drugs (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam and digoxin) will be administered together with standard dose rifampicin and 40 mg/kg rifampicin, respectively.
Blood samples will be taken to assess phenotyping metrics of the cocktail agents and rifampicin pharmacokinetic parameters.
The effect of high and standard dose rifampicin on the phenotyping metrics of the cocktail agents will be compared by using the bioequivalence approach
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
area under the curve
Time Frame: 24 hours
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area under the curve of probe drugs
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24 hours
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
January 7, 2021
Primary Completion (Actual)
August 12, 2021
Study Completion (Actual)
August 12, 2021
Study Registration Dates
First Submitted
August 20, 2020
First Submitted That Met QC Criteria
August 20, 2020
First Posted (Actual)
August 25, 2020
Study Record Updates
Last Update Posted (Actual)
August 17, 2021
Last Update Submitted That Met QC Criteria
August 16, 2021
Last Verified
August 1, 2021
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Anti-Infective Agents
- Central Nervous System Depressants
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anesthetics, Intravenous
- Anesthetics, General
- Anesthetics
- Excitatory Amino Acid Antagonists
- Excitatory Amino Acid Agents
- Purinergic Antagonists
- Purinergic Agents
- Gastrointestinal Agents
- Protective Agents
- Cardiotonic Agents
- Anti-Bacterial Agents
- Tranquilizing Agents
- Psychotropic Drugs
- Hypnotics and Sedatives
- Adjuvants, Anesthesia
- Anti-Anxiety Agents
- GABA Modulators
- GABA Agents
- Leprostatic Agents
- Respiratory System Agents
- Cytochrome P-450 Enzyme Inducers
- Anti-Ulcer Agents
- Proton Pump Inhibitors
- Cytochrome P-450 CYP3A Inducers
- Antitubercular Agents
- Phosphodiesterase Inhibitors
- Purinergic P1 Receptor Antagonists
- Central Nervous System Stimulants
- Antitussive Agents
- Antibiotics, Antitubercular
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C9 Inducers
- Digoxin
- Midazolam
- Dextromethorphan
- Rifampin
- Caffeine
- Omeprazole
- Tolbutamide
Other Study ID Numbers
- PHENORIF
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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