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TuberculosisPhase 1PHENORIFNCT04525235

Phenotyping of High Dose Rifampicin

A Phase 1 study testing phenotyping cocktail and rifampicin in people with Tuberculosis, run by Radboud University Medical Center at 2 sites in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Tuberculosis
What is being tested?
phenotyping cocktail and rifampicin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
2 sitesSouth Africa
Study dates
7 Jan 2021to 12 Aug 2021
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 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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:
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  • 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).

Trial locations and contacts

2 sites in 1 country.

South Africa2 sites

  • TASK

    Cape Town

  • UCT lung institute

    Cape Town

Other trials in South Africa

About this study

Official title: 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.

Conditions
Tuberculosis
Being tested
phenotyping cocktail, rifampicin
Medical subject headings
Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • phenotyping cocktailCombination product

    Also called digoxin, caffeine, tolbutamide, midazolam

    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

  • rifampicinDrug

    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

Study groups in NCT04525235
Study groupRoleWhat they receive
Rifampicin standard doseActive comparatorrifampicin standard dose + phenotyping cocktail
Receives: Combination Product: phenotyping cocktail; Drug: rifampicin
Rifampicin high doseExperimentalrifampicin high dose + phenotyping cocktail
Receives: Combination Product: phenotyping cocktail; Drug: rifampicin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. area under the curve

    area under the curve of probe drugs

    Measured: 24 hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Aug 2020
  2. Study start7 Jan 2021
  3. Primary completion12 Aug 2021
  4. Study completion12 Aug 2021

Resources

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
Other
Allocation
Non-randomised
Intervention model
Sequential
Model description
each participants will receive phenotyping probe drugs with the standard dose of rifampicin and with a high dose rifampicin in a fixed oreder
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04525235
Sponsor's protocol ID
PHENORIF
Acronym
PHENORIF
Status last verified
Aug 2021
First submitted
20 Aug 2020
Last updated
17 Aug 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Stemkens R, Jager Vd, Dawson R, Diacon AH, Narunsky K, Padayachee SD, Boeree MJ, van Beek SW, Colbers A, Coenen MJH, Svensson EM, Fuhr U, Phillips PPJ, Te Brake LHM, Aarnoutse RE; PanACEA consortium. Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 2023 Oct 18;67(10):e0068323. doi: 10.1128/aac.00683-23. Epub 2023 Sep 28.

    PubMed 37768317

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing phenotyping cocktail and rifampicin in people with Tuberculosis, run by Radboud University Medical Center at 2 sites in South Africa.

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 6 inclusion and 14 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 17 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in South Africa. 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?

area under the curve (time frame: 24 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 NCT04525235, 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 17 Aug 2021.

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