Multidrug-resistant TuberculosisPhase 4NCT01521364
Drug Interaction Study Between Linezolid and Clarithromycin in Tuberculosis Patients
A Phase 4 study testing Addition of different doses of clarithromycin. in people with Multidrug-resistant Tuberculosis and Extensively Drug-resistant Tuberculosis, run by University Medical Center Groningen at 1 site in Netherlands.
Trial summary
Future patients might benefit from a combination of linezolid (LIN) and clarithromycin (CLA) in the treatment of Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) due to possible synergistic activity as shown in in vitro experiments in different Mycobacteria strains. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multidrug-resistant Tuberculosis, Extensively Drug-resistant Tuberculosis
- What is being tested?
- Addition of different doses of clarithromycin.
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteNetherlands
- Study dates
- Dec 2011to Nov 2012
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥18 years old
- Signed informed consent
- Diagnosis of MDR/XDR-TB confirmed with standard microbiological criteria (culture-based, molecular or both)
- Treatment with linezolid 300mg twice daily per os.
Who cannot join
- Hypersensitivity to: linezolid, clarithromycin, erythromycin, or any macrolide antibiotics, or any of the excipients of linezolid or clarithromycin.
- Concomitant use with astemizole, cisapride, ergotamine derivatives (dihydroergotamine, ergotamine), monoamine oxidase inhibitors (phenelzine, isocarboxazid, selegiline, or moclobemide), pimozide, or terfenadine.
- Pregnancy or breast-feeding.
- Hypokalemia
- Concomitant use of other P-gp inhibitors/inducers, e.g. amiodarone, verapamil, digoxin, tipranavir/ritonavir, lovastatin, tariquidar, itraconazole, dipyridamol, erythromycin, ritonavir, quinidine.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Tuberculosis Center Beatrixoord
Haren, Provincie Groningen
About this study
Official title: The Pharmacokinetic Effect of Clarithromycin on the AUC0-12h of Linezolid in Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) Patients
Future patients might benefit from a combination of linezolid (LIN) and clarithromycin (CLA) in the treatment of Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) due to possible synergistic activity as shown in in vitro experiments in different Mycobacteria strains. The investigators observed increased LIN serum levels in three cases after combining LIN and CLA of which the investigators described one in a case report (Bolhuis et al). The investigators suggest to conduct a prospective pharmacokinetic study in MDR- and XDR-TB patients to quantify the above described interaction between LIN and CLA.
- Being tested
- Addition of different doses of clarithromycin.
- Keywords
- pharmacokinetic, drug-interaction, linezolid, clarithromycin, Mycobacterium tuberculosis
- Medical subject headings
- Tuberculosis, Multidrug-Resistant, Extensively Drug-Resistant Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Addition of different doses of clarithromycin.Drug
Also called Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082
At week 1, 250mg clarithromycin once a day will be added to linezolid therapy during two weeks.
At week 3, 500mg clarithromycin once a day will be added to linezolid therapy during to weeks.
| Study group | Role | What they receive |
|---|---|---|
| 0mg, 250mg, and 500mg claritromycin | Other | Patients receive 300mg linezolid twice a day during entire study. After one week, 250mg claritromycin once daily is added for a duration of two weeks.
After another two weeks, 250mg claritromycin is replaced by 500mg claritromycin once daily for another two weeks.
After this, there is a wash-out period of one week during which no claritromycine is administered. Receives: Drug: Addition of different doses of clarithromycin. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA).
The AUCs of linezolid will be measured at 3 time points after addition of 3 different clarithromycin dosages.
Samples were obtained before doseing and 1h, 2h, 3h, 4h, 8h, and 12h after administration of linezolid (and claritromycin depending on the period).
Measured: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).
Secondary outcomes (4)
Linezolid (LIN) and Clarithromycin (CLA) Pharmacokinetic Parameters, e.g. Tmax, Cmax, Cmin, T1/2, Cl.
Measured: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5 (500mg clarithromycin) and week 6 (baseline).
Number of Patients With Adverse Events (AEs)
To assess short-term safety and tolerability when combining linezolid (LIN) with clarithromycin (CLA) by monitoring AEs, i.e. gastro-intestinal effects, hyperlactatemia, haematological abnormalities and neuropathy.
Measured: Up to week 6
Pharmacokinetic Parameters, e.g. Tmax, T1/2, Cmax, Cmin, Cl, of Anti-TB Drugs That Are Co-administered as Part of the Continued Standard Care.
Measured: At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin)
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva.
The data will be used to clinically validate the analysis linezolid in saliva as surrogate marker for linezolid in plasma.
Measured: At week 3 (after co-administration of 250mg clarithromycin)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2012 (estimated)
- Study startDec 2011
- Primary completionOct 2012
- Study completionNov 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Multidrug-resistant TuberculosisStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, JWC Alffenaar, University Medical Center Groningen
- Investigators
- Jan-Willem C Alffenaar, PhD, PharmD, Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01521364
- Sponsor's protocol ID
- NL35534.042.11
- Other IDs
- 2011-000513-39
- Status last verified
- May 2013
- First submitted
- 13 Sep 2011
- Last updated
- 1 Jul 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Bolhuis MS, van Altena R, van Soolingen D, de Lange WC, Uges DR, van der Werf TS, Kosterink JG, Alffenaar JW. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. Eur Respir J. 2013 Dec;42(6):1614-21. doi: 10.1183/09031936.00001913. Epub 2013 Mar 21.
PubMed 23520311
Study at a glance
From the registry record, last updated by the sponsor on 1 Jul 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Pharmacokinetic Effect of Clarithromycin on the AUC0-12h of Linezolid in Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) Patients
- ClinicalTrials.gov ID
- NCT01521364
- Acronym / sponsor ID
- NL35534.042.11
- Keywords
- pharmacokinetic, drug-interaction, linezolid, clarithromycin, Mycobacterium tuberculosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Study start
- Dec 2011
- Primary completion
- Oct 2012 (actual)
- Study completion
- Nov 2012 (actual)
- First posted
- 30 Jan 2012 (estimated)
- Results
- Posted 1 Jul 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Future patients might benefit from a combination of linezolid (LIN) and clarithromycin (CLA) in the treatment of Multidrug-resistant and Extensively Drug-resistant Tuberculosis (MDR/XDR-TB) due to possible synergistic activity as shown in in vitro experiments in different Mycobacteria strains. The investigators observed increased LIN serum levels in three cases after combining LIN and CLA of which the investigators described one in a case report (Bolhuis et al). The investigators suggest to conduct a prospective pharmacokinetic study in MDR- and XDR-TB patients to quantify the above described interaction between LIN and CLA.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 0mg, 250mg, and 500mg claritromycin | Other | Drug: Addition of different doses of clarithromycin.Patients receive 300mg linezolid twice a day during entire study. After one week, 250mg claritromycin once daily is added for a duration of two weeks. After another two weeks, 250mg claritromycin is replaced by 500mg claritromycin once daily for another two weeks. After this, there is a wash-out period of one week during which no claritromycine is administered. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age ≥18 years old
- Signed informed consent
- Diagnosis of MDR/XDR-TB confirmed with standard microbiological criteria (culture-based, molecular or both)
- Treatment with linezolid 300mg twice daily per os.
Key exclusion criteria (5 listed)
- Hypersensitivity to: linezolid, clarithromycin, erythromycin, or any macrolide antibiotics, or any of the excipients of linezolid or clarithromycin.
- Concomitant use with astemizole, cisapride, ergotamine derivatives (dihydroergotamine, ergotamine), monoamine oxidase inhibitors (phenelzine, isocarboxazid, selegiline, or moclobemide), pimozide, or terfenadine.
- Pregnancy or breast-feeding.
- Hypokalemia
- Concomitant use of other P-gp inhibitors/inducers, e.g. amiodarone, verapamil, digoxin, tipranavir/ritonavir, lovastatin, tariquidar, itraconazole, dipyridamol, erythromycin, ritonavir, quinidine.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Addition of different doses of clarithromycin.Also: Clarithromycin, 250/500mg (Pharmachemie) RVG 029081/029082At week 1, 250mg clarithromycin once a day will be added to linezolid therapy during two weeks. At week 3, 500mg clarithromycin once a day will be added to linezolid therapy during to weeks. | Drug | 0mg, 250mg, and 500mg claritromycin |
Primary outcome
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA).
Time frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).
The AUCs of linezolid will be measured at 3 time points after addition of 3 different clarithromycin dosages. Samples were obtained before doseing and 1h, 2h, 3h, 4h, 8h, and 12h after administration of linezolid (and claritromycin depending on the period).
4 secondary outcomes
Linezolid (LIN) and Clarithromycin (CLA) Pharmacokinetic Parameters, e.g. Tmax, Cmax, Cmin, T1/2, Cl.
Time frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5 (500mg clarithromycin) and week 6 (baseline).
Number of Patients With Adverse Events (AEs)
Time frame: Up to week 6
Pharmacokinetic Parameters, e.g. Tmax, T1/2, Cmax, Cmin, Cl, of Anti-TB Drugs That Are Co-administered as Part of the Continued Standard Care.
Time frame: At week 1 (baseline), week 3 (250mg clarithromycin) and week 5 (500mg clarithromycin)
Area Under the Time Concentration Curve (AUC0-12h) of Linezolid in Saliva.
Time frame: At week 3 (after co-administration of 250mg clarithromycin)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jul 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 23520311Bolhuis MS, van Altena R, van Soolingen D, de Lange WC, Uges DR, van der Werf TS, Kosterink JG, Alffenaar JW. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. Eur Respir J. 2013 Dec;42(6):1614-21. doi: 10.1183/09031936.00001913. Epub 2013 Mar 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jan-Willem C Alffenaar, PhD, PharmD principal investigator
University Medical Center Groningen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Addition of different doses of clarithromycin. in people with Multidrug-resistant Tuberculosis and Extensively Drug-resistant Tuberculosis, run by University Medical Center Groningen at 1 site in Netherlands.
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 4 inclusion and 5 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 1 Jul 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Jul 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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 Time Concentration Curve (AUC0-12h) of Linezolid in Plasma After Addition of 0mg, 250mg, or 500mg Clarithromycin (CLA). (time frame: At week 1 (baseline), week 3 (250mg clarithromycin), and week 5(500mg clarithromycin).). 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 NCT01521364, 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 1 Jul 2013.