EARNEST Rifabutin Pharmacokinetics (PK) Substudy
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ClinicalTrials.gov Identifier: NCT01663168 |
Recruitment Status
: Unknown
Verified August 2012 by Justine Boles, Medical Research Council.
Recruitment status was: Recruiting
First Posted
: August 13, 2012
Last Update Posted
: August 13, 2012
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- Background and study aims?
Some of the drugs used to treat HIV (anti-retrovirals, or ARVs) can affect the blood levels of other drugs used to treat TB - called a "drug-drug interaction". The main drug used in second-line therapy, Aluvia (lopinavir/ritonavir), is one of the drugs that has this effect. This is why people on second-line ARVs usually cannot use one of the main TB drugs, "rifampicin", and instead will be prescribed a slightly different drug called "rifabutin", which is less affected by these drug-drug interactions. Although blood levels of rifabutin are not as badly affected by Aluvia as blood levels of rifampicin, rifabutin levels in the blood are still increased a lot by taking Aluvia at the same time. This could lead to higher levels of side-effects because there is more drug in the body. So in the past doctors have suggested that instead of taking rifabutin every day with Aluvia, it should only be taken three times a week, on Mondays, Wednesdays and Fridays. However, in the last 2 years, new studies have suggested that this three times a week regimen might not be enough and that it may not completely cure TB. So the purpose of this study is to find out whether taking rifabutin every day with Aluvia really does lead to more side-effects, and whether taking rifabutin three times a week with Aluvia really does lead to much lower levels of rifabutin in the blood.
- Who can participate?
This substudy is specifically for people who are already taking anti-TB drugs in EARNEST, or who need to start anti-TB drugs whilst they are in the EARNEST trial.
- What does the study involve?
Participants will be selected (by chance, chosen by a computer) to one of the following two rifabutin groups:
Group 1: Rifabutin (150 mg) taken three times a week on Monday/Wednesday/Friday Group 2: Rifabutin (150 mg) taken every day On these days, one capsule of rifabutin (150 mg) should be taken in the morning by mouth.
Participants will be asked to attend clinic 2 and 12 weeks after entering the sub-study then every 6 weeks until the end of their TB treatment, and then return to their usual EARNEST follow-up schedule. This is roughly the same visit schedule for people with TB who are usually seen more frequently than those without TB, whether or not the patients join this sub-study. The 2 week visit is specifically so the investigators can make sure participants are doing OK on rifabutin and to check carefully that they don't have any side-effects. At all these visits (including the day when participants enroll into the substudy) the investigators will take an extra 10 ml (two teaspoons) of blood to do laboratory tests for side-effects of rifabutin, and to measure the levels of rifabutin and other ARVs in the blood - these are called "pharmacokinetic" or "PK" studies. On the day of these visits, participants should not take their dose of rifabutin until after this blood draw, so the investigators can measure the lowest amount of drug likely in their blood. Instead, participants should bring the rifabutin dose to clinic, so that they can take it straight after the blood draw. At the visit 12 weeks after starting rifabutin, participants will need to stay in clinic for a second blood draw of ~3 ml (half a teaspoon) around 4 hours after they take the rifabutin dose immediately after the first blood draw. We use this second sample to see how quickly rifabutin enters the blood. At this special visit the investigators will make sure participants are first seen as early as possible, so they don't have to stay any longer than necessary for the second blood draw to be taken 4 hours later. After participants have completed their TB treatment they will stay in EARNEST until the end of the trial (144 weeks on second-line therapy).
- What are the possible benefits and risks of participating?
If participants are allocated to Group 1 (150 mg rifabutin three times a week), there is a risk that they may have lower levels of rifabutin in your blood and this may be less effective at treating the TB. However, participants should have fewer side-effects. In contrast, if participants are allocated to Group 2 (150 mg rifabutin daily), here is a risk that they may get more side-effects, but the levels of rifabutin in the blood should be more than high enough to have a good chance of curing the TB. Having blood taken may cause some discomfort and/or bruising in some people. It is currently impossible to know which rifabutin regimen would be best and participants may find in years to come that they may or may not have received the best treatment.
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Where is the study run from?
9 EARNEST sites in Uganda as follows: JCRC Kampala, IDI, San Raphael of St Francis Hospital (Nsambya), JCRC Mbarara, JCRC Mbale, JCRC Kabale, JCRC Kakira, JCRC Gulu
- When is study starting and how long is it expected to run?
Start 05/03/2012 finish on 31/01/2014
- Who is funding the study? Abbott
Condition or disease | Intervention/treatment | Phase |
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HIV Tuberculosis | Drug: Rifabutin | Phase 2 |

Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 140 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Toxicity and Pharmacokinetics of Different Rifabutin Doses in HIV-infected Adults and Adolescents Taking Lopinavir / Ritonavir as Second-line Anti-retroviral Therapy (ART) (EARNEST Rifabutin PK Substudy) |
Study Start Date : | December 2011 |
Estimated Primary Completion Date : | January 2014 |
Estimated Study Completion Date : | January 2014 |

Arm | Intervention/treatment |
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Active Comparator: Rifabutin three times a week
Rifabutin 150mg tablet three times a week (Mon-Wed-Fri) in combination with daily lopinavir/ritonavir taken as part of second-line ART for duration of TB treatment (24 weeks)
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Drug: Rifabutin
Other Name: Mycobutin
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Experimental: Rifabutin daily
Rifabutin 150mg tablet daily in combination with daily lopinavir/ritonavir taken as part of second-line ART for duration of TB treatment (24 weeks)
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Drug: Rifabutin
Other Name: Mycobutin
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- Grade 3/4 adverse events [ Time Frame: Minimum 24 weeks, maximum 100 weeks ]The primary analysis will be the difference in proportions ever experiencing one or more grade 3 or 4 adverse events (AEs) after substudy randomisation, with non-inferiority demonstrated if the upper limit of the 90% confidence interval around the risk difference(Group 2 - Group 1) lies below +20%.
- Rifabutin and its 25-o-desacetyl metabolite pharmacokinetic parameters (from a population PK model) [ Time Frame: 28 weeks ]Population PK models being developed at the University of Capetown for daily and thrice weekly rifabutin dosing will be used to estimate rifabutin PK parameters (time-concentration curve (AUC), trough (Cmin), and apparent oral clearance (CL/F)), which will be compared between groups using geometric means (ttest for the log-transformed values).
- Lopinavir/ritonavir pharmacokinetic parameters (from a population PK model) [ Time Frame: 28 weeks ]Population PK models being developed at the University of Capetown for daily and thrice weekly rifabutin dosing will be used to estimate lopinavir and ritonavir PK parameters (time-concentration curve (AUC), trough (Cmin), and apparent oral clearance (CL/F)), which will be compared between groups using geometric means (ttest for the log-transformed values).
- Raltegravir pharmacokinetic parameters (from a population PK model) [ Time Frame: 28 weeks ]Population PK models as above. Parameters include time-concentration curve (AUC), trough (Cmin), and apparent oral clearance (CL/F)
- Response to TB therapy [ Time Frame: 24 weeks or at relapse/recurrence (up to maximum 100 weeks) ]Culture positive at 24 weeks or subsequent relapse/recurrence
- Rifamycin resistance [ Time Frame: 24 weeks or at relapse/recurrence (up to maximum 100 weeks) ]

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 12 Years and older (Child, Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- HIV-1 infected adults/adolescents (12 years and older) receiving boosted protease inhibitor (almost exclusively lopinavir/ritonavir, Aluvia) containing second-line ART within the EARNEST trial
- Enrolled with or developing TB during EARNEST trial follow-up
- Currently receiving or planning to initiate rifabutin-containing anti-TB treatment (ie no contraindications to rifabutin)
- Who provide written informed consent
Exclusion Criteria:
- Patients who have already reached week 132 in the EARNEST trial at time of TB diagnosis will not be enrolled as practical considerations limit follow up to 12 weeks beyond the completion of the week 144 EARNEST visit
- Patients who have less than 10 weeks remaining in their course of TB treatment will not be enrolled as they will not contribute to the main PK evaluation at week 12 (window 10-14 weeks)

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01663168
Contact: Cissy Kityo Mutuluuza, MSc MBChB | +256 414 201 148 | ckityo@jcrc.org.ug | |
Contact: Nicholas Paton, MD FRCP | +65 6772 6988 | nick.paton@ctu.mrc.ac.uk |
Uganda | |
JCRC Fort Portal | Recruiting |
Fort Portal, Uganda | |
Contact: Mary Kiconco 256773291297 marykiconco@gmail.com | |
Contact: Christine Matama 256775461217 matamaabwooli@gmail.com | |
Sub-Investigator: Mary Kiconco, MBChB | |
Principal Investigator: Francis Kiweewa, MBChB | |
JCRC Gulu | Recruiting |
Gulu, Uganda | |
Contact: George Abongomera, MBChB 256471432407 gabongomera@jcrc.org.ug | |
Contact: Joseph Omongin, Dip Nurs 256702886034 omonginjoseph@yahoo.com | |
Principal Investigator: Francis Kiweewa, MBChB | |
Sub-Investigator: George Abongomera, MBChB | |
JCRC Kabale | Recruiting |
Kabale, Uganda | |
Contact: Hillary Alima, MBChB 256772412910 hillarybyaruhanga@yahoo.com | |
Contact: Agatha Nshabohurira, BSc 256782670101 nshabohurira@yahoo.com | |
Principal Investigator: Francis Kiweewa, MBChB | |
Sub-Investigator: Hillary Alima, MBChB | |
JCRC Kakira | Recruiting |
Kakira, Uganda | |
Contact: Samuel Kiirya, MBChB 256712489486 samuelkiirya@yahoo.co.uk | |
Contact: Dickens Atwondeire 256701684004 adickens2000@yahoo.co.uk | |
Principal Investigator: Francis Kiweewa, MBChB | |
Sub-Investigator: Samuel Kiirya | |
Infectious Diseases Institute (IDI) | Recruiting |
Kampala, Uganda | |
Contact: Andrew Kambugu, MMed MBChB 256414307290 akambugu@idi.co.uk | |
Contact: Ruth Nalumenya, BSc 256772661899 ruthnalug@yahoo.co.uk | |
Principal Investigator: Philippa Easterbrook, MD, MPH, FRCP | |
Sub-Investigator: Andrew Kambugu, MBChB | |
JCRC Kampala | Recruiting |
Kampala, Uganda | |
Contact: Francis Kiweewa, MBChB 256 414 270283 fkiweewa@jcrc.org.uk | |
Contact: Dinah Tumukunde, BSc 256 414 270 283 dtumukunde@jcrc.org.ug | |
Principal Investigator: Cissy Kityo Mutuluuza, MSc BMChB | |
Sub-Investigator: Peter Mugyenyi, MBChB, FRCP | |
San Raphael of St Francis Hospital, Nsambya | Recruiting |
Kampala, Uganda | |
Contact: Raymond Mwebaze, MB ChB 256772435383 mbayo2001@yahoo.com | |
Contact: Ishmail Senoga, MB ChB 256703818992 snoogie80@gmail.com | |
Principal Investigator: Pius Okong, MB ChB | |
Sub-Investigator: Raymond Mwebaze, MBChB | |
JCRC Mbale | Recruiting |
Mbale, Uganda | |
Contact: Mary Abwola, MBChB 256772583568 maryabwolacherire@yahoo.com | |
Contact: Fred Senono 256772688727 senonofred@yahoo.com | |
Principal Investigator: Francis Kiweewa, MBChB | |
Sub-Investigator: Mary Abwola, MBChB | |
JCRC Mbarara | Recruiting |
Mbarara, Uganda | |
Contact: Henry Mugerwa, MBChB 256485433545 hmugwera@hotmail.com | |
Contact: Abbas Lugemwa, MD 256485433545 alugemwa@ugabytes.org | |
Principal Investigator: Henry Mugerwa, MBChB | |
Principal Investigator: Francis Kiweewa, MBChB |
Principal Investigator: | Cissy Kityo Mutuluuza, MSc MBChB | Joint Clinical Research Centre (JCRC) |
Additional Information:
Responsible Party: | Justine Boles, Dr Cissy Kityo Mutuluuza, JCRC Deputy Director, Medical Research Council |
ClinicalTrials.gov Identifier: | NCT01663168 History of Changes |
Other Study ID Numbers: |
ISRCTN13074752 |
First Posted: | August 13, 2012 Key Record Dates |
Last Update Posted: | August 13, 2012 |
Last Verified: | August 2012 |
Keywords provided by Justine Boles, Medical Research Council:
HIV Tuberculosis Rifabutin HIV Protease Inhibitors EARNEST trial Randomized Controlled Trial |
Pilot Projects Second-line ART Drug Toxicity Pharmacokinetics Drug Interactions |
Additional relevant MeSH terms:
Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Ritonavir Lopinavir Rifabutin HIV Protease Inhibitors Protease Inhibitors Enzyme Inhibitors |
Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors Anti-Bacterial Agents Antibiotics, Antitubercular Antitubercular Agents |