EARNEST Rifabutin Pharmacokinetics (PK) Substudy

NCT01663168 | Unknown Phase 2

• 1 other identifier: ISRCTN13074752
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 9

Brief Summary

\- 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.

• 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

Conditions

HIV; Tuberculosis

Keywords

HIV; Tuberculosis; Rifabutin; HIV Protease Inhibitors; EARNEST trial; Randomized Controlled Trial; Pilot Projects; Second-line ART; Drug Toxicity; Pharmacokinetics; Drug Interactions

Outcome Measures

Primary Outcomes (1)

• Grade 3/4 adverse events

  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%.

  Minimum 24 weeks, maximum 100 weeks

Secondary Outcomes (5)

• Rifabutin and its 25-o-desacetyl metabolite pharmacokinetic parameters (from a population PK model)

  28 weeks

• Lopinavir/ritonavir pharmacokinetic parameters (from a population PK model)

  28 weeks

• Raltegravir pharmacokinetic parameters (from a population PK model)

  28 weeks

• Response to TB therapy

  24 weeks or at relapse/recurrence (up to maximum 100 weeks)

• Rifamycin resistance

  24 weeks or at relapse/recurrence (up to maximum 100 weeks)

Study Arms (2)

Rifabutin three times a week

ACTIVE COMPARATOR

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)

Drug: Rifabutin

Rifabutin daily

EXPERIMENTAL

Rifabutin 150mg tablet daily in combination with daily lopinavir/ritonavir taken as part of second-line ART for duration of TB treatment (24 weeks)

Drug: Rifabutin

Interventions

Rifabutin DRUG

Also known as: Mycobutin

Rifabutin daily; Rifabutin three times a week

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Justine Boles: lead
• Abbott: collaborator

Study Sites (9)

JCRC Fort Portal

Fort Portal, Uganda

RECRUITING

JCRC Gulu

Gulu, Uganda

RECRUITING

JCRC Kabale

Kabale, Uganda

RECRUITING

JCRC Kakira

Kakira, Uganda

RECRUITING

Infectious Diseases Institute (IDI)

Kampala, Uganda

RECRUITING

JCRC Kampala

Kampala, Uganda

RECRUITING

San Raphael of St Francis Hospital, Nsambya

Kampala, Uganda

RECRUITING

JCRC Mbale

Mbale, Uganda

RECRUITING

JCRC Mbarara

Mbarara, Uganda

RECRUITING

Related Links

• Click here for more information about this study: EARNEST Rifabutin PK substudy

MeSH Terms

Conditions

Tuberculosis; Drug-Related Side Effects and Adverse Reactions

Interventions

Rifabutin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Cissy Kityo Mutuluuza, MSc MBChB

  Joint Clinical Research Centre (JCRC)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cissy Kityo Mutuluuza, MSc MBChB

CONTACT

+256 414 201 148; ckityo@jcrc.org.ug

Nicholas Paton, MD FRCP

CONTACT

+65 6772 6988; nick.paton@ctu.mrc.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr Cissy Kityo Mutuluuza, JCRC Deputy Director

Study Record Dates

• First Submitted: July 30, 2012
• First Posted: August 13, 2012
• Study Start: December 1, 2011
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: August 13, 2012

Record last verified: 2012-08

Locations

UG (9)