EARNEST Rifabutin Pharmacokinetics (PK) Substudy

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2012 by Medical Research Council.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Abbott
Information provided by (Responsible Party):
Justine Boles, Medical Research Council
ClinicalTrials.gov Identifier:
NCT01663168
First received: July 30, 2012
Last updated: August 8, 2012
Last verified: August 2012
  Purpose

- 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


Condition Intervention Phase
HIV
Tuberculosis
Drug: Rifabutin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by Medical Research Council:

Primary Outcome Measures:
  • Grade 3/4 adverse events [ Time Frame: Minimum 24 weeks, maximum 100 weeks ] [ Designated as safety issue: Yes ]
    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%.


Secondary Outcome Measures:
  • Rifabutin and its 25-o-desacetyl metabolite pharmacokinetic parameters (from a population PK model) [ Time Frame: 28 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    Culture positive at 24 weeks or subsequent relapse/recurrence

  • Rifamycin resistance [ Time Frame: 24 weeks or at relapse/recurrence (up to maximum 100 weeks) ] [ Designated as safety issue: No ]

Estimated Enrollment: 140
Study Start Date: December 2011
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)
Drug: Rifabutin
Other Name: Mycobutin
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)
Drug: Rifabutin
Other Name: Mycobutin

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01663168

Contacts
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

Locations
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         
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         
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         
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         
Sponsors and Collaborators
Justine Boles
Abbott
Investigators
Principal Investigator: Cissy Kityo Mutuluuza, MSc MBChB Joint Clinical Research Centre (JCRC)
  More Information

Additional Information:
No publications provided

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
Study First Received: July 30, 2012
Last Updated: August 8, 2012
Health Authority: Uganda: Uganda National Council of Science and Technology (UNCST)

Keywords provided by Medical Research Council:
HIV
Rifabutin
HIV Protease Inhibitors
Tuberculosis
EARNEST trial
Randomized Controlled Trial
Pilot Projects
Second-line ART
Drug Toxicity
Pharmacokinetics
Drug Interactions

Additional relevant MeSH terms:
Rifabutin
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lopinavir
HIV Protease Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antitubercular
Antitubercular Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents

ClinicalTrials.gov processed this record on August 28, 2014