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The Effect of Intermittent Rifampicin on Raltegravir (RIFRAL)

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ClinicalTrials.gov Identifier: NCT01424826
Recruitment Status : Completed
First Posted : August 29, 2011
Last Update Posted : October 31, 2013
Sponsor:
Collaborator:
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Information provided by (Responsible Party):
Helen Reynolds, University of Liverpool

Study Description
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Brief Summary:
This study seeks to address the question of whether intermittent dosing of rifampicin influences the pharmacokinetics of raltegravir when co-administered. This study aims to look at what happens when rifampicin is taken 3 times a week with the standard dose and an increased dose of raltegravir. This is to find out the best dose of raltegravir to take when taking rifampicin 3 times a week. The study will be conducted in 18 healthy volunteers.

Condition or disease Intervention/treatment Phase
HIV Tuberculosis Drug: Raltegravir Drug: Rifampicin Phase 1

Detailed Description:

The aim of this study is to optimise the dosing of raltegravir when coadministered intermittently with rifampicin. The co-administration of rifampicin and antiretrovirals (ARVs) is both complicated and problematic due to the potent induction of metabolism by rifampicin. Rifampicin induces cytochrome P450 (CYP) enzymes, which results in reduced plasma concentrations of two groups of ARVs, the protease inhibitors (PIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). This pharmacokinetic interaction precludes the use of PIs and severely compromises the effectiveness of the NNRTI, nevirapine, as it potentially results in the loss of antiviral activity due to sub-therapeutic concentrations which will also lead to antiretroviral resistance.

Rifampicin also induces phase II enzymes including UDP-glucuronosyl transferase. The HIV integrase inhibitor, raltegravir, is primarily metabolised by UGT1A1 and therefore, there is the potential for a pharmacokinetic drug interaction with rifampicin. In fact, previous studies have shown a decrease in raltegravir AUC, CMAX, and C12 when co-administered with daily rifampicin. During directly observed therapy (DOTs) for TB, rifampicin is often given intermittently (e.g. 3 times a week). Although several studies have examined the interaction between raltegravir and daily rifampicin, currently there are no data regarding the pharmacokinetics of raltegravir when rifampicin is co-administered intermittently.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, 3 Phase Study to Determine the Effect of Intermittent Dosing of Rifampicin on the Pharmacokinetics of Raltegravir in Healthy Volunteers
Study Start Date : January 2012
Actual Primary Completion Date : June 2013
Actual Study Completion Date : July 2013

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U.S. FDA Resources

Arms and Interventions
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Intervention Details:
    Drug: Raltegravir
    400 mg bd for minimum of 28 days and maximum 35 days
    Drug: Rifampicin
    < 50 kg 600 mg 3 times/week for a minimum of 27 days and maximum of 34 days > 50 kg 900 mg 3 times/week for a minimum of 27 days and maximum of 34 days
    Drug: Raltegravir
    800 mg bd for 4 days

Outcome Measures
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Primary Outcome Measures :
  1. Change in raltegravir area under the curve (AUC) 0-12h [ Time Frame: Day 28 and day 33 ]

Secondary Outcome Measures :
  1. Number of participants with adverse events [ Time Frame: 40 days (up to + 7 days) ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements.
  • ≥ 18 years
  • Male or female subjects
  • A female may be eligible to enter and participate in the study if she:
  • Is of non-child-bearing potential defined as ether post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age)or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or
  • Is of child-bearing potential with a negative pregnancy test at screening and agrees to use one of the following methods of contraception to avoid pregnancy
  • Complete abstinence from intercourse from 2 weeks prior to administration of IP, throughout the study and for at least 4 weeks after discontinuation of all study medication
  • Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide)
  • Any intrauterine device (IUD) with published data showing that the expected failure rate is < 1 % per year
  • Any other method with published data showing that the expected failure rate is < 1 % PER YEAR
  • Hormonal contraception plus a barrier method. Hormonal contraception alone will not be considered adequate for inclusion into or participation in this study due to one of the study drugs being rifampicin.

All subjects participating in the study will be counseled on safer sexual practices including the use of effective barrier methods (e.g. male condom)

Exclusion Criteria:

  • Any significant acute or chronic medical condition
  • Pregnant or lactating women
  • Women of childbearing age unless using non hormonal contraception
  • Males who are not using contraception
  • Evidence of organ dysfunction or any clinically significant deviation from normal during screening including laboratory determinations such as abnormal LFTs
  • Positive blood screen for HIV-1 and 2 antibodies
  • Positive blood screen for hepatitis B or C antibodies
  • Positive IGRA screen for TB
  • Current or recent (within 3 months) gastrointestinal disease
  • Clinically relevant alcohol or drug use or history of alcohol or drug use that will hinder compliance with treatment, follow up procedures or evaluation of adverse effects
  • Use of proton pump inhibitors
  • Exposure to any investigational drug or placebo within 4 weeks of first dose of study drug
  • Consumption of grapefruit and Seville oranges or products containing grapefruit or Seville oranges within 1 week of first study drug and for the duration of the study
  • Use of any other drugs including over-the-counter medications and herbal preparations, within 2 weeks prior to first dose of study drug
  • Previous allergy to any of the constituents of the pharmaceuticals in this trial
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

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): NCT01424826


Locations
United Kingdom
Royal Liverpool & Broadgreen Univeristy Hospitals NHS Trust
Liverpool, United Kingdom, L7 8XP
Sponsors and Collaborators
Helen Reynolds
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Investigators
Principal Investigator: Saye Khoo University of Liverpool
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Helen Reynolds, Research Nurse, University of Liverpool
ClinicalTrials.gov Identifier: NCT01424826     History of Changes
Other Study ID Numbers: UoL000643
2010-021461-73 ( EudraCT Number )
First Posted: August 29, 2011    Key Record Dates
Last Update Posted: October 31, 2013
Last Verified: October 2013

Keywords provided by Helen Reynolds, University of Liverpool:
Healthy volunteers

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Raltegravir Potassium
Rifampin
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
 Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers