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Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

Primary Purpose

HIV Infections, Tuberculosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
efavirenz
raltegravir
raltegravir
Sponsored by
ANRS, Emerging Infectious Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring HIV, Tuberculosis, Pharmacokinetics, Raltegravir, France, Brazil, treatment naive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult patients (at least 18 years old)
  • Plasma HIV RNA > 1000 copies/ml
  • HIV-1-infection confirmed by ELISA and Western blot or Immunofluorescence
  • ART naïve patients or
  • ART for less than 3 months and more than 6 months ago ; an HIV resistance genotype at baseline showing no mutation to NNRTI and TDF or 3TC will be required
  • For women of childbearing age, negative urinary test for pregnancy and to accept contraceptive methods: condom use and intra-uterine device when possible or declare no wish of pregnancy in the coming year.
  • Confirmed or probable TB
  • TB treatment including rifampin started since 2 to 8 weeks before randomisation
  • Signed informed consent form
  • For French patients, to be affiliated to the National Health Care System

Exclusion Criteria:

  • HIV-2 infection (single or with HIV-1)
  • Woman who is pregnant or likely to become so, is breastfeeding or refuses to use contraception
  • ALT>2.5N, Hb <7g/dl, neutrophils < 750/mm3, platelet<50 000/mm3, bilirubin >5N, lipase >3N
  • Creatinine clearance <60ml/min as assessed by the Cockcroft method
  • Ongoing psychiatric pathology or any condition (including, but not limited to, the consumption of alcohol or drugs) which might, in the investigator's opinion, compromise the safety of treatment and/or patient compliance with the protocol
  • Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1)
  • Prior TB with a Mycobacterium tuberculosis strain resistant to rifampin
  • TB treatment started for more than 8 weeks before randomisation

Sites / Locations

  • Hospital Genral de Nova Iguaçu
  • Hospital Nossa Senhora da Coceiçao
  • Hospital Sanatorio Pertenon
  • Ipec/Fiocruz
  • Hospitral Universitario Pr Edgar Santos
  • STD/AIDS department
  • Hôpital Lariboisière
  • Hôpital Saint-Louis
  • CHI Villeneuve Saint Georges

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

1

2

3

Arm Description

efavirenz

raltegravir 400 mg

raltegravir 800 mg

Outcomes

Primary Outcome Measures

Virologic success, using Time to Loss of Virologic Response (TLOVR) algorithm: -Plasma HIV RNA below 50 copies/ml at week 20, confirmed at week 24 -Absence of permanent treatment discontinuation -Absence of death -Still follow-up at week 24

Secondary Outcome Measures

Proportion of patients with virologic response with the following definitions: - Plasma HIV RNA <50 copies/ml at week 24 - Rate of strategy discontinuation and treatment changes - Proportion of death - Proportion of patients loss to follow-up
Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml
Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 48
Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0
Evolution of CD4 cell counts from baseline to week 48
Frequency, type and time to a new AIDS-defining event or death
Frequency, type, time to grade 3 or 4 adverse event
Rate of success of TB treatment
Anti-TB resistance rate
Evolution of raltegravir and efavirenz trough concentration

Full Information

First Posted
January 13, 2009
Last Updated
July 16, 2013
Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
Gilead Sciences, Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT00822315
Brief Title
Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis
Official Title
Phase II Open-label Randomized Multicenter Trial to Compare the Efficacy and Safety of Two Different Doses of Raltegravir and Efavirenz, All in Combination With Tenofovir and Lamivudine, in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
July 2009 (undefined)
Primary Completion Date
November 2011 (Actual)
Study Completion Date
May 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
Gilead Sciences, Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Raltegravir is a potent antiretroviral agent that could be used as an alternative to efavirenz in HIV-1 infected patients with tuberculosis. However due to pharmacokinetic interactions, the optimal dose of raltegravir to be used in combination with rifampin is currently unknown. This phase II open-label randomized multicenter trial is designed to estimate the antiviral efficacy of two doses of raltegravir and one dose of efavirenz at week 24, in HIV-1 naive patients co-infected with active tuberculosis (TB) treated with rifampin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections, Tuberculosis
Keywords
HIV, Tuberculosis, Pharmacokinetics, Raltegravir, France, Brazil, treatment naive

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
155 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
efavirenz
Arm Title
2
Arm Type
Experimental
Arm Description
raltegravir 400 mg
Arm Title
3
Arm Type
Experimental
Arm Description
raltegravir 800 mg
Intervention Type
Drug
Intervention Name(s)
efavirenz
Intervention Description
tenofovir 245 mg / lamivudine 300 mg / efavirenz 600 mg
Intervention Type
Drug
Intervention Name(s)
raltegravir
Intervention Description
tenofovir 245 mg / lamivudine 300 mg / raltegravir 400 mg
Intervention Type
Drug
Intervention Name(s)
raltegravir
Intervention Description
tenofovir 245 mg / lamivudine 300 mg / raltegravir 800 mg
Primary Outcome Measure Information:
Title
Virologic success, using Time to Loss of Virologic Response (TLOVR) algorithm: -Plasma HIV RNA below 50 copies/ml at week 20, confirmed at week 24 -Absence of permanent treatment discontinuation -Absence of death -Still follow-up at week 24
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Proportion of patients with virologic response with the following definitions: - Plasma HIV RNA <50 copies/ml at week 24 - Rate of strategy discontinuation and treatment changes - Proportion of death - Proportion of patients loss to follow-up
Time Frame
24 weeks
Title
Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml
Time Frame
24 and 48 weeks
Title
Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 48
Time Frame
48 weeks
Title
Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0
Time Frame
At the time of virologic failure
Title
Evolution of CD4 cell counts from baseline to week 48
Time Frame
48 weeks
Title
Frequency, type and time to a new AIDS-defining event or death
Time Frame
Through out the trial
Title
Frequency, type, time to grade 3 or 4 adverse event
Time Frame
Through out the trial
Title
Rate of success of TB treatment
Time Frame
48 weeks
Title
Anti-TB resistance rate
Time Frame
48 weeks
Title
Evolution of raltegravir and efavirenz trough concentration
Time Frame
Through out the trial

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients (at least 18 years old) Plasma HIV RNA > 1000 copies/ml HIV-1-infection confirmed by ELISA and Western blot or Immunofluorescence ART naïve patients or ART for less than 3 months and more than 6 months ago ; an HIV resistance genotype at baseline showing no mutation to NNRTI and TDF or 3TC will be required For women of childbearing age, negative urinary test for pregnancy and to accept contraceptive methods: condom use and intra-uterine device when possible or declare no wish of pregnancy in the coming year. Confirmed or probable TB TB treatment including rifampin started since 2 to 8 weeks before randomisation Signed informed consent form For French patients, to be affiliated to the National Health Care System Exclusion Criteria: HIV-2 infection (single or with HIV-1) Woman who is pregnant or likely to become so, is breastfeeding or refuses to use contraception ALT>2.5N, Hb <7g/dl, neutrophils < 750/mm3, platelet<50 000/mm3, bilirubin >5N, lipase >3N Creatinine clearance <60ml/min as assessed by the Cockcroft method Ongoing psychiatric pathology or any condition (including, but not limited to, the consumption of alcohol or drugs) which might, in the investigator's opinion, compromise the safety of treatment and/or patient compliance with the protocol Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1) Prior TB with a Mycobacterium tuberculosis strain resistant to rifampin TB treatment started for more than 8 weeks before randomisation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beatriz Grinsztejn, MD
Organizational Affiliation
Fiocruz, Rio de Janiero, Brazil
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jean-Michel Molina, MD
Organizational Affiliation
Hôpital Saint-Louis, Paris, France
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Genral de Nova Iguaçu
City
Nova Iguaçu
Country
Brazil
Facility Name
Hospital Nossa Senhora da Coceiçao
City
Porto alegre
Country
Brazil
Facility Name
Hospital Sanatorio Pertenon
City
Porto Alegre
Country
Brazil
Facility Name
Ipec/Fiocruz
City
Rio de Janeiro
Country
Brazil
Facility Name
Hospitral Universitario Pr Edgar Santos
City
Salvador da Bahia
Country
Brazil
Facility Name
STD/AIDS department
City
Sao Paulo
Country
Brazil
Facility Name
Hôpital Lariboisière
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Name
Hôpital Saint-Louis
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Name
CHI Villeneuve Saint Georges
City
Villeneuve Saint Georges
ZIP/Postal Code
94195
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
24726095
Citation
Grinsztejn B, De Castro N, Arnold V, Veloso VG, Morgado M, Pilotto JH, Brites C, Madruga JV, Barcellos NT, Santos BR, Vorsatz C, Fagard C, Santini-Oliveira M, Patey O, Delaugerre C, Chene G, Molina JM; ANRS 12 180 Reflate TB study group. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014 Jun;14(6):459-67. doi: 10.1016/S1473-3099(14)70711-X. Epub 2014 Apr 9. Erratum In: Lancet Infect Dis. 2014 Jun;14(6):448.
Results Reference
derived

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Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

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