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Lopinavir/r Monotherapy Versus Abacavir/Lamivudine and Lopinavir/r for Limb Fat Recovery in Persons With Lipoatrophy (KRETA)

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ClinicalTrials.gov Identifier: NCT00865007
Recruitment Status : Completed
First Posted : March 19, 2009
Last Update Posted : March 22, 2013
Information provided by (Responsible Party):

Tracking Information
First Submitted Date  ICMJE March 18, 2009
First Posted Date  ICMJE March 19, 2009
Last Update Posted Date March 22, 2013
Study Start Date  ICMJE December 2008
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2009)
Absolute change in limb fat measured by DEXA at 48w [ Time Frame: 48 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2009)
  • Absolute change in limb-fat measured by DEXA at 96 weeks [ Time Frame: 96 weeks ]
  • Lipid changes at Week 24, 48, 72 and 96 [ Time Frame: 96 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Lopinavir/r Monotherapy Versus Abacavir/Lamivudine and Lopinavir/r for Limb Fat Recovery in Persons With Lipoatrophy
Official Title  ICMJE A Phase IV-III Comparative, Randomized, Open-label Study to Evaluate the Efficacy for the Recovery of Peripheral Fat (or of the Extremities) of Lopinavir/Ritonavir in Monotherapy Versus Abacavir/Lamivudine and Lopinavir/Ritonavir
Brief Summary The aim of this study is to evaluate the efficacy for the recovery of peripheral fat of lopinavir/ritonavir in monotherapy versus abacavir/lamivudine and lopinavir/ritonavir in subjects who developed lipoatrophy while receiving zidovudine plus lamivudine plus abacavir.
Detailed Description

After more than ten years since it was started, it has already been established that highly-active antiretroviral treatment (HAART) has caused a dramatic reduction in the morbidity and mortality of human immunodeficiency virus (HIV) infection. However, HAART is not exempt of limitations, namely, its toxicity in the long-term; this is of special importance now that treatment of HIV is chronic.

Most common HAART involves the use of two nucleoside reverse transcriptase inhibitors (nucleoside or nucleotide analogues, NRTIs) and either a protease inhibitor (PI) or a non-analogue reverse transcriptase inhibitor (NNRTI). However, there are other regimens that remove some of these families, such as those based on three NRTIs, ZDV+3TC+ABC.

HAART has been associated with a constellation of major metabolic adverse events, such as fat redistribution (lipodystrophy, lipoatrophy, lipohypertrophy-central obesity - or both) and hyperlipidemia (hypercholesterolemia and hypertriglyceridemia).

Lipoatrophy, specifically, occurs as a loss of subcutaneous fat mass in the upper and lower extremities, with the possible appearance of venomegaly in face and buttocks Lipoatrophy is particularly distressing not only for itself, but for its stigma component, affecting the quality of life and the psychological condition of the patient.This also has a direct impact on treatment compliance, that is reduced, and, therefore, at risk that the therapeutic regimen fails to be effective for resistances selection.

Although initially most metabolic adverse events were attributed to PIs, in recent years it has been shown that lipoatrophy specifically is related more to therapy with NRTIs than with PIs; specifically, d4T, ddI and ZDV.

One of the accepted strategies for the management of lipoatrophy in patients receiving therapy with ZDV is its replacement by other NRTI such as TDF or ABC, and consequently, a significant fat recovery is seen.

In a study where therapy with ZDV was discontinued and continued with NNRTIs (lopinavir/ritonavir-LPV/r and nevirapine-NVP) therapy, fat recovery in the extremities seemed to be higher than in patients where ZDV was replaced by ABC.

Lopinavir (ABT-378) is a potent protease inhibitor of HIV. The proven efficacy and safety of LPV/r-based HAART has led to its inclusion since 2003 in therapeutic guidelines as therapy of preferential start PI/r based.

With regard to its relationship with lipoatrophy, recent data have shown that LPV/r has a low risk induction profile.

In recent years data have been published on the use of LPV/r monotherapy: starting, and induction-maintenance after therapy with HAART with sustained undetectability for at least 6 months.

Given the aforementioned data, in those patients developing lipoatrophy while treated with ZDV+ABC+3TC, the approach of switching to a regimen in the absence of LPV/r-based nucleosides could be even more beneficial than just removing ZDV and maintaining them on a HAART containing LPV/r+ABC+3TC. Despite the fact that lipoatrophy associated with ABC/3TC is very low in treatment-naive patients, it has yet to be demonstrated that discontinuing even "benign" nucleosides could provide an additional benefit in patients that had already developed lipoatrophy.

Accordingly, the working hypothesis for this study would be as follows: the recovery or reversion of lipoatrophy would increase in patients receiving LPV/r in monotherapy vs those switching to a classic LPV/r-based HAART. The absence of any nucleoside would then be beneficial for fat recovery in the extremities.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • HIV Infection
  • Lipodystrophy
  • HIV Infections
Intervention  ICMJE
  • Drug: Monotherapy (Lopinavir/ritonavir)
    NRTI sparing
  • Drug: Monotherapy (Lopinavir/ritonavir) + ABC/3TC
    NRTI sparing regimen
Study Arms  ICMJE
  • Experimental: Monotherapy group
    Lopinavir/ritonavir (LPV/r).
    Intervention: Drug: Monotherapy (Lopinavir/ritonavir)
  • Active Comparator: Triple arm
    Lopinavir/ritonavir (LPV/r)+ ABC/3TC
    • Drug: Monotherapy (Lopinavir/ritonavir)
    • Drug: Monotherapy (Lopinavir/ritonavir) + ABC/3TC
Publications * Bernardino JI, Pulido F, Martinez E, Arrizabalaga J, Domingo P, Portilla J, Ocampo A, Munoz J, Torres R, Arribas JR; GESIDA-6008-KRETA Study Group. Switching to lopinavir/ritonavir with or without abacavir/lamivudine in lipoatrophic patients treated with zidovudine/abacavir/lamivudine. J Antimicrob Chemother. 2013 Jun;68(6):1373-81. doi: 10.1093/jac/dks540. Epub 2013 Feb 5.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 21, 2013)
Original Estimated Enrollment  ICMJE
 (submitted: March 18, 2009)
Actual Study Completion Date  ICMJE September 2012
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmation of the willingness of the patient to participate in this study after being informed on all the aspects of the trial that may influence their decision, signing and dating the written informed consent form approved by the Ethics Committee.
  • The patient is 18 years of age or older.
  • (Documented) HIV-1 infection.
  • Receiving treatment with ZDV+3TC+ABC (in continuous antiretroviral treatment, without discontinuation periods, for the past 6 months).
  • There is confirmation that during the 6 months prior to inclusion in the study the viral burdens were below 50 copies/mL.
  • A viral burden below 50 copies/mL no more than 30 days before starting the study.
  • No previous history of virological failure while on antiretroviral treatment with protease inhibitors (PIs). That is, they have never switched protease inhibitors for suspected or documented virological failure. The changes in protease inhibitor due solely to toxicity, simplification or optimization are acceptable.
  • Clinical evidence of moderate to severe lipoatrophy (according to the case definition as scoring >- 2. For inclusion in the study, the subject should have moderate to severe lipoatrophy in at least one site, and defined by the physician.
  • Absence of signs of acute disease.
  • Patient has not been treated for an active opportunistic infection within the 30 days prior to the baseline visit.
  • Patient with Karnofsky index >- 70.
  • During the study, the patient does not require and agrees not to take any of the following drugs that are contraindicated with LPV/r: astemizole, terfenadine, midazolam, triazolam, cisapride, certain ergot derivatives (ergotamine, dihydroergotamine, ergonovine, methylergonovine), pimozide, propafenone, and flecainide. Rifampin, a potent enzyme inducer, should not be administered with the study medication due to the possibility of a significant decrease in LPV/r concentrations during concomitant administration, nor drugs contraindicated with 3TC and ABC that in principle should not be being taken, as they are part of the treatment at the screening.
  • Patient agrees not to take any medication, including over-the-counter medicines, alcohol, drugs, or herbal preparations without the knowledge and approval of the principal investigator.
  • Laboratory tests have been performed on the patients in the past 30 days:
  • G/dL hemoglobin >8.0
  • Absolute neutrophil count 750 cells/microl
  • Platelet count 20,000/microl
  • ALT or AST <5 x upper normal limit (UNL)
  • Creatinine <1. 5 x UNL
  • Triglycerides <750 mg/dL.
  • For women, a negative result of a pregnancy test is available and they agree to use throughout the study a barrier contraceptive method of proven reliability in the investigator's opinion.

Exclusion Criteria:

  • Patients with a history of virological failure on treatment with PIs; that is, that they have at some point switched to PIs for confirmed or documented virological failure.
  • Patients with positive serum hepatitis B surface antigen.
  • Patients requiring treatment with drugs where combination with LPV/r is contraindicated.
  • Presence of active opportunistic disease or wasting syndrome or under antitumoral treatment with chemotherapy.
  • Patients treated in the previous 16 weeks with agents susceptible to insulin (glitazones or metformin), anabolic steroids, growth hormone or any agent that could interfere with the study drugs.
  • Active drug addiction or psychiatric disease that may prevent protocol compliance. Use of cannabis or being on methadone treatment are excepted, provided protocol compliance is not compromised in the investigator's opinion.
  • Pregnant women or nursing mothers, and women of childbearing age if they do not agree to use a barrier contraceptive method throughout the study of proven reliability in the investigator's opinion.
  • In the opinion of the principal investigator, the patient is unlikely to comply with the study protocol, or the patient is not eligible for any other reason.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00865007
Other Study ID Numbers  ICMJE GESIDA-6008
2008-003748-12 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Fundacion SEIMC-GESIDA
Original Responsible Party Jose Ignacio Bernardino, SEIMC-GESIDA Foundation
Current Study Sponsor  ICMJE Fundacion SEIMC-GESIDA
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Abbott
Investigators  ICMJE
Study Chair: Jose Ignacio Bernardino Hospital La Paz
Study Chair: Jose Ramon Arribas Hospital La Paz
PRS Account Fundacion SEIMC-GESIDA
Verification Date March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP