PREventing Progression of Adipose Tissue Redistribution
|First Received Date ICMJE||October 17, 2006|
|Last Updated Date||June 10, 2010|
|Start Date ICMJE||April 2006|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE||Not Provided|
|Original Primary Outcome Measures ICMJE
||Difference between the continuation arm (continuation of AZT+3TC) and the switch arm (switching AZT+3TC to TDF+FTC) in changes in limb fat over 48 weeks as measured by whole body DEXA.|
|Change History||Complete list of historical versions of study NCT00389194 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||PREventing Progression of Adipose Tissue Redistribution|
|Official Title ICMJE||A Randomized, Controlled, Open-Label, 48-Week Study of Continuing Successfully Suppressive Treatment in HIV-1 Infected Adults With First-Line Twice-Daily Zidovudine and Lamivudine-Based Regimens Versus Pro-actively Replacing of Zidovudine and Lamivudine by Once-Daily Emtricitabine and Tenofovir Disoproxil Fumarate to Prevent Progression of or Reverse Peripheral Lipoatrophy.|
|Brief Summary||The main objective of the study is to assess changes in fat distribution over 48 weeks of treatment in patients who currently successfully use zidovudine (AZT) and lamivudine (3TC) as part of their regimen and who will either continue these antiretrovirals or who will switch these antiretrovirals to tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Each of these medications is commonly used for the treatment of HIV-1 infection.|
Combinations of two nucleoside analogue RT inhibitors (NRTI) are by far the most commonly utilized backbone of combination antiretroviral regimens upon which additional third or fourth agents, a non-nucleoside RT inhibitor (NNRTI) or a (boosted) protease inhibitor (PI), confer sufficient potency for long-term efficacy. The choice of the specific two NRTI is made on the basis of potency and durability, short-and long-term toxicities, drug-drug interactions, the propensity to select for resistance mutations, and dosing convenience. Currently, the most frequently used NRTI combination is zidovudine plus lamivudine, often co-formulated as Combivir®.
The thymidine analogues NRTI have been implicated in the pathogenesis of the lipodystrophy syndrome and of peripheral lipoatrophy in particular. Exposure to zidovudine is associated with a slower and possibly lesser degree of limb fat loss than exposure to stavudine. The mechanisms by which thymidine analogue NRTI contribute to lipoatrophy remain uncertain, although there is evidence that drug-induced mitochondrial toxicity at the level of subcutaneous adipose tissue is involved2 3. NRTI are known inhibitors of mitochondrial DNA polymerase gamma and greater degrees of mtDNA depletion in subcutaneous adipose tissue are associated with greater loss of limb fat as measured by DEXA. In addition, NRTI may detrimentally affect mitochondrial function by mechanisms other than mtDNA depletion. It has also been postulated that the normal regional distribution of body fat may be under hypothalamic autonomic neuronal control, and that effects of NRTI on the central and/or peripheral autonomic pathways may be underlying the selective loss of fat in subcutaneous but not in central regions of the body4.
Withdrawal of thymidine analogues from the antiretroviral regimens of patients with clinical signs of lipodystrophy (and replacing it by abacavir or in more recent studies by tenofovir) has been demonstrated to be able to partially revert limb fat loss in a number of studies, including randomized placebo-controlled trials 5-10. Of note, most patients in these studies had stavudine replaced. Carr11 and Martin6 reported an increase in limb fat of 0.39 kg and 1.26 kg 24 and 104 weeks, respectively, after replacing stavudine or zidovudine by abacavir in the Mitox study (the majority of patients was on a stavudine-based regimen at entry, the minority on a ZDV-based regimen). Moyle8 reported an increase of 1.08 kg of limb fat 48 weeks after withdrawal of thymidine analogues. The reported increases in limb fat have been greatest in patients that were pretreated with stavudine compared to patients pretreated with zidovudine. The rate of peripheral fat loss is slower in patients using zidovudine compared to patients using stavudine, suggesting that patients using stavudine may have usually lost more peripheral fat to begin with than patients using zidovudine. Therefore the potential increase in peripheral fat after withdrawal of the thymidine analogue is expected to be greatest in patients using stavudine. The current study, in contrast to earlier studies, will be limited to patients who with respect to thymidine analogue exposure have solely been exposed to zidovudine and never to stavudine. In order to assure that participants in our study have already had the opportunity to lose a reasonable amount of peripheral fat, we will only include patients who have been continuously treated with zidovudine and lamivudine for at least 2 years. Nolan12 reported that treatment-naïve patients receiving zidovudine-based therapy, after 3 years had lost an average of 31% of limb fat compared to baseline12. Patients who continue to use zidovudine appear to continue to progressively loose limb fat at a rate of several percentage-points per year. By limiting our sample to patients who have been treated with zidovudine and lamivudine for over 2 years we can be confident that the average loss of limb fat is large enough to allow for an objectively measurable and statistically significant regain in limb fat to occur after discontinuation of zidovudine and lamivudine.
Continued treatment with zidovudine plus lamivudine is expected to result in a (further) decrease in the mass of peripheral adipose tissue. Switching to emtricitabine plus tenofovir disoproxil fumarate is expected to result in an increase or at least the absence of a further loss of peripheral adipose tissue. The combination of emtricitabine plus tenofovir disoproxil fumarate is an attractive backbone of antiretroviral combination therapy. This combination has potent antiretroviral activity, has a favorable resistance profile, ease of once-daily dosing, can be conveniently co-formulated in a single tablet, has no special food requirements, is well tolerated, and thus far has not been particularly associated with the occurrence of mitochondrial toxicity or lipoatrophy. With respect to the latter, the recent Gilead 903 trial has been very informative in the sense that no limb fat wasting (measured by DEXA) was observed between 96 and 144 weeks of treatment as opposed to the progressive limb fat loss which was seen in patients randomized to the stavudine-containing control arm13.
In this study we therefore aim to demonstrate a small but statistically significant mean increase in peripheral body fat in the patients who switch to emtricitabine and tenofovir disoproxil fumarate as opposed to a further decrease in peripheral fat in the patients who continue the use of zidovudine and lamivudine. Such increases in peripheral fat are not expected to be observable for the treating physicians and the patients themselves. However, the demonstration of even a small sub-clinical effect will provide important information for future patient management with respect to strategies on how to best prevent progressive lipoatrophy. The Mitox study demonstrated that substituting abacavir for stavudine resulted in an increase in limb fat of 390 grams after 24 weeks11. This increase was likewise not noticeable to clinicians and patients, and could only be detected with the use of DEXA scanning. Nevertheless, the results of Mitox had a huge impact on the management of patients: clinicians started to pro-actively substitute other compounds for stavudine, and to exclude stavudine from first-line regimens in order to prevent (progression of) lipoatrophy. If our study would demonstrate a similar increase in peripheral fat in patients substituting emtricitabine plus tenofovir disoproxil fumarate for zidovudine and lamivudine, this could potentially likewise impact on the continued long-term use of ZDV-based regimens. Although the cleanest comparison would be to replace only zidovudine by tenofovir disoproxil fumarate, we also replace lamivudine by emtricitabine. Given that most experts agree that the difference between lamivudine and emtricitabine is probably not very important and emtricitabine has the additional advantage of allowing the possible use of the fixed dose once daily combination of emtricitabine and tenofovir disoproxil fumarate (Truvada®), we have chosen to replace lamivudine by emtricitabine as well.
Purpose: Antiretroviral regimens containing emtricitabine plus tenofovir disoproxil fumarate might be associated with a lower incidence and severity of lipoatrophy. In this study we compare the effect of proactively switching zidovudine and lamivudine to emtricitabine plus tenofovir disoproxil fumarate on peripheral fat loss with continued lamivudine and zidovudine-based treatment in HIV-1 infected adults also receiving a non-nucleoside reverse transcriptase inhibitor or (boosted) protease inhibitor. In the patients who discontinue the use of zidovudine and switch to emtricitabine and tenofovir disoproxil fumarate we expect to demonstrate a regaining or at least a lack of further loss of peripheral adipose tissue.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
|Condition ICMJE||HIV Infections|
|Intervention ICMJE||Drug: continuing AZT+3TC or switching AZT+3TC to TDF+ FTC|
|Study Arms||Not Provided|
|Publications *||Cotter AG, Vrouenraets SM, Brady JJ, Wit FW, Fux CA, Furrer H, Brinkman K, Sabin CA, Reiss P, Mallon PW; PREPARE (Preventing Progression of Adipose Tissue Redistribution) Investigators. Impact of switching from zidovudine to tenofovir disoproxil fumarate on bone mineral density and markers of bone metabolism in virologically suppressed HIV-1 infected patients; a substudy of the PREPARE study. J Clin Endocrinol Metab. 2013 Apr;98(4):1659-66. doi: 10.1210/jc.2012-3686. Epub 2013 Feb 22.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Estimated Enrollment ICMJE||120|
|Completion Date||October 2008|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Netherlands|
|Removed Location Countries|
|NCT Number ICMJE||NCT00389194|
|Other Study ID Numbers ICMJE||PR-0095_01
Eudract number: 2005-005672-33
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||International Antiviral Therapy Evaluation Center|
|Collaborators ICMJE||Gilead Sciences|
|PRS Account||International Antiviral Therapy Evaluation Center|
|Verification Date||June 2010|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP