BASIC: Boosted Atazanavir or Saquinavir Induced Lipid Changes
|First Submitted Date ICMJE||October 17, 2006|
|First Posted Date ICMJE||October 18, 2006|
|Last Update Posted Date||June 11, 2010|
|Start Date ICMJE||July 2006|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||To assess the differences in changes in plasma lipids after once-daily saquinavir/ritonavir (2000/100 mg) or atazanavir/ritonavir (300/100 mg) each in combination with tenofovir disoproxil fumarate (300 mg QD) and emtricitabine (200 mg QD) for 24 weeks|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00389402 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||BASIC: Boosted Atazanavir or Saquinavir Induced Lipid Changes|
|Official Title ICMJE||A Randomised, Controlled, Open-Label, 48-Week, Study To Asses Differences in Changes In Plasma Lipid Profile Between Patients On Saquinavir/Ritonavir Or Atazanavir/Ritonavir In Combination With Tenofovir Disoproxil Fumarate And Emtricitabine As A First-line Regimen.|
|Brief Summary||The purpose of this study is to assess differences in changes in plasma lipids between patients on saquinavir/ritonavir or atazanavir/ritonavir in combination with tenofovir disoproxil fumarate and emtricitabine as a first-line regimen in patients previously naive for antiretroviral therapy. This study is an extension from the SSAR 2004/0002 which randomised patients over the same treatment arms.|
The main objective of the study is to measure changes in blood lipids during 48 weeks of treatment with saquinavir (SQV) / ritonavir (RTV) or atazanavir (ATV) / RTV, in combination with tenofovir (TDF) / emtricitabine (FTC). All of these medications are commonly used for the treatment of HIV-1 infection. When the initial anti-HIV therapy is selected, several important issues are considered such as the effectiveness, the possible long- and/or short-term side effects, the frequency of medication intake and the amount of pills that needs to be taken.
There is currently some concern about the long-term metabolic side effects of existing treatment regimens. Metabolic disorders, such as elevated blood lipids (including cholesterol) and a decreased sensitivity for insulin, which increases the chance of diabetes, pose an increased risk of cardiovascular disease. A large cohort study (the D:A:D study), executed worldwide, including in Dutch hospitals, has actually shown that the use of HIV combination therapy coincides with an increased risk of developing cardiovascular disease. A certain category of HIV inhibitors, the protease inhibitors, are particularly associated with elevated blood lipids. Results from the afore-mentioned worldwide study have recently indicated that in particular the use of protease inhibitors increases the risk of cardiovascular disease, which can to an important extent be explained by a change in the blood lipids caused by these medications. There are however some protease inhibitors, such as the recently developed drug atazanavir (ATV) and the protease inhibitor saquinavir (SQV) that has already been available for several years, which show no to only a little effect on blood lipids. SQV had the disadvantage of having to be dosed twice-daily, with many capsules (10-12 in total per day). Now that a new SQV tablet has been developed, the number of capsules to be taken per day has decreased dramatically (to only 4 in total per day) and moreover it has become possible in actual practice to take these capsules once per day. It is advisable, for both SQV and ATV, to combine the medication with one capsule of ritonavir (RTV), another protease inhibitor. This ensures that a reliable and effective level of SQV or ATV will be reached in the blood. RTV is associated with elevated blood lipids, but this effect is very limited in the low dosage that is used in combination with ATV or SQV. And as both SQV and ATV are combined with an equal amount of RTV, it is expected that their favorable effect on the blood lipids will be the same. For the same reason, the risk of cardiovascular disease is expected to be equally limited with the use of either of these two regimens.
In addition to long-term effects on the blood lipids, which poses a risk of cardiovascular disease, a disturbed fat distribution (lipodystrophy) is another frequently occurring complication in the treatment of HIV-1 infection. This disturbed fat distribution is associated with subcutaneous fat loss in some body parts (particularly the face, arms and legs, and buttocks) and with fat accumulation in other body parts (such as the abdomen, the back of the neck and female breasts). Subcutaneous fat loss is mainly associated with thymidine-containing nucleoside analogues like zidovudine (AZT) and stavudine (d4T). Previous studies in patients receiving antiretroviral treatment for the first time have shown that a combination of TDF / lamivudine (3TC) (the latter drug closely resembles FTC) does not lead to loss of subcutaneous fat (lipoatrophy), as opposed to the combination d4T / 3TC or AZT / 3TC. The cause of fat accumulation is however less clear, but often coincides with changes in blood lipids. The chance of the occurrence of fat accumulation could thus depend on the extent to which an HIV combination therapy coincides with an elevation of blood lipids.
As it is now becoming clear that there are initial therapies involving less risk of long-term side effects, it is important to develop therapy schedules that are safe with regard to these aspects. According to what has been described before, a combination of either ATV / RTV or SQV / RTV, administered together with TDF and FTC to prevent fat loss, would be a good initial regimen, as these combinations have little to no effect on the blood lipids and may therefore decrease the chance of fat accumulation. A big advantage of the use of combination therapy with protease inhibitors in combination with a low dose of RTV is that it largely diminishes the chance of the development of resistance to HIV protease inhibitors, even if the virus becomes detectable in the blood again after initial suppression - as opposed to the most commonly used alternative initial therapy in which non-nucleoside reverse transcriptase inhibitors are used instead of protease inhibitors. With the use of these drugs, the risk of resistance is much greater. It is therefore essential to better examine these protease-inhibitor-containing regimens, which are expected to have the advantage of producing a minimal effect on the lipid and sugar metabolism as well as a limited chance of resistance development.
In the BASIC study we want to show that SQV / RTV is comparable to ATV / RTV with regard to the effect on blood lipids. We will also look in detail at the effects on fat loss and fat accumulation, as well as on sugar metabolism and insulin sensitivity, in the hope that only very limited changes in these areas will be demonstrated.
One study in which patients were given their first antiretroviral treatment demonstrated a slight decrease in bone density (a form of bone loss) in the first year of treatment with TDF and FTC (which closely resembles 3TC). This did however not cause any clinical problems. It was very reassuring to see that a complete recovery of the bone density was again seen after this first year. Nevertheless we want to collect more data about the possible effects on the bone metabolism and for this reason we will perform two bone density assessments during this study. Finally, there are indications that the renal function in patients who are treated with TDF may become slightly disturbed. It is as yet not clear which method can most accurately estimate and detect these slight changes in renal function. For this reason, we plan to compare a number of different methods to estimate renal function as part of this study. For this purpose a number of additional relevant measurements will be obtained using the blood samples which are already being collected as part of the study anyway.
The main purpose of the study is to measure changes in the blood lipids and to compare these between patients who start with either an SQV / RTV-containing regimen or an ATV / RTV-containing regimen. In addition, the changes in fat distribution, sugar metabolism and insulin sensitivity will be compared between these groups. Possible changes in bone density and renal function will also be examined. Furthermore, the virologic effectiveness and overall safety of the two treatments will be evaluated and compared.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
|Condition ICMJE||HIV Infections|
|Study Arms||Not Provided|
|Publications *||Not Provided|
* 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||July 2008|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
Note: The site will calculate each patient's CrCl using the Cockcroft-Gault formula as shown below:
CrCl = [140 - age (yr)] × weight (kg) × constant 72 × serum creatinine (Cr) (mg/dL) where, constant = 1 for men and 0.85 for women.
|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||NCT00389402|
|Other Study ID Numbers ICMJE||05-IAT-0110
Eudract number: 2006-000666-37
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||International Antiviral Therapy Evaluation Center|
|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