LARD: Lopinavir/r or Fosamprenavir/r Switch to Atazanavir/r or Darunavir/r

• Sponsor: Community Research Initiative of New England (Other)
• Overall Status: Completed
• CT.gov ID: NCT00756730
• Collaborator: Tibotec Pharmaceutical Limited (Industry)
• Enrollment: 49
• Locations: 11
• Arms: 2
• Duration (Months): 33
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

For participants with HIV taking either lopinavir or fosamprenavir who have elevated triglycerides, this trial will study the change in triglycerides after switching protease inhibitors.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: ATV/r; Drug: DRV/r	Phase 4

Detailed Description

This Phase IV trial will look at lipid and virologic responses after a switch to a more lipid-friendly antiretroviral regimen. Participants will be randomized to receive either boosted atazanavir or boosted darunavir given once daily, along with background NRTIs. This 24-week study will require 4 visits after randomization for evaluation, monitoring, and lab studies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Open-label Study of Switch From Lopinavir/Ritonavir (LPV/r) or Fosamprenavir/Ritonavir (FPV/r) to Either Once Daily Atazanavir/Ritonavir (ATV/r) or Once Daily Darunavir/Ritonavir (DRV/r) (Plus Background Nucleoside Reverse Transcriptase Inhibitors) in Patients Experiencing Triglyceride Elevations While Receiving LPV/r or FPV/r.
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Other: Switch to DRV/r (800mg/100mg) QD We designed a study to determine if switching virologically suppressed patients on a regimen containing LPV/r or FPV/r to either DRV/r or ATV/r would result in improved TGs while maintaining virological suppression. For this arm the sbject switched to DRV/r at a dose 800mg/100mg QD for 24 weeks. Subjects will continue to maintain their background NRTI drugs throughout the screening period and during the entire study.	Drug: DRV/r; We designed a study to determine if switching virologically suppressed patients on a regimen containing LPV/r or FPV/r to either DRV/r or ATV/r would result in improved TGs while maintaining virological suppression. Switch to DRV/r at a dose 800mg/100mg QD for 24 weeks. Subjects will continue to maintain their background NRTI drugs throughout the screening period and during the entire study.
Other: Switch to ATV/r (300mg/100mg QD) We designed a study to determine if switching virologically suppressed patients on a regimen containing LPV/r or FPV/r to either DRV/r or ATV/r would result in improved TGs while maintaining virological suppression. For this are the subject switched to ATV/r at a dose of 300mg/100mg QD for 24 weeks. Subjects will continue to maintain their background NRTI drugs throughout the screening period and during the entire study	Drug: ATV/r; Switch to ATV/r at a dose of 300mg/100mg QD for 24 weeks. Subjects will continue to maintain their background NRTI drugs throughout the screening period and during the entire study.; Other Names: Atazanavir/r

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients That Experience 10% Decline in Triglycerides From Baseline to Week 24. [baseline, 24 weeks]

   A 10% decline in triglycerides (TGs) was determined to be clinically significant. The percentage of people that experienced a 10% decline was calculated by dividing the number who had a decline of 10% TGs by the total number of participants in the arm.

2. At Week 24 the Percentage of Subjects That Had Triglycerides Less Than 200 mg/dL [24 weeks]

3. The Change in Fasting Triglyceride Level From Baseline to Week 24 [Baseline to week 24]

Secondary Outcome Measures

1. Percent of Patients With HIV VL <200 Copies/mL at Week 4, 12 & 24 [Week 4, 12 & 24]

2. Difference in CD4 From Baseline to Week 24 [baseline to Week 24]

3. Total Cholesterol in the Two Study Groups at 24 Weeks [Week 24]

4. LDL Cholesterol at Week 24 [week 24]

5. HDL Cholesterol at Week 24 [24 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Currently receiving Antiretroviral Therapy (ART) regimen including LPV/r or FPV/r and

or equal to 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Patient must be on a stable regimen containing LPV/r or FPV/r for at least 12 weeks prior to screening.

• Documentation of an undetectable Human Immunodeficiency Virus (HIV) viral load (VL<400 copies/ml) using an FDA approved assay for a minimum of twelve weeks prior to screening AND undetectable HIV viral load using an FDA approved ultrasensitive assay at screening.

• No evidence of HIV protease resistance as defined by the Stanford HIV database

• Currently receiving first protease inhibitor unless switch to LPV/r or FPV/r was for non-virologic reasons

• Fasting triglycerides > 200 mg/dL

• No ongoing issues that in the opinion of the investigator would lead to decreased ability to comply with the study procedures

• If currently receiving a proton pump inhibitor, the dose is < omeprazole 20 mg or the equivalent dose of another proton pump inhibitor

• If patient is receiving another lipid lowering medication, it must be at a stable dose

Exclusion Criteria:

• Currently receiving an ART regimen other than > or equal to two NRTIs and either LPV/r or FPV/r

• Prior use of darunavir or atazanavir

• CDC Class C Illness diagnosed within 30 days of screening

• Patient is currently receiving the following Hydroxamethylglutaryl-coA (HMGCoA) reductase inhibitor medications (statins): pravastatin, lovastatin, simvastatin

• Patient is currently receiving a bile acid sequestrant (cholestyramine, colestipol, and colesevelam)

• Grade 3 or 4 Laboratory abnormalities as defined by a standardized grading scheme based on the DAIDS table with the following exceptions:

1. Pre-existing diabetes mellitus with asymptomatic, nonfasting glucose grade 3 elevations

2. Subjects with asymptomatic grade 3 fasting triglyceride or cholesterol elevations

• Clinical or laboratory evidence of clinically significant liver impairment/dysfunction disease or cirrhosis

• Note: Individuals co-infected with chronic hepatitis B or C viruses will be allowed to enter the trial if their condition is clinically stable and they will not require therapy during the course of the study. Individuals diagnosed with acute viral hepatitis at screening will not be allowed to enroll during acute phase

• Active substance abuse or significant psychiatric illness that in the opinion of the investigator might interfere with study compliance

• Use of any investigational agents 30 days prior to screening

• Life expectancy < 6 months in the opinion of the investigator

• Pregnancy or breast feeding

• Female subject of childbearing potential (i.e., heterosexually active, and not surgically sterile or at least two years post-menopausal) not using effective non-hormonal birth control methods or not willing to continue practicing these birth control methods from screening until the last trial related activity

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Spectrum Medical Group	Phoenix	Arizona	United States	85012
2	AIDS Healthcare Foundation	Los Angeles	California	United States	02319
3	Orlando Immunology Center	Orlando	Florida	United States	32803
4	Community Research Initiative	Boston	Massachusetts	United States	02215
5	Community Research Initiative - West	Springfield	Massachusetts	United States	01107
6	Abbott Northwestern Infectious Disease and Travel Clinic	Minneapolis	Minnesota	United States	55404
7	AIDS Community Health Center	Rochester	New York	United States	14804
8	Philadelphia Fight	Philadelphia	Pennsylvania	United States	19107
9	David M. Lee, M.D., P.A., a/b/a Uptown Physicians Group	Dallas	Texas	United States	75204
10	Nicholaos C. Bellos, MD, PA	Dallas	Texas	United States	75204
11	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Community Research Initiative of New England
• Tibotec Pharmaceutical Limited

Investigators

• Principal Investigator: Daniel J Skiest, MD, Community Research Initiative

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Community Research Initiative of New England
• ClinicalTrials.gov Identifier: NCT00756730
• Other Study ID Numbers: 08-09
• First Posted: Sep 22, 2008
• Last Update Posted: Aug 21, 2017
• Last Verified: Jul 1, 2017

• Keywords provided by Community Research Initiative of New England: lopinavir; ritonavir; atazanavir; fosamprenavir; darunavir; anti-retroviral; AIDS; HIV; LARD; triglyceride; protease inhibitors; treatment Experienced
• Additional relevant MeSH terms: HIV Infections; Atazanavir Sulfate

Study Results

Participant Flow

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Period Title: Overall Study
STARTED	25	24
COMPLETED	25	22
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD	Total
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r	Total of all reporting groups
Overall Participants	25	24	49
Age, Customized (years) [Mean (Full Range) ]
Mean (Full Range) [years]	48	46	47
Sex: Female, Male (Count of Participants)
Female	2 8%	2 8.3%	4 8.2%
Male	23 92%	22 91.7%	45 91.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 28%	12 50%	19 38.8%
Not Hispanic or Latino	18 72%	11 45.8%	29 59.2%
Unknown or Not Reported	0 0%	1 4.2%	1 2%
Region of Enrollment (participants) [Number]
United States	25 100%	24 100%	49 100%
CD4 Count (cells/mm3) [Mean (Full Range) ]
Mean (Full Range) [cells/mm3]	584	554	569
Viral Load (copies/mL) [Number]
Number [copies/mL]	NA	NA	0
Baseline antiretroviral medications - Protease inhibitors (participants) [Number]
Lopinavir/ritonavir (LPV/r)	23 92%	23 95.8%	46 93.9%
fosamprenavir/ritonavir (FPV/r)	2 8%	1 4.2%	3 6.1%
Baseline medications - Nucleoside analogs (Number) [Number]
viread (TDF)/emtriva (FTC)	15 60%	17 70.8%	32 65.3%
ziagen (ABC)/Epivir (3TC)	5 20%	5 20.8%	10 20.4%
other	5 20%	2 8.3%	7 14.3%
Lipid Lowering Medications (participants) [Number]
statin	6 24%	3 12.5%	9 18.4%
fibrate	5 20%	6 25%	11 22.4%
fish oil	5 20%	3 12.5%	8 16.3%
niacin	0 0%	1 4.2%	1 2%
none	9 36%	11 45.8%	20 40.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients That Experience 10% Decline in Triglycerides From Baseline to Week 24.
Description	A 10% decline in triglycerides (TGs) was determined to be clinically significant. The percentage of people that experienced a 10% decline was calculated by dividing the number who had a decline of 10% TGs by the total number of participants in the arm.
Time Frame	baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia. Neither subject met criteria for virologic failure.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Number [percentage of patients]	80	73

2. Secondary Outcome

Title	Percent of Patients With HIV VL <200 Copies/mL at Week 4, 12 & 24
Time Frame	Week 4, 12 & 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	24
Week 4	100 400%	100 416.7%
Week 12	100 400%	100 416.7%
Week 24	100 400%	100 416.7%

3. Secondary Outcome

Title	Difference in CD4 From Baseline to Week 24
Time Frame	baseline to Week 24

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Mean (Standard Error) [cells/mm^3]	10.75 (17.67)	14.28 (19.77)

4. Secondary Outcome

Title	Total Cholesterol in the Two Study Groups at 24 Weeks
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Mean (Full Range) [mg/dL]	195	195

5. Secondary Outcome

Title	LDL Cholesterol at Week 24
Time Frame	week 24

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Mean (Full Range) [mg/dL]	116	111

6. Secondary Outcome

Title	HDL Cholesterol at Week 24
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Mean (Full Range) [mg/dL]	38	40

7. Primary Outcome

Title	At Week 24 the Percentage of Subjects That Had Triglycerides Less Than 200 mg/dL
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Number [percentage of participants]	48 192%	55 229.2%

8. Primary Outcome

Title	The Change in Fasting Triglyceride Level From Baseline to Week 24
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia.

Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD	Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
Measure Participants	25	22
Mean (Full Range) [mg/dL]	-126	-88

Adverse Events

Time Frame	Baseline to 24 weeks
Arm/Group Title	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD		Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
Arm/Group Description	Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to DRV/r, 800mg/100mg QD		Virologically suppressed patients on a regimen containing Lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) were switched to ATV/r
All Cause Mortality
	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD		Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD		Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		1/24 (4.2%)
Gastrointestinal disorders
possible bowel obstruction	0/25 (0%)	0	1/24 (4.2%)	1
Psychiatric disorders
alcohol withdrawal/suicidal Ideation	0/25 (0%)	0	1/24 (4.2%)	1
Renal and urinary disorders
urosepsis	1/25 (4%)	1	0/24 (0%)	0
Other (Not Including Serious) Adverse Events
	Switch to Darunavir/Ritonavir (DRV/r) , 800mg/100mg QD		Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/25 (28%)		8/24 (33.3%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection (URI)	5/25 (20%)	5	5/24 (20.8%)	5
Skin and subcutaneous tissue disorders
Skin Rash	2/25 (8%)	2	1/24 (4.2%)	1
Vascular disorders
Erectile Dysfunction	0/25 (0%)	0	2/24 (8.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.