Immune Reconstitution of Lopinavir/Ritonavir-Based vs Efavirenz-based HAART in Advanced HIV Disease

• Sponsor: Rush University Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00775606
• Collaborator: University of Chicago (Other), University of Illinois at Chicago (Other), Ruth M. Rothstein CORE Center (Other), Abbott (Industry), Gilead Sciences (Industry)
• Enrollment: 15
• Locations: 4
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The ideal anti-HIV medications for patients with advanced HIV disease is unknown. There is evidence that anti-HIV regimens that contain protease inhibitors can enhance immune function better than regimens that do not contain protease inhibitors. This is a study that will determine the difference in immune enhancement capabilities between an anti-HIV regimen that contains the protease inhibitor - lopinavir-ritonavir, and a regimen that contains efavirenz. Both medications are recommended as first line treatments for HIV-infected patients. This study will recruit HIV-positive patients that need to start anti-HIV treatment because their CD4+ T-cells are below 200. The usual threshold for starting treatment is a CD4+ T-cell less than 350. Subjects will be randomized to treatment with either an anti-HIV regimen that contains lopinavir-ritonavir or a regimen that contains efavirenz. The study will determine the difference in immune reconstitution over 24 weeks of treatment with study medications. Among the immune parameters that will be measured is the ability of each subject to respond to vaccination with the tetanus-diphtheria vaccine and the 23-valent pneumococcal vaccine. Both vaccines are also recommended for HIV-positive patients but HIV-positive patients tend to have a lower response rate to these vaccines.

Condition or Disease	Intervention/Treatment	Phase
Acquired Immune Deficiency Syndrome	Drug: Lopinavir 400 mg/ritonavir 100 mg; Drug: Efavirenz	Phase 4

Detailed Description

DESIGN: ICE-001 is a phase IV, randomized, two-arm unblinded study, comparing the effect on immune reconstitution of open-label ritonavir (RTV)-enhanced lopinavir (LPV) to efavirenz (EFV), in combination with daily emtricitabine (FTC)/tenofovir (TDF) as initial therapy for HIV-1 infection in HIV-infected treatment naïve subjects with CD4+ T-cells less than 200 cells/ml.

DURATION: Subjects will participate in ICE-001 for approximately 48 weeks after starting study treatment.

SAMPLE SIZE: ICE-001 will enroll 60 subjects (30 per treatment arm).

POPULATION: HIV-1-infected, antiretroviral (ARV) drug-naïve (≤7 days of ARV treatment at anytime prior to study entry) men and women between18 to 60 years of age with plasma HIV-1 RNA levels >1000 copies/mL and CD4+ T-cell counts < 200 cells/ml obtained within 90 days prior to study entry.

STRATIFICATION: Subjects will be stratified at screening based on plasma HIV-1 RNA levels <100,000 and ≥100,000 copies/mL.

REGIMEN: At entry subjects will be randomized to one of the following:

• ARM A: LPV 400 mg/RTV 100 mg BID + FTC 200 mg/TDF 300 mg QD

• ARM B: EFV 600 mg QD/FTC 200 mg/TDF 300 mg fixed dose combination QD

The objective is to determine the differences in the degree of immune reconstitution in HIV-infected patients with a CD4+ T-cell count < 200 cells/ml who initiated treatment with LPV/RTV + FTC/TDF compared to EFV/FTC/TDF.

Study visits will occur at screening, pre-entry, entry and weeks 1, 4, 8, 12, 24 and 48 after study entry. Study medications will be provided at entry after randomization. At most study visits, clinical assessments, including histories, physical exams and determination of drug adherence, will occur. Blood for hematologic and metabolic safety assessments and for the assessment of immune parameters will be obtained. Immune parameters that will be measured include levels of T-cell apoptosis, maturation and activation. Frequencies of various T-cell subsets and other lymphocyte populations will also be done. Response to vaccination with tetanus-diphtheria vaccine and 23-valent pneumococcal polysaccharide vaccine (both given at week 8) will be measured.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 4 Study of the Effect on Immune Reconstitution of a Lopinavir/Ritonavir-Based Versus an Efavirenz-based HAART (Highly Active Antiretroviral Therapy) Regimen in Antiretroviral-Naïve Subjects With Advanced HIV Disease
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ARM A/Lopinar/ritonavir Subjects randomized to Arm A initiated Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Drug: Lopinavir 400 mg/ritonavir 100 mg; Lopinavir 400 mg/ritonavir 100 mg fixed dose combination BID + emtricitabine 200 mg/tenofovir 300 mg fixed dose combination QD; Other Names: Kaletra Truvada
Active Comparator: ARM B/Efavirenz Subjects randomized to Arm B initiated Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD	Drug: Efavirenz; Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg fixed dose combination QD; Other Names: Atripla

Outcome Measures

Primary Outcome Measures

1. CD4+ (Cluster of Differentiation 4) T-cell Apoptosis [24 weeks from treatment initiation (baseline and week 24)]

   Change in the percentage of naive CD4 T-cells undergoing apoptosis as measured by propidium iodide staining. This is a lab test that measures the percentage of naive CD4 T-cells that are undergoing cell death. The change in this measure is obtained by determining the difference between the percentage of naive CD4 T-cells undergoing apoptosis at week 24 of treatment and the percentage undergoing apoptosis at baseline.

Secondary Outcome Measures

1. CD4+ T-cell Change [24 weeks after treatment initiation (baseline and week 24)]

   This measures the change in CD4+ T-cells from baseline to week 24 of treatment.

2. Naive, Central Memory and Effector Memory CD4+ and CD8+ (Cluster of Differentiation 8) T-cell Frequency [4, 12 and 24 weeks after treatment initiation]

3. Activated and Regulatory CD4+ and CD8+ T-cell Frequencies [4, 12 and 24 weeks after treatment initiation]

4. Response to Immunization With Pneumococcus Polysaccharide and Tetanus-diphtheria Vaccines [4 weeks after treatment initiation]

   Response to immunization with pneumococcus polysaccharide and tetanus-diphtheria vaccines was not done due to small sample size

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. HIV-1 infection

2. The absence of exclusionary resistance mutations on a genotypic resistance assay

3. Antiretroviral (ARV) drug-naïve

4. Screening HIV-1 RNA >1000 copies/mL

5. Screening CD4+ T-cell count < 200 cells/ml

6. Laboratory values obtained within 30 days prior to study entry.

• Absolute neutrophil count (ANC) >500/mm3

• Hemoglobin >8.0 g/dL

• Platelet count >40,000/mm3

• AST (SGOT), ALT (SGPT), and alkaline phosphatase <5 x ULN

• Total bilirubin <2.5 x ULN

• Calculated creatinine clearance ≥60 mL/min (by Cockcroft-Gault equation)

1. For women of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to initiating study medications.

2. Contraception requirements

3. Men and women age >18 years and < 60 years.

4. Ability and willingness of subject or legal guardian/representative to give written informed consent.

Exclusion Criteria:

1. Currently breast-feeding.

2. Use of immunomodulators, vaccines, growth hormone, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.

3. Known allergy/sensitivity to study drugs, pneumococcal polysaccharide vaccine, tetanus-diphtheria vaccine

4. Receipt of pneumococcal polysaccharide vaccine or tetanus-diphtheria vaccine in the past 5 years.

5. Active drug or alcohol use or dependence

6. Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 14 days prior to study entry.

7. Requirement for any current medications that are prohibited with any study treatment.

8. Evidence of any major resistance-associated mutation on any genotype or evidence of significant resistance on any phenotype performed at any time prior to study entry

9. Current or anticipated imprisonment or involuntary incarceration in a medical facility for psychiatric or physical (e.g., infectious disease) illness

10. History of, or current bipolar disorder, major depression, schizophrenia or other psychotic disorders

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rush University Medical Center	Chicago	Illinois	United States	60612
2	University of Illinois Medical Center	Chicago	Illinois	United States	60612
3	Howard Brown Health Center	Chicago	Illinois	United States	60613
4	University of Chicago Hospital	Chicago	Illinois	United States	60637

Sponsors and Collaborators

• Rush University Medical Center
• University of Chicago
• University of Illinois at Chicago
• Ruth M. Rothstein CORE Center
• Abbott
• Gilead Sciences

Investigators

• Study Chair: Allan R. Tenorio, M.D., Rush University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Allan Tenorio, MD, MD, Rush University Medical Center
• ClinicalTrials.gov Identifier: NCT00775606
• Other Study ID Numbers: ICE-001
• First Posted: Oct 20, 2008
• Last Update Posted: Jun 9, 2014
• Last Verified: May 1, 2014

• Keywords provided by Allan Tenorio, MD, MD, Rush University Medical Center: AIDS, HIV
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes; Ritonavir; Lopinavir; Efavirenz

Study Results

Participant Flow

Pre-assignment Detail	Two subjects withdrew participation prior to starting study

Arm/Group Title	ARM A/Lopinavir-ritonavir	ARM B/Efavirenz
Arm/Group Description	Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD
Period Title: Overall Study
STARTED	8	5
COMPLETED	5	5
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	ARM A	ARM B	Total
Arm/Group Description	Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD	Total of all reporting groups
Overall Participants	8	5	13
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 100%	5 100%	13 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.5 (9.4)	30.6 (7.1)	33 (8.5)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	8 100%	5 100%	13 100%
Region of Enrollment (participants) [Number]
United States	8 100%	5 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	CD4+ (Cluster of Differentiation 4) T-cell Apoptosis
Description	Change in the percentage of naive CD4 T-cells undergoing apoptosis as measured by propidium iodide staining. This is a lab test that measures the percentage of naive CD4 T-cells that are undergoing cell death. The change in this measure is obtained by determining the difference between the percentage of naive CD4 T-cells undergoing apoptosis at week 24 of treatment and the percentage undergoing apoptosis at baseline.
Time Frame	24 weeks from treatment initiation (baseline and week 24)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ARM A/Lopinavir-ritonavir	ARM B/Efavirenz
Arm/Group Description	Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD
Measure Participants	5	5
Mean (Standard Deviation) [per cent]	-12.33 (12.34)	-8.01 (7.97)

2. Secondary Outcome

Title	CD4+ T-cell Change
Description	This measures the change in CD4+ T-cells from baseline to week 24 of treatment.
Time Frame	24 weeks after treatment initiation (baseline and week 24)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ARM A/Lopinavir-ritonavir	ARM B/Efavirenz
Arm/Group Description	Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD
Measure Participants	5	5
Mean (Standard Deviation) [cells/mm3]	176.83 (101.39)	102.6 (150.45)

3. Secondary Outcome

Title	Naive, Central Memory and Effector Memory CD4+ and CD8+ (Cluster of Differentiation 8) T-cell Frequency
Time Frame	4, 12 and 24 weeks after treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Activated and Regulatory CD4+ and CD8+ T-cell Frequencies
Time Frame	4, 12 and 24 weeks after treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Response to Immunization With Pneumococcus Polysaccharide and Tetanus-diphtheria Vaccines
Description	Response to immunization with pneumococcus polysaccharide and tetanus-diphtheria vaccines was not done due to small sample size
Time Frame	4 weeks after treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ARM A	ARM B
Arm/Group Description	Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD
Measure Participants	0	0

Adverse Events

Time Frame	Week 24
Arm/Group Title	ARM A/Lopinavir-ritonavir		ARM B/Efavirenz
Arm/Group Description	Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD		Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD
All Cause Mortality
	ARM A/Lopinavir-ritonavir		ARM B/Efavirenz
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ARM A/Lopinavir-ritonavir		ARM B/Efavirenz
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	ARM A/Lopinavir-ritonavir		ARM B/Efavirenz
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		0/5 (0%)
Hepatobiliary disorders
Grade 3 elevation in ALT	1/8 (12.5%)	1	0/5 (0%)	0

Limitations/Caveats

Study was terminated due to the slow recruitment and the small number of subjects.

More Information

Certain Agreements

Principal Investigators are NOT 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.