A Prospective, Open-label Trial of Two ABC/3TC Based Regimens in Late Presenter naïve Patients (CD4 <200 Cells/µL)

A Prospective, Open-label Trial of Two Abacavir/Lamivudine Based Regimen (ABC/3TC + Darunavir/Ritonavir or ABC/3TC + Raltegravir) in Late Presenter naïve Patients (With CD4 Count <200 Cells/µL - Advanced HIV Disease)

1. PROTOCOL SUMMARY This is a prospective, randomized open-label, 2 arm, 3-phase trial to compare the 48-weeks virological response of two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

1.1 Clinical Objectives: Primary Objective: To compare the 48-week virological response to two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

Secondary Objective: a) To compare immunological response at 48 weeks; b) To determine the safety and tolerability of the 2 regimens.

1.2 Study population: 350 in/out patients 1.3 Outcome Primary Endpoint

• Proportion of patients with HIV RNA<50 copies/mL after 48 weeks Secondary Endpoints(s)
• Change in CD4+ cell count from baseline through week 48
• Time to virological rebound 1.4 Study design: Multicentre, parallel group, randomised, open label, non-inferiority study 1.5 Treatment regimens: Arm A: abacavir/lamivudine 1 tablet once a day + raltegravir 400 mg (1 tablet twice a day) Arm B: abacavir/lamivudine 1 tablet once a day + ritonavir 100 mg + darunavir 800 mg once a day.

All drugs have been approved for the treatment of HIV infection. The study population will consist of 350 HIV-positive, HLA B5701-negative patients. At baseline, patients will be randomized 1:1 to start abacavir/lamivudine plus either raltegravir or darunavir/ritonavir. Randomization will be stratified on the basis of the screening CD4+ cell count (≤100 vs ≥100 cells/µL), to ensure balance across treatments groups 1.7 Criteria for Safety: Adverse events and laboratory assessments. 1.8 Statistical analysis: As this is a non-inferiority trial, we will calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and will calculate a 95% confidence interval for this. Non-inferiority of the raltegravir arm will be demonstrated if the lower limit of the 95% confidence interval is greater than -12%. In case non-inferiority will be met, analyses for superiority will be performed.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: abacavir/lamivudine + raltegravir; Drug: abacavir/lamivudine + darunavir/ritonavir

Detailed Description

1. PROTOCOL SUMMARY This is a prospective, randomized open-label, 2 arm, 3-phase trial to compare the 48-weeks virological response of two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

1.1 Clinical Objectives: Primary Objective: To compare the 48-week virological response to two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (DRV/r) vs abacavir/lamivudine + raltegravir (RAL) in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4+ counts < 200/mm3.

Secondary Objective:

1. To compare immunological response at 48 weeks;

2. To determine the safety and tolerability of the 2 regimens. 1.2 Study population: 350 inpatients or outpatients will be randomized 1.3 Outcome Primary Endpoint

   • Proportion of patients with undetectable viremia (HIV RNA<50 copies/mL) after 48 weeks Secondary Endpoints(s)
   • Change in CD4+ cell count from baseline through week 48
   • Time to virological rebound Safety endpoints
   • Incidence of adverse events (AEs)
   • Incidence of serious adverse events (SAEs)
   • Discontinuations due to adverse events
   • Incidence of grade 3 or 4 laboratory abnormalities. 1.4 Study design Multicentre, parallel group, randomised, open label, non-inferiority study 1.5 Planned sample size: The planned sample size for this trial is 350 patients 1.6 Treatment regimens: Arm A: abacavir/lamivudine 1 tablet once a day + raltegravir 400 mg (1 tablet twice a day) Arm B: abacavir/lamivudine 1 tablet once a day + ritonavir 100 mg + darunavir 800 mg once a day.

All drugs have been approved for the treatment of HIV infection. Administration: oral The study population will consist of 350 HIV-positive, HLA B5701-negative patients. At baseline, patients will be randomized 1:1 to start abacavir/lamivudine plus either raltegravir or darunavir/ritonavir. Randomization will be stratified on the basis of the screening CD4+ cell count (≤100 vs ≥100 cells/µL), to ensure balance across treatments groups 1.7 Criteria for Safety: Adverse events and laboratory assessments. 1.8 Statistical analysis: As this is a non-inferiority trial, we will calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and will calculate a 95% confidence interval for this. Non-inferiority of the raltegravir arm will be demonstrated if the lower limit of the 95% confidence interval is greater than -12%. In case non-inferiority will be met, analyses for superiority will be performed.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Modena, Italy, 41124
    • University of Modena and Reggio Emilia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females (inpatients or outpatients) aged 18-64 years who are HIV-1 antibody seropositive, with a CD4 count <200 cells/uL.
2. All patients should be antiretroviral-naive
3. All patients should be HLA B57 or HLA B5701 negative
4. Patients must have an HIV RNA level <500,000 copies/mL
5. Patients with an active opportunistic infection could be enrolled as long as this was diagnosed more than 2 weeks prior to screening.
6. Patients must meet the following laboratory criteria. Neutrophil count > 1,000 cells/mm3 Haemoglobin > 9.0 grams/dl (men and women) Platelet count ≥ 75,000 cells/mm3 Alkaline phosphatase < 3.0 the upper limit of normal ALT and AST < 3.9 times the upper limit of normal Total bilirubin < 1.5 times the upper limit of normal.
7. Female patients of childbearing potential must be willing to use a reliable form of contraception, which will include a medically approved form of barrier contraception.
8. Patients must be able to provide written consent to comply with study requirements.

Exclusion Criteria:

1. Patients with genotypic mutations for any of the study drugs.
2. Patients with an opportunistic infection diagnosed in the 2 weeks prior to screening.
3. Female patients who are pregnant or breastfeeding.
4. Patients who are receiving any investigational drug or anti-neoplastic radiotherapy/chemotherapy other than local skin radiotherapy within 12 weeks before randomization.
5. Patients with a current history of intravenous drug abuse, alcohol or substance abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: abacavir/lamivudine + raltegravir	Drug: abacavir/lamivudine + raltegravir; abacavir/lamivudine + raltegravir; Other Names: Isentress; Kivexa
Active Comparator: ABC/3TC + DRV/r; abacavir/lamivudine + darunavir/ritonavir	Drug: abacavir/lamivudine + darunavir/ritonavir; abacavir/lamivudine + darunavir/ritonavir; Other Names: Prezista; Norvir; Kivexa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV RNA Viral Load	The proportion of patients attaining an HIV RNA level <50 copies/mL after 48 weeks will be the primary outcome.	baseline and week 48

Collaborators and Investigators

• Sponsor: University of Modena and Reggio Emilia
• Investigators: Principal Investigator: Cristina Mussini, Professor, University of Modena and ReggioEmilia

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2013
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: July 5, 2013
• First Submitted That Met QC Criteria: July 11, 2013
• First Posted (Estimate): July 16, 2013

Study Record Updates

• Last Update Posted (Actual): April 23, 2019
• Last Update Submitted That Met QC Criteria: April 19, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: late presenter; naïve; advanced HIV disease
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Raltegravir Potassium; Ritonavir; Lamivudine; Darunavir; Abacavir; Dideoxynucleosides
• Other Study ID Numbers: RTLP (PRADAR); 2011-005973-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No