Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST)

This study has been completed.
Sponsor:
Collaborator:
European and Developing Countries Clinical Trials Partnership (EDCTP)
Information provided by (Responsible Party):
Justine Boles, Medical Research Council
ClinicalTrials.gov Identifier:
NCT00988039
First received: September 30, 2009
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

The trial aim is to ascertain what, if anything, needs to be combined with a boosted protease inhibitor (bPI) backbone in second-line therapy in order to maximize the chance of a good clinical outcome following WHO-defined failure on a first-line nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI-containing regimen with probable extensive NRTI and NNRTI resistance mutations.


Condition Intervention Phase
Human Immunodeficiency Virus
HIV
Drug: Aluvia + 2NRTIs
Drug: Aluvia + raltegravir
Drug: Aluvia monotherapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomised Controlled Trial to Evaluate Options for Second-line Therapy in Patients Failing a First-line 2NRTI + NNRTI Regimen in Africa

Resource links provided by NLM:


Further study details as provided by Medical Research Council:

Primary Outcome Measures:
  • Good HIV disease control defined as a composite endpoint consisting of all of: - No new WHO stage 4 events - CD4 count >250 cells/mm3 - viral load <10,000 copies/ml or >10,000 copies/ml with no PI resistance mutations [ Time Frame: week 96 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Good HIV disease control [ Time Frame: week 144 ] [ Designated as safety issue: No ]
  • Proportion with CD4 cell count >250 cells/mm3 [ Time Frame: week 96 and week 144 ] [ Designated as safety issue: No ]
  • Proportion with new or recurrent WHO stage 4 event [ Time Frame: week 96 and week 144 ] [ Designated as safety issue: Yes ]
  • Proportion of patients with plasma viral load <50 copies [ Time Frame: week 48, week 96 and week 144 ] [ Designated as safety issue: No ]
  • Adverse events [ Time Frame: During trial ] [ Designated as safety issue: Yes ]
  • Quality of life change from randomisation [ Time Frame: During trial ] [ Designated as safety issue: No ]
  • Neurocognitive function change from randomisation [ Time Frame: during trial ] [ Designated as safety issue: No ]
  • Healthcare costs [ Time Frame: During trial ] [ Designated as safety issue: No ]
  • Proportion with serious non-AIDS events [ Time Frame: Week 96 and week 144 ] [ Designated as safety issue: No ]

Enrollment: 1277
Study Start Date: March 2010
Study Completion Date: January 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: bPI + 2NRTIs Drug: Aluvia + 2NRTIs

Aluvia (lopinavir/ritonavir 400mg/100mg), twice daily

The choice of NRTIs will be at the discretion of the managing clinician and based on the local standard of care and drug availability, taking into account patient's previous drug exposure and side effects on first-line therapy.

Experimental: bPI + raltegravir Drug: Aluvia + raltegravir

Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily

raltegravir (400mg) twice daily

Experimental: bPI monotherapy Drug: Aluvia monotherapy

Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily

raltegravir (400mg) twice daily for the first 12 weeks only


Detailed Description:

The standard of care for second-line HIV therapy in patients who have failed a first-line NNRTI-based regimen is to combine a boosted protease inhibitor (bPI) with two (new) NRTIs. However, patients failing first-line therapy in roll-out programmes often have extensive NRTI resistance mutations that may compromise the efficacy of the NRTI drugs used in second-line therapy and it is likely that the virological potency of the second-line regimen is mostly due to the bPI. It is possible that the contribution of the NRTI drugs to efficacy may be outweighed by additional toxicity and cost. It is also possible that replacing the NRTI drugs with a new class of drug (integrase inhibitors) will improve outcome from second-line therapy, although if the boosted protease inhibitor alone is providing close to optimal response, incremental gains from adding a new class may be small.

The principal aims are to determine whether, in patients failing a first-line NRTI and NNRTI-containing regimen:

  • The use of bPI plus raltegravir (an integrase inhibitor) is superior to standard of care (bPI plus 2 new NRTIs) in achieving good HIV disease control at 96 weeks after randomisation
  • The use of bPI monotherapy, preceded by a 12-week induction period in combination with raltegravir, is non-inferior to standard of care in achieving good HIV disease control at 96 weeks after randomisation
  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Previously documented HIV infection on at least one standard antibody-based test
  • Age 12 years and above
  • Taking 2NRTI + NNRTI-based regimen continuously for at least 12 months
  • Naive to protease inhibitor therapy
  • Good adherence to ART in the 12 weeks prior to screening defined as missing medication on no more than 3 days in the prior month
  • Clinically stable and receiving treatment for any known opportunistic infections
  • HIV treatment failure defined by one or more of clinical, immunological or virological criteria defined in the protocol, including VL and CD4 at screening visit
  • Willing and able to give informed consent
  • Able to attend for regular study follow up visits

Exclusion Criteria:

  • Any major clinical contra-indications to the use of bPI, the NRTIs that are available to be selected for a second-line regimen or raltegravir
  • Known Hepatitis B carrier (Hepatitis B surface antigen positive if tested)
  • Requires concomitant medication with known major interactions with study drugs for which drug substitutions or dose alterations are not available or acceptable
  • Women who are currently pregnant or breastfeeding
  • Current participation in another clinical trial involving a treatment intervention (may be permitted in some circumstances, but must be discussed with MRC CTU)
  • Life expectancy of less than one month in the opinion of the treating physician
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00988039

Locations
Kenya
AMPATH Centre at Moi Teaching Referral Hospital
Eldoret, Kenya
Malawi
University of Malawi
Blantyre, Malawi
Mzuzu Central Hospital
Mzuzu, Malawi
Uganda
Joint Clinical Research Centre
Fort Portal, Uganda
JCRC
Gulu, Uganda
JCRC
Kabale, Uganda
JCRC
Kakira, Uganda
Joint Clinical Research Centre
Kampala, Uganda
Infectious Diseases Institute
Kampala, Uganda
San Raphael of St Francis Hospital Nsambya
Kampala, Uganda
Joint Clinical Research Centre
Mbale, Uganda
Joint Clinical Research Centre
Mbarara, Uganda
Zambia
University Teaching Hospital
Lusaka, Zambia
Zimbabwe
University of Zimbabwe Clinical Research Centre
Harare, Zimbabwe
Sponsors and Collaborators
Justine Boles
European and Developing Countries Clinical Trials Partnership (EDCTP)
Investigators
Study Director: Nicholas Paton, MD FRCP MRC CTU
  More Information

Additional Information:
No publications provided by Medical Research Council

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Justine Boles, Professor Nicholas Paton, Medical Research Council
ClinicalTrials.gov Identifier: NCT00988039     History of Changes
Other Study ID Numbers: U.1228.03.004.00021.01, IP_2007_33011_003, ISRCTN37737787
Study First Received: September 30, 2009
Last Updated: April 3, 2014
Health Authority: Uganda: National Council for Science and Technology
Uganda: National Drug Authority
Zimbabwe: Medicines Control Authority of Zimbabwe
Malawi: Pharmacy, Medicines and Poisons Board
Zambia: Zambia Pharmaceutical Regulatory Authority
Kenya: Pharmacy and Poisons Board

Keywords provided by Medical Research Council:
Human Immunodeficiency virus
second line therapy
raltegravir
aluvia
monotherapy
integrase inhibitor
protease inhibitor
Randomized Controlled Trial

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Integrase Inhibitors
Lopinavir
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
HIV Protease Inhibitors
Protease Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014