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

Primary Purpose

Human Immunodeficiency Virus, HIV

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Aluvia + 2NRTIs
Aluvia + raltegravir
Aluvia monotherapy
Sponsored by
Justine Boles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Human Immunodeficiency Virus focused on measuring Human Immunodeficiency virus, second line therapy, raltegravir, aluvia, monotherapy, integrase inhibitor, protease inhibitor, Randomized Controlled Trial

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • AMPATH Centre at Moi Teaching Referral Hospital
  • University of Malawi
  • Mzuzu Central Hospital
  • Joint Clinical Research Centre
  • JCRC
  • JCRC
  • JCRC
  • Infectious Diseases Institute
  • Joint Clinical Research Centre
  • San Raphael of St Francis Hospital Nsambya
  • Joint Clinical Research Centre
  • Joint Clinical Research Centre
  • University Teaching Hospital
  • University of Zimbabwe Clinical Research Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

bPI + 2NRTIs

bPI + raltegravir

bPI monotherapy

Arm Description

Outcomes

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

Secondary Outcome Measures

Good HIV disease control
Proportion with CD4 cell count >250 cells/mm3
Proportion with new or recurrent WHO stage 4 event
Proportion of patients with plasma viral load <50 copies
Adverse events
Quality of life change from randomisation
Neurocognitive function change from randomisation
Healthcare costs
Proportion with serious non-AIDS events

Full Information

First Posted
September 30, 2009
Last Updated
April 3, 2014
Sponsor
Justine Boles
Collaborators
European and Developing Countries Clinical Trials Partnership (EDCTP)
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1. Study Identification

Unique Protocol Identification Number
NCT00988039
Brief Title
Europe-Africa Research Network for Evaluation of Second-line Therapy
Acronym
EARNEST
Official Title
A Randomised Controlled Trial to Evaluate Options for Second-line Therapy in Patients Failing a First-line 2NRTI + NNRTI Regimen in Africa
Study Type
Interventional

2. Study Status

Record Verification Date
April 2014
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Justine Boles
Collaborators
European and Developing Countries Clinical Trials Partnership (EDCTP)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus, HIV
Keywords
Human Immunodeficiency virus, second line therapy, raltegravir, aluvia, monotherapy, integrase inhibitor, protease inhibitor, Randomized Controlled Trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1277 (Actual)

8. Arms, Groups, and Interventions

Arm Title
bPI + 2NRTIs
Arm Type
Active Comparator
Arm Title
bPI + raltegravir
Arm Type
Experimental
Arm Title
bPI monotherapy
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Aluvia + 2NRTIs
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Aluvia + raltegravir
Intervention Description
Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily
Intervention Type
Drug
Intervention Name(s)
Aluvia monotherapy
Intervention Description
Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily for the first 12 weeks only
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Good HIV disease control
Time Frame
week 144
Title
Proportion with CD4 cell count >250 cells/mm3
Time Frame
week 96 and week 144
Title
Proportion with new or recurrent WHO stage 4 event
Time Frame
week 96 and week 144
Title
Proportion of patients with plasma viral load <50 copies
Time Frame
week 48, week 96 and week 144
Title
Adverse events
Time Frame
During trial
Title
Quality of life change from randomisation
Time Frame
During trial
Title
Neurocognitive function change from randomisation
Time Frame
during trial
Title
Healthcare costs
Time Frame
During trial
Title
Proportion with serious non-AIDS events
Time Frame
Week 96 and week 144

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicholas Paton, MD FRCP
Organizational Affiliation
MRC CTU
Official's Role
Study Director
Facility Information:
Facility Name
AMPATH Centre at Moi Teaching Referral Hospital
City
Eldoret
Country
Kenya
Facility Name
University of Malawi
City
Blantyre
Country
Malawi
Facility Name
Mzuzu Central Hospital
City
Mzuzu
Country
Malawi
Facility Name
Joint Clinical Research Centre
City
Fort Portal
Country
Uganda
Facility Name
JCRC
City
Gulu
Country
Uganda
Facility Name
JCRC
City
Kabale
Country
Uganda
Facility Name
JCRC
City
Kakira
Country
Uganda
Facility Name
Infectious Diseases Institute
City
Kampala
Country
Uganda
Facility Name
Joint Clinical Research Centre
City
Kampala
Country
Uganda
Facility Name
San Raphael of St Francis Hospital Nsambya
City
Kampala
Country
Uganda
Facility Name
Joint Clinical Research Centre
City
Mbale
Country
Uganda
Facility Name
Joint Clinical Research Centre
City
Mbarara
Country
Uganda
Facility Name
University Teaching Hospital
City
Lusaka
Country
Zambia
Facility Name
University of Zimbabwe Clinical Research Centre
City
Harare
Country
Zimbabwe

12. IPD Sharing Statement

Citations:
PubMed Identifier
31077251
Citation
Shi Y, Thompson J, Walker AS, Paton NI, Cheung YB; EARNEST Trial Team. Mapping the medical outcomes study HIV health survey (MOS-HIV) to the EuroQoL 5 Dimension (EQ-5D-3 L) utility index. Health Qual Life Outcomes. 2019 May 10;17(1):83. doi: 10.1186/s12955-019-1135-8.
Results Reference
derived
PubMed Identifier
30060027
Citation
Thompson JA, Kityo C, Dunn D, Hoppe A, Ndashimye E, Hakim J, Kambugu A, van Oosterhout JJ, Arribas J, Mugyenyi P, Walker AS, Paton NI; Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team. Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial. Clin Infect Dis. 2019 Mar 19;68(7):1184-1192. doi: 10.1093/cid/ciy589.
Results Reference
derived
PubMed Identifier
28495562
Citation
Paton NI, Kityo C, Thompson J, Nankya I, Bagenda L, Hoppe A, Hakim J, Kambugu A, van Oosterhout JJ, Kiconco M, Bertagnolio S, Easterbrook PJ, Mugyenyi P, Walker AS; Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. Lancet HIV. 2017 Aug;4(8):e341-e348. doi: 10.1016/S2352-3018(17)30065-6. Epub 2017 May 8.
Results Reference
derived
PubMed Identifier
25014688
Citation
Paton NI, Kityo C, Hoppe A, Reid A, Kambugu A, Lugemwa A, van Oosterhout JJ, Kiconco M, Siika A, Mwebaze R, Abwola M, Abongomera G, Mweemba A, Alima H, Atwongyeire D, Nyirenda R, Boles J, Thompson J, Tumukunde D, Chidziva E, Mambule I, Arribas JR, Easterbrook PJ, Hakim J, Walker AS, Mugyenyi P; EARNEST Trial Team. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014 Jul 17;371(3):234-47. doi: 10.1056/NEJMoa1311274.
Results Reference
derived
Links:
URL
http://earnest.cineca.org/
Description
EARNEST trial website

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Europe-Africa Research Network for Evaluation of Second-line Therapy

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