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

Tracking Information
First Submitted Date ICMJE	September 30, 2009
First Posted Date ICMJE	October 1, 2009
Last Update Posted Date	April 4, 2014
Study Start Date ICMJE	March 2010
Actual Primary Completion Date	January 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: September 30, 2009)	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 ]
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT00988039 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: September 7, 2010)	Good HIV disease control [ Time Frame: week 144 ]; Proportion with CD4 cell count >250 cells/mm3 [ Time Frame: week 96 and week 144 ]; Proportion with new or recurrent WHO stage 4 event [ Time Frame: week 96 and week 144 ]; Proportion of patients with plasma viral load <50 copies [ Time Frame: week 48, week 96 and week 144 ]; Adverse events [ Time Frame: During trial ]; Quality of life change from randomisation [ Time Frame: During trial ]; Neurocognitive function change from randomisation [ Time Frame: during trial ]; Healthcare costs [ Time Frame: During trial ]; Proportion with serious non-AIDS events [ Time Frame: Week 96 and week 144 ]
Original Secondary Outcome Measures ICMJE; (submitted: September 30, 2009)	Good HIV disease control [ Time Frame: week 144 ]; Proportion with CD4 cell count >250 cells/mm3 [ Time Frame: week 96 and week 144 ]; Proportion with new or recurrent WHO stage 4 event [ Time Frame: week 96 and week 144 ]; Proportion of patients with plasma viral load <50 copies [ Time Frame: week 48, week 96 and week 144 ]; Adverse events [ Time Frame: During trial ]; Quality of life change from randomisation [ Time Frame: During trial ]; Neurocognitive function change from randomisation [ Time Frame: during trial ]; Healthcare costs [ Time Frame: During trial ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Europe-Africa Research Network for Evaluation of Second-line Therapy
Official Title ICMJE	A Randomised Controlled Trial to Evaluate Options for Second-line Therapy in Patients Failing a First-line 2NRTI + NNRTI Regimen in Africa
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
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Human Immunodeficiency Virus; HIV
Intervention ICMJE	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.; Drug: Aluvia + raltegravir Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily; Drug: Aluvia monotherapy Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily for the first 12 weeks only
Study Arms	Active Comparator: bPI + 2NRTIs Intervention: Drug: Aluvia + 2NRTIs; Experimental: bPI + raltegravir Intervention: Drug: Aluvia + raltegravir; Experimental: bPI monotherapy Intervention: Drug: Aluvia monotherapy
Publications *	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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: July 7, 2011)	1277
Original Estimated Enrollment ICMJE; (submitted: September 30, 2009)	1200
Actual Study Completion Date	January 2014
Actual Primary Completion Date	January 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	12 Years and older (Child, Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Kenya, Malawi, Uganda, Zambia, Zimbabwe
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00988039
Other Study ID Numbers ICMJE	U.1228.03.004.00021.01; IP_2007_33011_003; ISRCTN37737787
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Justine Boles, Medical Research Council
Study Sponsor ICMJE	Justine Boles
Collaborators ICMJE	European and Developing Countries Clinical Trials Partnership (EDCTP)
Investigators ICMJE	Study Director: Nicholas Paton, MD FRCP MRC CTU
PRS Account	Medical Research Council
Verification Date	April 2014
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP