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CompletedNCT01011413ENCORE1Updated Feb 21, 2020Results posted

Safety and Efficacy of Reduced Versus Standard Dose Efavirenz (EFV) Plus Two Nucleotides in Antiretroviral-naïve Adults.

A Phase 3 interventional study of Efavirenz 600mg and Efavirenz 400mg in HIV Infections, sponsored by Kirby Institute. Completed at 1 site in Australia. Open to participants aged 16 Years and older. Per ClinicalTrials.gov, last updated 2020-02-21.

Sponsored by Kirby Institute · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
636
Allocation
Randomized
Ages
16 Years and older
Sex
All
01

Study summary

Clinical data suggests that the standard dose of the anti-HIV medication, efavirenz (EFV), could be reduced without compromising its effectiveness. Lower drug doses could have fewer side effects and would make EFV more affordable. The purpose of this study is to compare the safety and effectiveness, over 96 weeks, of standard (600mg) versus reduced dose (400mg) EFV in controlling HIV as part of initial combination antiretroviral therapy.

Read the detailed description

In this international, multicenter trial, 630 HIV infected patients who have not received any previous treatment for their HIV-infection will be enrolled. Participants will be randomized equally (1:1) to receive Truvada (tenofovir and emtricitabine) with either the standard or reduced dose of EFV. Neither the study doctor nor the participant will know which treatment the participant is receiving. Physical examinations, laboratory analyses and questionnaires will be performed at the 11 study visits at screening, baseline (Week 0), Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96. The primary aim of this study is to compare between treatment groups the proportion of patients with undetectable HIV viral load (HIV RNA \< 200 copies/mL) after 48 weeks. Information on immune function, drug adherence, resistance to antiretrovirals, quality of life, mental state and HIV-related conditions will also be collected. Blood samples will be collected for future testing. Interim analyses will be performed when the first 125 participants in each treatment group reach week 24 and when all participants reach week 24. These interim analyses will provide an early check that the reduced dose of EFV suppresses HIV infection as effectively as the standard dose of EFV. A follow-up analysis will be performed when all participants reach week 96.

02

Conditions studied

  • HIV Infections

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Keywords

  • HIV
  • Antiretroviral Therapy (ART)
  • Efavirenz (EFV)
  • Dose reduction
03

In context

HIV Infections

4,258 studies on the registry are indexed under HIV Infections; 240 are open to participants now.

This study's enrollment of 636 is above the median of 83 across 3,251 interventional studies indexed under HIV Infections.

Browse HIV Infections studies →

Lead sponsor

Kirby Institute is the lead sponsor of 94 studies on the registry; 15 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
16 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • HIV-1 positive by licensed diagnostic test
  • aged >16 years of age (or minimum age as determined by local regulations or as legal requirements dictate)
  • 50 \< cluster of differentiation (CD)4 \<500 cells/µL
  • No prior AIDS-defining illness, using the Center for Diseases Control 1993 Case Definition (except pulmonary tuberculosis)
  • HIV RNA ≥1000 copies/mL
  • no prior exposure to antiretroviral therapy (ART) (including short course ART for preventing MTCT)
  • calculated creatinine clearance (CLCr) more than or equal to 50 mL/min (Cockcroft-Gault formula)
  • provision of written informed consent.

Exclusion criteria

Exclusion Criteria:

  • the following laboratory values:

    • absolute neutrophil count (ANC) \<500 cells/μL
    • hemoglobin \<7.0 g/dL
    • platelet count \<50,000 cells/μL
    • alanine aminotransferase and/or aspartate aminotransferase >5 x upper limit of normal
  • pregnant women or nursing mothers
  • active opportunistic or malignant disease not under adequate control
  • use of immunomodulators within 30 days prior to screening
  • use of any prohibited medications
  • current alcohol or illicit substance use that might adversely affect study participation
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
636 participants (actual)

Study arms

  • Active comparator
    600 milligram (mg) Efavirenz

    Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd)

    Drug: Efavirenz 600mg

  • Experimental
    400mg Efavirenz

    Eligible patients will be centrally randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd).

    Drug: Efavirenz 400mg

Interventions

  • DrugEfavirenz 600mg

    3 x EFV 200 milligram (mg) tablets once daily

    Also known as: Matrix EFV 200mg tablets

  • DrugEfavirenz 400mg

    2 x EFV 200 milligram (mg) tablets plus 1x matched EFV placebo tablet once daily

    Also known as: Matrix EFV 200mg tablets, Matrix EFV 200mg matched placebo tablets.

06

What researchers measure

Primary outcomes

  1. Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation

    Percentage of participants in each of the treatment arms with centrally quantified plasma HIV-1 RNA viral load \<200 copies/mL 48 weeks after randomisation.

    Time frame: 48 weeks

Secondary outcomes

  1. Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation

    Percentage of participants in each of the two treatment arms with plasma HIV-1 RNA \<400 copies/mL and \<50 copies/mL at 48 and 96 weeks after randomisation

    Time frame: Baseline and 2 years

  2. Mean Change From Baseline in CD4+ T-cell Count

    Mean change from baseline to week 96 in CD4+ T-cell count/mm3 between the two treatment arms

    Time frame: Baseline and 2 years

  3. Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality

    Number of participants in each randomised arm diagnosed with a serious non-AIDS defining event, who die from an AIDS-defining event, who die from a non-AIDS-defining event

    Time frame: up to 2 years

  4. Change From Baseline in Metabolic Endpoints

    Change from baseline to week 96 in fasted total cholesterol, high density cholesterol and low density cholesterol, and glucose between randomised treatment arms

    Time frame: Baseline and 2 years

  5. Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications

    AIDS Clinical Trials Group (ACTG) 7-day adherence questionnaire scores. Maximum value is all pills taken every day; minimum value is no pills taken per day. Higher scores indicate a better outcome.

    Time frame: 2 years

  6. Change From Baseline in Fasted Insulin Levels

    Change from baseline to week 96 in fasted insulin levels

    Time frame: Baseline and 2 years

  7. Change in Selected Serum Biochemical Parameters

    Change from baseline to week 96 in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels between randomised treatment arms

    Time frame: Baseline and 2 years

  8. Change From Baseline in Estimate Creatinine Clearance

    Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms

    Time frame: Baseline and 2 years

  9. Steady-state Efavirenz Concentrations

    Steady-state efavirenz mid-dosing interval plasma concentrations

    Time frame: Week 4

07

Results

Posted Feb 21, 2020

Participant flow

38 clinical centres (primary and tertiary care facilities) in 13 countries on 5 continents screened a total of 768 patents who had provided informed consent between Aug 4, 2011 and March 19, 2012.

Participant flow — Overall Study
Milestone600mg Efavirenz400mg Efavirenz
Started312324
Did not start study drug33
In modified itt309321
Died before week 4832
Lost to follow up before w4834
Withdrew consent before w4833
Attended w48 visit295311
Died between week 48 and 9623
Withdrew consent between week 48 and 9626
Lost to follow-up between week 48 and 96104
Completed286299
Not completed2625

Outcome measures

PrimaryPercentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation

Percentage of participants in each of the treatment arms with centrally quantified plasma HIV-1 RNA viral load \<200 copies/mL 48 weeks after randomisation.

Time frame:
48 weeks
Reported as:
Number · percentage of participants
Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation
percentage of participants600mg Efavirenz400mg Efavirenz
Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation92.2 (89.2 to 95.2)94.1 (91.5 to 96.7)
Statistical analysis
  • 600mg Efavirenz vs 400mg Efavirenz · Pearson's chi-squared · p = 0.05 (No adjustments were made for multiple comparisons)Pearson's chi-squared or Fisher's exact test derived p value was used
  • 600mg Efavirenz vs 400mg Efavirenz · Chi-squared · p = 0.05 (No adjustment for multiple comparisons)
SecondaryPercentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation

Percentage of participants in each of the two treatment arms with plasma HIV-1 RNA \<400 copies/mL and \<50 copies/mL at 48 and 96 weeks after randomisation

Time frame:
Baseline and 2 years
Reported as:
Number · participants
Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation
participants600 mg EfavirenzEfavirenz 400 mg
HIV-1 RNA <50cp/mL268277
HIV-1 RNA <400cp/mL280291
Statistical analysis
  • 600 mg Efavirenz vs Efavirenz 400 mg · Chi-squared · p = 0.05 (P-value not adjusted for multiple comparisons) · Difference between proportions: 0.05
SecondaryMean Change From Baseline in CD4+ T-cell Count

Mean change from baseline to week 96 in CD4+ T-cell count/mm3 between the two treatment arms

Time frame:
Baseline and 2 years
Reported as:
Mean · cells per mm3
Mean Change From Baseline in CD4+ T-cell Count
cells per mm3600mg Efavirenz400mg Efavirenz
Mean Change From Baseline in CD4+ T-cell Count209 (194 to 226)235 (218 to 252)
SecondaryClinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality

Number of participants in each randomised arm diagnosed with a serious non-AIDS defining event, who die from an AIDS-defining event, who die from a non-AIDS-defining event

Time frame:
up to 2 years
Reported as:
Count of participants · Participants
Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality
Participants600mg Efavirenz400mg Efavirenz
AIDS events714
AIDS event deaths20
non-AIDS deaths53
serious non-AIDS events33
No disease/death292301
SecondaryChange From Baseline in Metabolic Endpoints

Change from baseline to week 96 in fasted total cholesterol, high density cholesterol and low density cholesterol, and glucose between randomised treatment arms

Time frame:
Baseline and 2 years
Reported as:
Mean · mmol per Litre
Change From Baseline in Metabolic Endpoints
mmol per Litre600mg Efavirenz400mg Efavirenz
Total cholesterol mmol/L0.62 (0.53 to 0.71)0.54 (0.44 to 0.63)
HDL mmol/L0.35 (0.31 to 0.40)0.30 (0.26 to 0.34)
LDL mmol/L0.21 (0.13 to 0.29)0.16 (0.09 to 0.23)
Blood glucose mmol/L0.24 (0.07 to 0.4)0.40 (0.30 to 0.50)
SecondaryAdherence: Median Scores of Self-reported Adherence to Randomised Study Medications

AIDS Clinical Trials Group (ACTG) 7-day adherence questionnaire scores. Maximum value is all pills taken every day; minimum value is no pills taken per day. Higher scores indicate a better outcome.

Time frame:
2 years
Reported as:
Count of participants · Participants
Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications
Participants600mg Efavirenz400mg Efavirenz
All pills taken256271
Most pills taken712
About half pills taken11
No pills taken168
SecondaryChange From Baseline in Fasted Insulin Levels

Change from baseline to week 96 in fasted insulin levels

Time frame:
Baseline and 2 years
Reported as:
Mean · mU per litre
Change From Baseline in Fasted Insulin Levels
mU per litre600mg Efavirenz400mg Efavirenz
Change From Baseline in Fasted Insulin Levels-0.11 (-0.23 to 1.02)0.3 (-1.81 to 2.42)
SecondaryChange in Selected Serum Biochemical Parameters

Change from baseline to week 96 in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels between randomised treatment arms

Time frame:
Baseline and 2 years
Reported as:
Mean · Units per Litre
Change in Selected Serum Biochemical Parameters
Units per Litre600 mg EfavirenzEfavirenz 400 mg
Alanine aminotransferase6.53 (1.04 to 12.02)0.64 (-3.52 to 4.79)
Aspartate aminotransferase1.71 (-1.69 to 5.10)-1.23 (-3.67 to 1.21)
Alkaline phosphatase26.75 (22.9 to 30.61)21.23 (17.4 to 25.05)
SecondaryChange From Baseline in Estimate Creatinine Clearance

Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms

Time frame:
Baseline and 2 years
Reported as:
Mean · millilitres per minute
Change From Baseline in Estimate Creatinine Clearance
millilitres per minute600mg Efavirenz400mg Efavirenz
Change From Baseline in Estimate Creatinine Clearance-0.17 (-2.45 to 2.10)1.59 (-1.05 to 4.24)
SecondarySteady-state Efavirenz Concentrations

Steady-state efavirenz mid-dosing interval plasma concentrations

Time frame:
Week 4
Reported as:
Geometric mean · milligram per Litre
Steady-state Efavirenz Concentrations
milligram per Litre600mg Efavirenz400mg Efavirenz
Steady-state Efavirenz Concentrations2.85 (2.70 to 3.0)2.10 (2.01 to 2.20)

Adverse events

Collected over 96 weeks. Analyses were modified intention-to-treat which included all randomised participants who received at least one dose of study drug and had at least one follow-up visit. Number of participants in the modified ITT analysis at week 96 are: 321 for EFV 400mg and 309 for EFV 600mg. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
600mg Efavirenz7/309 (2.3%)25/309 (8.1%)273/309 (88.3%)
400mg Efavirenz3/321 (0.9%)23/321 (7.2%)286/321 (89.1%)
Most frequent serious events
Showing 10 of 42
Most frequent serious events
Event600mg Efavirenz400mg Efavirenz
gastroenteritisInfections and infestations3/3090/321
urosepsisInfections and infestations2/3090/321
anaemiaBlood and lymphatic system disorders0/3092/321
pyrexiaGeneral disorders0/3092/321
diverticulitisInfections and infestations1/3091/321
pneumoniaInfections and infestations1/3090/321
dengue feverInfections and infestations1/3090/321
perianal abscessInfections and infestations1/3090/321
cerebrovascular accidentVascular disorders1/3090/321
diarrhoeaGastrointestinal disorders1/3091/321
Most frequent other events
Showing 10 of 12
Most frequent other events
Event600mg Efavirenz400mg Efavirenz
dizzinessVascular disorders107/30985/321
upper respiratory tract infectionInfections and infestations36/30957/321
rashSkin and subcutaneous tissue disorders41/30957/321
diarrhoeaGastrointestinal disorders36/30933/321
abnormal dreamsPsychiatric disorders35/30928/321
headacheNervous system disorders34/30935/321
nasopharyngitisInfections and infestations18/30926/321
nauseaGastrointestinal disorders22/30914/321
insomniaPsychiatric disorders20/30920/321
coughRespiratory, thoracic and mediastinal disorders19/30919/321

Baseline characteristics

Age, Continuous
Age, Continuous(years)600mg Efavirenz400mg EfavirenzTotal
Mean35.8 ± 10.036.1 ± 10.036.0 ± 10.0
Sex: Female, Male
Sex: Female, Male(Participants)600mg Efavirenz400mg EfavirenzTotal
Female103100203
Male206221427
Race/Ethnicity, Customized
Race/Ethnicity, Customized(participants)600mg Efavirenz400mg EfavirenzTotal
African116118234
Asian103106209
White9097187
HIV transmission risk
HIV transmission risk(participants)600mg Efavirenz400mg EfavirenzTotal
heterosexual156156312
homo/bisexual134138272
injecting drug user/not known192746
CDC HIV infection clinical category
CDC HIV infection clinical category(participants)600mg Efavirenz400mg EfavirenzTotal
category A265264529
category B334679
category C111122
Median plasma HIV RNA
Median plasma HIV RNA(log10 copies per mL)600mg Efavirenz400mg EfavirenzTotal
Median4.73 (3.83 to 5.63)4.76 (3.92 to 5.60)4.75 (3.87 to 5.63)
Mean nadir cluster of differentiation (CD)4+ cell count
Mean nadir cluster of differentiation (CD)4+ cell count(cells per mm3)600mg Efavirenz400mg EfavirenzTotal
Mean252 ± 90248 ± 88250 ± 89
Hep B Sag +ve
Hep B Sag +ve(participants)600mg Efavirenz400mg EfavirenzTotal
Number121527

10 further baseline measures are reported on the registry.

08

Study locations

1 site
  • St Vincent's Hospital
    Sydney, New South Wales 2010, Australia
09

References and documents

Publications

  • ENCORE1 Study Group. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014 Apr 26;383(9927):1474-1482. doi: 10.1016/S0140-6736(13)62187-X. Epub 2014 Feb 10. Erratum In: Lancet. 2014 Apr 26;383(9927):1464. PubMed 24522178 ↗
  • ENCORE1 Study Group; Carey D, Puls R, Amin J, Losso M, Phanupak P, Foulkes S, Mohapi L, Crabtree-Ramirez B, Jessen H, Kumar S, Winston A, Lee MP, Belloso W, Cooper DA, Emery S. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015 Jul;15(7):793-802. doi: 10.1016/S1473-3099(15)70060-5. Epub 2015 Apr 12. Erratum In: Lancet Infect Dis. 2015 Jul;15(7):761. doi: 10.1016/S1473-3099(15)00090-0. PubMed 25877963 ↗
  • Winston A, Amin J, Clarke A, Else L, Amara A, Owen A, Barber T, Jessen H, Avihingsanon A, Chetchotisakd P, Khoo S, Cooper DA, Emery S, Puls R; ENCORE Cerebrospinal Fluid (CSF) Substudy Team; ENCORE Cerebrospinal Fluid CSF Substudy Team. Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. Clin Infect Dis. 2015 Apr 1;60(7):1026-32. doi: 10.1093/cid/ciu976. Epub 2014 Dec 11. Erratum In: Clin Infect Dis. 2015 Jul 1;61(1):143. doi: 10.1093/cid/civ348.. Avinghsanon, Anchalee [corrected to Avihingsanon, Anchalee]. PubMed 25501988 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 21, 2020, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01011413
Lead sponsor
Kirby Institute
Responsible party
Sponsor
First posted
Nov 11, 2009
Start date
Aug 2011
Primary completion
Jun 2013
Completion
Aug 2014
Results posted
Feb 21, 2020
Last update
Feb 21, 2020

Study contacts

David Cooper, Professor
principal investigator · Kirby Institute

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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