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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 600 milligram (mg) Efavirenz | Active Comparator | Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd) |
|
| 400mg Efavirenz | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Efavirenz 600mg | Drug | 3 x EFV 200 milligram (mg) tablets once daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Baseline and 2 years |
| Mean Change From Baseline in CD4+ T-cell Count |
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Inclusion Criteria:
Exclusion Criteria:
the following laboratory values:
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
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| Name | Affiliation | Role |
|---|---|---|
| David Cooper, Professor | Kirby Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St Vincent's Hospital | Sydney | New South Wales | 2010 | Australia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24522178 | Result | 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. | |
| 25877963 | Result |
| Label | URL |
|---|---|
| Kirby Institute (formerly National Centre for HIV Epidemiology and Clinical Research) | View source |
Not provided
768 screened:132 did not satisfy eligibility: 2 prior AIDS-defining illness; 3 previous antiretroviral therapy; 15 HIV RNA out of range; 44 cluster of differentiation (CD)4 count out of range; 13 lab values out of range; 2 pregnant; 9 intercurrent illness; 2 illicit substance use; 30 exceeded screen time; 4 clinician exclusion; 9 withdrew consent.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 600mg Efavirenz | Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd) Efavirenz: 3 x EFV 200mg tablets once daily |
| FG001 | 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). Efavirenz: 2 x EFV 200mg tablets plus 1x matched EFV placebo tablet once daily |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 600mg Efavirenz | Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd) Efavirenz: 3 x EFV 200mg tablets once daily |
| BG001 | 400mg Efavirenz |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | modified intention to treat including all randomised patients who took at least one dose of study medication AND attended at least one follow-up visit. | Posted | Number | 95% Confidence Interval | percentage of participants | 48 weeks |
|
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
Adverse event analysis 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 this modified ITT analysis at week 96 are: 321 for EFV 400mg and 309 for EFV 600mg
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 600mg Efavirenz | Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd) Efavirenz: 3 x EFV 200mg tablets once daily |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abscess | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| upper respiratory tract infection | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sean Emery | University of New South Wales | 02 9385 0900 | semery@kirby.unsw.edu.au |
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| ID | Term |
|---|---|
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| C098320 | efavirenz |
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| Efavirenz 400mg | Drug | 2 x EFV 200 milligram (mg) tablets plus 1x matched EFV placebo tablet once daily |
|
|
Mean change from baseline to week 96 in CD4+ T-cell count/mm3 between the two treatment arms |
| Baseline and 2 years |
| 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 | up to 2 years |
| 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 | Baseline and 2 years |
| 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. | 2 years |
| Change From Baseline in Fasted Insulin Levels | Change from baseline to week 96 in fasted insulin levels | Baseline and 2 years |
| 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 | Baseline and 2 years |
| Change From Baseline in Estimate Creatinine Clearance | Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms | Baseline and 2 years |
| Steady-state Efavirenz Concentrations | Steady-state efavirenz mid-dosing interval plasma concentrations | Week 4 |
| 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. |
| 25501988 | Derived | 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. |
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).
Efavirenz: 2 x EFV 200mg tablets plus 1x matched EFV placebo tablet once daily
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| HIV transmission risk | Number | participants |
|
| CDC HIV infection clinical category | As assessed by the Centres for Disease Control and Prevention (CDC) 1993 Revised Classification System for HIV Infection for Adolescents and Adults. Published in Morbidity and Mortality Weekly Report December 18, 1992 / 41(RR-17). Clinical category of HIV infection was assigned by the clinician based on the clinical conditions that define each of the three categories. Category A is the best, followed by category B and lastly category C. | Number | participants |
|
| Median plasma HIV RNA | Median | Inter-Quartile Range | log10 copies per mL |
|
| Mean nadir cluster of differentiation (CD)4+ cell count | Mean | Standard Deviation | cells per mm3 |
|
| Hep B Sag +ve | number of participants surface antigen positive | Number | participants |
|
| Hep C ab +ve | number of participants antibody positive | Number | participants |
|
| Mean creatinine clearance (mL/min) | Mean | Standard Deviation | mL per min |
|
| Mean total chol (mmol/L) | Mean | Standard Deviation | mmol per Litre |
|
| Mean HDL chol (mmol/L) | Mean | Standard Deviation | mmol per Litre |
|
| Mean LDL chol (mmol/L) | Mean | Standard Deviation | mmol per Litre |
|
| Mean triglycerides (mmol/L) | Mean | Standard Deviation | mmol per Litre |
|
| Insulin (mU/L) | Mean | Standard Deviation | mU per Litre |
|
| Glucose (mmol/L) | Mean | Standard Deviation | mmol per Litre |
|
| Current smoker | Number | participants |
|
| Mean BMI (kg/m^2) | Mean | Standard Deviation | kg per m2 |
|
|
|
|
| Secondary | 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 | Modified ITT including all randomised participants who took at least one dose of study medication and attended at least one follow-up visit | Posted | Number | participants | Baseline and 2 years |
|
|
|
|
| Secondary | 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 | modified ITT (all participants who received at least one dose of study treatment and attended at least one follow up visit, irrespective of treatment received) | Posted | Mean | 95% Confidence Interval | cells per mm3 | Baseline and 2 years |
|
|
|
| Secondary | 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 | modified ITT population | Posted | Count of Participants | Participants | up to 2 years |
|
|
|
| Secondary | 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 | Available data analysis | Posted | Mean | 95% Confidence Interval | mmol per Litre | Baseline and 2 years |
|
|
|
| Secondary | 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. | Number of participants attending week 96 visit | Posted | Count of Participants | Participants | 2 years |
|
|
|
| Secondary | Change From Baseline in Fasted Insulin Levels | Change from baseline to week 96 in fasted insulin levels | Available data analysis | Posted | Mean | 95% Confidence Interval | mU per litre | Baseline and 2 years |
|
|
|
| Secondary | 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 | Available data analysis | Posted | Mean | 95% Confidence Interval | Units per Litre | Baseline and 2 years |
|
|
|
| Secondary | Change From Baseline in Estimate Creatinine Clearance | Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms | Available data analysis | Posted | Mean | 95% Confidence Interval | millilitres per minute | Baseline and 2 years |
|
|
|
| Secondary | Steady-state Efavirenz Concentrations | Steady-state efavirenz mid-dosing interval plasma concentrations | Available data analysis | Posted | Geometric Mean | 90% Confidence Interval | milligram per Litre | Week 4 |
|
|
|
| 7 |
| 309 |
| 25 |
| 309 |
| 273 |
| 309 |
| EG001 | 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). Efavirenz: 2 x EFV 200mg tablets plus 1x matched EFV placebo tablet once daily | 3 | 321 | 23 | 321 | 286 | 321 |
| bacterial pyelonephritis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| pharyngitis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| appendicitis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| bacterial diarrhoea | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| diverticulitis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| gastroenteritis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| pneumonia | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| urosepsis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| dengue fever | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| perianal abscess | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| dizziness | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| haemorrhoids | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| gastrointestinal haemorrhage | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| cerebrovascular accident | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| diarrhoea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| vomiting | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| anal fissure | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| cerebral toxoplasmosis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| disseminated tuberculosis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| subdural haematoma | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| testicular seminoma stage II | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| priapism | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| testicular injury | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| anaemia | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
|
| lymphadenopathy | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
|
| pyrexia | General disorders | MedDRA (10.0) | Systematic Assessment |
|
| lip oedema | Immune system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Stevens-Johnson syndrome | Immune system disorders | MedDRA (10.0) | Systematic Assessment |
|
| nephrotic syndrome | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
|
| renal failure | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
|
| visual disturbance | Eye disorders | MedDRA (10.0) | Systematic Assessment |
|
| hepatitis C | Hepatobiliary disorders | MedDRA (10.0) | Systematic Assessment |
|
| skin laceration | Injury, poisoning and procedural complications | MedDRA (10.0) | Systematic Assessment |
|
| diabetes mellitus | Metabolism and nutrition disorders | MedDRA (10.0) | Systematic Assessment |
|
| non-Hodgkin's lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (10.0) | Systematic Assessment |
|
| headache | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| abortion spontaneous incomplete | Pregnancy, puerperium and perinatal conditions | MedDRA (10.0) | Systematic Assessment |
|
| depression | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
|
| pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| rash macro-papular | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| breast lump removal | Surgical and medical procedures | MedDRA (10.0) | Systematic Assessment |
|
| nasopharyngitis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| influenza | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| gastroenteritis | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| dizziness | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| diarrhoea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| nausea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| rash | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| abnormal dreams | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
|
| insomnia | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
|
| headache | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
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| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| non-AIDS deaths |
|
| serious non-AIDS events |
|
| No disease/death |
|
| HDL mmol/L |
|
|
| LDL mmol/L |
|
|
| Blood glucose mmol/L |
|
|
| About half pills taken |
|
| No pills taken |
|
| Aspartate aminotransferase |
|
|
| Alkaline phosphatase |
|
|