Estudio primario

No clasificado

A randomized, open-label trial to compare the efficacy, safety and tolerability of DRV/rtv (800/100 mg) q.d. versus DRV/rtv (600/100 mg) b.i.d. in early treatment-experienced HIV-1 infected subjects. - Once-daily Darunavir In treatment-experieNced patients (ODIN)

Año 2007
Autores [No se listan los autores]
Registro de estudios EU Clinical Trials Register
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INTERVENTION:

Product Name: TMC114 ethanolate Product Code: TMC114 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

darunavir CAS Number: 206361‐99‐1 Current Sponsor code: TMC114 (F032) Other descriptive name: TMC114 ethanolate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐ Product Name: TMC114 ethanolate Product Code: TMC114 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

darunavir CAS Number: 206361‐99‐1 Current Sponsor code: TMC114 (F030) Other descriptive name: TMC114 ethanolate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐ Trade Name: Norvir Product Name: Norvir Pharmaceutical Form: Capsule, soft INN or Proposed

INN:

ritonavir CAS Number: 155213‐67‐5 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

HIV‐1 ; MedDRA version: 9.1 Level: LLT Classification code 10020161 Term: HIV infection

INCLUSION CRITERIA:

Subjects who meet all of the following criteria are eligible for this trial. 1. Male or female subjects, aged 18 years or older. 2. Subjects with documented HIV‐1 infection. 3. Stable HAART regimen for at least 12 weeks at screening. Note: HAART is defined as potent anti‐HIV treatment usually including a combination of 3 or more drugs with activity against HIV whose purpose is to reduce viral load to undetectable. This regimen usually includes treatment with at least 2 NRTIs in combination with at least 1 additional ARV from the NNRTI and/or PIs classes or a combination of 3 NRTIs. 4. In the investigator’s opinion, NNRTIs are not a valid treatment option, because of the subject’s ARV treatment history, ARV resistance testing, medication‐taking behavior, safety and tolerance concerns, or other patient‐related factors. 5. Prescreening or/and screening plasma HIV‐1 RNA > 1,000 copies/mL (assayed by RNA PCR standard specimen procedure) on

HAART PRIMARY OUTCOME:

Main Objective: MAIN PHASE; To demonstrate non‐inferiority in virologic response, defined as a confirmed plasma viral load of < 50 HIV‐1 RNA copies/mL at Week 48 (as defined by the TLOVR algorithm), with DRV/rtv 800/100 mg q.d. versus DRV/rtv 600/100 mg b.i.d. in early ARV‐experienced patients with a non‐inferiority margin (delta) of 12%, when administered in combination with an individually selected OBR.; ; EXTENSION PHASE AFTER WEEK 48; To provide DRV/rtv access as a 600/100 mg b.i.d. dosage via an extension phase of the TMC114‐TiDP31‐C229 trial to subjects who completed the 48 weeks of treatment with DRV/rtv in the main phase of the trial and continue to benefit from this treatment, and who live in a region where DRV is not yet commercially available, not yet reimbursed by the public and/or private health system or can not be accessed from another source (e.g., access program, government program). In addition, information on safety of DRV/rtv in combination with other ARVs will be monitored. Primary end point(s): Demonstration of non‐inferiority in virologic response Secondary Objective: The secondary objectives are:; ‐ to evaluate safety and tolerabilityover 48 weeks; ; ‐ to evaluate the durability of efficacy over 48 weeks;; ‐ to evaluate the change in viral load from baseline;; ‐ to evaluate the percentage subjects with a confirmed plasma viral load < 400 HIV‐1 RNA copies/mL;; ‐ to evaluate the lipid effects of DRV/rtv q.d. versus b.i.d.;; ‐ to compare the immunologic response;; ‐ to evaluate resistance characteristics;; ‐ to evaluate DRV and ritonavir pharmacokinetics following q.d. and b.i.d. dosing and explore the PK/PD relationship between: 1) DRV and efficacy/safety and 2) ritonavir and safety for b.i.d. and q.d. regimens;; ‐ to determine and compare the subject‐reported antiretroviral (ARV) medication adherence in subjects treated with DRV/rtv 800/100 mg q.d. versus DRV/rtv 600/100 b.i.d., both administered in combination with an individually selected OBR, at baseline and over 48 weeks.

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Estudio primario

No clasificado

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV – Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial

Año 2023
Revista EClinicalMedicine
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BACKGROUND:

Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV).

METHODS:

SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108.

FINDINGS:

Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI.: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI.: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI.: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI.: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI.: 0.3, 1.0; p < 0.001)].

INTERPRETATION:

In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents.

FUNDING:

Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

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Estudio primario

No clasificado

Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART (cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, randomized, multicentre trial (IMEA 040 DATA trial).

Año 2016
Revista The Journal of antimicrobial chemotherapy
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<b>

OBJECTIVES:

</b>Boosted PIs are commonly prescribed in patients presenting with advanced HIV infection. We assessed the efficacy and tolerability of once-daily ritonavir-boosted atazanavir or darunavir plus two NRTIs in HIV-1-infected ART-naive patients with severe immunosuppression, targeting at least an 85% success rate at week 48.<b>

METHODS:

</b>This 48 week, open-label, non-comparative, randomized, multicentre trial included ART-naive patients with CD4 cell counts <200 cells/mm(3), with plasma HIV-1 RNA >1000 copies/mL and without genotypic mutations conferring resistance to the study drugs. Patients were randomized (1:1) to receive once-daily atazanavir/ritonavir (300/100 mg) or darunavir/ritonavir (800/100 mg) plus tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The primary endpoint was treatment success, defined as plasma HIV-1 RNA ≤50 copies/mL at week 48 and no permanent PI/ritonavir discontinuation. The study was registered with ClinicalTrials.gov (NCT01928407).<b>

RESULTS:

</b>One hundred and twenty patients were enrolled: 77% were men, 30% were born in Africa and 39% had AIDS. The median baseline CD4 and plasma HIV-RNA values were 69 cells/mm(3) and 5.4 log10 copies/mL. All but four patients received tenofovir disoproxil fumarate/emtricitabine. The week 48 treatment success rate was 66% (95% CI 54%-78%) with atazanavir/ritonavir and 80% (95% CI 68%-89%) with darunavir/ritonavir. The median CD4 cell count increased similarly in the two groups (Δweek 48 to week 0: +194 cells/mm(3)). Adverse events occurred in 23 and 18 patients, respectively.<b>

CONCLUSIONS:

</b>Despite good adherence, neither study regimen reached the predefined objective, suggesting a need for more potent regimens for patients with advanced HIV infection.

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Estudio primario

No clasificado

A randomised, controlled, opel-label trial to compare the efficacy, safety and tolerability of a treatment simplification by darunavir/ritonavir (DRV/r) 800/100 mg O.D. versus a triple combination therapy containing DRV/r in HIV-1 infected subjects with undetectable plasma HIV-1 RNA on their current treatments

Año 2006
Autores [No se listan los autores]
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INTERVENTION:

Product Name: Darunavir ethanolate (formerly known as TMC114) Product Code: DRV (formely known as TMC114) Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

darunavir CAS Number: 20636‐99‐1 Current Sponsor code: DRV (formely known as TMC114) Other descriptive name: Darunavir ethanolate (formely known as TMC114) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐ Trade Name: Norvir Product Name: Norvir Product Code: rtv Pharmaceutical Form: Capsule, soft INN or Proposed

INN:

ritonavir CAS Number: 155213‐67‐5 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

HIV‐1 ; MedDRA version: 9.1 Level: LLT Classification code 10020161 Term: HIV infection

PRIMARY OUTCOME:

Main Objective: To demonstrate non‐inferiority in efficacy of DRV/r versus the triple combination therapy containing DRV/r, with respect to confirmed virologic response, defined as plasma HIV‐1 RNA < 50 copies/mL at 48, 96 and 144 weeks.; ; Primary end point(s): Percentage of subjects with a plasma HIV‐1 RNA < 50 copies/mL at week 48, 96 and 144 by intent to treat (ITT) analyses. Secondary Objective: Compare; ‐safety+tolerabilityTreatmentSimplificationRegimen DRV/r monotherapy vs. triple combination therapy containing DRV/r; ‐immune response in terms changes CD4+T cell count from baseline over 48,96,144 wks treatment simplification regimen by DRV/r monotherapy with triple combination therapy containing DRV/r; ‐freq. development at least 1 new mutation in RTandPR gene; ‐changes laboratory parameters at all time points from baseline to 48,96,144 wks,both treatment groups; ‐subject‐reported antiretroviral medication adherence at baseline+evolution adherence over 48,96,144 wks,both treatment groups; ‐antiretroviral drug treatment cost over 48,96,144 wks,both treatment groups; Assess; ‐incidence+SeverityBodyCompositionChangesOver48,96,144Wks,BothTreatmentGroups; ‐+compareResolutionToxicitiesPresentAtScreeningVisitOver48,96,144 Wks,BothTreatmentGroups; Evaluate; +compareSubject‐reported Health‐RelatedQuality ofLife (HRQoL)AtBaseline+evolution HRQoL Over48,96,144Wks,BothTreatmentGroups

INCLUSION CRITERIA:

Subjects who meet all of the following criteria are eligible for this trial: Subjects with documented HIV‐1 infection. Male or female ages > 18 years old. Subjects who have voluntarily signed and dated the consent form. Subjects currently receiving HAART for at least 24 weeks. Note: HAART is defined as the combination of 2 NRTIs with at least 1 additional ARV from the NNRTI and/or PI class. A regimen with 3 NRTIs is allowed. Plasma HIV‐1 RNA < 50 copies/mL for at least 24 weeks prior to screening (two results must be documented). Subjects taking the same ARV combination for at least 8 weeks before screening. Subject and physician’s preference to change the current HAART regimen for reasons of simplification and/or toxicity (examples of toxicities include but are not limited to: CNS, gastrointestinal disturbances, jaundice, anaemia, nausea, neuropathy, paresthesia, hyperlipidaemia, glucose intolerance or diabete

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Estudio primario

No clasificado

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1.

Año 2020
Revista HIV research & clinical practice
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BACKGROUND:

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917).

OBJECTIVE:

To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (

AMBER:

viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance;

EMERALD:

prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent).

METHODS:

Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials).

RESULTS:

D/C/F/TAF demonstrated high Week 96 virologic responses (

AMBER:

85% [308/362];

EMERALD:

91% [692/763]) and low VF rates (

AMBER:

6% [20/362];

EMERALD:

1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFRcyst and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio.

CONCLUSIONS:

D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults.

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Estudio primario

No clasificado

A randomised, controlled, open-label trial to compare brachial artery reactivity and cardiovascular risk of a treatment simplification by darunavir/ritonavir (DRV/r) 800/100 mg O.D. versus a triple combination therapy containing DRV/r in HIV-1 infected subjects with undetectable plasma HIV-1 RNA on their current treatments.

Año 2008
Autores JANSSEN-CILAG
Registro de estudios EU Clinical Trials Register
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INTERVENTION:

Product Name: TMC114 etanolato Product Code: TMC114 Pharmaceutical Form: Coated tablet INN or Proposed

INN:

DARUNAVIR Current Sponsor code: TMC114 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐ Trade Name: NORVIR*4FL 84CPS MOLLI 100MG Pharmaceutical Form: Capsule, soft INN or Proposed

INN:

Ritonavir Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

HIV‐1 Infection ; MedDRA version: 9.1 Level: LLT Classification code 10020161 Term: HIV infection

PRIMARY OUTCOME:

Main Objective: To compare the change in brachial artery flow mediated vasodilation (FMD) from baseline to week 24 and 48 in the two study arms (DRV/r monotherapy versus a triple combination therapy containing DRV/r and 2 NRTIs). Primary end point(s): The primary parameter of the study is the change in brachial artery FMD from baseline to week 24. Brachial artery FMD is calculated as the percentage increase in brachial artery diameter with hyperemia induced relative to the resting brachial artery diameter. Secondary Objective: ·To evaluate and compare the efficacy of a treatment simplification by a DRV/r monotherapy versus a triple combination therapy with DRV/r in HIV‐infected patients at 48 weeks. ·To compare the change in circulating endothelial cells and of their precursors from baseline to week 48 ·To compare the change in mean LDL‐cholesterol, HDL‐cholesterol, triglycerides , HOMA‐IR and Frammingham risk score from baseline to week 24 and 48 in the two study arms ·To compare body fat changes by means of leg fat content analyzed in DEXA and visceral fat content in abdomen TC in the two study arms from baseline to week 48 ·To compare the measure of drug toxicity on mtDNA, (quantified as the amount of mtDNA per cell in isolated CD4+ T cells) and soluble factors involved in mitochondrial/metabolic alterations (leptin, adiponectin); from baseline to week 48 in the two study arms ·To compare lumbar and femoral neck T‐score from baseline to week 48

INCLUSION CRITERIA:

·Patients with documented HIV‐1 infection. ·Male or female aged > 18 years old. ·Patients who have voluntarily provided signed and dated consent forms. ·Patients have been receiving HAART for at least 24 weeks. ·Patients are currently on their first‐line treatment and this is HAART. Note: HAART is defined as the combination of 2 NRTIs with at least 1 additional ARV from the NNRTI and/or PI class*. A first line regimen with 3 NRTIs is allowed. ·Plasma HIV‐1 RNA < 50 cp/ml for at least 24 weeks before screening. ·Patient taking the same ARV combination for at least 8 weeks before screening. ·Preference for a more convenient regimen and/or any current or history of toxicity on actual regimen (examples of toxicities: CNS, gastrointestinal disturbances, jaundice, anaemia, nausea, neuropathy, paresthesia, hyperlipidaemia, glucose intolerance or diabetes, nephrolithiasis, lipodystrophy, hepatotoxicity, rash and skin related events, any other AE or intolerabilit

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Estudio primario

No clasificado

Phase 4 clinical trial, randomized to evaluate the effect on immune recovery of triple antiretroviral maintenance therapy (elvitegravir / cobicistat 150/150 mg + tenofovir + emtricitabine alapenamide 10 mg 200 mg) versus simplification of combination therapy (dolutegravir + lamivudine or darunavir / Cobicistat + lamivudine) in HIV-infected patients with sustained undetectable viremia.

Año 2017
Registro de estudios EU Clinical Trials Register
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INTERVENTION:

Trade Name: Tivicay® Product Name: Dolutegravir Pharmaceutical Form: Tablet Trade Name: Lamivudina Teva Product Name: Lamivudina Pharmaceutical Form: Tablet Trade Name: Rezolsta® Product Name: Darunavir Pharmaceutical Form: Tablet Trade Name: Rezolsta® Product Name: Cobicistat Pharmaceutical Form: Tablet

CONDITION:

Adult patients with HIV infection on stable therapy (= 6 months) with triple therapy and undetectable viremia for = 1 year. ; MedDRA version: 19.1 Level: LLT Classification code 10049838 Term: HIV viral load undetectable System Organ Class: 100000004848 ; MedDRA version: 19.1 Level: PT Classification code 10077716 Term: HIV viraemia System Organ Class: 10021881 ‐ Infections and infestations Therapeutic area: Not possible to specify

PRIMARY OUTCOME:

Main Objective: Evaluate the effect on immune recovery maintaining a triple antiretroviral therapy (elvitegravir / cobicistat 150/150 mg + tenofovir + emtricitabine alafenamide 10 mg 200 mg) versus combination therapy simplification (dolutegravir plus lamivudine or darunavir / cobicistat plus lamivudine) after 48 weeks Of treatment in HIV‐infected patients with sustained undetectable viremia. Primary end point(s): Changes in the CD4 + / CD8 + T lymphocyte ratio after 48 weeks of treatment. Secondary Objective: Evaluate whether a triple therapy based on (elvitegravir / cobicistat 150/150 mg + tenofovir alafenamide 10 mg + emtricitabine 200 mg) will lead to a greater decrease in immune activation and inflammation compared to simplification to bitherapy (dolutegravir plus lamivudine or darunavir / Cobicistat plus lamivudine) in HIV‐infected patients and sustained undetectable viremia. Timepoint(s) of evaluation of this end point: After 48 weeks of treatment.

SECONDARY OUTCOME:

Secondary end point(s): Changes in CD4 + / CD8 + T lymphocyte ratio after 96 weeks of treatment.; Changes after 48 and 96 weeks of treatment in:; Immunoactivation measured as HLA‐DR and CD38 expression on CD4 + and CD8 + T lymphocytes and plasma levels of sCD14.; Expression of the following markers on CD4 + and CD8 + T lymphocytes: Ki67, PD‐1, CD57, TRAIL, Annexin V and CD31.; Concentrations of the following proinflammatory mediators: IL‐1ß, IL‐1ra, IL‐2, IL‐6, IL‐10, IL‐17, IFN‐a and ?, IP‐10, MIP‐1 / 1ß and dimers D.; Changes in microbial translocation measured by plasma concentrations of LPS and 16S rDNA.; Changes in proviral DNA (HIV‐DNA) in PBMCs. Timepoint(s) of evaluation of this end point: Changes after 48 and 96 weeks of treatment according to variable.

INCLUSION CRITERIA:

‐ Patients with HIV infection and age = 18 years. ‐ Initiation of antiretroviral treatment after 01/01/2013 ‐ Undetectable viremia (<20 copies / ml for at least one year) with triple therapy. ‐ Nadir and CD4 + T lymphocyte count =200 / µl at the time of inclusion. Informed written consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 160 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20

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Estudio primario

No clasificado

Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1.

Año 2019
Revista Antiviral research
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Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (

D/C/F/TAF:

3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52-96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF.

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Estudio primario

No clasificado

High rates of virologic suppression achieved in HIV-1-infected adults rapidly starting antiretroviral therapy (ART) with the single-tablet regimen (STR) of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/ TAF) 800/150/200/10 mg regardless of baseline disease characteristics: Week 48 subgroup analyses from the phase 3 diamond trial

Año 2019
Revista Open Forum Infectious Diseases
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Background. Rapid initiation of ART requires that clinicians start therapy prior to having baseline laboratory Results. High rates of virologic suppression and retention were reported in the DIAMOND trial. Efficacy and safety are presented, according to baseline disease characteristics. Methods. DIAMOND (ClinicalTrials.gov: NCT03227861), a phase 3, single- arm, open-label, prospective, multicenter study, assessed efficacy/safety of D/C/F/ TAF in rapid initiation. Adults enrolled within 14 days of diagnosis and started D/C/F/ TAF without baseline laboratory results; investigators reviewed results as they became available. Primary endpoint was virologic suppression (HIV-1 RNA < 50 copies[c]/ mL; intent-to-treat (ITT); Food and Drug Administration [FDA] snapshot) at Week 48. Virologic suppression <50 c/mL and <200 c/mL were also assessed via an observed analysis, excluding patients with missing data. Results. Overall, 109 patients were enrolled; 25% had HIV-1 RNA ≥100,000 c/ mL and 21% had CD4+ < 200 cells/μL (Table 1). 21% of patients started therapy within 24 hours of diagnosis. At Week 48, 84%, and 88% of patients had HIV-1 RNA <50 c/mL and <200 c/mL (FDA snapshot), respectively. In the observed analysis, 96% and 100% of patients had HIV-1 RNA <50 c/mL and <200 c/mL, respectively, at Week 48. Earlier ART initiation, HIV-1 RNA <100,000 c/mL, and CD4+ >200 cells/μLwere associated with numerically higher virologic suppression rates (ITT-FDA snapshot; Table 2). No patient discontinued due to lack of efficacy or met protocol-defined virologic failure (PDVF) criteria. In the observed analysis, virologic suppression rates were consistent across all subgroups; all patients were suppressed <200 c/mL at Week 48. One patient discontinued due to an adverse event (AE); incidences of grade 3/4 (10%) and serious (9%) AEs were low, with no serious AEs related to study drug and no deaths. Conclusion. In the first phase 3 study of an STR in a rapid initiation model, no patients rapidly starting D/C/F/TAF discontinued therapy due to lack of efficacy or had PDVF through 48 weeks. High rates of virologic suppression were achieved and maintained with a variety of baseline characteristics, and treatment was safe and well tolerated, indicating D/C/F/TAF as a preferred ART option for patients rapidly starting treatment. (Table Presented).

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Estudio primario

No clasificado

A Phase IIIb, randomized, open-label study of the safety and efficacy of GSK1349572 (dolutegravir, DTG) 50 mg once daily compared to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily each administered with fixed-dose dual nucleoside reverse transcriptase inhibitor therapy over 96 weeks in HIV-1 infected antiretroviral naïve adult subjects.

Año 2012
Autores Viiv Healthcare
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INTERVENTION:

Product Name: dolutegravir Product Code: GSK1349572 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

dolutegravir CAS Number: 1051375‐19‐9 Current Sponsor code: GSK1349572 Other descriptive name: NA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Trade Name: Prezista Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

DARUNAVIR CAS Number: 206361‐99‐1 Current Sponsor code: DRV Other descriptive name: NA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐ Trade Name: Norvir Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

RITONAVIR CAS Number: 155213‐67‐5 Current Sponsor code: r Other descriptive name: NA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

HIV‐1 infection in ART‐naïve subjects. ; MedDRA version: 14.1 Level: LLT Classification code 10008922 Term: Chronic infection with HIV System Organ Class: 10021881 ‐ Infections and infestations Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: To demonstrate the non‐inferior antiviral activity of DTG 50 mg administered once daily compared to DRV/r 800 mg/100 mg once daily over 48 weeks in HIV‐1 infected therapy‐naïve subjects. Primary end point(s): The primary endpoint for this study will be the proportion of subjects with HIV‐1 RNA <50 c/mL through Week 48 using the snapshot (MSDF)algorithm. Secondary Objective: •To demonstrate the antiviral activity of DTG compared to DRV/r over 96 weeks; •To compare the effects of DTG and DRV/r on fasting glucose and lipids over time; •To compare the change in symptom distress score for subjects treated with DTG and DRV/r over time; •To compare the change in utility score, treatment satisfaction, and health related quality of life for subjects treated with DTG and DRV/r over time. •To compare the tolerability, long‐term safety, incidence of HIVassociated conditions, antiviral and immunologic activity of DTG to DRV/r over time; •To assess the development of viral resistance in subjects experiencing virologic failure; •To evaluate the effect of patient characteristics (i.e., demographic factors, HIV‐1 subtype) on response to DTG and DRV/r over time. Timepoint(s) of evaluation of this end point: Week 48

SECONDARY OUTCOME:

Secondary end point(s): Secondary Efficacy Endpoints •Time to viral suppression (<50 copies/mL) through Week 48; •Proportion of subjects with plasma HIV‐1 RNA <50 c/mL at Week 96; •Proportion of subjects with plasma HIV‐1 RNA <400 c/mL at Weeks 48 and 96; •Absolute values and change from baseline in plasma HIV‐1 RNA over time; •Absolute values and changes from baseline in CD4+ and CD8+ T cell counts over time; •Incidence of disease progression (HIV‐associated conditions, AIDS and death). Timepoint(s) of evaluation of this end point: Overtime through Weeks 48 and 96

INCLUSION CRITERIA:

Eligible subjects must: •be able to understand and comply with protocol requirements, instructions, and restrictions; •be likely to complete the study as planned; •be considered appropriate candidates for participation in an investigative clinical trial with oral medication (e.g., no active substance abuse, acute major organ disease). Laboratory results from the central laboratory services provided by this trial will be used to assess eligibility. If results from central laboratory services (e.g., genotypes results) will delay screening beyond the defined 28 day period, use of local laboratory services may be used only after consultation and agreement with the study medical monitor. Subjects eligible for enrollment in this study must meet all of the following: 1.HIV‐1 infected adults = 18 years of age; 2.A female, may be eligible to enter and participate in the study if she: a. is of non‐child‐bearing potential defined as either post‐menopausal (

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