NCT02431247

A Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Fixed Dose Combination (FDC) Versus a Regimen Consisting of Darunavir/Cobicistat FDC With Emtricitabine/Tenofovir Disoproxil Fumarate FDC in Treatment-naive HIV Type 1 Infected Subjects

Completed Phase 3 Results posted Last updated 28 September 2022

What this trial tests

Phase 3 trial testing Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC in Immunodeficiency Virus Type 1, Human in 725 participants. Completed in 30 September 2020.

Timeline

6 July 2015

Primary endpoint
2 March 2017

30 September 2020

Quick facts

Lead sponsor	Janssen Sciences Ireland UC
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	725
Start date	6 July 2015
Primary completion	2 March 2017
Estimated completion	30 September 2020
Sites	80 locations across France, Russia, Belgium, United Kingdom, Germany, Poland, Canada, Puerto Rico

Drugs / interventions tested

• Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC — full drug profile →
• DRV/COBI FDC — full drug profile →
• FTC/TDF FDC — full drug profile →
• D/C/F/TAF FDC - Matching Placebo — full drug profile →
• FTC/TDF FDC Matching Placebo — full drug profile →
• DRV/COBI FDC Matching Placebo

Conditions studied

• Immunodeficiency Virus Type 1, Human — all drugs for Immunodeficiency Virus Type 1, Human →

Sponsor

Janssen Sciences Ireland UC — full company profile →

Who can join

18 and older, any sex, with Immunodeficiency Virus Type 1, Human. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Less Than (<) 50 Copies Per Milliliter (Copies Per mL) (Virologic Response) at Week 48 Defined by Food and Drug Administration (FDA) Snapshot Approach Primary · At Week 48

Percentage of participants with a HIV-1 RNA \< 50 copies per mL were assessed using FDA snapshot approach which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. The snapshot approach classified participants into 3 outcome categories: 1) virologic success (HIV RNA \< 20/50/200 copies per mL at Week 48), 2) virologic failure (HIV RNA greater than or equal to \[\>=\] 20/50/200 copies per mL at Week 48), 3) no viral load data in the Week 48 visit window (discontin

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	91.4	88.1 – 94.1
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	88.4	84.7 – 91.5

Percentage of Participants With HIV-1 RNA <20 and 200 Copies Per mL at Weeks 48 and 96 Defined by FDA Snapshot Approach Secondary · At Weeks 48 and 96

Percentage of participants with HIV-1 RNA \< 20/200 copies per mL using FDA snapshot approach were reported. The snapshot approach classified participants into 3 outcome categories: 1) virologic success (HIV RNA \< 20/50/200 copies per mL at Week 48 and 96), 2) virologic failure (HIV RNA \>= 20/50/200 copies per mL at Week 48 and 96), 3) no viral load data in the Week 48 and 96 visit window (discontinued due to adverse event/death/other reason). The missing HIV-1 RNA is considered as non-response.

At week 48: <20 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	82.6	78.3 – 86.4
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	79.3	74.8 – 83.4

At week 48: <200 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	92.8	89.7 – 95.3
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	90.6	87.2 – 93.4

At week 96: <20 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	76.2	71.5 – 80.5
Switch to D/C/F/TAF	83.5	78.7 – 87.6

At week 96: <200 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	86.2	82.2 – 89.6
Switch to D/C/F/TAF	96.9	94.2 – 98.6

Percentage of Participants With HIV-1 RNA < 20, 50, and 200 Copies Per mL at Week 48 and 96 Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm Secondary · At Week 48 and 96

Percentage of participants with HIV-1 RNA less than (\<) 20, 50, and 200 copies per mL at Weeks 48 and 96 based on TLOVR algorithm were assessed. TLOVR requires sustained HIV-1 RNA \< 50 copies per mL; confirmed HIV-1 RNA \>= 50 copies per mL is considered as non-response (rebound); participant is considered non-responder after permanent discontinuation.

At Week 48: < 20 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	82.6	78.3 – 86.4
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	79.9	75.4 – 83.9

At Week 48: <50 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	91.2	87.8 – 93.9
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	88.7	85.0 – 91.8

At Week 48: <200 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	93.1	90.0 – 95.5
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	91.7	88.4 – 94.4

At Week 96: <20 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	73.2	68.3 – 77.7
Switch to D/C/F/TAF	78.4	73.2 – 82.9

At Week 96: <50 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	85.1	81.0 – 88.6
Switch to D/C/F/TAF	93.8	90.4 – 96.3

At Week 96: <200 Copies per mL

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	86.7	82.8 – 90.1
Switch to D/C/F/TAF	96.9	94.2 – 98.6

Change From Baseline in log10 HIV-1 RNA Levels at Week 48 Secondary · Baseline and Week 48

Change from baseline in log10 HIV-1 RNA levels were reported.

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	-2.95	± 0.044
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	-2.91	± 0.044

Change From Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Week 48 Secondary · Baseline and Week 48

The immunologic change was determined by changes in Cluster of CD4+ cell count. Change from baseline in CD4+ cell count at Week 48 were assessed.

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	190.49	± 10.472
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	172.01	± 10.458

Change From Baseline in Serum Creatinine at Week 48 Secondary · Baseline and Week 48

Change from baseline in serum creatinine at Week 48 was reported.

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	0.05	± 0.006
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	0.09	± 0.006

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Formula at Week 48 Secondary · Baseline and Week 48

Change from baseline in eGFRcr was calculated using the CKD-EPI equation as per which Stage 1 (normal or high GFR \[\>=90 mL/min\]); Stage 2 (Mild CKD \[60 to 90 mL/min\]); Stage 3 (Moderate CKD \[30 to 59mL/min\]); Stage 4 (Severe CKD \[15 to 29 mL/min\]); Stage 5 (End Stage CKD \[\<15 mL/min\]). The eGFRcr was assessed by calculating serum creatinine (Scr) using the equation: eGFRcr milliliter per minute per 1.72 meter square (mL/min/1.73m\^2) = 144\*(Scr/0.7)\^-0.329\*0.993\^age (Scr =\< 0.7 mg/dL) and eGFRcr mL/min/1.73m\^2 = 144\*(Scr/0.7)\^-1.209\*0.993\^age (Scr \>0.7 mg/dL) for female

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	-6.04	± 0.551
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	-9.16	± 0.559

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine by (Cockcroft-Gault Formula) at Week 48 Secondary · Baseline and Week 48

Change from baseline in eGFRcr by cockcroft-gault formula at Week 48. The eGFRcr was assessed by calculated creatinine clearance (CrCl) using the Cockcroft-Gault formula, and was assessed using CrCl \[mL/min\] = (140 - A) \* W / (72 \* C) \* R. Where A is age at sample date \[years\], W is body weight at specific visit (kilogram \[kg\]), C is the serum concentration of creatinine \[mg/dL\], R = 1 if the participant is male and = 0.85 if female.

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	-5.16	± 0.790
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	-11.20	± 0.802

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula at Week 48 Secondary · Baseline and Week 48

Change from baseline in eGFRcyst was calculated using the CKD-EPI equation as per which Stage 1 (normal or high GFR) \>= 90 indicates normal kidney function; Stage 2 (Mild CKD): 60 to 89 mL/min indicates mildly reduced kidney function; Stage 3 (Moderate CKD): 30 to 59 mL/min indicates moderately reduced kidney function; Stage 4 (Severe CKD): 15 to 29 mL/min indicates severely reduced kidney function; Stage 5 (End Stage of CKD): \<15 mL/min indicate very severe or end stage kidney failure. The eGFRcyst was assessed by calculated serum cystatin C (Scyst) using the equation: eGFRcyst mL/min/1.73m

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	5.32	± 0.525
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	2.92	± 0.532

Percentage of Participants With Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuations Due to Adverse Events Through Week 48 Secondary · Up to Weeks 48

AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Events with Grade 3 or higher (3=Severe; 4=life-threatening; 5=fatal) are events that significantly interrupt usual daily activity, require systemic drug therapy/other treatment and are, in many situations, considered unacceptable or intolerable events. SAE is any adverse event (AE) that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience,

Grade 3 AEs

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	4.7
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	4.4

Grade 4 AEs

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	0.6
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	1.7

SAEs

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	4.7
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	5.8

Premature discontinuations due to AEs

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	1.9
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	4.4

Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Week 48 Secondary · Baseline and Week 48

Change from baseline in UPCR at Week 48 was reported.

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	-15.72	-748.1 – 254.2
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	-10.53	-903.0 – 1546.1

Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) at Week 48 Secondary · Baseline and Week 48

Change from baseline in UACR at Week 48 was reported.

Group	Value	95% CI
D/C/F/TAF (Test) (Baseline to End of Extension [EOE])	-0.58	-226.5 – 143.8
DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)	-0.15	-640.4 – 969.6

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 60 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

D/C/F/TAF+ FTC/TDF (Test)

Serious: 47/362 (13%)

Deaths: 0/362

DRV/COBI+ FTC/TDF (Control) (Baseline to Switch)

Serious: 36/363 (10%)

Deaths: 1/363

Switch to D/C/F/TAF Group

Serious: 21/322 (7%)

Deaths: 1/322

Serious adverse events (87 terms)

Reaction	System	D/C/F/TAF+ FTC/TDF (Test)	DRV/COBI+ FTC/TDF (Control…	Switch to D/C/F/TAF Group
Appendicitis	Infections and infestations	—	—	—
Hepatitis A	Infections and infestations	—	—	—
Pneumonia	Infections and infestations	—	—	—
Suicide Attempt	Psychiatric disorders	—	—	—
Anogenital Dysplasia	Gastrointestinal disorders	—	—	—
Anal Abscess	Infections and infestations	—	—	—
Erysipelas	Infections and infestations	—	—	—
Anogenital Warts	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Suicidal Ideation	Psychiatric disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Toxic Skin Eruption	Skin and subcutaneous tissue disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Bone Marrow Oedema	Blood and lymphatic system disorders	—	—	—
Myocardial Infarction	Cardiac disorders	—	—	—
Anal Fistula	Gastrointestinal disorders	—	—	—
Haemorrhoids	Gastrointestinal disorders	—	—	—
Influenza Like Illness	General disorders	—	—	—
Non-Cardiac Chest Pain	General disorders	—	—	—
Pyrexia	General disorders	—	—	—
Vascular Stent Stenosis	General disorders	—	—	—
Cholangitis Sclerosing	Hepatobiliary disorders	—	—	—
Abscess Limb	Infections and infestations	—	—	—
Cellulitis	Infections and infestations	—	—	—
Clostridium Difficile Colitis	Infections and infestations	—	—	—
Diarrhoea Infectious	Infections and infestations	—	—	—

Other adverse events (23 terms — click to expand)

Reaction	System	D/C/F/TAF+ FTC/TDF (Test)	DRV/COBI+ FTC/TDF (Control…	Switch to D/C/F/TAF Group
Diarrhoea	Gastrointestinal disorders	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Headache	Nervous system disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Syphilis	Infections and infestations	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Pharyngitis	Infections and infestations	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—
Osteopenia	Musculoskeletal and connective tissue disorders	—	—	—
Gastroenteritis	Infections and infestations	—	—	—
Vitamin D Deficiency	Metabolism and nutrition disorders	—	—	—
Fatigue	General disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Pyrexia	General disorders	—	—	—
Chlamydial Infection	Infections and infestations	—	—	—
Asthenia	General disorders	—	—	—
Gonorrhoea	Infections and infestations	—	—	—
Respiratory Tract Infection	Infections and infestations	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Anxiety	Psychiatric disorders	—	—	—

Most-reported serious reactions: Appendicitis, Hepatitis A, Pneumonia, Suicide Attempt, Anogenital Dysplasia, Anal Abscess, Erysipelas, Anogenital Warts.

Data from ClinicalTrials.gov NCT02431247 adverse events section.

Sponsor's own description

The purpose of this study is to demonstrate non-inferiority in efficacy of a darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed dose combination (FDC) tablet versus Darunavir/Cobicistat (DRV/COBI) FDC coadministered with Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC in human immunodeficiency virus-1 (HIV-1) infected, antiretroviral (ARV) treatment naive adult participants.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Approved HIV reverse transcriptase inhibitors in the past decade.
   Li G, Wang Y, De Clercq E. · · 2022 · cited 71× · PMID 35847492 · DOI 10.1016/j.apsb.2021.11.009
2. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
   Eron JJ, Orkin C, Gallant J, Molina JM, et al · · 2018 · cited 58× · PMID 29683855 · DOI 10.1097/qad.0000000000001817
3. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
   Orkin C, Eron JJ, Rockstroh J, Podzamczer D, et al · · 2020 · cited 23× · PMID 31833849 · DOI 10.1097/qad.0000000000002463
4. Darunavir-cobicistat-emtricitabine-tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era.
   Squillace N, Bozzi G, Colella E, Gori A, et al · · 2018 · cited 11× · PMID 30464395 · DOI 10.2147/dddt.s147493
5. Abstract Supplement Oral Abstracts from the 23rd International AIDS Conference, 6-10 July 2020.
   · 2020 · cited 9× · PMID 32649039 · DOI 10.1002/jia2.25547
6. Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials.
   Lathouwers E, Wong EY, Brown K, Baugh B, et al · · 2020 · cited 9× · PMID 31516033 · DOI 10.1089/aid.2019.0111
7. Efficacy and safety of boosted darunavir-based antiretroviral therapy in HIV-1-positive patients: results from a meta-analysis of clinical trials.
   Antinori A, Lazzarin A, Uglietti A, Palma M, et al · · 2018 · cited 8× · PMID 29588457 · DOI 10.1038/s41598-018-23375-6
8. HIV Glasgow 2018, 28-31 October 2018, Glasgow, UK.
   · 2018 · cited 7× · PMID 30362663 · DOI 10.1002/jia2.25187