A Study of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Evaluated as a Fixed Dose Combination Regimen in Participants Switching From an Integrase Inhibitor Who Have Experienced Rapid Weight Gain (DEFINE)

• ClinicalTrials.gov Identifier: NCT04442737
• Recruitment Status: Active, not recruiting
• First Posted: June 23, 2020
• Last Update Posted: March 15, 2023
• Sponsor: Janssen Scientific Affairs, LLC
• Information provided by (Responsible Party): Janssen Scientific Affairs, LLC

Study Description

Brief Summary:

The purpose of this study is to assess the percent change in body weight when switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) (Immediate Switch Arm) compared to continuing the current integrase (INI) + tenofovir alafenamide/emtricitabine (TAF/FTC) antiretroviral (ARV) regimen (Delayed Switch Arm) in virologically-suppressed human immunodeficiency virus (HIV)-1 infected participants who have experienced rapid and significant body weight gain.

Condition or disease	Intervention/treatment	Phase
HIV-1	Drug: D/C/F/TAF FDC; Drug: TAF/FTC FDC; Drug: INI Based Regimen	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 103 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 4, Randomized, Active-Controlled, Open-label Study to Evaluate the Safety and Tolerability of Switching to Once-Daily Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Fixed-dose Combination (FDC) Regimen in Virologically-suppressed Human Immunodeficiency Virus Type 1 (HIV-1) Infected Participants Experiencing Rapid Weight Gain With an INI + TAF/FTC ARV Regimen
• Actual Study Start Date: July 1, 2020
• Estimated Primary Completion Date: August 11, 2023
• Estimated Study Completion Date: August 11, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: D/C/F/TAF FDC Arm (Immediate Switch); Participants will be immediately switched to a regimen of darunavir 800 milligram (mg)/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg (D/C/F/TAF) fixed-dose combination (FDC) once daily for 48 weeks.	Drug: D/C/F/TAF FDC; A FDC tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg will be administered once daily.
Active Comparator: INI + TAF/FTC Arm (Delayed Switch); Participants will continue to receive current baseline integrase (INI)-based regimen plus Tenofovir Alafenamide/Emtricitabine (TAF/FTC) antiretroviral (ARV) regimen for 24 weeks. After 24 weeks participants will switch to a regimen of D/C/F/TAF FDC once daily for an additional 24 weeks.	Drug: D/C/F/TAF FDC; A FDC tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg will be administered once daily.; Drug: TAF/FTC FDC; TAF/FTC ARV regimen will be administered once daily.; Drug: INI Based Regimen; The integrase (INI) inhibitors (for example, bictegravir, dolutegravir, elvitegravir/cobicistat, and raltegravir) will be administered in combination with TAF/FTC, as appropriate. Regimen may consist of a single tablet regimen or a combination of two separate pills.

Outcome Measures

Primary Outcome Measures :

1. Percent Change from Baseline in Body Weight at Week 24 [ Time Frame: Baseline and Week 24 ]
   Percent change from baseline in body weight at Week 24 will be reported.

Secondary Outcome Measures :

1. Change from Baseline in Absolute Body Weight at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in absolute body weight at Weeks 24 and 48 will be reported.
2. Percentage of Participants with Percent Change in Body Weight Greater Than (>) 3 Percent (%) at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
   Percentage of participants with % change in body weight >3% at Weeks 24 and 48 will be reported.
3. Percentage of Participants with Percent Change in Body Weight >5% at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
   Percentage of participants with % change in body weight >5% at Weeks 24 and 48 will be reported.
4. Change from Baseline in Body Mass Index (BMI) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in BMI at Weeks 24 and 48 will be reported.
5. Change from Baseline in Body Composition as Measured by Dual-energy X-ray Absorptiometry (DEXA) Scan at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in body composition (absolute mass of fat, lean body mass and total mass) as measured by DEXA scan at Weeks 24 and 48 will be reported.
6. Change from Baseline in Waist Circumference at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in waist circumference at Weeks 24 and 48 will be reported.
7. Change from Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in SBP and DBP from Baseline at Weeks 24 and 48 will be reported.
8. Change from Baseline in Fasting Lipids at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in fasting lipids at Weeks 24 and 48 will be reported. Fasting plasma lipids are measured to determine triglyceride or cholesterol concentrations.
9. Change from Baseline in Fasting Glucose at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
   Change from baseline in fasting glucose at Weeks 24 and 48 will be reported.
10. Change from Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in HOMA-IR at Weeks 24 and 48 will be reported.
11. Change from Baseline in Hemoglobin A1c (HbA1c) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in HbA1c at Weeks 24 and 48 will be reported.
12. Change from Baseline in Leptin at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in leptin at Weeks 24 and 48 will be reported.
13. Change from Baseline in Adiponectin at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in adiponectin at Weeks 24 and 48 will be reported.
14. Change from Baseline in the Percentage of Participants with Advanced Fibrosis as Assessed by Non-alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in the percentage of participants with advanced fibrosis according to the NAFLD fibrosis score at Weeks 24 and 48 will be reported. In participants with NAFLD Score less than (< ) -1.455, advanced liver fibrosis can be excluded with high accuracy and NAFLD Score greater than (>) 0.675, the presence of advanced liver fibrosis can be diagnosed with high accuracy. Scores between -1.455 and 0.675 are considered "indeterminate".
15. Change from Baseline in the Percentage of Participants at High Risk of Nonalcoholic Fatty Liver Disease (NASH) According to the Hypertension, Age, Insulin, Resistance (HAIR) Score at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in the percentage of participants at high risk of NASH according to the HAIR score at Weeks 24 and 48 will be reported. HAIR score ranges from 0-3 which is calculated by adding Hypertension = 1, ALT >40 IU=1, and insulin resistance (IR) index >5.0 = 1. A score of greater than or equal to (>=) 2 is high risk for NASH.
16. Percentage of Participants with a Dose-reduction or Complete Withdrawal of Anti-hypertensive, Anti-hyperglycemic, or Lipid Lowering Agents [ Time Frame: Baseline up to Weeks 24 and 48 ]
    Percentage of participants with a dose-reduction or complete withdrawal of anti-hypertensive, anti-hyperglycemic, or lipid lowering agents from baseline to Weeks 24 and 48 will be reported.
17. Percentage of Participants Initiating an Anti-hypertensive, Anti-hyperglycemic, or Lipid Lowering Agent [ Time Frame: Baseline up to Weeks 24 and 48 ]
    Percentage of participants initiating an anti-hypertensive, anti-hyperglycemic, or lipid lowering agent from baseline to Weeks 24 and 48 will be reported.
18. Percentage of Participants with any Grade Adverse Events (AEs) [ Time Frame: Up to 24 and 48 weeks ]
    Percentage of participants with any Grade AEs (related and not related) will be reported.
19. Percentage of Participants with Grade 3 and Grade 4 AEs [ Time Frame: Up to 24 and 48 weeks ]
    Percentage of participants with Grade 3 and Grade 4 AEs (related and not related) will be reported where Grade 3: Severe and Grade 4: Potentially life-threatening.
20. Percentage of Participants who Discontinued due to AEs [ Time Frame: Up to 24 and 48 weeks ]
    Percentage of participants who discontinued due to AEs will be reported.
21. Percentage of Participants with Serious Adverse Events (SAEs) [ Time Frame: Up to 24 and 48 weeks ]
    Percentage of participants with SAEs (related and not related) through Week 24 and Week 48 will be reported.
22. Change from Baseline in Biochemistry Tests [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in biochemistry tests (such as sodium, potassium, chloride, bicarbonate, blood urea nitrogen, serum creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, insulin, bilirubin [total, direct, indirect], alkaline phosphatase, calcium, calcium corrected for albumin, phosphate, albumin, total protein) through Weeks 24 and 48 will be reported.
23. Change from Baseline in Hematology Tests [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in hematology tests (hematocrit, hemoglobin, platelet count, red blood cell count, absolute neutrophil count, white blood cell count) through Weeks 24 and 48 will be reported.
24. Change from Baseline in Urinalysis Tests [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in urinalysis tests (specific gravity, pH, glucose, protein, blood ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase) through Weeks 24 and 48 will be reported.
25. Change from Baseline in Urine Chemistry Tests [ Time Frame: Baseline, Weeks 24 and 48 ]
    If applicable, change from baseline in urine chemistry tests (urine creatinine, urine sodium, urine phosphate, urine glucose, urine albumin, urine protein, serum creatinine) through Weeks 24 and 48 will be reported.
26. Percentage of Participants with Grade 3 and Grade 4 Laboratory Abnormalities [ Time Frame: Up to 24 and 48 weeks ]
    Percentage of participants with Grade 3 and Grade 4 laboratory abnormalities will be reported.
27. Percentage of Participants with Confirmed Virologic Rebound [ Time Frame: Up to Weeks 24 and 48 ]
    Percentage of participants with confirmed virologic rebound through Weeks 24 and 48 will be reported. Virologic rebound is defined as the 2 consecutive human immunodeficiency virus type-1 ribonucleic acid (HIV-1 RNA) values greater than or equal to (>=) 200 copies/milliliter (mL) at a scheduled or unscheduled visit after maintaining HIV-1 RNA less than (<) 50 copies/mL.
28. Percentage of Participants with Virologic Response (HIV-1 RNA<50 copies/mL) at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
    Percentage of participants with virologic response (HIV-1 RNA <50 copies/mL), at Weeks 24 and 48 according to the Food Drug Administration (FDA) snapshot algorithm will be reported.
29. Percentage of Participants with Virologic Failure (HIV-1 RNA ≥50 copies/mL) at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
    Percentage participants with virologic failure (HIV-1 RNA >=50 copies/mL) at Weeks 24 and 48 according to the FDA snapshot algorithm will be reported.
30. Percentage of Participants Having Virologic Response (HIV-1 RNA<200 copies/mL) at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
    Percentage participants with virologic response (HIV-1 RNA < 200 copies/mL) at Weeks 24 and 48 according to the FDA snapshot algorithm will be reported.
31. Percentage of Participants Having Virologic Failure (HIV-1 RNA ≥200 copies/mL) at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
    Percentage participants having virologic failure, that is HIV-1 RNA >= 200 copies/mL, at Weeks 24 and 48 according to the FDA snapshot algorithm will be reported.
32. Change from Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in CD4+ cell count at Weeks 24 and 48 will be reported.
33. Percentage of Participants with Pre-baseline Protease (PR), Reverse Transcriptase (RT), and Integrase (INI) Resistance-Associated Mutation (RAMs) [ Time Frame: Baseline (Day 1) ]
    Percentage of participants with pre-baseline PR, RT, and INI RAMs based on historical genotypes will be reported.
34. Percentage of Participant with Newly Identified Post-Baseline RAMS and Phenotypic Resistance Compared to Pre-baseline Resistance Tests [ Time Frame: Up to Week 48 ]
    Percentage of participant with newly identified post-baseline RAMs and phenotypic resistance compared to pre-baseline resistance tests when available, upon meeting confirmed virologic rebound through Week 48.
35. Percentage of Participants with Genotypic and Phenotypic Antiretroviral (ARV) Resistance for Meeting HIV-1 RNA Rebound Criteria up to Weeks 24 and 48 [ Time Frame: Up to Weeks 24 and 48 ]
    Percentage of participants with genotypic and phenotypic ARV resistance who are meeting HIV-1 RNA rebound criteria through Weeks 24 and 48 will be reported.
36. Change from Baseline in the Percentage of Participants who Have Bothersome Symptoms (Scores of 1, 2, 3 or 4) Across all Items of the HIV-Symptom Index (HIV-SI) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in the percentage of participants who have bothersome symptoms (scores of 1, 2, 3 or 4) across all items of the HIV-SI at Weeks 24 and 48 will be reported. The HIV-SI assesses 20 items which are evaluated on a scale of 0-4 where 0= I do not have this symptom to 4=It bothers me a lot'. Minimum HIV-SI score is 0 and maximum HIV-SI score is 80.
37. Change from Baseline in the Percentage of Participants who Have Any Symptoms (scores of 1, 2, 3 or 4) Across all Items of the HIV-Symptom Index (HIV-SI) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in the percentage of participants who have any symptoms (scores of 1, 2, 3 or 4) across all items of the HIV-SI at Weeks 24 and 48 will be reported.
38. Association Between Treatment Arm and Each Bothersome Symptom of the HIV-SI Adjusting for Baseline Variables at Week 24 [ Time Frame: Week 24 ]
    Association between treatment arm and each bothersome symptom of the HIV-SI adjusting for Baseline variables at Week 24 will be reported.
39. Patient Global Impression of Change (PGIC) Scale [ Time Frame: Weeks 24 and 48 ]
    The PGIC is a global index that is used to rate the overall status of the participant related to the participant's overall condition. It is rated by the participant and is based on the single question, "compared to before starting the study or compared to the Week 24 and Week 48 visits, my overall status is," where response choices include 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse.
40. Adherence Rate to Treatment at Weeks 4, 12 and 24 [ Time Frame: Weeks 4, 12, 24, 36 and 48 ]
    Adherence rate to treatment will be assessed by participant self-report using 4-day recall at Weeks 4, 12, 24, 36 and 48.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Body Mass Index (BMI) of greater than or equal to (>=) 18 kilogram per meter square (kg/m^2) at time of starting an integrase (INI)-based regimen plus Tenofovir Alafenamide/Emtricitabine (TAF/FTC) antiretroviral (ARV) regimen
• Documented human immunodeficiency virus (HIV)-1 infection
• Currently being treated with a stable ARV regimen consisting of an INI combined with TAF/FTC for >=6 consecutive months preceding the screening visit and experienced a >=10 percent (%) increase in body weight within a 36-month time period prior to screening and while on the current INI + TAF/FTC ARV regimen
• Documented evidence of being virologically suppressed while on the current stable INI+TAF/FTC ARV regimen prior to screening
• At least one plasma HIV-1 RNA measurement less than (<) 50 copies/milliliter (mL) occurring between 12 and 2 months prior to the screening visit while on the stable INI+ TAF/FTC ARV regimen and have HIV-1 RNA <50 copies/ mL at the screening visit

Exclusion Criteria:

• Known history of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma
• Known allergies, hypersensitivity, or intolerance to D/C/F/TAF fixed-dose combination (FDC) tablet or its excipients
• Active hepatitis B (HBV) or hepatitis C virus (HCV) infection
• Uncontrolled diabetes that will require treatment with insulin during the study period
• Evidence of Child Pugh Class C based on clinical laboratory testing and clinical evaluation
• History of failure on darunavir (DRV) treatment or known documented history of >=1 DRV resistance-associated mutations (RAM)
• Screening hepatic transaminases >5x the upper limit of the normal range
• Screening creatinine based estimated glomerular filtration rate (eGFRcr) <30 ml/min according to the Cockcroft-Gault formula for creatinine clearance
• Participants initiating or discontinuing concomitant medications associated with significant changes in weight within the last 90 days

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35222

United States, California

The Office of Franco Felizarta, MD

Bakersfield, California, United States, 93301

AIDS Health Foundation-Westside HCC

Beverly Hills, California, United States, 90211

Long Beach Education & Research Consultants

Long Beach, California, United States, 90813

United States, Florida

Midway Immunology and Research Center

Fort Pierce, Florida, United States, 34982

University of Miami

Miami, Florida, United States, 33136

Triple O Research Institute

West Palm Beach, Florida, United States, 33407

United States, Georgia

Atlanta ID Group

Atlanta, Georgia, United States, 30309

Medical College of Georgia

Augusta, Georgia, United States, 30912

The Corporation of Mercer University

Macon, Georgia, United States, 31201

Chatham County Health Department

Savannah, Georgia, United States, 31401

United States, Illinois

The Ruth M. Rothstein CORE Center

Chicago, Illinois, United States, 60612

United States, Louisiana

Care South Clinic

Baton Rouge, Louisiana, United States, 70806

United States, Maryland

Kaiser Permanente

Rockville, Maryland, United States, 20852

United States, Massachusetts

Community Research Initiative

Boston, Massachusetts, United States, 02129

United States, Michigan

Be Well Medical Center, PC

Berkley, Michigan, United States, 48072

Henry Ford Health System

Detroit, Michigan, United States, 48202

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Nebraska

University of Nebraska

Omaha, Nebraska, United States, 68106

United States, New Jersey

Saint Michaels Medical Center - Infectious Disease

Newark, New Jersey, United States, 07102

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

AIDS Healthcare Foundation-Research Center

New York, New York, United States, 10001

Mount Sinai Hospital-New York

New York, New York, United States, 10029

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Philadelphia Fight

Philadelphia, Pennsylvania, United States, 19107

United States, South Carolina

Palmetto Health - USC

Columbia, South Carolina, United States, 29203

United States, Texas

AIDS Arms Incorporated Trinity Health and Wellness Center

Dallas, Texas, United States, 75208

North Texas Infectious Diseases Consultants

Dallas, Texas, United States, 75246

Texas Centers for Infectious Disease Associates

Fort Worth, Texas, United States, 76104

Therapeutic Concepts - Donald R Watkins Foundation

Houston, Texas, United States, 77004

DCOL Center for Clinical Research

Longview, Texas, United States, 75605

United States, Virginia

Infectious Disease Associates of Central Virginia

Lynchburg, Virginia, United States, 24501

United States, Wisconsin

Vivent Health

Milwaukee, Wisconsin, United States, 53203

Sponsors and Collaborators

Janssen Scientific Affairs, LLC

Investigators

• Study Director: Janssen Scientific Affairs, LLC Clinical Trial; Janssen Scientific Affairs, LLC

More Information

• Responsible Party: Janssen Scientific Affairs, LLC
• ClinicalTrials.gov Identifier: NCT04442737
• Other Study ID Numbers: CR108757; TMC114FD2HTX4004 ( Other Identifier: Janssen Scientific Affairs, LLC )
• First Posted: June 23, 2020
• Last Update Posted: March 15, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu
• URL: https://www.janssen.com/clinical-trials/transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Weight Gain; Body Weight Changes; Body Weight