Early DOlutegravir/LAmivudine Switching After Virological Suppression (EDOLAS Study) (EDOLAS)

Efficacy and Safety of Early Switching to Dolutegravir/Lamivudine (DTG/3TC) From INSTI-based Three-drug Regimens in HIV-1-infected Adults Previously naïve Who Achieve Virological Suppression

Phase III, randomized, open-label, multicentre, active-controlled, non-inferiority study evaluating the efficacy and safety of early switching to dolutegravir/lamivudine (DTG/3TC) in single-pill, in HIV-1 infected individuals currently taking an INSTI-based three-drug first-line regimen for less than 18 months and who have been virologically suppressed with HIV-1 RNA <50 copies/mL

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: DOVATO

Detailed Description

The target population of this study is HIV-1-infected adults without previous virological failure, currently receiving any first-line, triple-drug ART having an INSTI (EVG/cobi, RAL QD, DTG, BIC) as anchor drug associated to any of the following dual NRTI backbone (ABC/3TC, TDF/FTC or TAF/FTC) with virological suppression (HIV-1 RNA < 50 copies/mL).

Participants will be randomly allocated 1:1 to switch to DTG/3TC 50/300 mg as a single pill qd until week 96 (Arm A, early switch) or to continue their INSTI-based ART triple regimen received at screening (Arm B, delayed switch) until week 52, when participants in Arm B with HIV-1 RNA< 50 cp/mL at week 48 will switch to DTG/3TC 50/300 mg qd as a single pill until week 100.

The drugs of both arms will be administered in an open-label manner throughout the entire duration of the study.

The primary analysis will take place after the last participant completes 52 weeks on therapy, to allow for the collection of a confirmatory viral load measurement in participants possibly presenting with HIV-1 RNA ≥50 cp/mL at the Week 48 visit.

If the second determination of HIV-1 RNA is <50 cp/mL, then the participant has not a virological rebound and will be considered eligible to switch to DTG/3TC at Week 52.

If the second determination of HIV-1 RNA is ≥50 cp/mL, then the participant will be considered protocol-defined virological failure, thus being ineligible to switch to DTG/ 3TC. These participants will be withdrawn from the study.

A preliminary interim analysis will be performed after 50% of the enrolled participants have reached the 24th week of study, always considering 4 weeks more (thus 28 weeks) to allow for the collection of a confirmatory viral load measurement in participants possibly presenting with HIV-1 RNA ≥50 copies/mL at Week 24.

At week 48, participants in Arm A (early switch) will continue DTG/3TC. At week 52, participants in Arm B (delayed switch) and with HIV-1 RNA < 50 copies/mL at week 48 will switch to DTG/3TC and will be followed until week 100.

The exploratory analyses at Week 96 will take place after the last participant completes 100 weeks on therapy, as needed, to allow for the collection of a confirmatory viral load measurement in participants presenting with HIV-1 RNA ≥50 copies/mL at Week 96.

• Study Type: Interventional
• Enrollment (Anticipated): 440
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Andrea Antinori, P.I.; Phone Number: 0655170546; Email: andrea.antinori@inmi.it
• Study Contact Backup: Name: Maddalena Plazzi, DM; Phone Number: 3384093449; Email: maria.plazzi@inmi.it

Study Locations

• Italy
  • BA
    • Bari, BA, Italy, 70124
      • Active, not recruiting
      • Azienda Ospedaliera Universitaria Policlinico di Bari
  • BG
    • Bergamo, BG, Italy, 24127
      • Not yet recruiting
      • Asst Papa Giovanni XXIII
      • Contact: Franco Maggiolo, P.I.; Phone Number: 3388172182; Email: fmaggiolo@asst-pg23.it
      • Contact: Claudia Suardi, D.M.; Phone Number: 0352673608; Email: csuardi@fondazionefrom.it
  • CT
    • Catania, CT, Italy, 95123
      • Active, not recruiting
      • ARNAS Garibaldi
  • FE
    • Ferrara, FE, Italy, 44124
      • Not yet recruiting
      • Azienda Ospedaliera Universitaria Ferrara
      • Contact: Laura Sighinolfi, P.I.; Phone Number: 3479146298; Email: l.sighinolfi@ospfe.it
  • FI
    • Firenze, FI, Italy, 50134
      • Active, not recruiting
      • Azienda Ospedaliera Universitaria Careggi
    • Firenze, FI, Italy, 50134
      • Not yet recruiting
      • Azienda Ospedaliera Universitaria Careggi
      • Contact: Massimo Antonio Di Pietro, P.I.; Phone Number: 057335111; Email: massimoantonio.dipietro@uslcentro.toscana.it
  • GE
    • Genova, GE, Italy, 16132
      • Not yet recruiting
      • Ospedale Policlinico San Martino di Genova
      • Contact: Antonio Di Biagio, P.I.; Phone Number: 3356269149; Email: adibiagioa@gmail.com
  • MI
    • Milano, MI, Italy, 20122
      • Active, not recruiting
      • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
    • Milano, MI, Italy, 20127
      • Recruiting
      • IRCCS Ospedale San Raffaele
      • Contact: Antonella Castagna, P.I.; Phone Number: 3466732894; Email: castagna.antonella@hsr.it
      • Contact: Elisabetta Carini, D.M.; Phone Number: 0226437934; Email: carini.elisabetta@hsr.it
    • Milano, MI, Italy, 20131
      • Not yet recruiting
      • ASST Fatebenefratelli Sacco
      • Contact: Stefano Rusconi, P.I.; Phone Number: 0250319761; Email: stefano.rusconi@unimi.it
    • Milano, MI, Italy, 20142
      • Not yet recruiting
      • ASST Santi Paolo e Carlo - Presidio San Paolo
      • Contact: Antonella d'Arminio Monforte, P.I.; Phone Number: 0281843046; Email: antonella.darminio@unimi.it
      • Contact: Valentina Minieri, D.M.; Phone Number: 0281844621; Email: valentina.minieri@gmail.com
    • Milano, MI, Italy, 20162
      • Active, not recruiting
      • ASST Grande Ospedale Metropolitano Niguarda
    • Monza, MI, Italy, 20900
      • Not yet recruiting
      • Ospedale San Gerardo di Monza
      • Contact: Giuseppe Lapadula, P.I.; Phone Number: 3396640107; Email: g.lapadula@asst.monza.it
  • MO
    • Modena, MO, Italy, 41124
      • Not yet recruiting
      • Azienda Ospedaliera Universitaria di Modena
      • Contact: Cristina Mussini, P.I.; Phone Number: 059422246; Email: cristina.mussini@unimore.it
  • PA
    • Palermo, PA, Italy, 90127
      • Active, not recruiting
      • A.O.U. Policlinico "Paolo Giaccone"
  • PD
    • Padova, PD, Italy, 35128
      • Not yet recruiting
      • Azienda Ospedaliera di Padova
      • Contact: Annamaria Cattelan, P.I.; Phone Number: 3337138916; Email: annamaria.cattelan@aopd.veneto.it
      • Contact: Maddalena Cipullo, D.M.; Email: maddalena.cipullo@aopd.veneto.it
  • PV
    • Pavia, PV, Italy, 27100
      • Not yet recruiting
      • Fondazione IRCCS Policlinico San Matteo
      • Contact: Roberto Gulminetti, P.I.; Phone Number: 3386784776; Email: r.gulminetti@smatteo.pv.it
  • RM
    • Roma, RM, Italy, 00133
      • Active, not recruiting
      • Policlinico Universitario Tor Vergata
    • Roma, RM, Italy, 00149
      • Recruiting
      • Istituto Nazionale per le Malattie Infettive "Lazzaro Spallanzani" IRCCS
      • Contact: Andrea Antinori, P.I.; Phone Number: 0655170546; Email: andrea.antinori@inmi.it
      • Contact: Maddalena Plazzi, D.M.; Phone Number: 3384093449; Email: maria.plazzi@inmi.it
    • Roma, RM, Italy, 00155
      • Not yet recruiting
      • A.O.U. Policlinico Umberto I
      • Contact: Gabriella d'Ettorre, P.I.; Phone Number: 3479650959; Email: gabriella.dettorre@uniroma1.it
    • Roma, RM, Italy, 00168
      • Active, not recruiting
      • Fondazione Policlinico Universitario A. Gemelli IRCCS
  • SI
    • Siena, SI, Italy, 53100
      • Active, not recruiting
      • Azienda Ospedaliera Universitaria Senese
  • SS
    • Sassari, SS, Italy, 07100
      • Active, not recruiting
      • Strutture Ospedaliere - Cliniche San Pietro - AOU Sassari
  • TO
    • Torino, TO, Italy, 10149
      • Not yet recruiting
      • Ospedale Amedeo di Savoia
      • Contact: Stefano Bonora, P.I.; Phone Number: 0114393860; Email: stefano.bonora@unito.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 documented infection;
• Aged 18 years or older at the time of signing the informed consent;

• Stable INSTI-based first-line three-drug ART (switch between different NRTIs are allowed; e.g. from TDF/FTC to TAF/FTC or ABC/3TC, from TAF/FTC to TDF/FTC or ABC/3TC, from ABC/3TC to TAF/FTC or TDF/FTC). Any change of INSTI will not be allowed. Only the following regimens will be allowed:

  • RAL 1200 mg QD plus TDF/FTC or TAF/FTC;
  • RAL 1200 mg QD plus ABC/3TC;
  • EVG/COBI/FTC/TDF or EVG/COBI/FTC/TAF;
  • DTG plus TDF/FTC or TAF/FTC;
  • DTG/ABC/3TC or DTG plus ABC/3TC;
  • BIC/TAF/FTC
• Previous INSTI-based first-line ART lasting less than 18 months before screening;
• To have reached a HIV-1 RNA <50 copies/mL during INSTI first-line therapy for less than 12 months. At least a single HIV-1 RNA determination below the threshold within the 6 months before enrollment is required (if a following determination in present, this should not be ≥50 copies (cp)/mL)
• HIV-1 RNA below 50 copies/mL at the screening visit;
• No known allergy or intolerance to the study drugs or their components or drugs of their class;

• A female person is eligible to enter the study if it is confirmed that she is:

  • Not pregnant confirmed by a negative serum pregnancy test at both Screening and Day1;
  • Not breastfeeding;
  • Of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy;
  • Of childbearing potential and agrees to utilize the protocol specified method of contraception (as defined in Appendix 1 -Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential) or be non-heterosexually active or practice sexual abstinence (defined as complete abstinence from penile-vaginal intercourse; periodic abstinence, e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception) from screening throughout the duration of study treatment and for at least two weeks following discontinuation of study drugs;
• Being able to comply with the protocol requirements and restrictions;
• Signature of written Informed Consent Form (participants or legal guardian) before that any protocol-specified assessments are conducted.

Exclusion Criteria:

A person will be considered not eligible for inclusion in this study if any of the following criteria apply:

• Having failed virologically;
• Having changed the INSTI drug;
• Any major INSTI- or NRTI-resistance-associated mutation documented before starting ART;
• Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study;

• Evidence of Hepatitis B virus (HBV) infection based on the results of testing at screening for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-Hbc), hepatitis B surface antigen antibody (anti-HBs) and, possibly, HBV DNA as follows:

  • Individuals positive for HBsAg are excluded;
  • Individuals negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded;
• HCV-RNA positivity needing for any hepatitis C virus (HCV) therapy during the study;
• Ongoing malignancy other than cutaneous Kaposi's sarcoma (not requiring systemic therapy), basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia;
• Active opportunistic infections requiring active treatment;
• Creatinine clearance of <50 mL/min/1.73m2 via CKD-EPI method;
• Individuals with severe hepatic impairment (Child Pugh class C) and/or unstable liver disease;
• Any verified Grade 4 laboratory abnormality at screening assessment;
• Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or ALT >3xULN and bilirubin >1.5xULN (with >35% direct bilirubin) at screening assessment;
• Receipt of investigational research agents within 30 days prior to study entry;
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening;
• Receipt of immunosuppressive medications or immune-modulators within the past 6 months;
• Individuals who in the investigator's judgment, poses a significant suicidality risk or with diagnosed major depression, Bipolar Disorders and Psychoses
• A life expectancy estimated as less than 2 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: ARM A; Participants in Arm A will be randomized to switch to DTG/3TC 50/300 mg QD until week 48 (early switch).	Drug: DOVATO; Dovato is a medicine for treating infection with human immunodeficiency virus type 1 (HIV-1), a virus that causes acquired immune deficiency syndrome (AIDS).; Other Names: dolutegravir/lamivudine
Other: ARM B; Participants in Arm B will continue the INSTI-based ART regimen until week 48, and then will be switched to DTG/3TC through week 96 (delayed switch).	Drug: DOVATO; Dovato is a medicine for treating infection with human immunodeficiency virus type 1 (HIV-1), a virus that causes acquired immune deficiency syndrome (AIDS).; Other Names: dolutegravir/lamivudine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-inferior efficacy of switching	Proportion of participants with virological rebound (viral load ≥50 copies/mL or premature discontinuations, irrespective of reason, with last viral load ≥50 copies/mL) at week 48	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of switching	Proportion of participants with HIV-1 RNA <50 copies/mL at week 48 (FDA Snapshot algorithm)	48 weeks
Safety and tolerability	Clinical and laboratory safety parameters; a descriptive analysis of all reported AEs and a quantitative analysis of AEs leading to treatment interruption/change will be used to evaluate long-term tolerability of the simplification treatment.	100 weeks
Immunologic response and dysfunction	Changes in CD4+ and CD8+ T-lymphocyte counts (absolute and percentage), and in CD4+/CD8+ ratio (as a measure of immune activation) in the peripheral blood from baseline to week 48 and 96.	100 weeks
Emergent drug resistance-associated mutations	Proportion of participants developing resistance-conferring mutations (to any drug class) by genotypic resistance test (GRT) in plasma or proviral DNA (in case of low viremia levels, <200 copies/mL) at protocol-defined virological failure (PDVF) will be cumulatively described throughout the study period.	100 weeks
RT and INSTI resistance-associated mutations	iral minority variants harboring resistance associated mutations (to any drug class) at the time of PDVF will be characterized in plasma or in proviral DNA (in case of low viremia levels, <200 copies/mL) by next generation sequencing. For the minority resistant variants detected (prevalence >1%), their resistance viral burden will be also evaluated.	100 weeks
Effects of the two strategies on Lipidic profile	Changes in fasting lipids (TC, LDL, HDL, non-HDL, TC/HDL) from baseline to w48 and 96.	96 weeks
Adherence levels to ARVs	Changes of self-reported adherence level and proportion of participants with different adherence level (95%; 90%; 80%) from baseline to week 48 and 96.	96 weeks
Evaluate neuropsychiatric symptoms.	Change in neuropsychiatric questionnaire scores, assessing mood, anxiety, sleep quality, and suicidality from baseline to week 24, 48 and 96.	96 weeks

Collaborators and Investigators

• Sponsor: Societa' Italiana Di Malattie Infettive E Tropicali
• Investigators: Principal Investigator: Andrea Andreoni, P.I., Policlinico Universitario Tor Vergata; Principal Investigator: Alessandra Bandera, P.I., Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; Principal Investigator: Alessandro Bartoloni, P.I., Azienda Ospedaliera Universitaria Careggi; Principal Investigator: Stefano Bonora, P.I., Ospedale Amedeo di Savoia; Principal Investigator: Antonio Cascio, P.I., A.O.U. Policlinico "Paolo Giaccone"; Principal Investigator: Antonella Castagna, P.I., IRCCS Ospedale San Raffaele; Principal Investigator: Annamaria Cattelan, P.I., Azienda Ospedaliera di Padova; Principal Investigator: Roberto Cauda, P.I., Fondazione Policlinico Universitario A. Gemelli, IRCCS; Principal Investigator: Benedetto Maurizio Celesia, P.I., ARNAS Garibaldi; Principal Investigator: Antonella d'Arminio Monforte, P.I., ASST Santi Paolo e Carlo - Presidio San Paolo; Principal Investigator: Antonio Di Biagio, P.I., Ospedale Policlinico San Martino di Genova; Principal Investigator: Massimo Antonio Di Pietro, P.I., Azienda Ospedaliera Universitaria Careggi; Principal Investigator: Massimiliano Fabbiani, P.I., Azienda Ospedaliera Universitaria Senese; Principal Investigator: Roberto Gulminetti, P.I., Fondazione IRCCS Policlinico San Matteo; Principal Investigator: Giuseppe Lapadula, P.I., Ospedale San Gerardo di Monza; Principal Investigator: Giordano Madeddu, P.I., Strutture Ospedaliere - Cliniche San Pietro - AOU Sassari; Principal Investigator: Franco Maggiolo, P.I., Asst Papa Giovanni XXIII; Principal Investigator: Cristina Mussini, P.I., Azienda Ospedaliero-Universitaria di Modena; Principal Investigator: Massimo Puoti, P.I., ASST Grande Ospedale Metropolitano Niguarda; Principal Investigator: Giuliano Rizzardini, P.I., ASST Fatebenefratelli Sacco; Principal Investigator: Stefano Rusconi, P.I., ASST Fatebenefratelli Sacco; Principal Investigator: Annalisa aracino, P.I., Azienda Ospedaliera Universitaria Policlinico di Bari; Principal Investigator: Laura Sighinolfi, P.I., Azienda Ospedaliera Universitaria Ferrara; Principal Investigator: Gabriella d'Ettorre, P.I., A.O.U. Policlinico Umberto I

Publications and helpful links

Helpful Links

• eCRF Home page

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2021
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: July 2, 2021
• First Submitted That Met QC Criteria: July 16, 2021
• First Posted (Actual): July 28, 2021

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 16, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir
• Other Study ID Numbers: 2019-004241-32

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No