Early DOlutegravir/LAmivudine Switching after virological suppression (EDOLAS Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Societa Italiana Di Malattie Infettive E Tropicali SIMIT

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

23 Mar 2021 → ongoing

Decision date (initial)

2024-12-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ViiV Healthcare

External identifiers

EU CT number

2024-518909-18-00

EudraCT number

2019-004241-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

• To evaluate efficacy and safety of an early switch to a two-drug regimen with DTG/3TC as single pill in participants who achieved and maintained a recent (less than 1 year) virological suppression with a three-drug INSTI-based ART, compared to continuing the INSTI-based three-drug first-line regimen. The primary analysis will be performed on the intention-to-treat (ITT) population as the proportion of participants with virologic rebound (one HIV-1 RNA 50 copies/mL) at Week 48 as defined by the US Food and Drug Administration (FDA) snapshot algorithm (non-inferiority margin 4%). An exploratory interim analysis will be performed after 50% of participants have completed 24 weeks of follow-up. After 48 weeks all the participants actively followed in the control group will switch to DTG/3TC as single pill (delayed switch), and the final evaluation will be performed after 96 weeks.

Secondary objectives 2

1. • To evaluate safety and tolerability of the two strategies over time; • To evaluate immunologic response and dysfunction (CD4+ and CD8+ absolute counts and percentage; CD4+/CD8+ ratio) in both arms; To test for emergent drug resistance-associated mutations (in integrase and reverse transcriptase) with standard genotypic assays (Sanger sequencing) in participants with protocol-defined virological failure (PDVF) in both arms; • To detect resistance-associated mutations (in integrase and reverse transcriptase) in participants with PDVF by means of a next generation sequencing assay detecting minority species at >1% prevalence • To evaluate the effects of the two strategies on fasting lipids (TC, LDL, HDL non-HDL, TC/ HDL) over time • To evaluate adherence levels to ARVs in both arms • To evaluate neuropsychiatric symptoms in both arms
2. Sub-studies (post-hoc analyses in subgroups of participants): • To evaluate the levels of residual plasma viremia at baseline and at weeks 24 and 48 in both arms; • To evaluate the levels of total HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) at baseline and at weeks 24 and 48, in both arms; • To evaluate the levels of cell-associated HIV-1 RNA in PBMCs, at baseline and at weeks 24 and 48, in both arms; • To evaluate the presence of minority RT integrase resistance mutations (at >1% prevalence) in PBMCs at baseline, and their impact on virological failure at weeks 24 and 48 in both arms; • To evaluate T cell activation (CD38+DR+) and senescence (CD28- CD57+ cells, PD-1+ cells) and the T helper profile (Th1, Th2, Th9, Th17, Th21) at baseline and at weeks 24 and 48, in both arms; • To evaluate B (naïve, memory, activated), NK (CD16+CD56bright, dim and neg) and monocyte subsets (inflammatory M1 and M2; anti-inflammatory M2) at baseline and at weeks 24 and 48, in both arms; • To evaluate regulatory cells (Treg and MDSC) at baseline and at weeks 24 and 48, in both arms; • To evaluate inflammation and pro-coagulation markers (soluble CD14, soluble CD163, IL-6, D-Dimer, high-sensitivity C-Reactive Protein) at baseline and at weeks 24 and 48, in both arms; • To evaluate urinary tubular damage markers [alpha1-microglobulin, beta2-microglobulin, retinal binding protein (RBP) and urinary albumin-creatinine ratio (uACR)] after switching to both arms; • To evaluate BMD change, total limb fat, trunk fat and lean body mass by DXA scan; To evaluate BMI, waist circumference, hip circumference and waist to hip ratioTo evaluate visceral adipose tissue, subcutaneous abdominal tissue and total adipose tissue by single slice CT. • To evaluate neurocognitive performance, plasma NFL concentrations; To evaluate patient-reported quality of life (QoL) and patients-reported outcomes (PROs).;

Conditions and MedDRA coding

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 design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. • HIV-1 documented infection • Age 18 years • To be treated as ART naïve for overall less than 18 months before screening/baseline • To receive a stable (not changed) INSTI-based first-line three-drug ART (see Target Population section for regimens allowed); switch between different NRTIs are allowed • 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) • Evidence of HbsAg negative less than 18 months before screening/baseline • No known allergy or intolerance to NRTIs, or INSTIs • Being able to comply with the protocol requirements • Informed consent signed

Exclusion criteria 1

1. • Having failed virologically • Having changed the INSTI drug • Any major INSTI- or NRTI-resistance-associated mutation documented before starting ART • Pregnancy or breast-feeding • HBsAg positivity • HCV-RNA positivity needing for any hepatitis C virus (HCV) therapy during the study • An active malignancy or opportunistic infection requiring active treatment • Women of childbearing potential not adopting an effective birth control system throughout the study period • Creatinine clearance of <50 mL/min/1.73m2 via CKD-EPI method • A life expectancy <2 years • Use of HIV immunotherapeutic vaccines; other experimental agents, ART drugs not otherwise specified in the protocol, cytotoxic chemotherapy, systemically administered immunomodulators • Individuals who in the investigator’s judgment, poses a significant suicidality risk; • Major Depression, Bipolar Disorders and Psychoses

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • 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.

Secondary endpoints 14

1. Proportion of participants with HIV-1 RNA <50 copies/mL at week 48 (FDA Snapshot algorithm)
2. Time to virological rebound (defined as the first of two consecutive HIV-1 RNA >=50 copies/mL)
3. 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.
4. 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.
5. Viral 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
6. 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.
7. Changes in fasting lipids (TC, LDL, HDL, non-HDL, TC/HDL) from baseline to w48 and 96. • Absolute changes as well as proportion of participants above clinically relevant thresholds will be used to evaluate the change of metabolic parameters over time. • Changes of self-reported adherence level and proportion of participants with different adherence level (95%; 90%; 80%) from baseline to week 48 and 96.
8. Change in neuropsychiatric questionnaire scores, assessing mood, anxiety, sleep quality, and suicidality from baseline to week 24, 48 and 96.
9. Virological Sub-study Changes in residual viremia (limit of detection: 3 copies/mL) from baseline to week 24 and 48. Percentage of participants with residual viremia at week 24 and 48. Impact of residual viremia at baseline on virological response. • Change in total HIV-1 DNA in PBMCs from baseline to week 24 and 48. • Impact of total DNA at baseline on virological response. • Change in level of cell-associated HIV-1 RNA in PBMCs from baseline to week 24 and 48.
10. •Impact of total DNA at baseline on virological response.•Change in level of cell-associated HIV-1 RNA in PBMCs from baseline to week 24 and 48. •Impact of cell-associated HIV-1 RNA in PBMCs at baseline on virological response. Correlations between cell-associated HIV-1 RNA in PBMCs,total HIV DNA,and RNA levels.Characterization of minority RT integrase resistance mutations(at >1% prevalence)and their relative abundance in PBMCs at baseline, and their impact on virological failure at 24 and 48wk
11. Immunological Sub-study •Impact of regimen switching on the percentage of activated(%CD38+DR+),senescent(CD28-CD57+)T-cell lymphocytes and on T helper profile(Th1, Th2,TH9, Th17, Th21);Impact of regimen switching on different B cell (naïve, memory and activated),NK and monocytes subsets and on regulatory cells (Treg and MDSC);. •Impact of regimen switching on the Principal Component analysis of immunological markers • Impact of regimen switching on inflammation and pro-coagulation markers
12. Renal bone and weight Sub-study Changes in urinary tubular damage markers [alpha1-microglobulin, beta2-microglobulin, retinal binding protein (RBP) and albumin-creatinine ratio (ACR)], from baseline to week 24 and 48. • BMD change by DXA scan. • Enrolled patients may also undergo only part of the evaluations planned for the substudy
13. Neurologic Sub-study • Change in neurocognitive performance assessed by a standardized neuropsychological battery (NPZ-14) from baseline to week 48 and 96. • Change in plasma NFL concentration from baseline to week 48 and 96
14. PROs and QoL Sub-study Change in QoL and PROs items from baseline to week 48 and 96 by standardized validate self-reported questionnaires.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Societa Italiana Di Malattie Infettive E Tropicali SIMIT

Sponsor organisation

Societa Italiana Di Malattie Infettive E Tropicali SIMIT

Address

Via Del Romito 63 A

City

Prato

Postcode

59100

Country

Italy

Scientific contact point

Organisation

Societa Italiana Di Malattie Infettive E Tropicali SIMIT

Contact name

Andrea Antinori

Public contact point

Organisation

Societa Italiana Di Malattie Infettive E Tropicali SIMIT

Contact name

Andrea Antinori

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications