ANRS0392s ELDORADO : Phase III, open-label, randomized, multicenter trial EvaLuating the non-inferiority of DORAvirine versus DOlutegravir based antiretroviral regimens in treatment-naïve people living with HIV-1 infection

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Inserm

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Virus Diseases [C02]

Trial duration

8 Jan 2025 → ongoing

Decision date (initial)

2024-08-19

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

The Global Health EDCT3 · MSD · ANRS MIE

External identifiers

EU CT number

2023-508626-10-00

ClinicalTrials.gov

NCT06203132

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Safety, Therapy, Efficacy

To assess the non-inferiority of doravirine (DOR) in association with tenofovir (TDF) and lamivudine (3TC), compared to dolutegravir (DTG) in association with tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC), in terms of virologic efficacy at week 48, measured by the proportion of subjects achieving HIV 1 RNA <50 copies/mL, in HIV-1 infected, treatment-naive subjects with pre-treatment viral load (HIV-1 RNA) ≥ 1,000 copies/mL.

Secondary objectives 30

1. Occurrence of obesity at Week 48 and Week 96
2. Occurrence of insulin resistance at Week 48 and Week 96
3. Occurrence of hypertension at Week 48 and Week 96
4. To assess the non-inferiority of doravirine in association with tenofovir and lamivudine, compared to dolutegravir in association with tenofovir and lamivudine or emtricitabine, in terms of virologic efficacy at week 96
5. Occurrence of virological failures
6. Occurrence of HIV-1 drug resistances in patients with confirmed virological failure
7. Virological efficacy at a threshold of HIV 1 RNA<200 copies/mL at Week 48 and Week 96
8. Virological efficacy at a threshold of HIV 1 RNA<1000 copies/mL at Week 48 and Week 96
9. Effect of baseline RT and integrase mutations on virological response at Week 48 and Week 96
10. Occurrence of combined overweight and obesity at Week 48 and Week 96
11. Occurrence of weight gain ≥10% absolute body weight at Week 48 and Week 96
12. Changes in absolute weight gain at Week 48 and Week 96
13. Occurrence of diabetes at Week 48 and Week 96
14. Safety and tolerability at Week 48 and Week 96
15. Changes in waist circumference, hip circumference and waist-to-hip ratio at Week 48 and Week 96.
16. Changes in fasting glycemia and insulin at Week 48 and at Week 96
17. Changes in fasting serum lipids at Week 48 and at Week 96
18. Changes in estimated glomerular filtration rate at Week 48 and at Week 96
19. Occurrence of cardiovascular abnormalities at Week 48 and Week 96
20. a. Changes in liver steatosis and clinically significant fibrosis at Week 48 and Week 96 b. Occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic-associated steatohepatitis (MASH) at Week 48 and Week 96
21. Changes in liver diseases biomarkers at Week 48 and Week 96
22. Changes in mental health and quality of life outcomes at Week 24, Week 48 and Week 96
23. Occurrence of Acquired Immune Deficiency Syndrome (AIDS), tuberculosis, Immune Reconstitution Inflammatory Syndrome (IRIS) or death at Week 48 and at Week 96
24. a. To describe antiretroviral drugs trough plasma concentration in each arm b. To assess the effect of antiretroviral drugs trough plasma concentration on virological response c. To determine DOR, DTG and M9 trough plasma concentration thresholds predictive of virological response. d. To assess the effect of antiretroviral drugs trough plasma concentration on safety endpoints
25. Changes in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio, at Week 48 and at Week 96
26. Adherence to ART at Week 48 and Week 96
27. a. To describe the distribution of CYP3A5/4 mutations according to ARV regimen b. To assess the impact of CYP3A5/4 mutations on PK c. To assess the impact of CYP3A5/4 mutations on virological response and side effects
28. Explore additional polymorphism (i.e., UGT1A1) according to literature update
29. Cost-effectiveness and budget impact of using DOR-based versus DTG-based antiretroviral regimens
30. a. Changes in truncal fat distribution at Week 48 and Week 96 b. Changes in adipose tissue markers and immune activation markers at Week 48 and Week 96 c. Changes in fat quality at Week 48

Conditions and MedDRA coding

HIV-1 infection

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Be at least 18 years of age on the day of signing the informed consent
2. Be HIV-1 positive as determined according to national testing strategies
3. Have a plasma HIV-1 RNA ≥1000 copies/mL within 30 days prior to the randomization
4. Have HIV treatment indication based on physician assessment according to local treatment guidelines
5. Be naïve to antiretroviral therapy (ART) for the treatment of HIV infection including investigational antiretroviral agents
6. For cisgender women or transgender men of childbearing potential i.e. of childbearing age who are not menopausal, or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or not refraining from sexual activity: negative urinary test for pregnancy and acceptance to use contraceptive methods
7. Understand the study procedures and voluntarily agree to participate by giving written informed consent for the trial
8. For participants in France, be affiliated to a Social Security program or CMU (Universal Health Cover)

Exclusion criteria 14

1. Has ongoing (pulmonary or extra-pulmonary) active tuberculosis
2. Has any other history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study or interfere with the subject’s participation for the full duration of the study, such that it is not in the best interest of the subject to participate
3. Is infected with HIV-2 or co-infected with HIV-1 and HIV-2
4. Has received cabotegravir long acting or dapivirine pre-exposure prophylaxis (PrEP)
5. Has received oral pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) in the past three months or has had no negative HIV-1 serology performed
6. Has documented or known resistance or possible resistance to study drugs as defined by the ANRS MIE AC43 Resistance group
7. Has the following laboratory values at screening visit, within 30 days prior to the randomization: AST (SGOT) and ALT (SGPT) >4.0 x upper limit of normal (ULN) - estimated glomerular filtration rate at time of screening <60 mL/min/1.73m², based on the CKD-EPI equation
8. Has participated in a study with an investigational compound/device within 30 days prior to signing informed consent or anticipates participating in such a study involving an investigational compound/device during the course of this study
9. Has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this study or is anticipated to need them during the course of the study
10. Requires or is anticipated to require any of the prohibited or contraindicated medications noted in the trial protocol
11. Has significant hypersensitivity or other contraindication to any of the components of the study drugs
12. Is pregnant, breastfeeding, or expecting to conceive at any time during the study
13. Has any condition, which might, in the investigator’s opinion, compromise the safety of treatment and/or patient’s adherence to study procedures
14. Is a person under guardianship or deprived of freedom by a judicial or administrative decision

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 48 under allocated treatment using the FDA snapshot algorithm (window period of 42-54 weeks); subjects not achieving viral success will be described according to the FDA snapshot recommendation

Secondary endpoints 30

1. Occurrence of obesity at Week 48 and at Week 96
2. Proportion of subjects with newly measured HOMA≥2 at Week 48 and Week 96 as compared to baseline
3. Proportion of subjects with hypertension newly detected at Week 48 and Week 96 compared to baseline.
4. Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 96 under allocated treatment using the FDA snapshot algorithm with a window period of 90 to 102 weeks; subjects not achieving viral success will be described according to the FDA snapshot recommendation
5. Proportion of confirmed virological failures occurring up to Week 48 and up to Week 96
6. Frequency of HIV-1 drug resistances in participants with a confirmed virological failure
7. Proportion of subjects achieving HIV 1 RNA<200 copies/mL under allocated treatment at Week 48 and Week 96
8. Proportion of subjects achieving HIV 1 RNA<1000 copies/mL under allocated treatment at Week 48 and Week 96
9. Frequency of RT and integrase mutations at baseline and impact on the virological response at Week 48 and Week 96
10. Occurrence of combined overweight and obesity at Week 48 and at Week 96
11. Proportion of subjects with ≥10% absolute weight gain from baseline at Week 48 and Week 96
12. Change from baseline in absolute weight at Week 48 and at Week 96
13. Proportion of subjects with diabetes newly detected at Week 48 and Week 96 compared to baseline
14. Any adverse event of any grade and those graded 3-4 at Week 48 and Week 96
15. Change from baseline in waist and hip circumferences and waist-to-hip ratio at Week 48 and Week 96
16. Change from baseline in fasting glycemia and insulin at Week 48 and at Week 96
17. Change from baseline in fasting serum lipids at Week 48 and at Week 96
18. Change from baseline in estimated glomerular filtration rate at Week 48 and at Week 96
19. Change from baseline in cardiovascular parameters (blood pressure profile, electrocardiographic and echocardiographic damages) at Week 48 and Week 96
20. Change from baseline in mean patient CAP and LSM measurements at Week 48 and Week 96 and occurrence at Week 48 and Week 96 of: a. Liver steatosis, clinically significant liver fibrosis and cirrhosis b. MASLD and MASH
21. Changes from baseline in Fib-4, VCTE and FAST scores at Week 48 and Week 96 and presence at baseline or occurrence of CSF defined as Fib-4 ≥2.67 or FAST score > 0.67
22. Change from baseline in EQ-5D-3L, HIVTSQ, DASS-21, PSQI, WHOQOL HIV-BREF scores at Week 24, Week 48 and Week 96
23. Proportion of subjects with AIDS (defined as having CDC stage 3/C or WHO stage 4), tuberculosis, IRIS or death at Week 48 and Week 96
24. a, b, c, d. DOR, DTG and M9 trough plasma concentration in samples taken pre-dose at Week 4, Week 24, Week 48 and Week 96
25. Change from baseline in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio, at Week 48 and at Week 96
26. Adherence to ART by (1) pill count (considering a pill count adherence ratio <95% as sub-optimal adherence), (2) 4-days and 1-month recall questions at every trial visit, (3) by TFV-DP quantification in dried blood spots (LC/MS) at Week 48 and Week 96
27. a. Type and frequency of alleles variants in the gene coding for CYP3A5/4 b. Impact of CYP3A5/4 mutations on pharmacokinetics of DOR, DTG and M9, c. Virological response and side-effects depending on CYP3A5/4 mutations
28. Assess additional polymorphism of UGT1A1 at baseline
29. Cost-effectiveness measured by (1) Incremental health benefits of using one regimen compared to the other (in DALYs and QALYs), (2) Incremental economic costs of using one regimen compared to the other (USD), (3) Budget impact of changing from one regimen to the other (USD)
30. a. Change from baseline in truncal fat distribution at Week 48 and Week 96. b. Change from baseline in adipose tissue markers (adiponectin, leptin) and immune activation markers (sCD14, sCD163) at Week 48 and Week 96. c. Change from baseline (by abdominal subcutaneous surgical biopsy) in fat pathology, gene expression and global transcriptome analysis (RT-PCR and RNAseq) at Week 48

Investigational products

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

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Inserm

Sponsor organisation

Inserm

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Inserm

Contact name

Lator Solange

Public contact point

Organisation

Inserm

Contact name

Lator Solange

Locations

1 EU/EEA country · 9 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 17 files

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

Application history

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