DORAvirine Versus DOlutegravir Based Antiretroviral Regimens in Treatment-naïve People Living With HIV-1 Infection

Phase 3RecruitingNCT06203132

ANRS, Emerging Infectious Diseases610 enrolled

Overview

Phase III trial evaluating doravirine as an alternative to dolutegravir in treatment naïve people living with HIV-1 infection.

Phase III, multicenter, open-label, randomized, non-inferiority clinical trial which aims to assess the non-inferiority of doravirine in association with tenofovir and lamivudine, as compared to dolutegravir in association with tenofovir and lamivudine or emtricitabine. This trial will be implemented in Brazil, Cameroon, Côte d'Ivoire, France, Mozambique and Thailand. Six hundred and ten patients will be enrolled and followed for 96 weeks after entry in the trial (=ART initiation). Primary endpoint will assess virological 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 endpoints are planned at W48 and W96.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

610

Conditions

HIV-1-infection

Interventions

Doravirine + tenofovir DF + lamivudineDRUG

Oral administration

Dolutegravir + tenofovir DF + lamivudine or emtricitabineDRUG

Oral administration

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Be at least 18 years of age on the day of signing the informed consent. * Be HIV-1 positive as determined according to national testing strategies * Have a plasma HIV-1 RNA ≥1000 copies/mL within 30 days prior to the randomization, * Have HIV treatment indication based on physician assessment according to local treatment guidelines * Be naïve to antiretroviral therapy (ART) including investigational antiretroviral agents * For 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 * Understand the study procedures and voluntarily agree to participate by giving written informed consent for the trial. Non-inclusion Criteria: * Has ongoing (pulmonary or extra-pulmonary) tuberculosis * 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. * Is infected with HIV-2 or co-infected with HIV-1 and HIV-2 * Has received cabotegravir long acting or dapivirine pre-exposure prophylaxis (PrEP). * 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 * Has documented or known resistance or possible resistance to study drugs (in France and where national guidelines recommend screening for primary resistance before starting first-line ART) as defined by the ANRS MIE AC43 Resistance group * 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 * Estimated glomerular filtration rate at time of screening \<60 mL/min/1.73m², based on the CKD-EPI equation * 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. * 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 * Requires or is anticipated to require any of the prohibited or contraindicated medications noted in the trial protocol. * Has significant hypersensitivity or other contraindication to any of the components of the study drugs. * Is pregnant, breastfeeding, or expecting to conceive at any time during the study. * Has any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to study procedure. * Is a person under guardianship or deprived of freedom by a judicial or administrative decision

Locations (19)

Hospital Geral de Nova Iguaçu

Nova Iguaçu, Rio de Janeiro, Brazil

Outcomes

Primary Outcomes

Non-inferiority of doravirine in combination with tenofovir and lamivudine as compared to dolutegravir in combination with tenofovir and lamivudine or emtricitabine in terms of virological efficacy at week 48

The non-inferiority will be assessed in terms of virologic efficacy at week 48 under allocated treatment using the FDA snapshot algorithm (window period of 42-54 weeks), and measured by the proportion of subjects achieving a rate of 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. The rate of HIV 1 RNA will be measured by RT-PCR.

Time frame: Week 48

Secondary Outcomes

Occurrence of obesity

Obesity will be defined as having BMI≥30 kg/m² for Caucasian and African population and BMI≥27.5 kg/m² for Asian populations.

Time frame: Week 48; Week 96

Occurrence of insulin resistance

Proportion of subjects with newly measured HOMA≥2 as compared to baseline HOMA will be calculated with the following formula (glucose levels in mmol/L, insulin levels in mIU/L): HOMA =(glucose ×insulin)÷22.5

Time frame: Week 48; Week 96

Occurrence of hypertension

Proportion of subjects with hypertension newly detected compared to baseline. Hypertension will be defined as either being prescribed new anti-hypertension medication and/or by having diastolic blood pressure \>90 mmHg AND/OR systolic blood pressure \>140 mmHg during visit and confirmed during subsequent visit \> 15 days after.

Time frame: Week 48; Week 96

Non-inferiority of DOR in association with TDF and 3TC, compared to DTG in association with TDF and 3TC or FTC, in terms of virologic efficacy

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

Central Contacts

Anthony L'HOSTELLIER

CONTACT

33 (0)5 57 57 47 11 anthony.lhostellier@u-bordeaux.fr

Olivier MARCY, Dr

CONTACT

33 (0)5 57 57 13 93 olivier.marcy@u-bordeaux.fr

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Laboratory on Clinical research on AIDS-INI FIOCRUZ

Rio de Janeiro, Rio de Janeiro, Brazil

RECRUITING

Hôpital Central de Yaoundé

Yaoundé, Cameroon

RECRUITING

Centre de prise en charge de Recherche et de Formation (CEPREF)

Abidjan, Côte d’Ivoire

NOT_YET_RECRUITING

Centre Médical de Suivi des Donneurs de Sang (CMSDS) - Centre National de Transfusion Sanguine (CNTS)

Abidjan, Côte d’Ivoire

NOT_YET_RECRUITING

CHU de Treichville, Service des Maladies Infectieuses et Tropicales (SMIT)

Abidjan, Côte d’Ivoire

RECRUITING

CHU Bordeaux Pellegrin - Service des Maladies Infectieuses et Tropicales

Bordeaux, France

RECRUITING

CHU Bordeaux St André - Service de Médecine Interne

Bordeaux, France

RECRUITING

CHU Montpellier - Hôpital La Colombière - Service des Maladies Infectieuses et Tropicales

Montpellier, France

RECRUITING

CHU Nantes Hôtel Dieu - Service des Maladies infectieuses et tropicales

Nantes, France

RECRUITING

...and 9 more locations

Occurrence of virological failures

Proportion of confirmed virological failures. Virological failure will be defined as 1) confirmed HIV-1 RNA ≥ 200 copies/mL after initial response with HIV-1 RNA \< 50 copies/mL at any time during the study or 2) non-response defined as either confirmed HIV-1 RNA ≥ 200 copies/mL at Week 24 or Week 36 (or any other unscheduled visit in-between) or confirmed HIV-1 RNA ≥ 50 copies/mL at Week 48, Week 72 and Week 96 (or any other unscheduled visit in-between).

Time frame: Virological failure

Occurrence of HIV-1 drug resistances in patients with confirmed virological failure

Frequency of HIV-1 drug resistances in participants with a confirmed virological failure. Drug resistances will be defined according to the last version of the ANRS algorithm and to the last version of the Stanford algorithm.

Time frame: Virological Failure

Virological efficacy at a threshold of HIV 1 RNA<200 copies/mL

Proportion of subjects achieving HIV 1 RNA\<200 copies/mL under allocated treatment

Time frame: Week 48; Week 96

Virological efficacy at a threshold of HIV 1 RNA<1000 copies/mL

Proportion of subjects achieving HIV 1 RNA\<1000 copies/mL under allocated treatment

Time frame: Week 48; Week 96

Effect of baseline RT and integrase mutations on virological response

Frequency of RT and integrase mutations at baseline and impact on the virological response

Time frame: Week 48; Week 96

Occurrence of combined overweight and obesity

Combined overweight and obesity will be defined as having BMI≥25 kg/m² for Caucasian and African populations and BMI≥23 kg/m² for Asian populations

Time frame: Week 48; Week 96

Occurrence of weight gain ≥10% absolute body weight

Proportion of subjects with ≥10% absolute weight gain from baseline

Time frame: Week 48; Week 96

Changes in absolute weight gain

Absolute weight gain will be calculated by simply subtracting the follow-up weight from baseline weight measured according to protocol procedures

Time frame: Week 48; Week 96

Occurrence of diabetes

Proportion of subjects with diabetes newly detected compared to baseline. Diabetes will be defined as either being prescribed new medication for diabetes mellitus and/or having a fasting glycemia ≥1.26 g/L during visit and confirmed during subsequent visit \> 15 days after and/or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L).

Time frame: Week 48; Week 96

Safety and tolerability

Any adverse event of any grade and those graded 3-4

Time frame: Week 48; Week 96

Changes in waist circumference, hip circumference and waist-to-hip ratio

Change from baseline in waist and hip circumferences and waist-to-hip ratio

Time frame: Week 48; Week 96

Changes in fasting glycemia and insulin

Change from baseline in fasting glycemia and insulin

Time frame: Week 48; Week 96

Changes in fasting serum lipids

Change from baseline in fasting serum lipids. The fasting serum lipids analyzed will be total cholesterol, HDL, LDL and triglycerides.

Time frame: Week 48; Week 96

Changes in estimated glomerular filtration rate

Change from baseline in estimated glomerular filtration rate. Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-EPI equation

Time frame: Week 48; Week 96

Occurrence of cardiovascular abnormalities

Change from baseline in cardiovascular parameters (blood pressure profile, electrocardiographic and echocardiographic damages). These cardiovascular parameters assessments will be measured through an electrocardiogram, a transthoracic echocardiography and an ABPM, a 24-hour blood pressure Holter.

Time frame: Week 48; Week 96

Changes in liver steatosis and clinically significant fibrosis

Change from baseline in mean patient CAP and LSM measurements and occurrence of: Liver steatosis defined by CAP ≥ 263 dB/m2, and clinically significant liver fibrosis and cirrhosis defined by LSM ≥ 8.0 kPa and LSM ≥ 12.5 kPa, respectively

Time frame: Week 48; Week 96

Occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic-associated steatohepatitis (MASH)

Change from baseline in mean patient CAP and LSM measurements and occurrence of: MASLD defined by the presence of liver steatosis with at least one cardiometabolic risk-factor (overweight/obesity; pre-or diabetes; hypertension; hypertriglyceridemia or low-HDL; and MASH defined by the presence of at least CSF in people with MASLD.

Time frame: Week 48; Week 96

Changes in liver diseases biomarkers

Changes from baseline in Fib-4, VCTE and FAST scores and presence at baseline or occurrence of: CSF defined as Fib-4 ≥ 2.67 and FAST score \> 0.67 (high probability of MASH)

Time frame: Week 48; Week 96

Changes in mental health and quality of life outcomes

Change from baseline in EQ-5D-3L, HIVTSQ, DASS-21, PSQI, WHOQOL HIV-BREF scores

Time frame: Week 24; Week 48; Week 96

Occurrence of Acquired Immune Deficiency Syndrome (AIDS), tuberculosis, Immune Reconstitution Inflammatory Syndrome (IRIS) or death

Proportion of subjects with AIDS (defined as having CDC stage 3/C or WHO stage 4), tuberculosis, IRIS or death

Time frame: Week 48; Week 96

Description of antiretroviral drugs trough plasma concentration in each arm

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

Time frame: Week 4; Week 24; Week 48; Week 96

Assessment of the effect of antiretroviral drugs trough plasma concentration on virological response

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

Time frame: Week 4; Week 24; Week 48; Week 96

Determining DOR, DTG and M9 trough plasma concentration thresholds predictive of virological response

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

Time frame: Week 4; Week 24; Week 48; Week 96

Assessment of the effect of antiretroviral drugs trough plasma concentration on safety endpoints

DOR, DTG and M9 trough plasma concentration in samples taken pre-dose

Time frame: Week 4; Week 24; Week 48; Week 96

Changes in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio

Change from baseline in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio

Time frame: Week 48; Week 96

Adherence to ART

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). ARV pill burden will also be an endpoint in order to study the relation between adherence and ARV pill burden.

Time frame: Week 48; Week 96

Description of the distribution of CYP3A5/4 mutations according to ARV regimen

Type and frequency of alleles variants in the gene coding for CYP3A5/4

Time frame: Study long

Assessment of the impact of CYP3A5/4 mutations on PK

Impact of CYP3A5/4 mutations on pharmacokinetics of DOR, DTG and M9

Time frame: Study long

Assessment of the impact of CYP3A5/4 mutations on virological response and side effects

Virological response and side-effects depending on CYP3A5/4 mutations

Time frame: Study long

Explore additional polymorphism (i.e. UGT1A1) according to literature update

Assess additional polymorphism of UGT1A1

Time frame: Baseline

Cost-effectiveness and budget impact of using DOR-based versus DTG-based antiretroviral regimens

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)

Time frame: Study long

Changes in truncal fat distribution in a sub-group of cisgender women enrolled in the trial

Change from baseline in truncal fat distribution. Truncal fat repartition will be measured by the proportion of fat tissue using DEXA-scanner assessment

Time frame: Week 48; Week 96

Changes in adipose tissue markers and immune activation markers in a sub-group of cisgender women enrolled in the trial

Change from baseline in adipose tissue markers (adiponectin, leptin) and immune activation markers (sCD14, sCD163). Measurement will be made on stored serum samples by immunonephelometry or ELISA.

Time frame: Week 48; Week 96

Changes in fat quality in a sub-group of cisgender women enrolled in the trial

Change from baseline (by abdominal subcutaneous surgical biopsy) in fat pathology, gene expression and global transcriptome analysis (RT-PCR and RNAseq). Measurement will be made on an abdominal fat tissue biopsy sample fixed for immunohistochemistry (Red Sirius, collagen 6, fibronectine, TFG-beta, alpha-SMA) and frozen for gene expression analysis by RT-PCR of markers of adipogenesis (PPARG, CEPBA), beiging (PRDM16, PGC1A), lipogenesis (FAS), adipocyte function (GLUT4), fibrosis (COL4, COL6, FN, TGFB, LOX, ASMA) and mDNA level (mDNA gene and nDNA).

Time frame: Week 48