Opti-DOR

A Randomised, Phase 3 Non-inferiority Study of DOR/3TC/TDF compared to DTG/TAF/FTC in Participants Infected with HIV-1 Starting First-line Antiretroviral Therapy

Study Sites

Multiple sites- in Johannesburg (Gauteng) and Somkhele (KZN), South Africa

Study Objectives

Primary objective:

• To evaluate the antiretroviral activity of DOR/3TC/TDF compared to DTG/TAF/FTC in the first line treatment, as assessed by the percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48.

Secondary Objectives:

• To evaluate the antiretroviral activity of DOR/3TC/TDF compared to DTG/TAF/FTC, as assessed by the percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96.
• To evaluate the antiretroviral activity of DOR/3TC/TDF compared with DTG/TAF/FTC, as assessed by the percentage of participants with HIV-1 RNA <200 copies/mL at Week 48 and Week 96.
• Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥ 1000 copies/mL at week 24 or ≥ 200 copies/mL after week 24).
• To evaluate the immunologic effect of DOR/3TC/TDF compared with DTG/TAF/FTC, as assessed by the mean change from baseline in CD4+ T-cell count at Week 48 and Week 96.
• To evaluate the safety and tolerability of DOR/3TC/TDF compared with DTG/TAF/FTC as assessed by review of accumulated safety data through study duration.
• To evaluate the effect of DOR/3TC/TDF compared with DTG/TAF/FTC on weight, as assessed by the mean change from baseline to Week 48 and Week 96.
• To evaluate the effects on body composition, hematology, fasting lipid and metabolic profiles, renal function, liver function of DOR/3TC/TDF compared with DTG/TAF/FTC, as assessed by the mean change from baseline to Week 48 and Week 96 in these parameters.

Exploratory Objectives:

• To evaluate the pharmacokinetics of DOR in pregnant women.
• To evaluate the safety and tolerability of DOR in pregnant women.

To describe Patient-Reported Outcomes (PROs), assessing quality of life questionnaire, sleep questionnaire, mental health, food intake questionnaire, for participants who received DOR/3TC/TDF compared with DTG/TAF/FTC overtime.

Participant Population

Female or male, adult participants, who are ART naïve, meeting below inclusion/exclusion criteria.

Inclusion/ Exclusion Criteria

Inclusion criteria:

1. ≥18 years old, male or female.
2. Documented laboratory diagnosis of infection with HIV-1 (positive enzyme-linked immunosorbent assay HIV-1 antibody test) at screening, with no baseline DOR resistance.
3. Is ART naïve.
4. BMI≥ 25 kg/cm2.
5. VL >500 copies/ml.
6. Must sign an ICF indicating that he or she understands the purpose of, and procedures required for the study, and is willing to participate in the study.
7. Female participants of childbearing potential (WOCBP) are eligible to participate if willing to use highly effective contraception methods from enrolment for the duration of the study.

Exclusion criteria:

1. Is currently participating in any other interventional study or participated in a study with an investigational drug within 60 days of screening.
2. Is pregnant, breastfeeding or intends to become pregnant or breastfeed during the study.
3. Has active TB co-infection and requires anti-TB treatment.
4. Has unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones); Child-Pugh C.
5. Has pre-existing physical or mental condition (including substance abuse disorder and suicide risk) which, in the opinion of the Investigator, may interfere with the participant’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
6. Clinically unstable in the investigator’s opinion (any pre-existing medical or laboratory abnormalities must be deemed to be stable by the investigator prior to study enrolment).
7. Has estimated creatinine clearance <60mL/min per Cockcroft-Gault formula.
8. Is taking, and is unable to discontinue, any of the following prohibited medications: carbamazepine, oxcarbazepine, phenobarbital, phenytoin; the antimycobacterial rifampicin, rifapentine; St. John’s Wort (Hypericum perforatum); mitotane; enzalutamide; lumacaftor.

Study Design

This is an open label, randomised, phase 3, two-arm study conducted over 96 weeks.

The study includes a screening period (days -60 to -1), enrolment visit (day 0), and a 96-week treatment follow-up period.

Approximately 600 male and female participants infected with HIV-1 eligible for first-line therapy, will be randomly assigned in a 1:1 ratio (approximately 300 participants per treatment group) to either Treatment Group 1 (DOR/3TC/TDF) or Treatment Group 2 (DTG/TAF/FTC). All medications will be administered in an open label design.

Efficacy Endpoints

Primary Endpoint

Percentage of participants with HIV-1 RNA <50 copies/mL at Week 48

Secondary Endpoints

• Percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96
• Percentage of participants with HIV-1 RNA <200 copies/mL at Week 48 and Week 96
• Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥ 1000 copies/mL at week 24 or ≥ 200 copies/mL after week 24)
• Mean change from baseline in CD4+T-cell count at Week 48 and Week 96
• Mean change from baseline in weight at Week 48 and Week 96
• Mean change from baseline in body composition, haematology, fasting lipic and metabolic profiles, renal function, liver function at Week 48 and Week 96
• Percentage of participants who experience AEs and percentage of participants who discontinue study intervention due to AEs through Week 48

Statistical Methods for Key Efficacy Analyses

For the primary hypothesis (H1), DOR/3TC/TDF will be considered non-inferior to DTG/TAF/FTC if the lower bound of the 2-sided 95% CI for the between-treatment difference in the percentage of participants with HIV-1 RNA <50 copies/mL at Week 48 (DOR/3TC/TDF minus DTG/TAF/FTC) is greater than -10 percentage points (non-inferiority margin). The CI will be based on the unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The modified FDA snapshot algorithm will be used to handle missing data for the analysis of the primary efficacy hypothesis. Details are provided in section 9.6.1.

Statistical Methods for Key Safety Analysis

For overall safety endpoints, specific AEs, and safety topics of special interest that meet predefined threshold rules, point estimates and 2-sided 95% CIs for the differences between treatment groups (DOR/3TC/TDF minus DTG/TAF/FTC) in the percentages of participants with events will be provided using the unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. Inferential analyses with 2-sided CIs and p-values obtained using MMRM model will be provided for the differences between groups (DOR/3TC/TDF minus DTG/TAF/FTC) in the mean change from baseline in weight at Week 48 and Week 96.  Details are provided in section 9.6.2.

Special participant populations during study

Pregnancy:

All eligible women of childbearing potential (and where possible their partners) will be counselled about the potential risks associated with pregnancy during the trial and the uncertainty of long-term effects of antiretroviral therapy on infant outcome. Additionally they will be required to use highly effective contraception methods from enrolment for the duration of the study.

For women on DOR-containing regimens, who become pregnant during the study and elect to stay in the study: change to DTG-containing regimen (maintaining TDF/3TC) if pregnancy is ≤ 8 weeks gestation; will be closely monitored monthly from 20 weeks gestation; have two foetal ultrasound evaluations to determine gestational age and a second to detect foetal anomalies at 18 – 22 weeks gestation;  thorough physical examination of the infant will be performed within 7 days of birth, assessing for any congenital anomalies, and infants further followed up to  12 months. Additional PK sampling will be done on participants on group 1 (DOR containing regime). In addition, pregnant women will be referred to their local clinic or appropriate level of care for their routine antenatal care.

TB: The management of each arm if the participant develops TB on study drug will be as follows:

• Treatment Group 1: (DOR/3TC/TDF) – switched to DTG + TDF/FTC (double dose DTG- 50mg twice daily)
• Treatment Group 2: (DTG/TAF/FTC) – DTG daily dose will be increased to 50 mg twice daily (12-hourly), until two weeks after TB treatment is completed; TAF will be switched to TDF 300 mg daily, for duration of TB treatment. TAF can be restarted two weeks after completion of TB treatment.

Investigational Medicinal Product

Treatment Group 1: DOR 100 mg + 3TC 300 mg + TDF  300mg administered once daily orally as a co-formulated FDC tablet.

Treatment Group 2: DTG 50 mg + TAF 25 mg + FTC 200 mg administered once daily orally as a co-formulated FDC tablet.

Sample size

600 participants

Study duration

96 weeks