Hiv
Conditions
Brief summary
This is an open label, randomised, two-arm switch study over 48 weeks in which virally suppressed participants on a stable combined ART regimen will be randomised (1:1) to an immediate switch to 3TC/TDF/DOR (immediate switch arm, N=30) for the duration of the 48-week study, or to maintaining their current cART followed by a switch to 3TC/TDF/DOR from week 24-48 (delayed switch arm, N=30). Participants will be monitored for the length of the study (48 weeks) plus a 30-day follow-up period. If patients withdraw or are withdrawn from the study treatment prematurely, an early termination visit (ETV) should occur within 30 days post withdrawal. The hypothesis of the study is that a switch to Delstrigo, which is a combination of tenofovir disoproxil, lamivudine and doravirine (TDF/3TC/DOR) has a favourable impact on lipid metabolism, glucose, weight, body composition and hepatic steatosis.
Detailed description
Open-label, 2 arm, multi-centre, non-inferiority switch study. Sample size: 60 participants Participant population: HIV-1 infected patients on stable and suppressive triple cART. IMP: Delstrigo (300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil, 300 mg of lamivudine and 100 mg of doravirine \- TDF/3TC/DOR) Study setting: Patients will be identified through HIV clinic visits by their direct study medical care team and visits will be captured on a participant-screening log. A Trial Management Team will facilitate the project and liaise with participating sites in study set-up and progress. Dose and Route of Administration: Experimental arm (baseline visit switch group, N=30): One DOR/TDF/3TC tablet taken orally once daily for 48 weeks. Control arm (deferred switch group, N=30): Participants will continue their current triple cART regimen for 24 weeks, and then switched to taking one TDF/3TC/DOR tablet orally once daily (24 -48 weeks). Primary Objective To quantify the effect on lipid profile (change from baseline in total fasting cholesterol to Week 24) of switching from suppressive, stable cART containing ABA/3TC or TAF/FTC plus dolutegravir or bictegravir to Delstrigo (TDF/3TC/DOR) in HIV positive patients. Secondary Objectives To investigate the effect of switch on: 1. Body composition changes when measured by Total Body DXA at week 24 and 48 and by waist circumference 2. Change in insulin sensitivity from baseline to week 24 and 48 by HOMA-IR (glucose & insulin levels) 3. PBMC cholesterol and cholesteryl levels 4. Adipocytokines by assessing adiponectin, leptin 5. Pituitary hormones (TSH, LH, FSH, IGF-1, Testosterone) 6. Estimated cardiovascular risk (QRISK3 and D:A:D equations) 7. Hepatic steatosis and fibrosis by transient elastography-CAP (FibroScan® with the CAP probe) 8. Dietary, Quality of Life (EuroQoL), and Sleep quality (Pittsburgh Sleep Quality Index) Questionnaires 9. Renal safety by uPCR, eGFR Potential Exploratory Objectives Platelet aggregation & endothelial markers, metabolomics
Interventions
DRUGDELSTRIGO 100Mg-300Mg-300Mg Tablet
Delstrigo (300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil, 300 mg of lamivudine and 100 mg of doravirine \- TDF/3TC/DOR)
Sponsors
Chelsea and Westminster NHS Foundation Trust
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infected, 18 years or older * On stable \& suppressive triple cART containing ABA/3TC or TAF/FTC plus dolutegravir or bictegravir for at least 6 months * No evidence of resistance to TDF, 3TC, or DOR * No laboratory abnormalities, medical/psychiatric conditions or alcohol/drug use considered a barrier to participation by investigators * Women who are of childbearing potential and sexually active need to use the hormonal contraceptive methods, associated with inhibition of ovulation, listed in the protocol: * Implant * Depot injection * Intra-uterine device or system * Oral hormonal contraception A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. * Men who are sexually active and have partners who are women of childbearing potential must be using an adequate method of contraception to avoid pregnancy (male condom or sterilisation confirmed prior to the subject's entry into the study)
Exclusion criteria
* History of virological failure on an NNRTI in absence of a post-failure genotypic resistance test proving absence of resistance to DOR * Concomitant medication contra-indicated with TDF, FTC or DOR * Haemoglobin \<9 g/dL * Platelets \<80,000/mm3 * Creatinine clearance \<50 mL/min * AST or ALT ≥5N * Acute Hepatitis A infection. * Concomitant DAA for anti-HCV therapy * Known acute or chronic viral hepatitis B or C. o Individuals with positive anti-HCV results, but with HCV RNA not detected may be included on the trial. * Pregnant or breastfeeding women, or individuals actively trying to conceive * History of osteoporosis or bone fractures/loss * Hypersensitivity to the active substance or to any of the excipients in tenofovir disoproxil fumarate, lamivudine and/or doravirine formulations * Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Quantify the Effect on Lipid Profile | 24 weeks | To quantify the effect on lipid profile (change from baseline in total fasting cholesterol to Week 24) of switching from suppressive, stable cART containing ABA/3TC or TAF/FTC plus dolutegravir or bictegravir to Delstrigo (TDF/3TC/DOR) in HIV positive patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Treatment-related Adverse Events by Week 48 | 48 weeks | Percentage of patients with treatment-related adverse events by week 48 |
| Median Change in Body Fat Content (g) Measured by Total Body Dexa at Week 24 and 48 | 48 weeks | Median change in body fat content (g) measured by Total body dexa at week 24 and 48 |
| Body Composition Changes When Measured by Waist Circumference at Week 24 and 48 | 48 weeks | Body composition changes when measured by waist circumference at week 24 and 48 |
| Change in Insulin Sensitivity From Baseline to Week 24 and 48 by HOMA-IR (Glucose & Insulin Levels) | 48 weeks | HOMA-IR is calculated by glucose \& insulin levels and provides a single unit of measure |
| PBMC Cholesterol and Cholesteryl Levels | 48 weeks | PBMC cholesterol and cholesteryl levels |
| Adipocytokines by Assessing Adiponectin, Leptin | 48 weeks | Adipocytokines by assessing adiponectin, leptin |
| Pituitary Hormones (TSH, LH, FSH, IGF-1, Testosterone) | 48 weeks | Pituitary hormones (TSH, LH, FSH, IGF-1, Testosterone) |
| Estimated Cardiovascular Risk (QRISK3 Equation) | 48 weeks | Estimated cardiovascular risk (QRISK3 equation) |
| Estimated Cardiovascular Risk (D:A:D Equation) | 48 weeks | Estimated cardiovascular risk (D:A:D equation) |
| Hepatic Steatosis and Fibrosis by Transient Elastography-CAP (FibroScan® With the CAP Probe) | 48 weeks | Hepatic steatosis and fibrosis by transient elastography-CAP (FibroScan® with the CAP probe) |
| Dietary Preferences (Using Food Preference Questionnaire for Adolescents and Adults) | 48 weeks | Dietary preferences (using Food preference questionnaire for adolescents and adults) |
| Quality of Life (EuroQoL Questionnaire) | 48 weeks | Quality of Life (EuroQoL questionnaire) |
| Sleep Quality (Pittsburgh Sleep Quality Index Questionnaire) | 48 weeks | Sleep quality (Pittsburgh Sleep Quality Index questionnaire) |
| Renal Safety by uPCR | 48 weeks | Renal safety by uPCR |
| Renal Safety by eGFR | 48 weeks | Renal safety by eGFR |
Countries
United Kingdom
Participant flow
Recruitment details
19 participants were consented to the study (as per clinicaltrials.gov definition of enrolled). However, only 13 of these participants went on to be randomised into either arm delayed switch or immediate switch. Therefore, the 6 participants cannot be catagorise into this table.
Pre-assignment details
Please see recruitment details.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Overall Number of Baseline Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex/Gender, Customized Sex/Gender Female | 0 Participants |
| Sex/Gender, Customized Sex/Gender Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 6 / 7 | 3 / 6 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 |
Outcome results
None listed