Investigating if switching HIV patients from stable combined antiretroviral therapy to Delstrigo has fewer unwanted side effects e.g. weight gain, while being just as effective at maintaining an undetectable HIV viral load
| ISRCTN | ISRCTN42856592 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN42856592 |
| EudraCT/CTIS number | 2021-006507-15 |
| IRAS number | 1004705 |
| ClinicalTrials.gov number | NCT05289986 |
| Secondary identifying numbers | CRF006, IRAS 1004705 |
- Submission date
- 09/06/2022
- Registration date
- 21/09/2022
- Last edited
- 13/10/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Combination antiretroviral therapy (cART) HIV treatments are associated with increased quality of life and normalisation of life expectancy in people living with HIV. However, long-term use of certain cARTs can lead to side effects such as weight gain through exposure to drug-related toxicity. This study investigates if a switch to Delstrigo (a combination of tenofovir disoproxil, lamivudine and doravirine) might result in improvement or stabilisation of metabolic parameters (lipids and weight), while providing the same effectiveness and quality of care as existing treatments for HIV.
Who can participate?
People aged 18 years and over living with HIV on stable and suppressive cART.
What does the study involve?
The trial will last 48 weeks plus a screening visit and a follow-up visit. This includes seven visits to the clinic and one telephone visit. Blood and urine samples will be taken, as well as a DEXA scan and CAP Fibroscan to measure body fat and liver function.
What are the possible benefits and risks of participating?
The potential risks to participants include switching to a new regimen; there is the potential for new adverse events, as well as a possible risk of loss of virological control. Such risks will be managed through regular assessment of HIV viral load as well as the CD4:CD8 ratio. Adverse events will be closely monitored and followed up. Delstrigo is a combination of tenofovir disoproxil, lamivudine and doravirine, and each carries its own risks. Lamivudine has been linked to increased early embryonic deaths in rabbits and not much data is available on the effects during human development and in pregnant and breastfeeding women for all three drugs. Therefore, participants or participants with partners who are pre-menopausal and sexually active will be asked to use contraception. Pregnant or breastfeeding women will not be able to join the trial. Female participants of childbearing potential are required to take a pregnancy test as part of screening to join the trial and as part of the 30-day follow-up at the end of their participation in the trial. Delstrigo has been found to exacerbate hepatitis B, and the researchers therefore exclude participants with hepatitis B and C. Delstrigo provides some risk of kidney damage so kidney markers and performance are monitored by measuring creatinine clearance and excluding potential participants with <50 ml/min. Finally, the researchers perform regular scans to monitor bone density and mineralisation in participants to reduce the risk of participants developing any bone defects. Participants will have to adhere to other restrictions (such as fasting for 8 hours before certain visits) as detailed in the participant information sheet. These restrictions will be explained in full to all participants.
Where is the study run from?
Chelsea and Westminster Hospital NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
June 2022 to October 2024
Who is funding the study?
Merck Sharp and Dohme (UK)
Who is the main contact?
Dr Tess Cheetham, tess.cheetham@nhs.net
Contact information
Scientific
Research & Development Office
Unit G2
Harbour Yard
London
SW10 0XD
United Kingdom
| Phone | +44 (0)20 33158209 |
|---|---|
| tess.cheetham@nhs.net |
Study information
| Study design | Open randomized controlled parallel-group cross over trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Switch from stable combined antiretroviral therapy containing abacavir/lamivudine or emtricitabine/tenofovir alafenamide plus dolutegravir or bictegravir to tenofovir disoproxil fumarate/lamivudine/doravirine in people living with HIV: Impact on lipids, body composition, insulin sensitivity, neuroendocrine function and inflammation markers |
| Study acronym | Meta-D |
| Study objectives | Primary objectives: To quantify the effect on lipid profile (change from baseline in total fasting cholesterol to Week 24) of switching from suppressive, stable combined antiretroviral therapy (cART) containing abacavir (ABA)/lamivudine (3TC) or emtricitabine/tenofovir alafenamide (FTC/TAF) plus dolutegravir or bictegravir to Delstrigo (tenofovir disoproxil fumarate [TDF]/3TC/doravirine [DOR]) in HIV-positive patients. Secondary objectives: To investigate: 1. The safety and tolerability of switch from stable cART to Delstrigo 2. Glucose and lipid changes including insulin sensitivity and cholesterol levels 3. Changes in body composition including body fat content and waist-to-hip ratio 4. Comparison of cardiovascular risk changes 5. Patient reported outcomes including dietary preferences, quality of life and sleep quality 6. Changes in hepatic steatosis and fibrosis 7. Changes in renal parameters |
| Ethics approval(s) | Approval pending, ref: 22/LO/0468 |
| Health condition(s) or problem(s) studied | Human immunodeficiency virus-1 (HIV-1) |
| Intervention | 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 maintain 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. Drug: Delstrigo 100 mg - 300 mg - 300 mg tablet (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) Experimental: immediate switch arm Experimental arm (baseline visit switch group, n = 30): one DOR/TDF/3TC tablet taken orally once daily for 48 weeks. Active comparator: delayed switch arm 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). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Doravirine, lamivudine, tenofovir disoproxil fumarate |
| Primary outcome measure | Lipid biochemistry (total cholesterol, cholesterol fractions and triglycerides) in the blood of participants will be analysed at baseline and compared to Week 24 after switching to Delstrigo without a change in detectable HIV RNA levels. Should a change in HIV RNA levels be detected and confirmed, then the trial will stop for that participant. |
| Secondary outcome measures | Safety and tolerability: 1. Percentage of patients with treatment-related adverse events by week 48 (including the severity of adverse events and occurrence of treatment discontinuations due to tolerability) 2. Changes in CD4 count and CD4:CD8 ratio measured by dividing the CD4 cell count by the CD8 cell count at screening, weeks 24 and 48 3. Occurrences and details of viral resistance measured using genotypic assay when needed: HIV viral load (VL)>200 copies/ml Lipids and glucose: 4. Insulin sensitivity assessed by HOMA-IR (glucose and insulin levels) from baseline to weeks 24 and 48 5. PBMC cholesterol and cholesteryl levels measured using blood test at 48 weeks 6. Adipocytokines by assessing adiponectin and leptin measured using blood test at 48 weeks 7. Pituitary hormones (TSH, LH, FSH, IGF-1, testosterone) measured using blood test at 48 weeks Body composition: 8. Median change in body fat content (g) measured by total body dual-energy x-ray absorptiometry (DXA) at weeks 24 and 48 9. Waist-to-hip ratio measured using a tape measure at weeks 24 and 48 Cardiovascular risk: 10. Estimated cardiovascular risk assessed using the QRISK3 equation at 48 weeks 11. Estimated cardiovascular risk assessed using the D:A:D equation at 48 weeks Patient-recorded outcome measures: 12. Dietary preferences measured using a food preference questionnaire for adolescents and adults at 48 weeks 13. Quality of life measured using the EuroQoL questionnaire at 48 weeks 14. Sleep quality measured using the Pittsburgh Sleep Quality Index questionnaire at 48 weeks 15. Treatment satisfaction measured using HIV Treatment Satisfaction Questionnaire at 48 weeks Hepatic impact: 16. Hepatic steatosis and fibrosis measured using transient elastography - CAP score (measured by FibroScan® with the CAP probe) at 48 weeks Renal impact: 17. Renal parameters assessed by urine protein/creatinine ratio (uPCR) at 48 weeks 18. Renal parameters assessed by estimated glomerular filtration rate (eGFR) at 48 weeks Exploratory endpoint: Platelet aggregation, endothelial markers and metabolism measured using metabolomics. This will include investigation of the metabolic changes associated with study treatments at weeks 0 and 48 |
| Overall study start date | 07/06/2022 |
| Completion date | 31/10/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 60 |
| Key inclusion criteria | 1. HIV-1 infected, 18 years or older 2. On stable & suppressive triple cART for at least 6 months 3. No evidence of resistance to DOR, 3TC or TDF 4. No laboratory abnormalities, medical/psychiatric conditions or alcohol/drug use considered a barrier to participation by investigators 5. 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 and detailed in Appendix IV of the protocol: 5.1. Implant 5.2. Depot injection 5.3. Intra-uterine device or system 5.4. 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 participant’s entry into the study) as described in Appendix IV of the protocol |
| Key exclusion criteria | 1. History of virological failure on a non-nucleoside reverse transcriptase inhibitors (NNRTI) in the absence of a post-failure genotypic resistance test proving the absence of resistance to DOR 2. History of virological failure on an 3TC and TDF in absence of a post-failure genotypic resistance test proving the absence of resistance to DOR (INSTI mutations that will lead to the need of administering DOR twice daily are considered as resistance to DOR – and the participant will be considered NOT eligible) 3. Concomitant medication contra-indicated with DOR, 3TC or TDF 4. Haemoglobin <9 g/dl 5. Platelets <80,000/mm³ 6. Creatinine clearance <50 ml/min 7. AST or ALT ≥5N 8. Acute Hepatitis A infection 9. Concomitant DAA for anti-HCV therapy 10. Known acute or chronic viral hepatitis B or C 11. Individuals testing positive for HBcAb, but negative HBsAg/HBeAg, may be included in the trial 12. Individuals with positive anti-HCV results, but with HCV RNA not detected may be included in the trial 13. Pregnant or breastfeeding women, or individuals actively trying to conceive 14. History of osteoporosis or bone fractures/loss 15. Hypersensitivity to the active substance or to any of the excipients in tenofovir disoproxil fumarate, lamivudine and/or doravirine formulations |
| Date of first enrolment | 31/10/2022 |
| Date of final enrolment | 31/10/2023 |
Locations
Countries of recruitment
- Spain
- United Kingdom
Study participating centre
United Kingdom
Sponsor information
Hospital/treatment centre
Research & Development Office
Unit G2
Harbour Yard
London
SW100XD
England
United Kingdom
| Phone | +44 (0)20 331 56825 |
|---|---|
| damon.foster2@nhs.net | |
| Website | http://www.chelwest.nhs.uk/ |
"ROR" |
https://ror.org/02gd18467 |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- MSD United Kingdom, Merck Sharp & Dohme, Merck Sharp & Dohme Corp., MSD
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/10/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Submission to regulatory authorities The anonymised study results will be presented at international medical conferences and published in research journals. Personal data will not be identifiable in the study database, clinical study report, or in any publication arising from the study. The anonymised primary research data set will be available to share with future researchers. Participants will be informed of this possibility within the informed consent form and participant information sheet. Any data sharing will comply with the General Data Protection Regulation (GDPR)/Data Processing Agreement and the scope of participant consent. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
13/10/2023: At the request of the researcher (tess.cheetham@nhs.net) this record will no longer be updated. Please refer to the record on clinicaltrials.gov for the most up-to-date version (https://www.clinicaltrials.gov/study/NCT05289986). Contact details updated.
21/09/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 01/09/2022.
09/06/2022: Trial's existence confirmed by the HRA.
