The Effect on Lipid Profile of Switching to Delstrigo in HIV Positive Patients (META-D)

Switch From Stable cART Containing ABA/3TC or TAF/FTC Plus Dolutegravir or Bictegravir to TDF/3TC/Doravirine in People Living With HIV: Impact on Lipids, Body Composition, Insulin Sensitivity, Neuroendocrine Function and Inflammation Markers

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If patients withdraw or are withdrawn from the study treatment prematurely, an early termination visit (ETV) should occur within 30 days post withdrawal.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.

Study Overview

• Status: Recruiting
• Conditions: Hiv
• Intervention / Treatment: Drug: DELSTRIGO 100Mg-300Mg-300Mg Tablet

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

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Damon Foster; Phone Number: 02033156825; Email: damon.foster2@nhs.net
• Study Contact Backup: Name: Martha Bullimore; Phone Number: 02033152560; Email: m.bullimore@nhs.net

Study Locations

• United Kingdom
  • London, United Kingdom, SW10 9NH
    • Recruiting
    • Chelsea And Westminster Hospital NHS Foundation Trust
    • Principal Investigator: Graeme Moyle, Dr
    • Contact: Martha Bullimore; Phone Number: 02033152560; Email: m.bullimore@nhs.net
  • London, United Kingdom, WC1E6JB
    • Not yet recruiting
    • Mortimer Market Centres
    • Contact: Tess Cheetham; Phone Number: 02033156825; Email: tess.cheetham@nhs.net
    • Principal Investigator: Alejandro Arenas-Pinto, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: immediate switch arm; Experimental arm (baseline visit switch group, N=30): One DOR/TDF/3TC tablet taken orally once daily for 48 weeks. 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.	Drug: DELSTRIGO 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)
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). 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.	Drug: DELSTRIGO 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To quantify the effect on lipid profile	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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with treatment-related adverse events by week 48	Percentage of patients with treatment-related adverse events by week 48	48 weeks
Median change in body fat content (g) measured by Total body dexa at week 24 and 48	Median change in body fat content (g) measured by Total body dexa at week 24 and 48	48 weeks
Body composition changes when measured by waist circumference at week 24 and 48	Body composition changes when measured by waist circumference at week 24 and 48	48 weeks
Change in insulin sensitivity from baseline to week 24 and 48 by HOMA-IR (glucose & insulin levels)	HOMA-IR is calculated by glucose & insulin levels and provides a single unit of measure	48 weeks
PBMC cholesterol and cholesteryl levels	PBMC cholesterol and cholesteryl levels	48 weeks
Adipocytokines by assessing adiponectin, leptin	Adipocytokines by assessing adiponectin, leptin	48 weeks
Pituitary hormones (TSH, LH, FSH, IGF-1, Testosterone)	Pituitary hormones (TSH, LH, FSH, IGF-1, Testosterone)	48 weeks
Estimated cardiovascular risk (QRISK3 equation)	Estimated cardiovascular risk (QRISK3 equation)	48 weeks
Estimated cardiovascular risk (D:A:D equation)	Estimated cardiovascular risk (D:A:D equation)	48 weeks
Hepatic steatosis and fibrosis by transient elastography-CAP (FibroScan® with the CAP probe)	Hepatic steatosis and fibrosis by transient elastography-CAP (FibroScan® with the CAP probe)	48 weeks
Dietary preferences (using Food preference questionnaire for adolescents and adults)	Dietary preferences (using Food preference questionnaire for adolescents and adults)	48 weeks
Quality of Life (EuroQoL questionnaire)	Quality of Life (EuroQoL questionnaire)	48 weeks
Sleep quality (Pittsburgh Sleep Quality Index questionnaire)	Sleep quality (Pittsburgh Sleep Quality Index questionnaire)	48 weeks
Renal safety by uPCR	Renal safety by uPCR	48 weeks
Renal safety by eGFR	Renal safety by eGFR	48 weeks

Collaborators and Investigators

• Sponsor: Chelsea and Westminster NHS Foundation Trust
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: January 26, 2022
• First Submitted That Met QC Criteria: March 11, 2022
• First Posted (Actual): March 22, 2022

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: CRF006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

The investigators will be provided reasonable access to statistical tables, figures, and relevant reports.

Sponsor will also provide the investigators with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

The procedures and timing for public disclosure of the results summary and for development of a manuscript for publication will be in accordance with sponsor policies.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No