Efficacy of Doravirine + Dolutegravir Dual Therapy in the Context of Antiretroviral Therapy Switch (DORDOL)

Efficacy of Doravirine + Dolutegravir Dual Therapy in the Context of Antiretroviral Therapy Switch (DORDOL)

Combination antiretroviral therapy (cART) HIV treatments are associated with increased quality of life, and a normalisation of life expectancy in people living with HIV. However, long-term use of cART can lead to side-effects through exposure to drug-related toxicity.

For this reason researchers are interested in looking at alternative therapies that might expose patients to fewer and less severe side effects while providing the same quality of care as antiretroviral therapies most often used to treat HIV.

The purpose of this study is to investigate if the study drug combination that is being tested (doravirine + dolutegravir) is safe compared with other triple cART regimens.

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Doravirine; Drug: Dolutegravir; Other: Triple cART regimen

Detailed Description

A randomised, open label study to assess the efficacy of switching from suppressive triple cART to doravirine + dolutegravir dual cART in people living with HIV (PLWH) with an undetectable viral load

A computer-based software will randomise participants 2:1 to either the (1) experimental arm (early switch group) to take two-pill regimen for 96 weeks, or (2) control arm (delayed switch group) where participants continue their current triple cART regimen for 48 weeks, then switch to the two-pill regimen for another 48 weeks.

Viral load will be measured at each study visit to determine the percentage of participants in each treatment arm with undetectable plasma HIV RNA levels at week 48.

Additional research urine and bloods will be taken, as well as questionnaires completed at baseline and every 24 weeks to further investigate safety, tolerability, and quality of life from switch of suppressive triple cART to doravirine + dolutegravir dual cART.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Research Regulatory Compliance Manager; Phone Number: 020 3315 6825; Email: chelwest.research@nhs.net

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Imperial College Healthcare NHS Trust
    • Contact: Tara Tamang; Email: tara.tamang@nhs.net
  • London, United Kingdom, SW10 9NH
    • Recruiting
    • Chelsea & Westminster Hospital NHS Foundation Trust
    • Contact: Research Regulatory Compliance Manager; Phone Number: 02033158209; Email: chelwest.research@nhs.net
    • Contact: Phone Number: 020 3315 6825
    • Principal Investigator: Marta Boffito
  • London, United Kingdom, NW1 0PE
    • Recruiting
    • Mortimer Market Centre
    • Contact: Rubina Choudhry; Email: contact.noclor@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 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 for at least 6 months
• No evidence of resistance to DOR or DTG
• No laboratory abnormalities, medical/psychiatric conditions or alcohol/drug use considered a barrier to participation by investigators

• Women who are pre-menopausal and sexually active should be on one of the following methods of contraception:

  • Implant
  • Depot injection
  • Intra-uterine device or system
  • Oral hormonal contraception

Exclusion Criteria:

• History of virological failure on an NNRTI in absence of a post-failure genotypic resistance test proving absence of resistance to DOR
• History of virological failure on an INSTI in absence of a post-failure genotypic resistance test proving absence of resistance to DTG (INSTI mutations that will lead to the need of administering DTG twice-daily are considered as resistance to DTG - and the subject will be considered NOT eligible)
• Concomitant medication contra-indicated with DTG or DOR
• Haemoglobin <9 g/dL
• Platelets <80,000/mm3
• Creatinine clearance <30 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.

  • Individuals testing positive for HBcAb, but negative HBsAg/HBeAg, may be included on the trial.
  • Individuals with positive anti-HCV results, but with HCV RNA not detected may be included on the trial.
• Pregnant or breastfeeding women

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; Two-pill regimen, doravirine (100 mg) + dolutegravir (50 mg) tablets taken orally once daily for 96 weeks.	Drug: Doravirine; Antiretroviral, Non-nucleoside Reverse Transcriptase Inhibitor; Other Names: Pifeltro; Drug: Dolutegravir; Antiretroviral, Integrase strand transfer inhibitors; Other Names: Tivicay
Other: Delayed Switch; Participants will continue their current triple cART regimen for 48 weeks. Patients will then be switched to two-pill regimen, doravirine (100 mg) + dolutegravir (50 mg) tablets taken orally once daily for 48 weeks.	Drug: Doravirine; Antiretroviral, Non-nucleoside Reverse Transcriptase Inhibitor; Other Names: Pifeltro; Drug: Dolutegravir; Antiretroviral, Integrase strand transfer inhibitors; Other Names: Tivicay; Other: Triple cART regimen; Participant standard triple cART regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with undetectable plasma HIV RNA levels at Week 48	Undetectable will be defined as plasma HIV RNA levels of <50 copies/ml. Any patient with HIV RNA levels >50 copies/ml at analysis time points will have a repeat test	48 weeks from randomisation (+/- 7 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients treated on each treatment arm with HIV viral load less than 50 copies/ml to determine absolute efficacy of study treatments	Proportion of patients treated on each treatment arm with HIV viral load less than 50 copies/ml at weeks and 24, 72 and 96.	96 weeks from randomisation (+/- 7 days)
Frequency and severity of adverse events to determine safety and tolerability of study treatments	Occurrence of adverse events (including laboratory results), severity of adverse events and occurrence of treatment discontinuations measured through adverse event reporting by sites.	96 weeks from randomisation (+/- 7 days)
Changes in CD4 count and CD4:CD8 ratio to determine safety and tolerability of study treatments	CD4 count and CD4:CD8 ratio will be measured at screening and compared to measurements in both arms weeks 24, 48, 72 and 96	96 weeks from randomisation (+/- 7 days)
Scores from participant-recorded outcome measures on quality of life to determine safety and tolerability of study treatments	Scores from participant-recorded outcome measures at weeks 0, 24, 48, 72 and 96: EuroQoL EQ-5D-3L Questionnaire Score from 0 to 100 (with 100 as best outcome)	96 weeks from randomisation (+/- 7 days)
Scores from participant-recorded outcome measures on patient treatment satisfaction to determine safety and tolerability of study treatments	Scores from participant-recorded outcome measures at weeks 0, 24, 48, 72 and 96: Patient Treatment Satisfaction Questionnaire At week 0: Score from 0 to 6 (with 6 as best outcome) All other visits: Score -3 to +3 compared to week previous (with higher score best outcome)	96 weeks from randomisation (+/- 7 days)
Scores from participant-recorded outcome measures on sleep quality to determine safety and tolerability of study treatments	Scores from participant-recorded outcome measures at weeks 0, 24, 48, 72 and 96: Pittsburgh Sleep Quality Index (PSQI) Score range for each PSQI evaluation ranges from 0 to 21 (with 0 as best outcome)	96 weeks from randomisation (+/- 7 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Neurofilament light chains (sNFL) comparison	NFL serum levels as measured at weeks 0, 48, 96.	96 weeks from randomisation (+/- 7 days)
Telomerase length comparison	Telomerase length measurements from samples taken at weeks 0, 48, 96.	96 weeks from randomisation (+/- 7 days)
Digit span tests comparison	Comparison of test results taken at weeks 0, 48, 96: • Digit span forward and backward nb - At Torino site only	96 weeks from randomisation (+/- 7 days)
Trail making tests comparison	Comparison of test results taken at weeks 0, 48, 96: • Trail making test A and B nb - At Torino site only	96 weeks from randomisation (+/- 7 days)
Verbal fluency tests comparison	Comparison of test results taken at weeks 0, 48, 96: • Phonemic verbal fluency nb - At Torino site only	96 weeks from randomisation (+/- 7 days)
Groove pegboard tests comparison	Comparison of test results taken at weeks 0, 48, 96: • Groove pegboard for dominant and non-dominant hand nb - At Torino site only	96 weeks from randomisation (+/- 7 days)
Bisyllabic words tests comparison	Comparison of test results taken at weeks 0, 48, 96: • Serial repetition of bisyllabic words test nb - At Torino site only	96 weeks from randomisation (+/- 7 days)
Metabolomics comparison	Comparison of liquid chromatography mass spectrometry (LC-MS) based metabolomics analysis on plasma and urine samples taken at weeks at week 0, 48, 96.	96 weeks from randomisation (+/- 7 days)

Collaborators and Investigators

• Sponsor: Chelsea and Westminster NHS Foundation Trust
• Investigators: Principal Investigator: Marta Boffito, MD PhD FRCP, Chelsea and Westminster NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2022
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2027

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: May 14, 2021
• First Posted (Actual): May 19, 2021

Study Record Updates

• Last Update Posted (Actual): October 25, 2023
• Last Update Submitted That Met QC Criteria: October 24, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Dolutegravir; cART; Doravirine
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: CW004; 2020-003928-17 (EudraCT Number)

Drug and device information, study documents

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