Second-line Switch to Dolutegravir Study

NCT04229290 | Completed Phase 4 DMC

• 1 other identifier: 2SD
• Study Type: interventional
• Target: 795
• Locations: 1 country
• Sites: 4

Brief Summary

Kenya has the 4th largest HIV burden in the world with about 1.6 million people living with HIV. Of these, just over 1 million are on antiretroviral therapy (ART). Current national guidelines recommend a first line regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTI) plus an integrase strand transfer inhibitor (INSTI) or a non-nucleoside reverse transcriptase inhibitor(NNRTI). Second line regimens are composed of 2 NRTI plus a ritonavir boosted protease inhibitor(PIr). This is based on evidence showing good clinical outcomes on this regimen. PIr are associated with side effects including an increase in cardiovascular disease risk and, have significant drug to drug interactions that complicate management of other conditions such as tuberculosis. INSTIs have been shown in one study to be an alternative to PIr in second line regimens when combined with fully active NRTIs. It is not clear if this would still be the case if the activity of the NRTIs was not known. The investigators will evaluate the efficacy of switching from a PIr to a dolutegravir based second line ART regimen. Hypothesis: switching virologically suppressed patients from a PIr based second line to a dolutegravir based second line is non-inferior to continuing on a PIr based second line. Objectives: The primary objective will be to evaluate the non-inferiority of switching to a DTG containing regimen relative to maintaining a PI/r containing second-line regimen in virologically suppressed, INSTI-naive HIV-1 positive adults (≥ 18 years old) as determined by having HIV-1 RNA ≥ 50 copies/ml at week 48. Secondary objectives will be to assess the impact of such a switch on CD4 count, safety and tolerability. Methods: Open-label, randomized, non-inferiority, multisite trial over 48 weeks, describing the efficacy and safety of switching from a second-line ARV regimen containing a ritonavir-boosted protease inhibitor (PI/r) plus 2 NRTIs to DTG plus 2 NRTIs in patients with virological suppression (HIV-1 RNA \< 50 copies/ml) for at least 12 weeks and with no prior INSTI exposure. Adult participants will be randomized at baseline to remain on their pre-enrollment PI/r or switch to DTG. Participants will continue the NRTIs from their pre-enrollment regimen in both arms. A total of 766 participants(388 per arm) will be recruited from 4 sites in Kenya Conclusion: This study seeks to inform guidelines around the efficacy and safety of alternative second line regimens.

Conditions

HIV-1-infection

Keywords

HIV; Second-line; Switch; Protease inhibitor; Dolutegravir; Treatment experienced; Non-inferiority

Outcome Measures

Primary Outcomes (1)

• Virologic failure

  Proportion of participants with HIV-1 RNA ≥ 50 copies/ml at week 48 (by US Food and Drug Administration snapshot algorithm, modified to allow for changes in NRTIs for clinical reasons)

  48 weeks

Secondary Outcomes (15)

• Virologic failure

  24 weeks

• Treatment success

  24 and 48 weeks

• CD4 count

  24 and 48 weeks

• Weight

  24 and 48 weeks

• Body mass index

  24 and 48 weeks

Study Arms (2)

Dolutegravir

EXPERIMENTAL

Participants in this arm will have a switch from a protease inhibitor based second line regimen to Dolutegravir maintaining the same NRTI backbone

Drug: Dolutegravir

Protease Inhibitor

ACTIVE COMPARATOR

Participants in this arm will be maintained on their protease inhibitor based second line regimen

Drug: Dolutegravir

Interventions

Dolutegravir DRUG

Switch of virally suppressed participants to Dolutegravir

Also known as: DTG

Dolutegravir; Protease Inhibitor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able and willing to understand and comply with the protocol requirements, instructions and restrictions
• Able and willing to give informed consent
• Age 18 years or above
• Documented HIV-1 infection as confirmed by HIV-antibody testing as per the Kenya National Guidelines
• Has been receiving a second-line ARV regimen containing a PI/r (DRV/r, ATV/r or LPV/r) and 2 NRTIs for at least 24 weeks
• Documented HIV-1 RNA viral load \< 50 copies/ml at least 12 weeks prior to enrollment and no viral rebound between the first viral load \< 50 copies/ml and the screening viral load
• HIV-1 RNA viral load \< 50 copies/ml at screening (within 28 days prior to enrollment)
• If female and of childbearing potential, is using effective contraception and is willing to continue using effective contraception throughout the study period (as defined in Appendix 5). Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and age of 45 years or above) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy

You may not qualify if:

• Any prior use of integrase inhibitor
• Documented HIV-2 infection
• Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
• Has AST and/or ALT at least 5-times greater than the upper limit of normal in conjunction with hepatitis B virus infection (HBV) or hepatitis C virus infection (HCV). Note: patients can enter the study with chronic HBV or HCV if AST and ALT are less than 5-times greater than the upper limit of normal and, in the investigators opinion, their medical status will not interfere with assessments or completion of the study
• Is both HBsAg positive and has a CrCl below 50 ml/min (as estimated using the Cockcroft-Gault estimate for glomerular filtration rate)
• Advanced renal insufficiency requiring dialysis
• If female, currently pregnant or breastfeeding, or intending to become pregnant during the study period
• Documented opportunistic infection within 4 weeks prior to the study enrolment
• Investigator opinion that the patient should switch from PI/r to DTG immediately for clinical reasons (including Grade 3 or 4 lipid abnormalities at screening or enrollment)
• Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the study
• History or presence of allergy to the study drugs or their components

Sponsors & Collaborators

• University of Nairobi: lead
• ViiV Healthcare: collaborator

Study Sites (4)

Kiambu Level 5 Hospital

Kiambu, Kenya

Location

Jaramogi Oginga Odinga Teaching and Referral Hospital

Kisumu, Kenya

Location

Kenyatta National Hospital

Nairobi, Kenya

Location

Thika Level 5 Hospital

Thika, Kenya

Location

Related Publications (1)

• Ombajo LA, Penner J, Nkuranga J, Mecha J, Mburu M, Odhiambo C, Ndinya F, Aksam R, Njenga R, Wahome S, Muiruri P, Eshiwani S, Kimani M, Ngugi C, Pozniak A. Second-Line Switch to Dolutegravir for Treatment of HIV Infection. N Engl J Med. 2023 Jun 22;388(25):2349-2359. doi: 10.1056/NEJMoa2210005.

  PMID: 37342923 DERIVED

MeSH Terms

Interventions

dolutegravir

Study Officials

• Loice Achieng, MD, MSC

  University of Nairobi

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomised controlled, open label clinical trial

Study Record Dates

• First Submitted: January 7, 2020
• First Posted: January 18, 2020
• Study Start: February 12, 2020
• Primary Completion: September 16, 2021
• Study Completion: September 16, 2021
• Last Updated: January 27, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Beginning 6 months after article publication and for a period of 36 months
• Access Criteria: Researchers that provide a methodologically sound proposal and whose proposal has been approved by an independent review committee

Locations

KE (4)