Cardiovascular Risk in HIV Patients Switching From a Boosted Protease Inhibitor (PI) to Dolutegravir (DTG)

NCT ID: NCT02098837

Last Updated: 2018-04-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 415 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-30
• Study Completion Date: 2017-12-04

Brief Summary

The purpose of the study is to investigate the benefits of switching away from a kind of drug called a boosted protease inhibitor (PI) to a new drug called dolutegravir on patients' cardiovascular health (the health of their hearts). Patients are currently taking two other anti-HIV drugs, called nucleoside reverse transcriptase inhibitors (NRTIs), with their boosted PIs; these NRTIs will not be changed throughout the study. In order to compare the boosted PI and dolutegravir more accurately, half of study participants will be switched to dolutegravir immediately, and the other half will be switched after 48 weeks of continuing on the boosted PI.

Boosted PIs are associated with increased heart and circulation risk so it is hoped that switching from a boosted PI to dolutegravir will improve the health of the patients' hearts. Dolutegravir is a drug for HIV treatment which has been approved for use in HIV patients in the US and Europe. Clinical trials using dolutegravir have found that it is effective at suppressing the HIV virus, and it is at least as effective as the other drugs.

This study will also investigate the safety (in terms of other side effects and the routine blood tests which the investigators ordinarily use to monitor patients' treatment) and monitor effectiveness, patients' viral load and CD4 counts, when patients switch treatment from a boosted PI to dolutegravir. Viral load is the amount of the HIV virus they have in their blood, and CD4 count is a measure of a type of cell that is in their immune system. We also aim to improve patients' cardiovascular health in general by providing them with information on how to live a healthy lifestyle (eg improving their diet, stopping smoking etc).

Detailed Description

Study Design: Randomised, non-inferiority strategic trial over 96 weeks with early or delayed switch from an ARV regimen containing a boosted PI plus 2 NRTIs to dolutegravir (DTG) plus 2 NRTIs in patients having achieved complete virological suppression for more than 24 weeks (HIV-1 RNA <50 c/ml). Patients will be randomised to switch at baseline or at 48 weeks.

Study visits will take place at screening, baseline, weeks 4 (immediate switch group only), 12, 24, 36, 48, 52 (deferred switch group only), 60, 72, 84 and 96, plus a follow up visit 28 days after the last dose of study medication.

Routine investigations will include viral load, CD4, haematology (including haemoglobin, white cell count and differential, platelets), biochemistry (including sodium, potassium, creatinine, albumin, glucose, ALT, ALP, total bilirubin, total cholesterol, HDL, LDL, triglycerides), quality of life questionnaires (EuroQL), urine sample (for haematuria, proteinuria, glycosuria, leukocytes, nitrate & pregnancy test in WOCBP)

Conditions

HIV

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Immediate switch

Patients will be randomised to switch from a boosted PI to dolutegravir at baseline.

Group Type: ACTIVE_COMPARATOR

Dolutegravir

Intervention Type: DRUG

Dolutegravir 50mg once daily

Deferred switch

Patients will be randomised to switch from a boosted PI to dolutegravir after 48 weeks.

Group Type: ACTIVE_COMPARATOR

Dolutegravir

Intervention Type: DRUG

Dolutegravir 50mg once daily

Interventions

Dolutegravir

Dolutegravir 50mg once daily

Intervention Type: DRUG

Other Intervention Names

Tivicay

Eligibility Criteria

Inclusion Criteria

• Patient volunteers who meet all of the following criteria are eligible for this trial:

1. Is male or female aged over 50, OR aged over 18 years with a Framingham risk score above 10%

2. Has documented HIV-1 infection

3. Has signed the Informed Consent Form voluntarily

4. Is willing to comply with the protocol requirements

5. Has been receiving an ARV regimen containing a boosted PI (darunavir, atazanavir, lopinavir, or fosamprenavir) plus 2NRTIs for >24 weeks

6. Has stable virological suppression (plasma HIV-RNA <50 copies/mL for >24 weeks)

7. If female and of childbearing potential, is using effective birth control methods and is willing to continue practising these birth control methods during the trial and for at least 2 weeks after the last dose of study medication. Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and ≥45 years) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy

8. If a heterosexually active male, he is using effective birth control methods and is willing to continue practising these birth control methods during the trial and until follow-up visit

Exclusion Criteria

• Patients meeting 1 or more of the following criteria cannot be selected:

1. Infected with HIV-2

2. Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs

3. Has acute viral hepatitis including, but not limited to, A, B, or C

4. Has chronic hepatitis B and/or C with AST and/or ALT >5 x ULN Note: Subjects can enter trial with chronic HBV if HBV-DNA undetectable at screen (and no detectable result in last 6 months) and with chronic HCV if not expected to require treatment during the trial period.

5. Any investigational drug within 30 days prior to the trial drug administration

6. History of exposure to any ARVs other than PIs or NRTIs except if switch was for tolerability/toxicity (NOTE: patients who have previously taken part in single drug trials for less than 14 days need not be excluded, or for virological failure with a genotypic resistance test without mutations

7. Any prior evidence of primary viral resistance based on the presence of any major resistance-associated mutation to backbone NRTI

8. History of prior virological failure,eg 2 consecutive HIV-1 RNA >50 c/ml -at or after week 32 following first ART initiation or confirmed rebound viraemia >200 copies/ml after having a VL of <50 copies/ml without resistance test or with significant mutations to any other ARV regimen (NOTE: Switch for toxicity or tolerability with wild type virus does not count as virological failure)

9. Dialysis or renal insufficiency (creatinine clearance < 50ml/min)

10. History of decompensated liver disease (AST or ALT≥5x the upper limit of normal (ULN) or ALT ≥ )3 x ULN and bilirubin ≥ 1.5 x ULN with > 35% direct bilirubin.

11. Unstable liver disease (as defined by the presence of ascities, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), know biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones))

12. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification

13. If female, currently pregnant or breastfeeding

14. Opportunistic infection within 4 weeks prior to first dose of DTG

15. Clinical decision that a switch of antiretroviral therapy should be immediate

16. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, except: asymptomatic grade 3 glucose, amylase or lipid elevation or asymptomatic grade 4 triglyceride elevation (re-test allowed).

17. 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 trial.

18. History or presence of allergy to the study drug or their components

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St Stephens Aids Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jose Gatell, Dr

Role: PRINCIPAL_INVESTIGATOR

Spanish healthcare system

Locations

Insititute Of Tropical Medicine Antwerp

Antwerp, , Belgium

CHU Saint-Pierre

Brussels, , Belgium

Universitaire Ziekenhuis Gent

Ghent, , Belgium

Hopital de la Croix Rousse

Lyon, , France

Service des Maladies Infectieuses et Tropicales du CHU de NANTES

Nantes, , France

Hopital Saint Louis

Paris, , France

Pitié-Salpêtrière Hospital

Paris, , France

Hospital Bichat Claude-Bernard

Paris, , France

Universitätsklinikum Bonn

Bonn, , Germany

Universitätsklinikum Essen

Essen, , Germany

Klinikum der Goethe-Universität Frankfurt

Frankfurt, , Germany

ICH Infektiologisches Centrum Hamburg

Hamburg, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Santa Maria Annunziata di Firenze

Florence, , Italy

San Paolo Hospital

Milan, , Italy

Azienda Ospedaliera - Polo Universitario 'Luigi Sacco'

Milan, , Italy

Universitaria di Modena

Modena, , Italy

Universitario Alicante

Alicante, , Spain

Hospital General Universitario de Elche

Alicante, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Clinic Barcelona

Barcelona, , Spain

Universitari de Bellvitge

Barcelona, , Spain

IrsiCaixa

Barcelona, , Spain

Hospital Ramon y Cajal

Madrid, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Elton John Centre

Brighton, , United Kingdom

Southmead Hospital

Bristol, , United Kingdom

Bart's Hospital

London, , United Kingdom

Royal Free Hospital

London, , United Kingdom

St Thomas Hospital

London, , United Kingdom

Chelsea & Westminster Hospital

London, , United Kingdom

St Mary's Hospital

London, , United Kingdom

Mortimer Market Centre

London, , United Kingdom

Countries

Belgium; France; Germany; Italy; Spain; United Kingdom

References

Waters L, Assoumou L, Gonzalez-Cordon A, Rusconi S, Domingo P, Gompels M, de Wit S, Raffi F, Stephan C, Masia M, Rockstroh J, Katlama C, Behrens GMN, Moyle G, Johnson M, Fox J, Stellbrink HJ, Guaraldi G, Florence E, Esser S, Gatell JM, Pozniak A, Martinez E; NEAT 022 Study Group. Limited Weight Impact After Switching From Boosted Protease Inhibitors to Dolutegravir in Persons With Human Immunodeficiency Virus With High Cardiovascular Risk: A Post Hoc Analysis of the 96-Week NEAT-022 Randomized Trial. Clin Infect Dis. 2023 Mar 4;76(5):861-870. doi: 10.1093/cid/ciac827.

Reference Type: DERIVED

PMID: 36259527 (View on PubMed)

Saumoy M, Sanchez-Quesada JL, Assoumou L, Gatell JM, Gonzalez-Cordon A, Guaraldi G, Domingo P, Giacomelli A, Connault J, Katlama C, Masia M, Ordonez-Llanos J, Pozniak A, Martinez E, Podzamczer D. Atherogenicity of low-density lipoproteins after switching from a protease inhibitor to dolutegravir: a substudy of the NEAT022 study. J Antimicrob Chemother. 2022 Jun 29;77(7):1980-1988. doi: 10.1093/jac/dkac117.

Reference Type: DERIVED

PMID: 35411401 (View on PubMed)

Gatell JM, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, Fox J, Martinez E, Stellbrink HJ, Guaraldi G, Masia M, Gompels M, De Wit S, Florence E, Esser S, Raffi F, Stephan C, Rockstroh J, Giacomelli A, Vera J, Bernardino JI, Winston A, Saumoy M, Gras J, Katlama C, Pozniak AL; European Network for AIDS Treatment 022 (NEAT022) Study Group. Immediate Versus Deferred Switching From a Boosted Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen in Virologically Suppressed Patients With High Cardiovascular Risk or Age >/=50 Years: Final 96-Week Results of the NEAT022 Study. Clin Infect Dis. 2019 Feb 1;68(4):597-606. doi: 10.1093/cid/ciy505.

Reference Type: DERIVED

PMID: 29912307 (View on PubMed)

Other Identifiers

NEAT 22/SSAT 060

Identifier Type: -

Identifier Source: org_study_id