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

HIV Clinical Trial

Official title:

An Open Label Study Examining the Efficacy and Cardiovascular Risk of Immediate Versus Deferred Switch From a Boosted PI to Dolutegravir (DTG) in HIV Infected Patients With Stable Virological Suppression

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02098837
• Other study ID #: NEAT 22/SSAT 060
• Status: Completed
• Phase: Phase 4
• First received: March 20, 2014
• Last updated: April 6, 2018
• Start date: April 2014
• Est. completion date: December 4, 2017

Study information

• Verified date: April 2018
• Source: St Stephens Aids Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 415
• Est. completion date: December 4, 2017
• Est. primary completion date: November 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV

Intervention

Drug:
• Dolutegravir
Dolutegravir 50mg once daily

Locations

Country	Name	City	State
Belgium	Insititute Of Tropical Medicine Antwerp	Antwerp
Belgium	CHU Saint-Pierre	Brussels
Belgium	Universitaire Ziekenhuis Gent	Gent
France	Hopital de la Croix Rousse	Lyon
France	Service des Maladies Infectieuses et Tropicales du CHU de NANTES	Nantes
France	Hopital Saint Louis	Paris
France	Hospital Bichat Claude-Bernard	Paris
France	Pitié-Salpêtrière Hospital	Paris
Germany	Universitätsklinikum Bonn	Bonn
Germany	Universitätsklinikum Essen	Essen
Germany	Klinikum der Goethe-Universität Frankfurt	Frankfurt
Germany	ICH Infektiologisches Centrum Hamburg	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Italy	Santa Maria Annunziata di Firenze	Firenze
Italy	Azienda Ospedaliera - Polo Universitario 'Luigi Sacco'	Milan
Italy	San Paolo Hospital	Milan
Italy	Universitaria di Modena	Modena
Spain	Hospital General Universitario de Elche	Alicante
Spain	Universitario Alicante	Alicante
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	IrsiCaixa	Barcelona
Spain	Universitari de Bellvitge	Barcelona
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario La Paz	Madrid
United Kingdom	Elton John Centre	Brighton
United Kingdom	Southmead Hospital	Bristol
United Kingdom	Bart's Hospital	London
United Kingdom	Chelsea & Westminster Hospital	London
United Kingdom	Mortimer Market Centre	London
United Kingdom	Royal Free Hospital	London
United Kingdom	St Mary's Hospital	London
United Kingdom	St Thomas Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
St Stephens Aids Trust

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Virological suppression	Maintenance of virological suppression (ie HIV-1 RNA <50 c/ml) after 48 weeks	48 weeks
Primary	Total cholesterol	Change from baseline in total cholesterol at week 48	48 weeks
Secondary	Virological Suppression	Maintenance of virological suppression (ie HIV-1 RNA <50 c/ml) at week 24 and 96	24 - 96 weeks
Secondary	CD4 count from baseline	Change in CD4 count from baseline to week 24, 48 and 96	24 - 96 weeks
Secondary	Baseline in total cholesterol	Change from baseline in total cholesterol at weeks 24 and 96	24 - 96 weeks
Secondary	Change from baseline to lipid values	Change from baseline to lipid values (LDL, HDL, triglycerides and TC:HDL ratio) and Framingham and DAD scores at weeks 24, 48 and 96	24 - 96 weeks
Secondary	Safety	Safety (clinical and laboratory adverse events) at weeks 24, 48 and 96	24 - 96 weeks
Secondary	Changes in markers of inflammation	Changes in markers of inflammation at baseline, week 48 and week 96	48 - 96 weeks
Secondary	Tolerability	Tolerability (EuroQoL questionnaire) at weeks 24, 48 and 96	24 - 96 weeks
Secondary	Changes in markers of coagulation	Changes in markers of coagulation at baseline, week 48 and week 96	48 - 96 weeks
Secondary	Changes in markers of endothelial dysfunction	Changes in markers of endothelial dysfunction at baseline, week 48 and week 96	48 - 96 weeks
Secondary	Change to arterial stiffness augmentation index at weeks 48 and 96	Change from baseline to arterial stiffness augmentation index at weeks 48 and 96	48 - 96 weeks
Secondary	Change to average thickness of common carotid artery walls at weeks 48 and 96	Change from baseline to average thickness of common carotid artery walls at weeks 48 and 96	48 - 96 weeks