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Early Simplified: A Trial to Compare the Efficacy of Standard of Care Combination Antiretroviral Therapy With a Simplified Dolutegravir Monotherapy in Patients With a Primary HIV-1 Infection

Primary Purpose

Monotherapy, Dolutegravir, Primary HIV Infection

Status
Unknown status
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Dolutegravir
Standard of care combinational antiretroviral therapy
Sponsored by
University of Zurich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Monotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Informed Consent as documented by signature,
  • All patients ≥18 years with a documented primary HIV-infection undergoing standard of care cART (i.e., one active drug from the class of either the PIs, or the NNRTIs, or the INSTIs, in combination with two active drugs from the class of NRTIs) with no previous structured treatment interruption and with a suppressed viral load (defined as 50 copies/ml) during the previous 48 weeks,
  • Participant of the Swiss HIV Cohort Study

Exclusion Criteria:

  • Patients not willing to sign the informed consent form,
  • Presence of ≥1 major integrase inhibitor resistance associated mutation according to the Sanford algorithm1,
  • History of ≥2 consecutive plasma viremia levels >400 copies/ml at least two weeks apart,
  • Ongoing (i.e., replicating) hepatitis B virus infection,
  • Hemoglobin < 10 g/dl (men) and < 9 g/dl (women) at the time of enrolment,
  • Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product,
  • Women who are pregnant or breast feeding,
  • Intention to become pregnant during the course of the study,
  • Lack of safe contraception,
  • Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc.),
  • Known or suspected non-compliance, drug or alcohol abuse,
  • Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant,
  • Participation in another study with investigational drug within the 30 days preceding and during the present study,
  • Previous enrolment into the current study,
  • Enrolment of the investigator, his/her family members, employees and other dependent persons.

Sites / Locations

  • University Hospital Zurich, University of Zurich

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Dolutegravir monotherapy

Standard of care combination antiretroviral therapy

Arm Description

92 patients will be simplified to once daily dolutegravir monotherapy.

46 patients will go on with standard of care combination antiretroviral therapy consisting of either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor or a integrase inhibitor in combination with two nucleoside reverse transcriptase inhibitors.

Outcomes

Primary Outcome Measures

Proportion of individuals with a viral failure [defined as ≥2 plasma viremia levels >50copies/ml at least two weeks apart] at week 48 or before.
The study seeks primarily to determine the efficacy (i.e., proportion of patients with a viral failure [defined as ≥2 plasma viremia levels >50copies/ml at least two weeks apart] at week 48 or before) of a simplified monotherapy (i.e., DTG) compared to a standard of care HIV triple-therapy in patients with a PHI treated with early ART under long term suppressive ART for at least 48 weeks.

Secondary Outcome Measures

Quantification of latent HIV-1 reservoir by measurement of proviral DNA and cell-associated RNA at baseline (time point of randomization), and at week 48
Proportion of individuals with a CSF HIV-1 RNA <50copies/ml in the CSF at week 48 after treatment simplification.
Proportion of patients with an adverse event at week 48.
Proportion of patients with a severe adverse event at week 48.
Time to viral failure (defined as ≥2 plasma viremia levels >50copies/ml at least two weeks apart) at week 48.
Proportion of individuals with blips (defined as one viral load >50 and <400 copies/ml with a next viral load <50 copies/ml) at week 48.
Change from baseline CD4+ cell count from baseline at week 48.
Proportion of individuals with new onset of proximal tubular renal dysfunction at week 48.
Creatinine clearance change from baseline at week 48.
Lipidic profile changes from baseline at week 48.
Proportion of individuals developing a new CDC-event at week 48.
Proportion of individuals withdrawing consent at week 48.
Proportion of individuals being lost to follow-up at week 48.
Proportion of individuals switching assigned treatment for any cause at week 48.

Full Information

First Posted
September 15, 2015
Last Updated
October 11, 2018
Sponsor
University of Zurich
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1. Study Identification

Unique Protocol Identification Number
NCT02551523
Brief Title
Early Simplified: A Trial to Compare the Efficacy of Standard of Care Combination Antiretroviral Therapy With a Simplified Dolutegravir Monotherapy in Patients With a Primary HIV-1 Infection
Official Title
A Prospective, Randomised, Controlled, Open-label, Non-inferiority Trial to Compare the Efficacy of Standard of Care Combination Antiretroviral Therapy With a Simplified Dolutegravir Monotherapy in Patients With a Primary HIV-1 Infection Under Suppressive Early Standard of Care Antiretroviral Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Unknown status
Study Start Date
November 2016 (undefined)
Primary Completion Date
October 2018 (Anticipated)
Study Completion Date
February 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Zurich

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Long term toxicity of combination antiretroviral therapy (cART) is a substantial contributor to morbidity and mortality in chronically infected HIV positive individuals. To date it is still debated, whether long term nucleoside reverse transcriptase inhibitors (NRTI's) -sparing regimens are practicable or even superior compared to standard of care cART in terms of efficacy, safety and tolerability. In addition, data about efficacy of integrase inhibitor (INSTI) based monotherapy is lacking. We aim at investigating the efficacy of standard of care combination antiretroviral therapy with a simplified dolutegravir monotherapy in patients with a primary HIV-1 infection under suppressive early standard of care antiretroviral therapy. Briefly, hundred-thirty-eight patients with a documented primary HIV1- infection (PHI) will be recruited from the Zurich Primary HIV-1 Infection Study (ZHPI), which is an open label, non-randomized, observational, single-center study (http://clinicaltrials.gov, ID 5 NCT00537966). All subjects formerly underwent early cART consisting of either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a INSTI in combination with two NRTIs at the time point of enrolment in the ZPHI and must be under a fully suppressive ART (i.e., <50 copies/ml) for at least 48 weeks at the time point of randomisation. The primary end point is the proportion of individuals with a viral failure at week 48 or before.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Monotherapy, Dolutegravir, Primary HIV Infection, Treatment Efficacy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
101 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dolutegravir monotherapy
Arm Type
Experimental
Arm Description
92 patients will be simplified to once daily dolutegravir monotherapy.
Arm Title
Standard of care combination antiretroviral therapy
Arm Type
Active Comparator
Arm Description
46 patients will go on with standard of care combination antiretroviral therapy consisting of either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor or a integrase inhibitor in combination with two nucleoside reverse transcriptase inhibitors.
Intervention Type
Drug
Intervention Name(s)
Dolutegravir
Intervention Description
92 patients will be simplified to once daily dolutegravir monotherapy
Intervention Type
Drug
Intervention Name(s)
Standard of care combinational antiretroviral therapy
Primary Outcome Measure Information:
Title
Proportion of individuals with a viral failure [defined as ≥2 plasma viremia levels >50copies/ml at least two weeks apart] at week 48 or before.
Description
The study seeks primarily to determine the efficacy (i.e., proportion of patients with a viral failure [defined as ≥2 plasma viremia levels >50copies/ml at least two weeks apart] at week 48 or before) of a simplified monotherapy (i.e., DTG) compared to a standard of care HIV triple-therapy in patients with a PHI treated with early ART under long term suppressive ART for at least 48 weeks.
Time Frame
48 weeks
Secondary Outcome Measure Information:
Title
Quantification of latent HIV-1 reservoir by measurement of proviral DNA and cell-associated RNA at baseline (time point of randomization), and at week 48
Time Frame
Week48
Title
Proportion of individuals with a CSF HIV-1 RNA <50copies/ml in the CSF at week 48 after treatment simplification.
Time Frame
Week 48
Title
Proportion of patients with an adverse event at week 48.
Time Frame
Week 48
Title
Proportion of patients with a severe adverse event at week 48.
Time Frame
Week 48
Title
Time to viral failure (defined as ≥2 plasma viremia levels >50copies/ml at least two weeks apart) at week 48.
Time Frame
Week 48
Title
Proportion of individuals with blips (defined as one viral load >50 and <400 copies/ml with a next viral load <50 copies/ml) at week 48.
Time Frame
Week 48
Title
Change from baseline CD4+ cell count from baseline at week 48.
Time Frame
Week 48
Title
Proportion of individuals with new onset of proximal tubular renal dysfunction at week 48.
Time Frame
Week 48
Title
Creatinine clearance change from baseline at week 48.
Time Frame
Week 48
Title
Lipidic profile changes from baseline at week 48.
Time Frame
Week 48
Title
Proportion of individuals developing a new CDC-event at week 48.
Time Frame
Week 48
Title
Proportion of individuals withdrawing consent at week 48.
Time Frame
Week 48
Title
Proportion of individuals being lost to follow-up at week 48.
Time Frame
Week 48
Title
Proportion of individuals switching assigned treatment for any cause at week 48.
Time Frame
Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Informed Consent as documented by signature, All patients ≥18 years with a documented primary HIV-infection undergoing standard of care cART (i.e., one active drug from the class of either the PIs, or the NNRTIs, or the INSTIs, in combination with two active drugs from the class of NRTIs) with no previous structured treatment interruption and with a suppressed viral load (defined as 50 copies/ml) during the previous 48 weeks, Participant of the Swiss HIV Cohort Study Exclusion Criteria: Patients not willing to sign the informed consent form, Presence of ≥1 major integrase inhibitor resistance associated mutation according to the Sanford algorithm1, History of ≥2 consecutive plasma viremia levels >400 copies/ml at least two weeks apart, Ongoing (i.e., replicating) hepatitis B virus infection, Hemoglobin < 10 g/dl (men) and < 9 g/dl (women) at the time of enrolment, Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product, Women who are pregnant or breast feeding, Intention to become pregnant during the course of the study, Lack of safe contraception, Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc.), Known or suspected non-compliance, drug or alcohol abuse, Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, Participation in another study with investigational drug within the 30 days preceding and during the present study, Previous enrolment into the current study, Enrolment of the investigator, his/her family members, employees and other dependent persons.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dominique L Braun, MD
Organizational Affiliation
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Zurich, University of Zurich
City
Zurich
ZIP/Postal Code
8091
Country
Switzerland

12. IPD Sharing Statement

Citations:
PubMed Identifier
30601950
Citation
Braun DL, Turk T, Tschumi F, Grube C, Hampel B, Depmeier C, Schreiber PW, Brugger SD, Greiner M, Steffens D, De Torrente-Bayard C, Courlet P, Neumann K, Kuster H, Flepp M, Bertisch B, Decosterd L, Boni J, Metzner KJ, Kouyos RD, Gunthard HF. Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial. Clin Infect Dis. 2019 Oct 15;69(9):1489-1497. doi: 10.1093/cid/ciy1131.
Results Reference
derived

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Early Simplified: A Trial to Compare the Efficacy of Standard of Care Combination Antiretroviral Therapy With a Simplified Dolutegravir Monotherapy in Patients With a Primary HIV-1 Infection

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