Clinical trial NCT02401828: The Dolutegravir Antiretroviral Mono-Therapy for HIV Trial
Official title: The Dolutegravir Antiretroviral Mono-Therapy for HIV Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Human Immunodeficiency Virus
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2015-03-30
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 48-week open label randomized phase IV investigator initiated intervention study. The purpose of this study is to evaluate whether HIV-1 suppression can be maintained by DTG monotherapy in HIV-1 infected, virologically suppressed patients on cART.

104 adults fulfilling the in and exclusion criteria and on stable cART will be randomized over 2 investigational arms.

The first arm will contain the direct switch population. This population will switch directly from stable cART to Dolutegravir mono-therapy on baseline visit.

The second arm will contain the delayed-switch population. This group will switch from stable cART to Dolutegravir monotherapy 24 weeks after baseline visit.

The main goal is to investigate if Dolutegravir mono-therapy could be non-inferior to cART in virological suppressed HIV-1 infected adults.

If a interim analysis (performed when 40 patients on dolutegravir monotherapy have passed week 12) shows that it is safe to continue the study, an additional 30 patients will be included on top of the 104 patients needed for the primary endpoint analysis. In contrast to the primary endpoint population, these additional 30 patients will have a CD4 nadir \<200 but a CD4 \>350 at the time of the screening visit. Besides that, these 30 patients will have to fulfill all other in and exclusion criteria of the primary endpoint population (specifically a viral load never \>100.000). These 30 patients are part of a pilot study looking at the possibility to broaden the eligible population in a future larger randomized clinical trial.

Detailed description: DTG Monotherapy will be considered non-inferior to cART if the lower bound of the one sided 97.5%CI for the difference in proportion of patients reaching the primary endpoint is not lower than -12%. For this purpose, a sample size of 52 per arm would provide 80% power at alpha 0.025 to establish non-inferiority of DTG monotherapy compared with cART when the primary endpoint success rate is 95% in both treatment arms.

Eligibility criteria: Inclusion Criteria:

* Documented HIV-1 positive by ELISA or Western Blot or Plasma HIV-RNA \>1000 c/ml.
* 18 years or older.
* HIV-RNA ≤50 copies/mL for ≥24 weeks.
* Historical baseline HIV-RNA plasma load \<100.000 c/ml
* CD4 count nadir pre-cART ≥200 cells/mm3
* Not on strong UGT1A1 or CYP3A4 inducing agents as stated in DTG SPC.
* General medical condition does not interfere with trial procedures (on investigators' discretion)
* Females should have no plans of becoming pregnant during the next 18 months after the baseline visit
* Females are eligible if:

  1. They do not plan to become pregnant during the study
  2. Negative screening pregnancy test and uses one of the following methods: 1.Abstinence from penile/vaginal intercourse during the study; 2.Double barrier contraceptive methods 1 of which must be condom.

Exclusion Criteria:

* Previous virological failure on any ART.
* Patient without documented anti-HBs antibodies.
* Subjects positive for hepatitis B at screening (HBsAg+).
* Any documented genotypic HIV-1 resistance with at least low-level resistance according to stanford HIV drug resistance database
* No record of the historical baseline plasma viral load available
* Subjects with concomitant CDC-C opportunistic infections within 90 days of screening.
* Subjects with history of allergy to INI.
* Subjects with creatinine clearance \<50mL/min according to CKD-EPI.
* Subjects with hepatic impairment of at least Child-Pugh B.
* Exposure to experimental drug or experimental HIV-1 vaccine within 90 days of start of DTG.
* Screening ALT \>5x ULN or ALT\>3xULN and bilirubin \>2 ULN.
* Patient (man or woman) planning or hoping to conceive a child/become pregnant during the study
* Patients who cannot take DTG 2 hours before or 6 hours after antacids, calciumcarbonate or iron supplements.

Primary outcomes:
measure: Efficacy of dolutegravir monotherapy in maintaining virological suppression in the on-treatment population
timeFrame: 24 weeks
Secondary outcomes:
measure: Time to loss of virological response (TLOVR) in the OT population
timeFrame: 1 week
measure: Efficacy of dolutegravir monotherapy in maintaining virological suppression in the entire study population (ITT)
timeFrame: 24 weeks
measure: Efficacy of dolutegravir monotherapy in maintaining virological suppression in the on-treatment population
timeFrame: 48 weeks
measure: Evaluate safety of Dolutegravir monotherapy (Acquired resistance & Adverse Events according to CDC 4.0)
timeFrame: 60 weeks
measure: Evaluate the evolution of CD4 associated HIV-1 reservoir
timeFrame: 48 weeks
measure: Evaluate the number and type of INI resistance mutation in patients with virological failure
timeFrame: 48 weeks
measure: Evaluate CD4 cell count change
timeFrame: 48 weeks
measure: Evaluate changes in renal function after 24 and 48 weeks of dolutegravir monotherapy
timeFrame: 48 weeks
measure: Cost effectiveness of DTG monotherapy
timeFrame: 48 weeks
measure: Evaluate change in BMD after 24 and 48 weeks of dolutegravir mono-therapy
timeFrame: 48 weeks
measure: Exploratory analysis of blood pressure, weight, BMI, fasting serum lipids, Framingham risk score, ATP-III treatment goals and inflammatory markers after 24wks of dolutegravir mono-therapy
timeFrame: 48 weeks
measure: Efficacy of dolutegravir monotherapy in maintaining virological suppression in the on-treatment population
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid Holland
Study officials:
affiliation: Erasmus Medical Center
name: Bart Rijnders, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wijting IEA, Lungu C, Rijnders BJA, van der Ende ME, Pham HT, Mesplede T, Pas SD, Voermans JJC, Schuurman R, van de Vijver DAMC, Boers PHM, Gruters RA, Boucher CAB, van Kampen JJA. HIV-1 Resistance Dynamics in Patients With Virologic Failure to Dolutegravir Maintenance Monotherapy. J Infect Dis. 2018 Jul 24;218(5):688-697. doi: 10.1093/infdis/jiy176.
citation: Wijting I, Rokx C, Boucher C, van Kampen J, Pas S, de Vries-Sluijs T, Schurink C, Bax H, Derksen M, Andrinopoulou ER, van der Ende M, van Gorp E, Nouwen J, Verbon A, Bierman W, Rijnders B. Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial. Lancet HIV. 2017 Dec;4(12):e547-e554. doi: 10.1016/S2352-3018(17)30152-2. Epub 2017 Oct 26.