E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Evaluation of the efficacy and safety of a switch from cART to dolutegravir monotherapy in HIV |
Evaluatie van de effectiviteit en veiligheid van een switch van cART naar dolutegravir monotherapy voor HIV |
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E.1.1.1 | Medical condition in easily understood language |
Therapy of HIV |
behandeling van HIV |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy and safety of a switch from cART to dolutegravir monotherapy |
Evaluatie van de effectiviteit en veiligheid van een switch van cART naar dolutegravir monotherapy voor HIV |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect on biochemical markers (renal/liver/lipids), HIV reservoir, BMD, and cost effectiveness. |
Biochemie markers mbt nieren, lever, vetten, reservoir, botdichtheid, en kosteneffectiviteit |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
In a pilot study version 1.0 on 30 additional patients, the objective is to evaluate the safety of a direct switch to DTG monotherapy in patients with CD4 nadir pre-cART <200 cells/mm3, given that these patients have a CD4 cell of >350 cells/mm3 on current cART at screening. The same other in- and exclusion criteria and follow up will be used. This pilot will only be started if at least 40 patients in the main study have passed week 12, and no more than 3 patients have experienced per protocol defined treatment failure. |
In een sub- pilotstudie versie 1.0 op 30 andere patienten (buiten de 104 patienten om) zullen we bekijken hoe veilig een directe switch naar DTG monotherapie is in patienten met een CD4 nadir pre-CART <200 cellen/mm3 onder voorwaarde dat deze patienten een CD4 getal >350 hebben op hun huidige behandeling bij screening. Dezelfde in- en exclusie criteria en follow up zullen worden gebruikt. Deze te starten substudie zal alleen worden gestart wanneer minimaal 40 patienten week 12 in de main studie hebben gepasseerd waarvan er niet meer dan 3 patienten falen hebben ervaren volgens ons protocol gedefineerd. |
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E.3 | Principal inclusion criteria |
18 years or older
On cART and HIV-RNA <50 for last >24 weeks
pre-cART: baseline HIVRNA <100.000 (unless measured during acute HIV)
pre-cART: CD4 nadir >200
Not on co-medication inducing UGT1A1/CYP3A4 as stated in DTG SPC
General medical condition does not interfere with trial procedures
A secondary objective is to test viralogical suppression in patients with a pre-cART CD4 count nadir of below 200
cells/mm3. For this N=30 pilot study, the same inclusioncriteria as mentioned above will apply, except for the CD4
count nadir pre-cART ≥200 cells/mm3 inclusion criterium. The 30 patients for this pilot study will need to have a
pre-cART CD4 count BELOW 200 cells/mm3 with a CD4 count >350 cells/mm3 at the time of the screening visit. |
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E.4 | Principal exclusion criteria |
Planning to be pregnant
No use of double barrier contraceptive methods
Previous virological failure on any ART.
Patient without documented anti-HBs antibodies prior to vaccination, and unwilling to undergo vaccination against hepatitis B.
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.
For the N=30 pilot study, the same exclusion criteria as mentiioned above will apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in percentage of patients who switch to DTG monotherapy as compared to controls on conventional continued cART with HIV-RNA <200 c/mL at week 24 by OT analysis. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The time to loss of virological response (TLOVR) defined as the first of two confirmed HIV-RNA >50 c/mL at least 1 week apart.
Percentage of patients with virological suppression with HIV-RNA <200 c/mL at week 24 by OT analysis in the entire study population which consists of the
24 by OT analysis in the entire study population (n=104) which consists of the immediate switchers group (n=52) and the delayed switchers from the control arm (n=52).
To evaluate the efficacy of DTG monotherapy in maintaining virological suppression with HIV-RNA <200 at week 12 by OT analysis.
immediate switchers group and the delayed switchers from the control arm (n=104).
Difference in percentage of patients with HIV-RNA <50, <200 c/mL at week 24 and 48 by OT and ITT analysis.
Evaluation of safety (acquired resistance, and AE according to CTC 4.0) of DTG monotherapy.
Evolution of CD4 associated HIV reservoir (total/integrated HIV-DNA, 2LTR) at baseline, week 24 and week 48.
Number and type of INI resistance mutations in case of confirmed HIV-RNA >200 c/mL at any time-point.
Difference in change in CD4 cell count at week 48.
Changes from baseline to week 24 and 48 in blood-pressure, weight, BMI, fasting serum lipids, Framingham risk score, ATP-III treatment goals, inflammatory markers, renal function, urinalysis, bone mineral density at hip and spine.
Cost-effectiveness of DTG monotherapy
Viral suppression in HIV-patients on DTG monotherapy with pre-cART CD4 nadir below 200 cells/mm3. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 12, week 24 and week 48. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of the trial is when the last person included completes his/her last visit at week 48. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |