| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus-1 infection |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 demonstrate the non-inferior antiviral activity of switching to DTG +3TC once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, ART therapy (ART)-experienced, virologically suppressed subjects. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate the antiviral activity of switching to DTG+3TC once daily compared to continuation of TBR over 48 weeks.
To demonstrate the antiviral activity of switching to DTG+3TC once daily compared to continuation of TBR over 24 weeks, 96 weeks and 144 weeks.
To evaluate the immune effects of DTG+3TC once daily compared to continuation of TBR over 24, 48, 96 and 144 weeks.
To evaluate the safety and tolerability of DTG+3TC once daily compared to TBR over time.
To evaluate the effects of DTG+3TC once daily on fasting lipids over time compared to TBR.
To assess viral resistance in subjects meeting Virologic Withdrawal Criteria.
To evaluate renal (in urine and blood) and bone (in blood) biomarkers in subjects treated with DTG+3TC compared to TBR.
To assess health related quality of life for subjects treated with DTG+3TC compared to TBR. |
|
| 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 |
A pharmacokinetic (PK) substudy in the DTG+3TC arm will be conducted to evaluate DTG and 3TC concentrations using a sparse PK sampling approach at designated visits. In addition, intensive PK samples will be collected from a subgroup of subjects (approximately 30) enrolled at selected sites with the capability to perform intensive PK sampling.
Exploratory Objectives
-To assess the steady-state DTG and 3TC exposure in HIV-1 infected patients.
-To characterize the DTG and 3TC steady-state PK of the DTG/3TC FDC in HIV-1 infected patients.
Exploratory Endpoints
-Steady state plasma PK parameters of DTG and 3TC will be assessed using intensive PK collected at week 4.
-Population estimates of PK parameters (e.g. apparent clearance [CL/F], apparent volume of distribution [V/F]) using DTG and 3TC intensive and sparse plasma concentrations at Weeks, 4, 8, 12, 24, 36 and 48. |
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| E.3 | Principal inclusion criteria |
1. Aged 18 years or older (or older where required by local regulatory agencies), at the time of signing the informed consent.
2. HIV-1 infected men or women.
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.
4. Plasma HIV-1 RNA <50 c/mL at Screening.
5. Must be on uninterrupted ART for at least 6 months prior to screening. Only the following regimens are allowed:
a. Subjects on a TAF-based regimen for at least 6 months as the initial regimen, or
b. Subjects who switched from a TDF first regimen to TAF, without any changes to the other drugs in their regimen, and have been on the TAF-based regimen for at least 3 months immediately prior to Screening, i.e., the only switch made is from TDF to TAF. This switch must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for suspected or established treatment failure. A switch from a PI boosted with RTV to the same PI boosted with cobicistat is allowed (and vice versa).
6. Male or Female
A female subject is eligible to participate if she is not pregnant [as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative urine hCG test at Randomization (a local serum hCG test at Randomization is allowed if it can be done, and results obtained, within 24 hours prior to randomization)], not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
- Pre-menopausal females with one of the following:
o Documented tubal ligation
o Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
o Hysterectomy
o Documented Bilateral Oophorectomy
- Post-menopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
All subjects participating in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.
7. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Eligible subjects or their legal guardians must sign a written Informed Consent Form before any protocol-specified assessments are conducted.
8. Subjects enrolled in France must be affiliated to, or a beneficiary of, a social security category. |
|
| E.4 | Principal exclusion criteria |
1. Women who are breastfeeding or plan to become pregnant or breastfeed during the study.
2. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 disease [CDC, 2014], EXCEPT cutaneous Kaposi’s sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/mm3 are NOT exclusionary.
3. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification.
4. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
5. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV DNA as follows:
-Subjects positive for HBsAg are excluded.
-Subjects negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
Note: Subjects positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded. Anti-HBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and NOT anti-HBc IgM.
6. Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study, or anticipated need for HCV therapy based on interferon or for any drugs that have a potential for adverse drug-drug interactions with study treatment throughout the entire study period.
7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Subjects who are at least 7 days post completed treatment are eligible.
8. History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
9. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia.
10. Subjects who in the investigator’s judgment, poses a significant suicidality risk.
11. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
12. Treatment with any of the following agents within 28 days of Screening
-radiation therapy
-cytotoxic chemotherapeutic agents
-any systemic immune suppressant
13. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
14. Use of any regimen consisting of single or dual ART.
15. Any evidence of major NRTI mutation or presence of any major INSTI resistance-associated mutation in any available prior resistance genotype assay test result, if known, must be provided to ViiV after screening and before randomization for review by ViiV Virology.
16. Any verified Grade 4 laboratory abnormality.
17. Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN) or ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin).
18. Creatinine clearance of <50 mL/min/1.73m2 via CKD-EPI method.
19. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.
20. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements ≥50 c/mL.
21. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement ≥50 c/mL.
22. Any drug holiday during the 6 months prior to Screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns.
23. Any history of switch to another regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV-1 RNA ≥400 c/mL.
24. Subjects enrolled in France (or in other countries as required by local regulations or Ethics Committee/Institutional Review Board [IRB]) who:
-participated in any study using an investigational drug or vaccine during the previous 60 days or 5 half-lives, or twice the duration of the biological effect of the experimental drug or vaccine, whichever is longer, prior to screening for the study, or
-participate simultaneously in another clinical study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Virologic failure endpoint as per FDA snapshot category at Week 48 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Proportion of subjects with plasma HIV-1 RNA <50 copies c/mL at Week 48 using the Snapshot algorithm for the ITT-E population
2) Virologic failure endpoint as per FDA snapshot category at Weeks 24, 96 and 144; Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Weeks 24, 96 and 144 using the Snapshot algorithm for the ITT-E population
3) Change from Baseline in CD4+ cell count and in CD4+/CD8+ cell counts ratio at weeks 48, 96 and 144; Incidence of disease progression (HIV-associated conditions, AIDS, and death) through Weeks 24, 48, 96,
and 144
4) Incidence and severity of AEs and laboratory abnormalities through 144 weeks; Proportion of subjects who discontinue treatment due to AEs through 144 weeks
5) Change from Baseline in fasting lipids at weeks 24, 48, 96 and 144
6) Incidence of observed genotypic and phenotypic resistance to ARVs for subjects meeting Virologic withdrawal Criteria
7) Change from Baseline in renal and bone biomarkers at Weeks 24, 48, 96 and 144
8) Change from Baseline in health status using EQ-5D-5L at Weeks 24, 48, 96 and 144 (or Withdrawal from the study) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 48 weeks
2) 24, 96 and 144 weeks
3) 24, 48, 96 and 144 weeks
4) 144 weeks
5) 24, 48, 96 and 144 weeks
6) During study when event occurred
7) 24, 48, 96 and 144 weeks
8) 24, 48, 96 and 144 weeks (or withdrawal from the study) |
|
| 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 | Yes |
| 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 | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| non-inferiority switch study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| ≥3-drug tenofovir alafenamide (TAF) based regimen (TBR) |
|
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Japan |
| United States |
| Belgium |
| France |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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