| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus-1 infection |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 non-inferior antiviral activity of DTG + 3TC versus DTG + TDF/FTC at 48 weeks in HIV-1-infected, ART-naïve subjects |
|
| E.2.2 | Secondary objectives of the trial |
-To demonstrate the antiviral activity ofDTG+3TCversusDTG+TDF/FTC at24,96and144weeks; -To evaluate the antiviral activity,immunological effects,and incidence of disease progression(HIV-associated conditions,AIDS and death)ofDTG+3TCcompared toDTG+TDF/FTCover time;-To assess viral resistance in subjects meeting confirmed virologic withdrawal(CVW)criteria;-To evaluate the safety and tolerability ofDTG+TDF/FTCover time;-To evaluate renal biomarkers(in urine and blood)and bone biomarkers(in blood)in subjects treated withDTG+3TC compared to DTG+TDF/FTC; -To evaluate the effects of DTG + 3TC on
fasting lipids compared to DTG +TDF/FTC over time;-To evaluate the effect of patient demographics and baseline characteristics on response toDTG+3TC compared to DTG+TDF/FTC over time; -To assess change in health-related quality-of-life for subjects treated withDTGplus3TCcompared toDTG+TDF/FTC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligible subjects must:
•be able to understand and comply with protocol requirements, instructions, and restrictions;
•be likely to complete the study as planned;
•be considered appropriate candidates for participation in an investigative clinical trial with oral medication (e.g. no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country).
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. HIV-1 infected adults 18 years of age, (or older, if required by local regulations), at the time of signing the informed consent.
2.Screening plasma HIV-1 RNA of 1000 c/mL to <= 100,000 c/mL. If an independent review of accumulated data from other clinical trials investigating the DTG plus 3TC dual regimen is supportive of the DTG plus 3TC treatment regimen, enrolment will be opened to subjects with Screening plasma HIV-1 RNA of 1000 c/mL to <= 500,000 c/mL;
3.Antiretroviral-naïve (defined as <=10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection). Subjects who received HIV post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP) in the past are allowed as long as the last PEP/PrEP dose was > 1 year from HIV diagnosis or there is documented HIV seronegativity between the last prophylactic dose and the date of HIV diagnosis.
4.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 Screening and negative urine test at Baseline), 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:
•Documented tubal ligation
•Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
•Hysterectomy
•Documented Bilateral Oophorectomy
•Postmenopausal defined as 12 months of spontaneous amenorrhea and ≥45 years of age [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and oestradiol levels consistent with menopause is confirmatory (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) (see Section 13.3) 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 also be counselled 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.
5.Subject or the subject’s legal representative capable of giving signed informed consent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
6.Subjects enrolled in France: A subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1.Women who are breastfeeding or plan to become pregnant or breastfeed during the study; 2.Any evidence of an active Center for Disease Control and Prevention (CDC) Stage 3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells/mm3. 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 HBV infection based on the results of testing at Screening for HBV surface antigen (HBsAg), HBV core antibody (anti-HBc), HBV surface antibody (anti-HBs or HBsAb), 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.
6.Anticipated need for any HCV therapy during the first 48 weeks of the study and for HCV therapy based on interferon or 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 14 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; other localised malignancies require agreement between the investigator and the Study Medical Monitor for inclusion of the subject. 10.Subjects who in the investigator’s judgment, poses a significant suicidality risk. Recent history of suicidal behaviour and/or suicidal ideation may be considered as evidence of serious suicide risk.
EXCLUSIONARY TREATMENTS PRIOR TO SCREENING OR DAY 1
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 i.radiation therapy, ii.cytotoxic chemotherapeutic agents, iii.any systemic immune suppressant;
13.Treatment with any agent, except recognised ART as allowed above (inclusion criterion 3.), with documented activity against HIV-1 in vitro within 28 days of first dose of study treatment; 14.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 study treatment. 15.Subjects enrolled in France (and other countries as required by local
regulations or ethics committees/IRBs): the subject has participated in any study using an investigational drug 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 the subject will participate simultaneously in another clinical study.
LABORATORY VALUES OR CLINICAL ASSESSMENTS AT SCREENING
16.Any evidence of pre-existing viral resistance based on the presence of any major resistance-associated mutation [IAS-USA, 2014] in the Screening result or, if known, in any historical resistance test result. NOTE: retests of disqualifying Screening genotypes are not allowed. 17.Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening period to verify a result. 18.Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject’s participation in the study of an investigational compound.
19.Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >= 1.5xULN (with >35% direct bilirubin); 20.Creatinine clearance of <50 mL/min/1.73 m2 via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with plasma HIV-1 RNA <50 copies/mL (c/mL) at Week 48 using the FDA Snapshot algorithm [Missing, Switch or Discontinuation = Failure (MSD=F)] for the intent-to-treat exposed (ITT-E) population |
|
| 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 c/mL using the FDA Snapshot algorithm (MSD=F) for the ITT-E population
2)Time to viral suppression (HIV-1 RNA <50 c/mL);
3)Absolute values and changes from Baseline in CD4+ cell counts
4)Incidence of disease progression (HIV-associated conditions, AIDS and death).
5)Incidence of treatment-emergent genotypic and phenotypic resistance to DTG and 3TC or TDF/FTC in subjects meeting CVW criteria
6)Incidence and severity of adverse events (AEs) and laboratory abnormalities;
7)Proportion of subjects who discontinue treatment due to AEs
8)Change from Baseline in renal and bone biomarkers
9)Change from Baseline in fasting lipids;
10)The incidence of Grade 2 or greater laboratory abnormalities in fasting LDL cholesterol
11)Proportion of subjects by patient subgroup(s) (e.g. by age, gender, Baseline CD4+ cell count) with plasma HIV-1 RNA <50 c/mL using the Snapshot algorithm for the ITT-E population
12)Change from Baseline in CD4+ cell counts by patient subgroups
13)Change from Baseline in health related quality of life using EQ-5D-5L |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Weeks 24, 96 and 144
2) During study when event occurred
3)Weeks 24, 48, 96 and 144;
4)During study when event occurred
5)During study when event occurred
6)During study when event occurred
7)over 24, 48, 96 and 144 weeks
8)Weeks 24, 48, 96 and 144
9) Weeks 24, 48, 96, and 144;
10) Weeks 24, 48, 96, and 144;
11) at Weeks 24, 48, 96 and 144
12) Weeks 24, 48, 96 and 144
13)Weeks 4, 24, 48, 96, and 144 (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 | 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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 |
| Double blind Week 1 to 96. Open label week 96 to 148 |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Korea, Republic of |
| Mexico |
| South Africa |
| Taiwan |
| United States |
| France |
| Netherlands |
| Romania |
| Spain |
| Germany |
| Italy |
| Belgium |
| Portugal |
| Russian Federation |
| Ukraine |
| United Kingdom |
|
| 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
|
| The end of the study is defined as the last subject’s last visit |
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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 | 1 |
| 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 | 1 |
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