| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10020160 |
| E.1.2 | Term | HIV disease |
| 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 DTG/ABC/3TC FDC once daily compared to ATV+RTV+TDF/FTC FDC each administered once daily over 48 weeks in HIV-1 infected ART naïve women. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the antiviral and immunological activity and incidence of disease progression (HIV-associated conditions, AIDS and death) of DTG/ABC/3TC FDC once daily compared to ATV+RTV+TDF/FTC FDC once daily over time;
-To compare the safety, tolerability, and laboratory parameters of DTG/ABC/3TC FDC once daily to ATV+RTV+TDF/FTC FDC once daily over time;
-To assess the development of viral resistance in subjects who meet confirmed virologic withdrawal criteria;
-To evaluate renal markers (in urine and blood), and bone markers (in blood) in subjects treated with DTG/ABC/3TC FDC compared to ATV+RTV+TDF/FTC FDC;
- To assess treatment satisfaction, and change in health-related quality-of-life for subjects treated with DTG/ABC/3TC FDC compared to ATV+RTV+TDF/FTC FDC;
- To evaluate the effect of patient characteristics (i.e., demographic factors, HIV-1 subtype, Baseline CD4) on response to DTG/ABC/3TC FDC compared to ATV+RTV+TDF/FTC FDC over time. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. HIV-1 infected females (gender at birth) ≥ 18 years of age;
2. A female, may be eligible to enter and participate in the study if she:
a. is of non-child-bearing potential either defined as post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral
oophorectomy or,
b. is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
- Refer to Appendix 6, Section 11.6 of protocol : Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential.
Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of IP.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 of effective barrier methods (e.g. male condom/spermicide).
3. HIV-1 infection as documented by Screening plasma HIV-1 RNA ≥500 c/mL;
4. Documentation that the subject is negative for the HLA-B*5701 allele;
5. Antiretroviral-naïve (<=10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection);
6. Signed and dated written informed consent is obtained from the subject or the subject’s legal representative prior to screening;
7. 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. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary medical conditions
1. Women who are pregnant or breastfeeding;
2. Women who plan to become pregnant during the first 48 weeks of the study.
3. Any subject who has had a medical intervention for gender reassignment;
4. Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease (Section 11.1). Exceptions include cutaneous Kaposi’s sarcoma not requiring systemic therapy and historic CD4+ cell counts of <200 cells/mm3.
5. Subjects with any degree of hepatic impairment;
6. Subjects positive for hepatitis B (+HBsAg) at Screening, or anticipated need for HCV therapy during the study;
7. History or presence of allergy to the study drugs or their components or drugs of their class;
8. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator
and the Study medical monitor for inclusion of the subject;
9. Subjects who in the investigator’s judgment, poses a significant suicidality risk.
Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk;
10. History of osteoporosis with fracture or requiring pharmacologic therapy with bisphosphonates (e.g., alendronate, ibandronate, risedronate, zoledronic acid), antiresorptive medications (e.g., denosumab, strontium ranelate, teriparatide), and estrogen receptor modulators (e.g., raloxifene, tamoxifen). Use of calcium and vitamin D is permitted.
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: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses (a detailed list is provided in the SPM);
13. Treatment with any agent, except recognized ART as allowed above (Section 4.2), with documented activity against HIV-1 in vitro within 28 days of first dose of IP;
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 IP;
15. Subjects enrolled in France: 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.
Exclusionary Laboratory Values or Clinical Assessments at Screening
16. Any evidence of primary viral resistance based on the presence of any major resistance-associated mutation [IAS USA, 2012] in the Screening result or, if known, any historical resistance test result. Note: retests of Screening genotypes are not allowed;
17. Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid abnormalities (total cholesterol, triglycerides, High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL) cholesterol). 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. Subject has CrCL of <50 mL/min via Cockroft-Gault method;
21. Corrected QT interval (QTc (Bazett)) ≥450msec or QTc (Bazett) ≥480msec for subjects with bundle branch block
The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for this study will be the proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm (Missing, Switch or Discontinuation = Failure) 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) |
Secondary efficacy endpoints will include: the proportion of subjects with plasma HIV-1 RNA <50 c/mL and <400 c/mL over time; absolute values and change from Baseline in plasma HIV-1 RNA over time; absolute values and changes from Baseline in CD4+ cell counts over time, and incidence of disease progression (HIV-associated conditions, AIDS and death).
Safety endpoints will include: incidence and severity of adverse events (AEs) and laboratory abnormalities; the proportion of subjects who discontinue treatment due to AEs; absolute values and changes over time in laboratory parameters; change from Baseline in fasting lipids and glucose; changes from Baseline in renal and bone markers.
Heath outcomes endpoints will include: Change from Baseline in health related quality of life using SF-12 at Week 48, and treatment satisfaction (using the HIV Treatment Satisfaction Questionnaire) for subjects treated with DTG/ABC/3TC FDC and those treated with ATV+RTV+TDF/FTC FDC at weeks 4, 12, 24, and 48 (or withdrawal from the study).
Virology endpoints will include the incidence of treatment emergent genotypic and phenotypic resistance in subjects who meet confirmed virologic withdrawal criteria.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints to be assessed at various timepoints in the study; subjects are required to attend visits at Baseline, Weeks 4, 12, 24, 36 and 48. Subjects randomized to DTG/ABC/3TC may continue treatment and attend visits at 12 week intervals after Week 48 until drug is commercially available. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Canada |
| France |
| Italy |
| Mexico |
| Portugal |
| Puerto Rico |
| Russian Federation |
| South Africa |
| Spain |
| Thailand |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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