| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus - 1 (HIV-1) infection |
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| E.1.1.1 | Medical condition in easily understood language |
| Human Immunodeficiency Virus - 1 (HIV-1) infection |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 assess the antiviral activity of DTG/3TC in antiretroviral naïve HIV-1 infected adolescents. |
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| E.2.2 | Secondary objectives of the trial |
To assess the early antiviral activity of DTG/3TC and to determine the extended long term (≥48 weeks) safety, tolerability, and viral response of DTG/3TC in antiretroviral naïve HIV-1 infected adolescents.
To evaluate the effect of DTG/3TC on immunologic response from baseline to 24 and 48 weeks.
To assess the safety and tolerability of DTG/3TC in HIV-1 infected adolescents at 24 and 48 weeks.
To assess DTG and 3TC exposure and to evaluate the steady-state pharmacokinetics of DTG and 3TC in HIV-1 infected adolescents.
To assess development of viral resistance to DTG and 3TC in participants experiencing protocol-defined virologic failure (i.e. meeting confirmed virologic withdrawal criteria).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. HIV-1 infected adolescents more than equal to 12 to less than 18 years of age at the time of signing the informed consent form.
2. Weight more than equal to 25 kg at the time of signing the informed consent form.
3. Screening plasma HIV-1 RNA between 1,000 and less than equal to 500,000 c/mL.
4. Antiretroviral-naïve (defined as no prior therapy with any antiretroviral agent for the treatment of HIV following a diagnosis of HIV-1 infection).
- Participants who received antiretroviral therapy for prevention of mother to child transmission of HIV in the first 3 months of life are allowed.
- Participants who received HIV post-exposure prophylaxis (PEP) or preexposure prophylaxis (PrEP) in the past are allowed as long as the last PEP/PrEP dose was more than 6 months from HIV diagnosis or there is documented HIV seronegativity at least 2 months after the last prophylactic dose and prior to the date of HIV diagnosis. The study site must have documentation of the seronegative test available and placed into the study source documents.
5. Male or female.
A female participant 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 hCG test before Enrollment) and not lactating.
Female participants who are of child bearing potential and who are engaging in sexual activity that could lead to pregnancy, must agree to use one of the birth control methods listed in Appendix 10 (Section 12.10) of the protocol from 28 days prior to the first dose of study medication, and until 4 weeks after the last dose of study medication (and completion of the Follow-up visit). Condoms are recommended in addition, because their appropriate use is the only contraception method effective for preventing HIV-1 transmission.
The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception.
All participants 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.
6. The participant’s parent(s) or legal guardian or the participant is capable of giving signed informed consent as described in Section 12.4.3 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Where applicable, participants must provide written assent. |
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| E.4 | Principal exclusion criteria |
1. Females 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 and/or Category C or WHO Stage 4 disease (Appendix 6, Section 12.6of the protocol), except cutaneous Kaposi’s sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells/mm3 or CD4% <15%.
3. Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification (Section 12.2 of the protocol).
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:
- Participants positive for HBsAg are excluded;
- Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
NOTE: Participants 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 (See Section 12.11, Appendix 11: Decision Flow- Screening Tests for Hepatitis B Virus Serology, Interpretation and Action).
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). Participants who are at least 24 hours post completed treatment are eligible.
8. History or sensitivity to any of the study medications or their components or drugs of their class, or a history of drug or other allergy that in the opinion of the Investigator or Medical Monitor contraindicates participation.
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 localized malignancies require agreement between the investigator and the Study Medical Monitor for inclusion of the participant.
10. Participants 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.
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 with documented activity against HIV-1 in vitro within 28 days of first dose of study treatment.
14. Receipt of any prohibited mediation listed in Section 7.9.2 of the protocol and inability or unwillingness to switch to an alternative medication.
15.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.
16. Any evidence of pre-existing viral resistance based on the presence of any major resistance-associated mutation [International Antiviral Society -USA, 2017] 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 participant’s participation in the study of an investigational compound.
19. Alanine aminotransferase (ALT) more than equal to 5 times the upper limit of normal (ULN) or ALT more than equal to 3xULN and bilirubin more than equal to 1.5xULN (with >35% direct bilirubin).
20. Creatinine clearance of <50 mL/min/1.73 m2 using the Schwartz equation method.
21. Children who are wards of the state or government. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of participants with plasma HIV-1 RNA less than 50 c/mL at Week 48 using the Snapshot algorithm (ITT-E population.
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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) |
• Proportion of participants with plasma HIV 1 RNA <200 and <50 copies/mL at Week 24, Week 96 and Week 144.
• Proportion of participants with plasma HIV 1 RNA <200 copies/mL at Week 48
• Incidence and severity of AEs and laboratory abnormalities through 144 weeks
• Proportion of participants who discontinue treatment due to AEs through 144 weeks
• Safety and tolerability assessments at Weeks 96 and 144.
• Viral load monitoring after Week 48 through Week 144
• Change from baseline in CD4+ and CD8+ cell count and ratio at Week 24 and 48.
• Incidence of disease progression (HIV associated conditions, acquired immunodeficiency syndrome (AIDS), and death) through Weeks 24 and 48.
• Incidence and severity of AEs and laboratory abnormalities through 24 and 48 weeks
• Proportion of participants who discontinue treatment due to AEs through 24 and 48 weeks
• Steady-state plasma PK parameters of DTG and 3TC will be assessed using intensive PK collected in a subset of participants.
• Incidence of observed genotypic and phenotypic resistance to DTG and 3TC for participants meeting confirmed virologic withdrawal criteria. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 96, week 144, end of study |
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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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Kenya |
| South Africa |
| Thailand |
| United States |
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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
|
| The end of the study is defined as the date of the last visit of the last participant in the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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