| 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 |
Base Study:
1) To evaluate the non-inferior antiretroviral activity of MK-1439A q.d. compared to ATRIPLA q.d. as measured by the proportion of subjects achieving HIV-1 RNA <50 copies/mL (by the Abbott RealTime HIV-1 Assay) at Week 48.
2) To evaluate the safety and tolerability of MK-1439A q.d. compared with ATRIPLA™ q.d. as measured by the proportion of subjects with neuropsychiatric adverse events in the following categories:
-Dizziness
-Sleep disorders and disturbances
-Altered Sensorium
|
|
| E.2.2 | Secondary objectives of the trial |
Base Study:
1)Safety and tolerability of MK-1439A q.d. compared to ATRIPLA™q.d. as assessed by review of accumulated safety data by Week 48 and Week 96 AND as measured by proportion of subjects with neuropsychiatric adverse events in the following categories:
•Depression and suicide/self-injury
•Psychosis and psychotic disorders
And events across the categories of: dizziness, sleep disorders, altered sensorium AND as measured by the time to discontinuation from study due to an AE.
2)Effect of MK-1439A q.d. compared to ATRIPLA™q.d. on fasting LDL C and HDL C as measured by the mean change from baseline at Week 48.
3)Immunologic effect of MK-1439A q.d. compared to ATRIPLA™q.d., as measured by the change from baseline in CD4 cell count at Week 48 and Week 96.
4)Superior antiretroviral (ARV) activity of MK-1439A q.d. compared to ATRIPLA q.d. as measured by the proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 48 AND at Week 96 5)Evaluate PK of MK-1439 and the PK-PD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.be at least 18 years of age on the day of signing the informed consent
2.understand the study procedures and voluntarily agree to participate by giving written informed consent (or have a legal representative provide written informed consent, if considered acceptable by local regulatory agencies and/or ERCs/IRBs) for the trial. The subject or his/her legal representative (if considered acceptable by local
regulatory agencies and/or ERCs/IRBs)may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
3.be HIV-1 positive as determined by a positive result on an enzyme-immunoassay, have screening plasma HIV-1 RNA (determined by the central laboratory) ≥1000 copies/mL within 45 days prior to the treatment phase of this study, and have HIV treatment indicated based on physician assessment. Local treatment guidelines should be considered in the decision to initiate therapy.
4.be naïve to ART including investigational antiretroviral agents.
5.have the following laboratory values at screening within 45 days prior to the treatment phase of this study: a) Alkaline phosphatase ≤3.0 x upper limit of normal b)AST (SGOT) and ALT (SGPT) ≤5.0 x upper limit of normal c)Hemoglobin ≥9.0 g/dL (if female) or ≥10.0 g/dL (if male)
6. calculated creatinine clearance at the time of screening ≥ 50 mL/min., based on the Cockcroft-Gault equation
7.clinically stable with no signs or symptoms of active infection at the time of entry into the study.
8.be highly unlikely to become pregnant or to impregnate a partner.
In order to be eligible for participation in the study extension 1 at the Week 96 visit, the subject must:
9. have completed the Week 96 visit.
10. be considered, in the opinion of the investigator, to have derived benefit from study participation through Week 96.
11. be considered, in the opinion of the investigator, a clinically appropriate candidate for an additional 96 weeks of treatment with MK-1439A following the end of the base study.
12. understand the procedures in the study extension 1 and provide written informed consent to enter the study extension, thus continuing for approximately 2 years beyond the base study.
In order to be eligible to continue receiving study treatment in study extension 2 at the
Week 192 visit, the subject must:
13. have completed the Week 192 visit.
14. be considered, in the opinion of the investigator, to have derived benefit from MK-1439A by Week 192 of the study.
15. be considered, in the opinion of the investigator, a clinically appropriate candidate for an additional 2 years (additional 96 weeks) of treatment with MK-1439A.
16. understand the procedures in study extension 2 and have provided written informed consent to enter study extension 2, thus continuing until MK-1439A is commercially available once approved in the local country, or for up to approximately 2 years (whichever comes first) beyond study extension 1.
In order to be eligible to continue receiving study treatment in study extension 3 at the Week 288 visit, the subject must:
17. have completed the Week 288 visit.
18. be considered, in the opinion of the investigator, to have derived benefit from MK-1439A by Week 288 of the study.
19. be considered, in the opinion of the investigator, a clinically appropriate candidate for an additional 2 years (additional 96 weeks) of treatment with MK-1439A.
20. understand the procedures in study extension 3 and have provided written informed consent to enter study extension 3, thus continuing until MK-1439A is commercially available once approved in the local country, or for up to approximately 2 years (whichever comes first) beyond study extension 2. |
|
| E.4 | Principal exclusion criteria |
1.has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study or interfere with the subject’s participation for the full duration of the study, such that it is not in the best interest of the subject to participate.
2.is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history of drug or alcohol abuse or dependence. The nature and potential clinical context of the subject's illicit drug use, in relation to their exclusion from this trial, will be at the discretion of the Investigator.
3.has been treated for a viral infection other than HIV-1, such as hepatitis B, with an agent that is active against HIV-1, including, but not limited to, adefovir, tenofovir, entecavir, emtricitabine, or lamivudine.
4.has documented or known resistance to study drugs including MK-1439, efavirenz, emtricitabine, lamivudine, and/or tenofovir, as defined below:
a.Resistance to MK-1439 or efavirenz for the purpose of this study includes the following NNRTI mutations: L100I, K101E, K101P, K103N, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, P225H, F227C, F227L, F227V, M230L, M230I
b.Resistance to emtricitabine, lamivudine and tenofovir includes the following mutations: K65R, M41L, T69S (insertion complex), Q151M, M184I, M184V, L210W, T215F, T215Y, K219E, K219Q, D67N, K70R and K70E.
5.has participated in a study with an investigational compound/device within 30 days prior to signing informed consent or anticipates participating in such a study involving an investigational compound/device during the course of this study.
6.has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this study or is anticipated to need them during the course of the study.
Note: Short courses of corticosteroids (e.g., as for asthma exacerbation) will be allowed.
7.requires or is anticipated to require any of the prohibited medications noted in the protocol.
8.has significant hypersensitivity or other contraindication to any of the components of the study drugs as determined by the investigator.
9.has a current (active) diagnosis of acute hepatitis due to any cause.
10. has evidence of decompensated liver disease manifested by the presence of or a history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver diseases or has liver cirrhosis and a CPT score > 9.
11. is pregnant, breastfeeding, or expecting to conceive.
12.is female and is expecting to donate eggs (at any time during the study) or is male and is expecting to donate sperm (at any time during the study).
13.is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of subjects achieving HIV-1 RNA < 50 copies/mL (by the Abbott RealTime HIV-1 Assay) at Week 48. The primary safety endpoint is the proportion of subjects with certain neuropsychiatric adverse events by Week 48 in the following categories: dizziness, sleep disorders and disturbances and altered sensorium. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Safety and tolerability by Week 48 and Week 96
2.Fasting LDL-C as measured by the mean change from baseline at Week 48
3.Fasting non-HDL-C as measured by the mean change from baseline at Week 48
4.Proportion of subjects with neuropsychiatric AEs in the following categories by Week 48: depression and suicide/self-injury and psychosis and psychotic disorders.
5.Proportion of subjects with at least one neuropsychiatric AE in any of the 5 categories of: dizziness, sleep disorders and disturbances, altered sensorium, depression and suicide/self-injury, and psychosis and psychotic disorders.
6.Time to discontinuation from study due to an adverse experience
7.Change from baseline in CD4 cell count at Week 48 and Week 96
8.The proportion of subjects achieving HIV-1 RNA
< 50 copies/mL (by the Abbott RealTime HIV-1 Assay) at Week 96
9.The proportion of subjects achieving HIV-1 RNA
< 40 copies/mL (BLoQ) (by the Abbott RealTime HIV-1 Assay) at Week 48 and Week 96
10. PK of MK-1439 and the PK-PD association |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Treatment Weeks 48 and 96 |
|
| 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 | Yes |
| 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 for the base study then open-label for the study extensions |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 38 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Guatemala |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| Puerto Rico |
| South Africa |
| Taiwan |
| Thailand |
| United States |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Belgium |
| Denmark |
| Portugal |
| Russian Federation |
| 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
|
| Last subject’s last study-related phone call or visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| 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 | 9 |
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