| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral naïve HIV-infected patients. |
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| E.1.1.1 | Medical condition in easily understood language |
| Human immunodeficiency virus type 1 (HIV-1) infection in HIV-infected patients not treated previously. |
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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 | 18.1 |
| 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 |
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| 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 |
Part I
1. Objective: Evaluate the safety and tolerability of MK-1439, at the studied doses, compared to efavirenz, each in combination with TRUVADA™ for 24 weeks.
2. Objective: Evaluate the antiretroviral activity of MK-1439, at the studied doses, compared to efavirenz, each in combination with TRUVADA™ for 24 weeks, as measured by the proportion of patients with HIV RNA <40 copies/mL at Week 24.
Part I and Part II Combined
1. Objective: Evaluate the safety and tolerability of MK-1439, at the final selected dose, compared to efavirenz, each in combination with TRUVADA™ for 24 weeks.
2. Objective: Evaluate the central nervous system adverse events (CNS events) associated with the use of the final selected dose of MK-1439 compared with efavirenz, each in combination with TRUVADA™ as measured by the proportion of patients with CNS events by Week 8 and by Week 24.
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| E.2.2 | Secondary objectives of the trial |
Part I
Objective: Evaluate the antiretroviral activity and immunological effect of MK-1439, at the studied doses, compared to efavirenz, each in combination with TRUVADA™ for 24 weeks, as measured by a) proportion of patients with HIV RNA <200 copies/mL at Week 24, and b) change from baseline in CD4 cell count at Week 24.
Part I and Part II Combined
1. Objective: Evaluate the antiretroviral activity and immunological effect of MK-1439, at the final selected dose, compared to efavirenz, each in combination with TRUVADA™ at 24 weeks, as measured by a) proportion of patients with HIV RNA <200 copies/mL at Week 24, and b) change from baseline in CD4 cell count at Week 24.
2. Objective: Evaluate the safety and antiretroviral activity and immunological effect of MK-1439, at the final selected dose, compared to efavirenz, each in combination with TRUVADA™ for 48 and 96 weeks. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is a male or female of at least 18 years of age on the day of signing the informed consent. Patient provides written informed consent for the trial. The patient will also provide consent for Future Biomedical Research; however, the patient may participate in the main trial without participating in Future Biomedical Research.
2. Patient is HIV-1 positive as determined by a positive ELISA and has screening plasma HIV RNA (completed by the central laboratory) ≥ 1,000 copies/mL within 45 days prior to the treatment phase of this study.
3. Patient has a screening CD4 cell count ≥100 cells/mm3(completed by the central laboratory) within 45 days prior to the treatment phase of this study.
4. Patient is naïve to antiretroviral therapy (ART).
5. Patient has had the following laboratory values within 45 days prior to the treatment phase of this study:
a) Serum creatinine within normal limits.
b) INR ≤1.2
c) Urinalysis within normal limits.
Note: Clinically insignificant abnormalities on urinalysis may be permitted after retest, provided these are documented as clinically insignificant per investigator.
d) Hemoglobin ≥9.0 g/dL (if female) or ≥10.0 g/dL (if male).
e) Absolute neutrophil count ≥1000/mm3.
f) Platelet count ≥100,000/ mm3.
g) Total serum bilirubin less than or equal to the upper limit of normal.
h) Alkaline phosphatase <1.5 x upper limit of normal.
i) AST (SGOT) and ALT (SGPT) <1.5 x upper limit of normal.
6. In the opinion of the investigator, the patient should be considered clinically stable with no signs or symptoms of acute infection, at the time of entry into the study; i.e., clinical status and all chronic medications should be unchanged for at least 2 weeks prior to the start of treatment in this study.
7. Patient who is of reproductive potential agrees to:
• True abstinence: Abstinence is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., abstinence only on certain calendar days, abstinence only during ovulation period, use (or have their of symptothermal method, use of post-ovulation method) and withdrawal are not acceptable methods of
contraception].
• Personal use (or partner use) of 2 acceptable methods of birth control throughout the study and for 12 weeks post study. Acceptable methods of birth control are: oral contraceptives, intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, implantable contraceptives and vasectomy. |
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| E.4 | Principal exclusion criteria |
1. Male patient is planning to impregnate or provide sperm donation for the duration of the study plus an additional 12 weeks. Female patient is pregnant or breast-feeding, or expecting to conceive or donate eggs for the duration of the study plus an additional 12 weeks.
2. Patient has received any approved or experimental antiretroviral agents or is anticipated to receive such medications (beyond those outlined as study medication in this protocol) during the course of the study.
3. Patient has used any immunomodulators or immunosuppressive therapy within one month prior to treatment in this study. Short courses of corticosteroids (e.g., as for asthma exacerbation) are allowed.
4. Patient requires or is anticipated to require any of the prohibited medications noted in Section 3.2.1.
5. Patient has been treated for a viral infection other than HIV, such as hepatitis B, with an agent that is active against HIV including but not limited to adefovir, tenofovir disoproxil fumarate, lamivudine, emtricitabine, or entecavir.
Note: Patients may be enrolled if treatment occurred prior to the diagnosis of HIV.
6. Patient has significant hypersensitivity or other contraindication to any of the components of the study drugs (emtricitabine, tenofovir disoproxil fumarate, and/or efavirenz).
7. Patient has documented or known HIV resistance to emtricitabine, tenofovir disoproxil fumarate, and/or efavirenz, based on genotypic resistance analysis.
8. Patient has a history of renal or urinary obstructive disease, requires dialysis (hemodialysis, continuous ambulatory peritoneal dialysis [CAPD], or other forms of dialysis), or has a calculated creatinine clearance at time of screening of ≤80 mL/min, based on the Cockcroft-Gault equation which is as follows (and 0.85 times this value for females):
Clcr (mL/min) = (140–age) x weight (in kg)____
72 x serum creatinine (mg/dL)
9. Patient with active Hepatitis C virus (HCV) co-infection (defined as detectable HCV RNA) or Hepatitis B virus (HBV) co-infection (defined as HBsAg positive). Patients with prior/inactive HCV infection (defined as undetectable HCV RNA) or past HBV infection (defined as HBsAg negative and HBsAb positive) may be enrolled.
10. Patient has a history of alcohol or other substance abuse which in the opinion of the investigator would interfere with patient compliance or safety.
11. Patient has any condition or prestudy laboratory abnormality, or history of any illness, which, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering the study drugs to the patient.
12. Patient has participated in a study with an investigational compound/device within one month of signing informed consent or is anticipating to participate in such a study involving an investigational compound/device during the course of this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients achieving HIV RNA <40 copies/mL at Week 24, and the safety and tolerability of MK-1439 compared with efavirenz when each is given in combination with TRUVADA™ through Week 24. |
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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) |
1) Frequency of CNS events by Weeks 8 and 24. Secondarily, longer-term safety and efficacy data will be evaluated at Week 48 and Week 96.
2) Efficacy Endpoints: Proportions of Patients With Virologic Responses, Change from Baseline in CD4 cell counts, Time-to-Loss-Of-Virologic-Response (TLOVR), Virologic Failure, Resistance.
3) Safety Endpoints: Adverse Experiences, Central Nervous System (CNS) Events, Predefined Limits of Change in Laboratory Parameters.
4) PK Endpoints |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| France |
| Germany |
| Italy |
| Mexico |
| Netherlands |
| Poland |
| Puerto Rico |
| Romania |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
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| 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
|
| Last visit of last patient. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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