| 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 | 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 |
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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 |
Base Study:
To evaluate the antiretroviral activity of MK-1439 100 mg q.d., compared to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as measured by the proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 48.
Study Extension:
To assess data on long-term efficacy and safety of MK-1439 100 mg q.d. administered for up to 192 weeks (approximately 4 years) total in subjects enrolled in the study extension 1.
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| E.2.2 | Secondary objectives of the trial |
Base Study:
(1) To evaluate the safety and tolerability of MK-1439 100 mg q.d., compared to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as assessed by review of the accumulated safety data at Week 48 and Week 96.
(2) To evaluate the effect on fasting serum lipids of MK-1439 100 mg q.d. compared to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as measured by mean change from baseline in fasting serum lipids at Week 48.
(3) To evaluate the safety and tolerability of MK-1439 100 mg q.d. compared to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRU VADA™ or EPZICOM™/KIVEXA™, as measured by the time to discontinuation from study due to an adverse experience.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Future Biomedical Research |
|
| 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) for the trial.
3. be HIV-1 positive as determined by a positive result on an enzymeimmuno assay, 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 antiretroviral therapy (ART) including investigational antiretroviral agents.
5. have the following laboratory values at screening within 45 days prior to the treatment phase of this study:
- Alkaline phosphatase ≤3.0 x upper limit of normal
- AST (SGOT) and ALT (SGPT) ≤5.0 x upper limit of normal
6. have a calculated creatinine clearance at time of screening ≥50mL/min, based on the Cockcroft-Gault equation which is as follows :
Clcr (mL/min) = (140-age) x weight (in kg)/72 x serum creatinine (mg/dL) for males and Clcr (mL/min) = [(140-age) x weight (in kg)/72 x serum creatinine (mg/dL)] x 0.85 for females
7. in the opinion of the investigator, be considered 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 since the subject meets at least one of the following categories: a) The
subject is a male who is not of reproductive potential, defined as a male who has azoospermia (whether due to having had a vasectomy or due to
an underlying medical condition). b) The subject is a female who is not of reproductive potential, defined as a female who either: (1) is
postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR (3) has a
congenital or acquired condition that prevents childbearing. c) The subject is a female or a male who is of reproductive potential and agrees
to avoid becoming pregnant or impregnating a partner while receiving study drug and for 14 days after the last dose of study drug by
complying with one of the following: (1) practice abstinence† from heterosexual activity OR (2) use (or have their partner use) acceptable
contraception during heterosexual activity. Contraceptives containing ethinyl estradiol cannot be used as a method
of birth control in the base study due to an interaction with ritonavir which may reduce their effectiveness. Therefore, it is recommended that a
condom or other non-hormonal method of contraception should be used instead. Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
• intrauterine device (IUD)
• vasectomy of a female subject's male partner
Combination method (requires use of two of the following):
• diaphragm with spermicide (cannot be used in conjunction with
cervical cap/spermicide)
• cervical cap with spermicide (nulliparous women only)
• contraceptive sponge (nulliparous women only)
• male condom or female condom (cannot be used together)
During the study extensions, subjects may use hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection.
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's
preferred and usua l lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
For study extension 1 participation, 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 by Week 96.
11.be considered, in the opinion of the investigator, a clinically appropriate candidate for 96 weeks of treatment.
12.understand the procedures in study extension 1 and provide written informed consent.
For study extension 2 participation, the subject must:
13. have completed the Week 192 visit.
14. be considered, in the opinion of the investigator, to have derived benefit from MK1439 by Week 192.
15. be considered, in the opinion of the investigator, a clinically appropriate candidate for additional 96 weeks of treatment with MK-1439.
16. understand the procedures in the study extension and have provided written informed consent, thus continuing until MK-1439 is locally available or for up to approximately 2 years (whichever comes first) beyond study extension 1. |
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| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
1. has a history or current evidence of any condition, therapy, laboratory abnormali ty 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.
Note: Subjects may be enrolled if treatment occurred prior to the diagnosis of HIV.
4. has documented or known resistance to study drugs including MK-1439, darunavir, ritonavir, emtricitabine, tenofovir, abacavir and/or lamivudine, as defined below:
a. Resistance to MK-1439, for the purpose of this study, includes mutants containing the following 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 darunavir/ritonavir includes any of the following PI mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, or L89V.
c. Resistance to emtricitabine, tenofovir, abacavir and lamivudine includes the following mutations: M184V/I, K65R, M41L, D67N, K70R/E, T69S, L210W,
T215Y/F, K219Q/E, L74V, and Y115F.
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 (Refer to Section 5.5).
8. has significant hypersensitivity or other contraindication to any of the components of the study drugs.
9. has a current (active) diagnosis of acute hepatitis due to any cause.
Note: Subjects with chronic hepatitis B and C may enter the study as long as they fulfill all entry criteria, have stable liver function tests, and have no significant impairment of hepatic synthetic function (significant impairment of hepatic synthetic function is defined as a serum albumin <2.8 mg/dL or an INR >1.7 in the absence of another explanation for the abnormal laboratory value).
10. is pregnant, breastfeeding, or expecting to conceive at any time during the study.
11. 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.
12 is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 48. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy Endpoints
- The proportion of subjects achieving HIV-1 RNA <40 copies/mL at Week 96.
- Change from baseline in CD4 cell count
- Time to Loss Of Virologic Response (TLOVR)
- Protocol Defined Virologic Failure (PDVF)
- Viral Resistance.
Safety Endpoints
- Change From Baseline in Fasting Lipids
- Adverse Experiences
- Time to Discontinuation from Study Due to Adverse Experience
- Predefined Limits of Change in Laboratory Parameters |
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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 | No |
| 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) | 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 | No |
| 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 base study, then open-label for additional 192 weeks (study extensions 1 and 2) |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Chile |
| Colombia |
| Mexico |
| Peru |
| South Africa |
| United States |
| Russian Federation |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Romania |
| Spain |
| Puerto Rico |
| 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 visit of last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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