| 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 | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 evaluate the effect of a switch to MK-1439A compared with continuation of ATRIPLA on the incidence of Grade 2 or worse CNS toxicity (defined as at least one toxicity listed on the CNS toxicity questionnaire) at Week 12. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the effect of a switch from ATRIPLA to MK-1439A compared with continuation of ATRIPLA on the incidence of Grade 2 or worse CNS toxicity at Week 4 and at 24 weeks after the switch; To compare the change from baseline in CNS toxicity scores at Weeks 4 and 12 and at 24 weeks after the switch; To evaluate the effect of a switch from ATRIPLA to MK-1439A on fasting lipids measured by the change from baseline to Week 12 and at 24 weeks after the switch; To evaluate a switch from ATRIPLA to MK-1439A on virologic suppression as measured by the proportion of subjects with HIV-1 RNA below the limit of quantification (<40copies/mL) and <50 copies/mL at 24 weeks after the switch; To evaluate a switch from ATRIPLA to MK-1439A on continued immunologic restoration measured by change from baseline CD4 cell count and 24 weeks after the switch; To evaluate safety and tolerability of a switch from ATRIPLATM to MK-1439A through Week 12 and at 24 weeks after switch. |
|
| 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 |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time |
|
| E.3 | Principal inclusion criteria |
1. 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. Have had documentation of HIV-1 RNA < 50 copies/mL for at least 12 weeks prior to screening while on ATRIPLATM.
4. Have plasma HIV-1 RNA levels BLoQ (<40copies/mL) at the screening visit.
5. If genotyping was performed at any point prior to screening and results are available, the subject must have no known resistance mutations to any of the study agent components.
6. have at least one EFV-associated CNS toxicity of Grade 2 or worse intensity both at the time of screening and at Study Day 1 (BL); at least one of the Grade 2 or worse intensity CNS toxicity present at screening must also be present at Study day 1 with Grade 2 or worse intensity.
EFV associated CNS toxicity is defined as one of the following conditions listed on the CNS toxicity questionnaire: dizziness, depression/low mood, insomnia/sleeplessness, anxiety/nervousness, confusion, impaired concentration/attention, headache, somnolence/daytime sleepiness, aggressive mood/behavior, abnormal dreams.
7. have the following laboratory values at screening :
a) Alkaline phosphatase ≤ 3.0 x upper limit of normal (ULN) 0 b) AST (SGOT) and ALT (SGPT) ≤ 5.0 x ULN
c) Hemoglobin ≥9.0 g/dL (if female) or ≥10.0 g/dL (if male).
8. Calculated creatinine clearance ≥ 50mL/min
9. 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 (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).
10. be highly unlikely to become pregnant or to impregnate a partner
Study Extension 1 Eligibility:
11. have completed the Study Week 24 (for ISG) or Study Week 36 (for
DSG) visit.
12. be considered, in the opinion of the investigator, to have derived benefit from study participation through Study Week 24 (for ISG) or Study Week 36 (for DSG).
13. 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.
14. understand the procedures in the study extension 1 and provide written informed consent to enter the study extension 1, thus continuing for approximately 2 years (96 weeks) beyond the base study.
Study Extension 2 Eligibility:
15. have completed the Study Week 120 (for ISG) or Study Week 132 (for DSG) visit.
16. be considered, in the opinion of the investigator, to have derived benefit from MK-1439A by Study Week 120 (for ISG) or Study Week 132 (for DSG).
17. 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.
18. understand the procedures in the study extension and provide written informed consent to enter study extension 2, thus continuing treatment with MK-1439A until it is locally available or for up to approximately 2 years (whichever comes first) beyond study extension 1. |
|
| 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 ongoing Grade 4 CNS toxicity during screening period that requires a prompt change in ART.
4. 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, emtricitabine, entecavir, lamivudine or tenofovir.
5. has documented or known resistance to study drugs including MK-
1439, EFV (Efavirenz), lamivudine, emtricitabine and/or tenofovir
(based on genotyping performed prior to the initiation of treatment with
ATRIPLATM) 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 lamivudine, emtricitabine and tenofovir includes the following mutations: K65R, M41L, T69S (insertion complex), Q151M, M184I, M184V, L210W, T215F, T215Y, K219E, K219Q, D67N, K70R, K70E.
6. 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.
7. 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
8. requires or is anticipated to require any of the prohibited medications noted in the protocol
9. has significant hypersensitivity or other contraindication to any of the components of the study drugs as determined by the investigator
10. has a current (active) diagnosis of acute hepatitis due to any cause.
11. 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 Child-Pugh Class C score or Pugh-Turcotte (CPT) score > 9.
12. is pregnant, breastfeeding, or expecting to conceive.
13. 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).
14. 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 proportion of subjects with at least one CNS toxicity of at least Grade 2 intensity at Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of subjects with at least one CNS toxicity of at least Grade 2 intensity at Week 4
2. Change from baseline in the proportion of subjects with at least one CNS toxicity of at least Grade 2 intensity at 24 weeks post-switch
3. Change from baseline in CNS toxicity score at Weeks 4 and 12
4. Change from baseline in CNS toxicity score at 24 weeks post-switch
5. The proportion of subjects with HIV-1 RNA < 50 copies/mL (and <40 copies/mL) at 24 weeks post-switch
6. Change from baseline in fasting lipids at Week 12
7. Change from baseline in fasting lipids at 24 weeks post-switch
8. Change from baseline in CD4 cell count at 24 weeks post-switch
9. Overall safety and tolerability through Week 12
10. Overall safety and tolerability through 24 weeks post-switch
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 4 and 12 and 24 weeks after the switch. |
|
| 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) | 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.8.1.7.1 | Other trial design description |
| Blinded treatment for the first 12 weeks, open label treatment thereafter |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| LPLV - Last Patient Last Visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
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