Switch to MK-1439A (once a day) from a Ritonavir-boosted Protease Inhibitor regimen in HIV-1 infected subjects

• Register: EUCTR
• Last refreshed on: 20 November 2023
• Main ID: EUCTR2014-005550-18-AT
• Date of registration: 18/05/2015
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: Switch to MK-1439A (once a day) from a Ritonavir-boosted Protease Inhibitor regimen in HIV-1 infected subjects
• Scientific title: A Phase III Multicenter, Open-Label, Randomized Study to Evaluate a Switch to MK-1439A in HIV-1-Infected Subjects Virologically Suppressed on a Regimen of a Ritonavir-boosted Protease Inhibitor and Two Nucleoside Reverse Transcriptase Inhibitors (NRTIs). SUBTITLE: Amendment to Include Switches From Additional Antiretroviral Regimens - Switch to MK-1439A from PI, EVG- or NNRTI-based regimen for HIV-1 infection
• Date of first enrolment: 22/06/2015
• Target sample size: 660
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-005550-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Denmark, France, Germany, Guatemala, Israel, Italy, Korea, Republic of, Mexico, New Zealand, Peru, Poland, Puerto Rico, Russian Federation, South Africa, Spain, Switzerland, Taiwan, United Kingdom, United States

Contacts

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Key inclusion & exclusion criteria

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 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 plasma HIV-1 RNA levels BLoQ (<40 copies/mL by the Abbott RealTime HIV-1 Assay as determined by the central laboratory) at the screening visit.
4. have been receiving antiretroviral therapy with a ritonavir- or cobicistat-boosted PI (specifically atazanavir, darunavir or lopinavir) or cobicistat-boosted elvitegravir or an NNRTI (specifically, efavirenz, nevirapine or rilpivirine), each given in combination with 2 NRTIs (and no other ART) continuously with HIV-1 RNA at undetectable levels for =6 months prior to the screening visit (as measured at =2 sequential time points) and have no history of prior virologic failure.
5. be receiving his/her first or second PI-based antiretroviral regimen
6. have no history of using any approved or experimental NNRTI for any length of time.
7. have had a genotype prior to starting his/her initial antiretroviral regimen and have no known resistance to any of the study agents (MK-1439, TDF, or lamivudine).
8. be on either no lipid-lowering therapy or on a stable dose of lipid-lowering therapy at the time of enrollment
9. have the following laboratory values at screening within 30 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)
10. Have a calculated creatinine clearance at the time of screening = 50 mL/min
11. be clinically stable with no signs or symptoms of active infection at the time of entry into the study.
12. be highly unlikely to become pregnant or to impregnate a partner.

In order to be eligible for participation in the study extension at the
Week 48 visit, the subject must:
13. have completed the Week 48 visit.
14. be considered, in the opinion of the investigator, to have derived
benefit from study participation through Week 48.
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 the study extension 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 144 visit the subject must:
17. have completed the week 144 visit
18. be considered, in the opinion of the investigator, to have derived benefit from MK-1439A by Week 144 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 the study extension and have provided written informed consent to enter study extension 2, thus continuing until MK-1439A is locally available or for up to approximately 2 years (whichever comes first) be
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, emtricitabine, entecavir, lamivudine or tenofovir.
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, lamivudine, and/or tenofovir, as defined below:
a. Resistance to MK-1439 for the purpose of this study is considered to include the following NNRTI mutations (as single mutations or components of double or triple mutations): L100I, K101E, K101P, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181I, Y181V, Y188C, Y188H, Y188L, G190S, H221Y, L234I, P225H, F227C, F227L, F227V, M230L, M230I.
b. Resistance to 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.
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 Child-Pugh Class C score or Pugh-Turcotte (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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Virus Diseases [C02]

Human Immunodeficiency Virus-1 infection
MedDRA version: 20.1 Level: LLT Classification code 10068341 Term: HIV-1 infection System Organ Class: 100000004862

Intervention(s)

Product Name: 1439A
Product Code: MK-1439A
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: doravirine
Other descriptive name: MK-1439
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: LAMIVUDINE
CAS Number: 134678-17-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-
INN or Proposed INN: TENOFOVIR DISOPROXIL FUMARATE
CAS Number: 202138-50-9
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-

Pharmaceutical Form: Tablet
INN or Proposed INN: RITONAVIR
CAS Number: 155213-67-5
Other descriptive name: Ritonavir
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
INN or Proposed INN: LOPINAVIR
CAS Number: 192725-17-0
Other descriptive name: Lopinavir
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Pharmaceutical Form: Tablet
INN or Proposed INN: RITONAVIR
CAS Number: 155213-67-5
Other descriptive name: Ritonavir
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Pharmaceutical Form: Tablet
INN or Proposed INN: DARUNAVIR
CAS Number: 206361-99-1
Other descriptive name: Darunavir
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 600-

Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ATAZANAVIR
CAS Number: 198904-31-3
Other descriptive name: atazanavir
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-

Trade Name: Tybost 150 mg film-coated tablets
Product Name: Cobicistat
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: COBICISTAT
CAS Number: 1004316-88-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentra

Primary Outcome(s)

Secondary Objective: To evaluate the:
1. effect on fasting LDL-C and fasting non-HDL-C of a switch to MK- 1439A on Study Day 1 compared with continuation of a ritonavirboosted, PI-based regimen for 24 weeks
2. non-inferior antiretroviral activity of an immediate switch to MK- 1439A on Study Day 1 compared with continuation of a ritonavir-or obicistat-boosted PI-based or cobicistat-boosted elvitegravir-based or NNRTI-based regimen for 24 weeks, superior antiretroviral activity of an immediate switch to MK-1439A on Study Day 1 compared with continuation of a ritonavir-or cobicictat-boosted PI –based or cobicistatboosted elvitegravir-based or NNRTI-based regimen for 24 weeks
3. antiretroviral activity of an immediate switch to MK-1439A on Study Day 1 compared with continuation of a ritonavir-or cobicistat-boosted PI-based or cobicistat-boosted elvitegravir-based or NNRTI-based regimen for 24 weeks

Refer to protocol for additional secondary objectives

Primary end point(s): The primary efficacy hypothesis of this study compares the proportion of subjects maintaining HIV-1 RNA <50 copies/mL at Study Week 48 in the Immediate Switch Group with the proportion of subjects maintaining HIV-1 RNA <50 copies/mL at Study Week 24 in the Delayed Switch Group.

Main Objective: To evaluate the non-inferior antiretroviral activity of an immediate switch to MK-1439A on Study Day 1 compared with continuation of a ritonavir- or cobicistat-boosted PI-based or cobicistat-boosted
elvitegravir-based or NNRTI-based regimen for 24 weeks, as measured by the proportion of subjects maintaining HIV-1 RNA <50 copies/mL by the Abbott RealTime HIV-1 Assay at Study Week 48 in the Immediate Switch Group and at Study Week 24 in the Delayed Switch Group.

Timepoint(s) of evaluation of this end point: Study Week 48 in the Immediate Switch Group and Study Week 24 in the Delayed Switch Group

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Study Week 24 and 48

Secondary end point(s): Secondary and exploratory measurements for efficacy include the proportion of subjects maintaining HIV-1 RNA <40 copies/ mL, the proportion of subjects with HIV-1 RNA =50 copies/mL based on the FDA snapshot approach, change from baseline in CD4 cell counts, time to loss of virologic response (TLVOR), and viral resistance for subjects who meet the virologic failure criteria and whose virus can be amplified.

Secondary ID(s)

MK-1439A-024

2014-005550-18-DE

NCT02397096

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Ethics review

Status: Approved
Approval date: 27/05/2015
Contact: