臨床研究等提出・公開システム

A Phase 3, Randomized, Clinical Study in HIV-1-Infected Heavily Treatment-Experienced Participants Evaluating the Antiretroviral Activity of Blinded Islatravir (ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/ISL), Each Compared to Placebo, and the Antiretroviral Activity, Safety, and Tolerability of Open-Label DOR/ISL

DOR/ISL in heavily treatment-experienced participants

35

Of the 35 participants randomized in this study, a mean age was 48.5 years, 77.1% were male and 22.9% were female. Overall, 57.1% of participants were White, 31.4% were Black or African American, and 5.7% were Asian.

Seven participants were randomized to Arm 1 (Islatravir [ISL] + ART), 14 participants to Arm 2 (Doravirine [DOR] + ART), 7 participants to Arm 3 (DOR/ISL + ART), and 7 participants to Arm 4 (placebo + ART). All participants received study intervention. At the data cutoff (21-Nov-2022), 7, 12, 4, and 7 participants in Arm 1 (ISL + ART), Arm 2 (DOR + ART), Arm 3 (DOR/ISL + ART), and Arm 4(placebo + ART), respectively, were ongoing in the study, and 2 participants in Arm 2 (DOR + ART) and 3 participants in Arm 3 (DOR/ISL + ART) discontinued from the study.

Accumulated safety data through Week 49: - No participants died during the study. - Serious adverse events (SAEs) were reported for 14.3% (1/7) participant (COVID-19 pneumonia and SARS-CoV-2 sepsis) in Arm 1 (ISL + ART) and 7.1% (1/14) participant (postoperative wound infection) in Arm 2 (DOR + ART). - Non-serious adverse events (AEs) were reported for 71.4% (5/7) participants in Arm 1 (ISL + ART), 85.7% (12/14) participants in Arm 2 (DOR + ART), 85.7% (6/7) participants in Arm 3 (DOR/ISL + ART), and 85.7% (6/7) participants in Arm 4 (placebo + ART). AEs reported in >20% of participants in any group were diarrhoea (28.6%), COVID-19, creatinine renal clearance decreased, and lymphocyte count decreased (21.4% each), and these were reported in Arm 2 (DOR + ART).

<Primary Endpoints> Efficacy: -A total of 35 participants were included in efficacy analysis population. -The percentage of participants with a >=0.5 log10 decrease in HIV-1 RNA from baseline (Day 1) to Day 8 was 28.6% in Arm 1 (ISL + ART), 78.6% in Arm 2 (DOR + ART), 85.7% in Arm 3 (DOR/ISL + ART), and 0% in Arm 4 (placebo + ART). Safety: -A total of 35 participants were included in safety analysis population. -The percentage of participants with one or more AEs up to Week 25 was 42.9% in Arm 1 (ISL + ART), 85.7% each in Arm 2 (DOR + ART), Arm 3 (DOR/ISL + ART), and Arm 4 (placebo + ART). Similarly, 71.4% in Arm 1 (ISL + ART) and 85.7% each in Arm 2 (DOR + ART), Arm 3 (DOR/ISL + ART) and Arm 4 (placebo + ART) experienced one or more AEs up to Week 49. -Overall, 7.1% of participants in Arm 2 (DOR + ART) and 14.3% of participants in Arm 3 (DOR/ISL + ART) discontinued study treatment due to AE(s) up to Week 25. Similarly, 14.3% of participants each in Arm 2 (DOR + ART) and Arm 3 (ISL/DOR + ART) discontinued study treatment due to AE(s)up to Week 49.

Efficacy: -From baseline (Day 1) to Day 8, the mean change in HIV-1 RNA (log10 copies/mL) was-0.44 in Arm 1 (ISL + ART), -0.96 in Arm 2 (DOR + ART), -1.23 in Arm 3 (DOR/ISL + ART), and 0.03 in Arm 4 (placebo + ART). -From baseline (Day 1) to Day 8, a >=1.0 log10 decrease in HIV-1 RNA was observed for 14.3% of participant in Arm 1 (ISL + ART), 50.0% in Arm 2 (DOR + ART), 85.7% in Arm 3 (DOR/ISL + ART), and 0% in Arm 4 (placebo + ART). -From baseline (Day 1) to Day 8, 14.3% of participants in Arm 2 (DOR + ART) had HIV-1 RNA <40 copies/mL, and 14.3% of participants in Arm 3 (DOR/ISL + ART) had HIV-1 RNA <200 copies/mL. -At Week 49, 71.0% of participants receiving DOR/ISL + optimized background therapy (OBT) had HIV-1 RNA levels <40 copies/mL. -At Week 49, the mean change from baseline (Day 1) in CD4+ T-cell count (log10 copies/mL) was 86.9 cells/mm3 in participants receiving DOR/ISL + OBT.

Efficacy: In HIV-1-infected heavily treatment-experienced participants, addition of DOR/ISL (100 mg/0.75 mg) to a failing ART regimen may provide virologic benefit. In addition, DOR/ISL in combination with OBT may provide sustained HIV-1 suppression through 49 weeks of treatment. Safety: In HIV-1-infected heavily treatment-experienced participants, DOR/ISL + ART is generally well tolerated through 49 weeks of treatment.

Yes

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Tanaka Yoshiyuki

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

JPCT@msd.com

MSDJRCT inquiry mailbox

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

+81-3-6272-1957

JPCT@msd.com

completed

May. 13, 2020

Interventional

randomized controlled trial,double blind,placebo control,parallel assignment

treatment purpose

3

- Is HIV-1 positive.
- Has been receiving the same baseline ART for >=3 months prior to signing the Informed Consent Form/Assent Form.
- Weighs >=35 kg.
- Has at least triple-class resistance (must include nucleoside reverse transcriptase inhibitor [NRTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], and resistance to either protease inhibitor (PI) or integrase strand transfer inhibitor (InSTI), based on central laboratory-based resistance or proviral DNA resistance testing at the Screening Visit, or historical resistance testing within 12 months of screening.
- Has =<2 fully active antiretroviral drugs remaining among all antiretroviral classes that can be effectively combined to form a viable regimen based on resistance, tolerability, safety, drug access, or acceptability to participant.
- If female, is not pregnant or breastfeeding, and is: 1) not a woman of childbearing potential (WOCBP); 2) a WOCBP and uses an acceptable method of contraception/is abstinent; or 3) a WOCBP and has a negative pregnancy test within 24 hours of the first dose of study medication.

- Has HIV type 2 (HIV-2) infection.
- Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator.
- Has hepatitis B virus (HBV) co-infection (defined as hepatitis B surface antigen [HBsAg]-positive or HBV deoxyribonucleic acid [DNA] positive) and is not currently being treated for HBV.
- Has a history or current evidence of any condition, therapy (including active TB co-infection), laboratory abnormality or other circumstance (including drug or alcohol abuse or dependence) that might, in the opinion of the investigator, confound the results of the study or interfere with study participation for the full study duration.
- Is taking or is anticipated to require any of the prohibited therapies from the Screening Visit and throughout the study treatment period.
- Is taking DOR as part of his/her current failing antiretroviral regimen.
- Is taking efavirenz (EFV), etravirine, or nevirapine.
- Is currently participating in or has participated in an interventional clinical study with an investigational compound or device from the Screening Visit through the study treatment period.
- Is female and is expecting to conceive or donate eggs at any time during the study.

Both

HIV-1 infection

- Part1: Arm1
HTE participants with HIV-1 infection take ISL 0.75 mg once daily (QD) in combination with failing ART from Day 1 to Day 7
- Part1: Arm2
HTE participants with HIV-1 infection take DOR 100 mg QD in combination with failing ART from Day 1 to Day 7
- Part1: Arm3
HTE participants with HIV-1 infection take 100 mg DOR/0.75 mg ISL FDC QD in combination with failing ART from Day 1 to Day 7
- Part1: Arm4
HTE participants with HIV-1 infection take placebo QD in combination with failing ART from Day 1 to Day 7

- Part2:
100 mg DOR/0.75 mg ISL fixed dose combination (FDC) QD + optimized background therapy from Day 8 to Week 97.

- To evaluate the antiretroviral activity of DOR/ISL compared to placebo, each given in combination with failing ART as assessed by the percentage of participants achieving >=0.5 log10 decrease in HIV 1 RNA from study baseline (Day 1) to Day 8 (Part 1).
The change from baseline in HIV-1 RNA will be determined at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay with a lower limit of detection (LLOD) of 40 copies/mL.
- To evaluate the safety and tolerability of DOR/ISL as assessed by review of the accumulated safety data through Week 25 and Week 49.
- AEs
- AEs leading to discontinuation of study intervention

- To evaluate the antiretroviral activity of ISL and DOR, each compared to placebo, when each is given in combination with failing ART, as assessed by the percentage of participants achieving >=0.5 log10 decrease in HIV 1 RNA from study baseline (Day 1) to Day 8 (Part 1).
The change from baseline in HIV-1 RNA will be determined at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay with a lower limit of detection (LLOD) of 40 copies/mL.
- To further evaluate the antiretroviral activity of DOR/ISL, ISL, and DOR each compared to placebo, when each is given in combination with failing ART (Part 1) .
The change from baseline in HIV-1 RNA will be determined at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay with a lower limit of detection (LLOD) of 40 copies/mL.
- mean change in HIV-1 RNA from study baseline (Day 1) to Day 8
- percentage of participants achieving >=1.0 log10 decrease in HIV-1 RNA from study baseline (Day 1) to Day 8
- To further evaluate the antiretroviral activity of DOR/ISL compared to ISL and DOR, when each is given in combination with failing ART (Part 1)
- percentage of participants achieving >=0.5 log10 decrease in HIV-1 RNA from study baseline (Day 1) to Day 8
- mean change in HIV-1 RNA from study baseline (Day 1) to Day 8
- percentage of participants achieving >=1.0 log10 decrease in HIV-1 RNA from study baseline (Day 1) to Day 8
- To evaluate the antiretroviral activity of DOR/ISL + OBT in Part 2 as assessed by the following at Week 25, Week 49, and Week 97 compared to study baseline (Day 1) and Part 2 baseline (Day 8):
- percentage of participants achieving >=0.5 log10 decrease in HIV-1 RNA
- percentage of participants achieving >=1.0 log10 decrease in HIV-1 RNA
- mean change in HIV-1 RNA
- percentage of participants achieving HIV-1 RNA <200 copies/mL
- percentage of participants achieving HIV-1 RNA <50 copies/mL
- percentage of participants achieving HIV-1 RNA <40 copies/mL
- To evaluate the development of viral drug resistance to DOR, ISL, or components of OBT through the study duration (Part 1 and Part 2).
- To evaluate the impact of study baseline (Day 1) antiviral resistance on virologic outcome at Week 25, Week 49, and Week 97 (Part 2).
- To evaluate the change in CD4+ T cell counts from both study baseline (Day 1) and Part 2 baseline (Day 8) at Week 25, Week 49, and Week 97 (Part 2).

Mar. 26, 2020