Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/26/02/09

Date of Protocol:

05-09-2024

Study Title:	An Open-Label, Randomized Controlled Trial of Pramipexole versus Escitalopram to Treat Major Depressive Disorder (MDD) and Comorbid MDD with Mild Neurocognitive Disorder (MND) in Persons with HIV
Study Objectives:	1.1Primary Objectives To compare pramipexole to escitalopram in the treatment of MDD (and comorbid MDD with MND) based on the Beck Depression Inventory-II (BDI-II/BDI-2) total score [Beck 1996] from baseline to week 24. To evaluate the safety of pramipexole and escitalopram in PWH having MDD (and comorbid MDD with MND) from baseline to week 24. Secondary Objectives To compare pramipexole to escitalopram in the treatment of MDD using MDD caseness, neurocognitive outcomes, and functional status from baseline to week 24. To compare the depression, neurocognitive, and functional status outcomes in PWH with MDD alone and with comorbid MDD with MND treated with pramipexole versus escitalopram from baseline to week 24. To compare the impact of pramipexole and escitalopram on all outcomes above by female versus male sex (assigned at birth) from baseline to week 24. To determine the impact of pramipexole compared to escitalopram on the measure of HIV-1 RNA viral load in the peripheral blood. Exploratory Objectives To characterize associations between escitalopram trough concentrations and treatment efficacy (BDI-II/BDI-2 total score) as well as participant adverse events (adverse event frequency, severity, and discontinuation rates). To characterize associations between escitalopram trough concentrations and genetic polymorphisms that affect metabolizing enzymes of escitalopram (known metabolizing enzymes include CYP2C19, CYP2D6, and CYP3A4). To explore associations between cerebrospinal fluid (CSF) concentrations of escitalopram and BDI-II/BDI-2 total score. To evaluate adverse events potentially related to drug interactions between antiretroviral therapy (ART) and escitalopram and pramipexole, respectively. Substudy Objective CSF Substudy To compare the impact of pramipexole and escitalopram on biomarker outcomes in a CSF substudy of participants with MDD alone.
Laymans Summary:	SCHEMA A5402 An Open-Label, Randomized Controlled Trial of Pramipexole versus Escitalopram to Treat Major Depressive Disorder (MDD) and Comorbid MDD with Mild Neurocognitive Disorder (MND) in Persons with HIV DESIGN A phase II, randomized, open-label, two-arm clinical trial evaluating the safety and efficacy of pramipexole extended release (ER) versus escitalopram for the treatment of major depressive disorder (MDD) and comorbid MDD with mild neurocognitive disorder (MND) in persons with HIV (PWH). Participants will be assessed comprehensively and briefly at intercurrent visits to monitor for toxicity, response to therapy, and to assess for dose changes. An optional substudy to evaluate treatment impact on the cerebrospinal fluid (CSF) profile will be conducted in a subset of up to 36 participants. DURATION 24 weeks SAMPLE SIZE 186 participants, 93 per treatment arm POPULATION PWH having a diagnosis of MDD alone or with comorbid MDD and MND ≥18 to ≤70 years old On antiretroviral therapy (ART) for at least 3 months With HIV-1 RNA < 200 copies/mL within 90 days prior to randomization REGIMEN Participants will be randomized 1:1 to: Arm 1 Pramipexole ER: Administered orally starting at 0.375 mg/day, increasing to 0.75 mg/day after 6 days, and then increasing by 0.75 mg every 6 days to a maximum of 4.5 mg/day at week 6 (by participant tolerance), and continuing through week 24. Arm 2 Escitalopram: Administered orally starting at 5 mg/day, increasing to 10 mg/day at weeks 2-3, to 15 mg/day at weeks 4-5, and then to the maximum of 20 mg/day at week 6 (by participant tolerance), and continuing through week 24. HYPOTHESIS AND STUDY OBJECTIVES Hypotheses Pramipexole will result in superior outcomes in persons with HIV (PWH) with major depressive disorder (MDD) and comorbid MDD with mild neurocognitive disorder (MND), compared to escitalopram. Pramipexole and escitalopram will be safe in PWH with MDD and comorbid MDD and MND. Primary Objectives To compare pramipexole to escitalopram in the treatment of MDD (and comorbid MDD with MND) based on the Beck Depression Inventory-II (BDI-II/BDI-2) total score [Beck 1996] from baseline to week 24. To evaluate the safety of pramipexole and escitalopram in PWH having MDD (and comorbid MDD with MND) from baseline to week 24. Secondary Objectives To compare pramipexole to escitalopram in the treatment of MDD using MDD caseness, neurocognitive outcomes, and functional status from baseline to week 24. To compare the depression, neurocognitive, and functional status outcomes in PWH with MDD alone and with comorbid MDD with MND treated with pramipexole versus escitalopram from baseline to week 24. To compare the impact of pramipexole and escitalopram on all outcomes above by female versus male sex (assigned at birth) from baseline to week 24. To determine the impact of pramipexole compared to escitalopram on the measure of HIV-1 RNA viral load in the peripheral blood. Exploratory Objectives To characterize associations between escitalopram trough concentrations and treatment efficacy (BDI-II/BDI-2 total score) as well as participant adverse events (adverse event frequency, severity, and discontinuation rates). To characterize associations between escitalopram trough concentrations and genetic polymorphisms that affect metabolizing enzymes of escitalopram (known metabolizing enzymes include CYP2C19, CYP2D6, and CYP3A4). To explore associations between cerebrospinal fluid (CSF) concentrations of escitalopram and BDI-II/BDI-2 total score. To evaluate adverse events potentially related to drug interactions between antiretroviral therapy (ART) and escitalopram and pramipexole, respectively. Substudy Objective CSF Substudy To compare the impact of pramipexole and escitalopram on biomarker outcomes in a CSF substudy of participants with MDD alone.
Abstract of Study:	We propose a randomized, open-label, phase II clinical trial to evaluate the efficacy and safety of pramipexole ER (starting at 0.375 mg/day, increasing to 0.75 mg/day after 6 days, and then increasing by 0.75 mg every 6 days to a maximum of 4.5 mg/day at week 6 and continuing through week 24, by participant tolerance) [Ceccarelli 2017] versus escitalopram (starting at 5 mg/day at week 1, increasing to 10 mg/day at weeks 2-3, to 15 mg/day at weeks 4-5, and then to the maximum of 20 mg/day at week 6 and continuing through week 24, by participant tolerance) for the treatment of PWH having MDD alone or having comorbid MND and MDD [Gershon 2019].Sample Size Considerations: N=186, 93 per treatment arm, to be recruited from qualified US and non-US sites. An optional substudy to evaluate treatment impact on the CSF profile will be conducted at US sites only in a subset of up to 36 participants.