E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
HIV persistence during antiretroviral therapy |
HIV infektion |
|
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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10073675 |
E.1.2 | Term | HIV infection CDC category unspecified |
E.1.2 | System Organ Class | 100000004862 |
|
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 perform a detailed characterization of the numeric, phenotypic, and functional properties of circulating HIV-1-specific T cells and NK cells during MGN1703 treatment |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of MGN1703 administration in HIV infected patients
• To evaluate the effect of MGN1703 on circulating monocytes and pDC cell activation, quantity, and phenotype (activated vs. resting)
• To evaluate the effect of MGN 1703 on HIV-1 transcriptional activity in circulating CD4+ cells and on low level viremia
• To evaluate the effect of MGN1703 on the size of the HIV-1 reservoir
• To characterize the immunological effects of MGN1703 in the gut
• To determine the effect of MGN1703 on the quantity of HIV-1 RNA/DNA in the gut
• To investigate the impact of MGN1703 on the levels of soluble inflammatory markers in plasma |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Documented HIV-1 infection
• Age >18 years
• CD4+ T-cell count >350/µL at screening
• On cART (for a minimum of 12 months)
• Able to give informed consent |
|
E.4 | Principal exclusion criteria |
• Pregnancy as determined by a positive urine beta-hCG (if female)
• Males or females who are unwilling or unable to use barrier contraception during sexual intercourse for the entire study period.
• Currently breast-feeding (if female)
• Viral load (HIV RNA) > 50 copies/mL
• Contraindication to receive MGN1703 as per current investigator brochure
• Presence of acute bacterial infection or undiagnosed febrile condition
• Concurrent chronic systemic immune therapy or immunosuppressant medication, including continuous systemic steroid treatment within the last 2 weeks prior to randomization
• Use of antibiotic therapy within the last 2 weeks prior to randomization
• Known HBV or HCV infection
• Any medical, psychiatric, social, or occupational condition or other responsibility that, in the judgment of the Principal Investigator (PI), would interfere with the evaluation of study objectives (such as severe alcohol abuse, severe drug abuse, dementia)
• Unable to follow protocol regimen |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Part A: Changes in proportions of activated NK cells
Part B: Change in HIV-1 DNA in circulating total CD4+ T cells.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Visits 1, 1b, 2, 4, 5, 6, 8, 10, 11, 11b, 12, 13, 14, 15
Part B: Visits 16, 20 and 24 |
|
E.5.2 | Secondary end point(s) |
PART A
• Safety evaluation, as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), suspected unexpected serious adverse reactions (SUSAR), and dose-limiting toxicity (Visits 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11b, 12, 13, 14, 15)
• Absolute T, NK, and NKT cell counts and phenotypic properties will be characterized using standard cell marker panels (Visits 1, 1b, 2, 4, 5, 6, 8, 10, 11, 11b, 12, 13, 14, 15)
• Functional properties of cytotoxic T cells, NK, and NKT cells will be investigated by analysing cytokine secretion properties (Visits 2, 4, 12, 14)
• Change in the capacity of CD8 T cells and NK cells to mediate inhibition of viral replication ex vivo (Visits 2, 4, 12, 14)
• Change in ADCC (Visits 1, 3, 11, 15)
• Gene expression changes and global genomic change in methylation pattern of integrated HIV (Visits 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15)
• Dynamics of HIV-1 DNA, episomal HIV-1 DNA (2-LTR), and nonspliced HIV-1 RNA in circulating total CD4+ T cell (Visits 1, 2, 3, 4, 11, 12, 13, 14, 15)
• Change from baseline in numeric and phenotypic characteristics of monocytes (e.g. CD169 expression), pDCs, and B cells (Visits 2, 4, 12, 14)
• Plasma HIV-RNA, as measured by the single copy assay and NAT (Visits 1, 2, 3, 4, 11, 13, 14, 15)
• Change from baseline in HIV-1 DNA, episomal HIV-1 DNA (2-LTR), and unspliced HIV-1 RNA in rectal gut mucosa (Visits 1b, 11b)
• Change from baseline in immune cell activation and function in rectal gut mucosa as measured by flow cytometry (Visits 1b, 11b)
• Plasma cytokines (e.g. IL-6, IL-8, IP-10) and immune activation biomarker levels (Visits 1, 1b, 2, 3, 4, 5, 6, 8, 10, 11, 11b, 12, 13, 14, 15)
• Genetic, virological, and immunological predictors of treatment response (Visits 1, 1b, 2, 3, 4, 5, 6, 8, 10, 11, 11b, 12, 13, 14, 15)
• If virus is induced compare sequence of blood vs. gut virus to see if the stimulated virus is from a specific anatomical compartment (Visits 1b, 11b)
PART B
Part B:
• Time from stopping ART to viral rebound ( >5,000 c/mL)
• Safety evaluation, as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), suspected unexpected serious adverse reactions (SUSAR), and dose-limiting toxicity.
• Change from baseline to end of study in functional measures of the HIV-1 reservoir (e.g. as measured by a viral outgrowth assay or TILDA)
• Absolute monocyte, DC, T, NK, and NKT cell counts and phenotypic properties will be characterized using standard cell marker panels.
• Functional properties of cytotoxic T cells, NK, and NKT cells will be investigated by analyzing cytokine secretion properties.
• Plasma HIV-RNA
• Change from baseline in HIV-1 DNA, episomal HIV-1 DNA (2-LTR), and unspliced HIV-1 RNA in rectal gut mucosa
• Change from baseline in immune cell activation and function in rectal gut mucosa as measured by flow cytometry |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Specific visit numbers for each secondary endpoint are given with the bullet point above |
|
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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | No |
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
|
(Part A). The end of the part A is study Visit 15. This is 12 weeks after the initial MGN1703 dosing.
(Part B). The end of part B is study Visit 24. This is 6-8 weeks after the last MGN1703 dosing. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |