| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 |
| The primary objective is to assess the immune-mediated effect on plasma VL (HIV-1 RNA) of the HIV therapeutic vaccine Vacc-4x with GM-CSF adjuvant when administered prior to HIV latent reservoir activation by the HDACi romidepsin in HIV patients on ART. |
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| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of Vacc-4x when administered prior to the HDACi romidepsin in HIV patients on ART.
To explore the effect of Vacc-4x on HIV viral reservoir size in CD4 T cells when ad-ministered prior to the HDACi romidepsin in HIV patients on ART.
To explore virus production induced by romidepsin
To assess the potential additive antiviral effect of two additional booster injections of Vacc-4x when administered prior to the HDACi romidepsin in HIV patients on ART.
To explore the effects of Vacc-4x on immune responses to HIV when Vacc-4x is admin-istered prior to the HDACi romidepsin in HIV patients on ART.
To explore the effects of Vacc-4x on selected markers of inflammation when adminis-tered prior to the HDACi romidepsin in HIV patients on ART. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects.
2. Age ≥18 to ≤ 55 years.
3. All subjects must have a serologically documented HIV diagnosis.
4. Subjects receiving ART according to the national and/or International guidelines and recommendations observed by the trial centers.
5. ART maintained without interruption for at least 3 years prior to randomization.
6. Plasma HIV RNA maintained <20 copies/mm3. Should the subject have a record of a viral blip, the blip should have been documented by record of a negative HIV RNA test before the observed blip and a re-controlled negative HIV RNA after the observed blip.
7. CD4 count ≥500 cells/mm3 at screening.
8. Documented CD4 nadir of ≥250 cells/mm3.
9. Capability and availability to comply with trial constraints and requirements; evaluation by the investigators, acceptance and signature of the ICF.
10. If available, preART viral load levels and CD4 levels values must be taken within 6 months of ART initiation.
a. Note: Patient are still eligible if these data are not available.
11. Subjects who have never received Vacc-4x. |
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| E.4 | Principal exclusion criteria |
1. Subjects with contraindications (hypersensitivity included) to Leukine®, see Appendix 1.
2. Subjects with contraindications to the practice of i.d. injections.
3. Subjects who have received a HIV experimental therapeutic or preventive vaccination or immune-modulatory or interleukin-based treatment within 3 years of randomization.
4. Subjects with a history of treatment with chemotherapeutic agents within 2 years of ran-domization.
5. Subjects on a Protease Inhibitor-based regimen during three months preceding randomization.
6. History of any latency activating agent, notably HDACi use within 24 months preceding randomization.
7. Any vaccinations within 4 weeks of randomization, excluding influenza vaccinations.
8. Any acute and clinically significant infection within the last 4 weeks of randomization.
9. Subjects with a history of AIDS defining condition.
10. Clinical abnormalities, as determined by physical examination alone, indicative of chronic active disease states. Subjects with acute or chronic conditions which are either non-stabilized or not in remission as per the investigator's opinion.
11. Subjects with a history of clinically significant cardiac disease, symptomatic or asymptomatic arrhythmias, syncope episodes, or additional risk factors for Torsades de Pointes (e.g. heart failure, congenital long QT syndrome).
12. Subjects receiving concomitant medication according to Appendix 5.
13. Subjects with a history of current or past:
a. HBV infection.
b. HBV/HDV infection.
c. HCV infection.
14. Subjects with recurrent Herpes Zoster.
15. Subjects with recurrent herpes infection (HSV-1 or HSV-2 reactivation) that cannot be controlled with valaciclovir.
16. Subjects with clinically significant laboratory abnormalities:
a. Hemoglobin ≤12 g/dL
b. Platelet count ≤150 x109/L
c. Absolute neutrophil count ≤2.0x109/L
d. Hepatic transaminases (AST or ALT) ≥1.5 x ULN
e. Serum total bilirubin ≥1.5 x ULN
f. Specific or standard (CRP and CBC) ≥1.5 x ULN
g. eGFR ≤60 mL/min (based on serum creatinine or other appropriate validated markers)
h. Serum potassium, magnesium, phosphorus outside ≥1.5 x ULN/LLN
17. Subjects with acute or chronic major psychiatric conditions (i.e. schizophrenia, major depression or bipolar disease) which are either non-stabilized or not in remission as per the investigator's clinical assessment, or are in need of continual psycho-active medications.
18. Subjects with a history of multiple sclerosis including subjects in remission.
19. Subjects with a history of substance and/or alcohol abuse/dependency within the last 24 months prior to randomization.
20. Males who are unwilling to use barrier contraception during the entire course of the present trial.
21. ECG at screening that shows QTc >450 msec for males and >470 msec for women when calculated using the Fridericia formula from either lead V3 or V4.
22. Subjects who have switched ART regimens more than once due to resistance or intolerance.
23. Females of childbearing potential*).
*) Females of non-childbearing potential are defined as:
- Women who have not reached menarche or
- Women who have not had menses within the past 12 months and who do have an FSH ≥40 IU/L or
- Women who have not had menses within the past 24 consecutive months if an FSH measurement is not available
- Women who have undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy).
Confirmation of the lack of childbearing potential is required.
Written documentation or oral communication from a clinician or clinician’s personnel documented in source documents of one of the following must be provided: Physician report/letter, operative report or other source documentation in the patient record, dis-charge summary, FSH measurement elevated into the menopausal range (as established by the reporting laboratory). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Plasma HIV RNA levels below 20 copies/mL 72 h after each of the three romidepsin infusions. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Virological Endpoints
- Change from baseline in CA US HIV RNA at visits 6, 9, 12-25.
- Change from baseline in proviral DNA at visits 6, 9, 12, 13, 24 and 25.
- Change from baseline in plasma HIV-1 RNA (single-copy assay) at 2 h, 24 h and 72 h after each of the three romidepsin infusions.
Immunological and Inflammatory Endpoints
- Change from baseline in CD4 and CD8 counts at visits 13, 24 and 25.
- Change from baseline in CD4/CD8 ratio at visits 13, 24 and 25.
- Change from baseline in T cell proliferation to visits 6, 9, 12, 13, 21, 22, and 23.
- Change from baseline in intracellular cytokines to visits 6, 9, 12, 13, 21, 22, and 23.
- Change from baseline in hs-CRP to visits 13 and 25.
- Change from baseline in IP-10 to visits 13 and 25.
- Change from baseline in D-dimer to visits 13 and 25
- Change from baseline in sTNF1 and sTNF2 to visits 13 and 25.
Pharmacodynamic Endpoint
- Histone H3 acetylation to visits 13-21 and 24.
Safety Endpoints
- Number of AEs
- Number of ARs
- Number of SAEs
- Number of SARs
- Number of SUSARs
- Laboratory safety parameters.
- Plasma concentrations of romidepsin prior to romidepsin administration, close to the end of the infusion (3:45-4:00 h after infusion start) and at visits 14, 15, 17, 18, 20 and 21.
Serological Endpoint
- Change from baseline in Anti-Vacc C5 Ab levels to visit 13 and visit 25 (or EOT). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | 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.8.2 | 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 | 3 |
| 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 | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| European Union |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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