| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus type 1 infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Human Immunodeficiency Virus type 1 infection |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| 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 |
| The primary objective is to compare the safety and tolerability of the THV01 therapeutic HIV-1 vaccination by treatment group and versus placebo from W0 to W24. |
|
| E.2.2 | Secondary objectives of the trial |
One secondary objective is to compare the safety and tolerability of the THV01 therapeutic HIV-1 vaccination by treatment group and versus placebo:
- From W-7 or W-2 (baseline) to W0;
- From W24 to W36 or early termination;
- From W36 to W88 or early termination.
Another secondary objective of the study is to compare the cellular immune responses by treatment group and versus placebo:
- From W-7 or W-2 (baseline) to W0;
- From W0 to W24;
- From W24 to W36 or early termination;
- From W36 to W88 or early termination.
One of the exploratory objectives is a long-term follow-up of the study with monitoring visits three times per year, during five years post-prime vaccination, to monitor:
- Safety
- Cellular immune response
- Viral reservoirs
- Presence of IMP in blood
- Sequencing of circulating virus. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient infected with clade B HIV-1;
2. Confirmation of a Gag clade B genotyping performed at screening;
3. Patient must be treated by a triple agents therapy for more than 12 months at baseline: two nucleosidic reverse transcriptase inhibitors plus one boosted protease inhibitor, or two nucleosidic reverse transcriptase inhibitors plus one non nucleosidic reverse transcriptase inhibitor;
4. Patient must be treated for more than 60 days at baseline by two (2) nucleosidic reverse transcriptase inhibitors plus a ritonavir boosted protease inhibitor treatment among darunavir+ritonavir or lopinavir+ritonavir;
5. Patient’s HIV plasma viral load must have remained ≤ 150,000 copies mL-1 at any monitoring time (apart measurement during primo-infection if recorded);
6. Patient with HIV plasma viral load persistently ≤ 50 copies mL-1 during the 12 months prior to screening;
7. Patient’s CD4+ T cells count ≥ 300 cells per mm3 at any time since diagnosis;
8. Patient’s CD4+ T cells count < 500 cells per mm3 at least once from diagnosis to initiation of antiretroviral treatment
9. Patients with CD4+ T cells count ≥ 600 cells per mm3 at baseline;
10. Man or woman aged 18-55 years;
11. Patient with haematological and biochemical laboratory parameters as follows and within 7 days of baseline:
Haemoglobin > 9.0 g dL-1;
Absolute neutrophil count ≥ 750 mm-3;
Platelets ≥ 100,000 mm-3;
Total serum creatinine ≤ 1.3 x ULN (upper limit of normal);
Creatinine clearance > 50 mL min-1 by the Cockcroft-Gault equation within 60 days of entry ;
Prothrombin time (PT) < 1.2 x ULN;
Total serum bilirubin < 2.0 x ULN (a higher total bilirubin value may be permitted if the subject was taking atanazir or indinavir and the elevation in total bilirubin is due to increased unconjugated bilirubin);
Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 1.5 x ULN;
Serum lipase less than or equal to 2.0 x ULN;
12. Patient should be able and willing to comply with study visits and procedures as per protocol;
13. Patient should understand, sign and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures being performed;
14. Patient should be affiliated to a social security regimen (for French sites);
15. Patients must agree to use in addition to the condom, a second method (one for the patient and one for the partner) of medically acceptable form of contraception during the study and for 3 months after end of study or early termination;
16. Women of childbearing potential will enter the study after confirmed menstrual period and a negative pregnancy test In case of pregnancy suspicion, a pregnancy test must be performed immediately. |
|
| E.4 | Principal exclusion criteria |
1. HIV-2 infection;
2. Patient treated by HIV entry or fusion inhibitors;
3. Patient treated by HIV integrase inhibitors as no safety data, in case of treatment interruption are available for such patients and as these molecules are usually prescribed for patients having medical resistance records;
4. Patient displaying any HIV protease inhibitor resistance mutation as listed in the current version of the HIV drug resistance database (Stanford University);
5. Patient having undergone virological failure as defined by a viral load ≥ 500 copies mL-1 confirmed by a second measure, since initiation of treatment;
6. More than 2 blips with viral load comprised between 50 and 500 copies mL-1 during the 12 months prior inclusion;
7. History of an AIDS-defining clinical illness;
8. Concomitant AIDS-related opportunistic disease;
9. History of allergic disease, anaphylaxis or reactions likely to be triggered or exacerbated by any component of the vaccine such as lactose;
10. Acute or chronic infectious disease other than AIDS (include but not limited to viral hepatitis such as hepatitis B and hepatitis C, active tuberculosis, active syphilis, HTLV-1, HTLV-2);
11. Acute, chronic or history of clinically relevant pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable CNS pathology, angina or cardiac arrhythmias, or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history;
12. Severe hepatic impairment;
13. Serious dyslipidaemia;
14. Severe disorders of blood coagulation;
15. Known or suspected allergy to egg phospholipids, soy proteins and/or peanut;
16. Acute, chronic or history of immunodeficiency or autoimmune disease other than HIV infection;
17. Unstable asthma (defined as sudden acute attacks occurring in less than three hours without an obvious trigger, hospitalisation for asthma in the last two years); food or wine induced asthma;
18. History of malignancy unless there has been surgical excision that is considered to have achieved cure;
19. Active malignancy that may require chemotherapy or radiation therapy;
20. Seizure disorder or any history of prior seizure;
21. Subjects planning to receive a prophylactic or therapeutic vaccination during the study except Influenza immunization;
22. Subjects who received any vaccination for the 3 months prior the first injection;
23. Subjects having an infective exacerbation as defined as a requirement of inhaled, oral, or intravenous antibiotics at W-2 or later;
24. Serious illness requiring systemic treatment and/or hospitalization within 7 days prior to baseline;
25. Pregnant or breast-feeding women;
26. Any contraindication of intramuscular injection;
27. Active drug or alcohol abuse or dependence;
28. Any condition, which in the opinion of the investigator, could compromise the subject's safety or adherence to the study protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Occurrence of at least one grade 3 or higher adverse event including signs/symptoms, lab toxicities and/or clinical events possibly, probably or definitely related to study treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
#1 Occurrence of at least one grade 3 or higher adverse event including signs/symptoms, lab toxicities and/or clinical events possibly, probably or definitely related to study treatment.
#2 Monitoring the cellular immune response by cytokines and integrins quantification (IL-2; TNF-a; IFN-g; MIP-1b; CD40L and CD103); by monitoring the polyclonal activation (CD38; HLA-DR; CD45RA; CDR7 staining) and by ELISPOTs in the treatment group versus placebo.
# Exploratory objectives
- Long term safety;
- Long term cellular immune response assessment; (CD4+/CD8+ ratio; cytokines quantification; monitoring of the polyclonal activation);
- Long term quantification of the viral DNA in HIV reservoirs;
- Long term quantification of the IMP presence in patients' blood by PCR;
- Sequencing of the circulating HIV sequence in patients'blood by PCR. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timing of endpoint #1:
- from baseline to W0;
- from W24 to W36;
- from W36 to W88 or early termination.
Timing of endpoint #2:
- from baseline to W0: at W-2 or W-7 (depending on baseline date);
- from W0 to W24: at W0; W4; W9; W12 and W24;
- from W24 to W36 or early termination: at W28 and W36;
- from W36 to W88 or early termination: at W48; W64 and W88 or early termination.
Timing of exploratory objectives:
3 times per year during 5 years post-primo administration. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 11 |
| 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 | 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
|
| The long-term follow-up of the trial is planned to end in Q2 2019 (5 years post-prime IMP administration of the last patient enrolled). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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