| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000807 |
| E.1.2 | Term | Acute 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 |
| To see whether a strategy of immediate treatment of primary HIV-1 infection, with 4-drug combination ART, followed by immunisation with 2 anti-HIV vaccines and reactivation of "sleeping" cells containing HIV (‘the reservoir’) using the HDACi (vorinostat) will reduce the HIV reservoir significantly more than using 4-drug combination ART alone. |
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| E.2.2 | Secondary objectives of the trial |
The secondary research questions including the following
1) to describe how safe the approach is for patients. The safety aspects are documented in two ways, using the results of laboratory tests, ECGs (a tracing of the heart) and clinical assessment by the research staff;
2) measuring the HIV reservoir by measuring the amount of HIV DNA (genes) in different types on immune cells circulating in the blood;
3) measuring the amount of circulating HIV virus in the blood using an extra sensitive test called an ultrasensitive viral load assay;
4) looking at the change in the way the immune system is responding to HIV;
5) and assessing how much activity there is in the immune system through looking at the immune cells themselves and some of the proteins (biomarkers) they are making.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged ≥18 to ≤60 years old
2. Able to give informed written consent including consent to long-term follow-up
3. Should be enrolled within a maximum of 4 weeks of a diagnosis of primary HIV-1 infection confirmed by one of the following criteria:
a. Positive HIV-1 serology within a maximum of 12 weeks of a documented negative HIV-1 serology test result (can include point of care test (POCT))
b. A positive p24 antigen result and a negative HIV antibody test
c. Negative antibody test with either detectable HIV RNA or proviral DNA
d. PHE RITA test algorithm (a) reported as “Incident” confirming the HIV-1 antibody avidity is consistent with recent infection (within the preceding 16 weeks)
e. Weakly reactive or equivocal 4th generation HIV antibody antigen test
f. Equivocal or reactive antibody test with <4 bands on western blot
4. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females)
5. Weight ≥50kg (b)
6. Willing to start immediate cART and be randomised to continue cART alone or cART plus intervention (HIV vaccines plus HDACi) at week 24
7. Willing and able to comply with visit schedule and provide blood sampling
(a)using current cut-offs for optical density as defined by PHE
(b)females aged <20 years of age, and weighing <65kg and <168cm in height will need to have an estimation of blood volume (EBV) prior to enrolment, >3500mL before to participate. This circumstance is unlikely to arise as most women between the ages of 18 to 20 years would be of child-bearing potential (CBP) and excluded on that basis.
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| E.4 | Principal exclusion criteria |
1. Women of child bearing potential (WCBP) (a)
2. In women with intact ovaries and no uterus, any planned egg donation anytime in the future to a surrogate
3. Intention to donate sperm or father a child within 6 months of the intervention
4. Co-infection with hepatitis B (surface antigen positive or detectable HBV DNA levels in blood) or hepatitis C (HCV RNA positive)
5. Any current or past history of malignancy
6. Concurrent opportunistic infection or other comorbidity or comorbidity likely to occur during the trial e.g.past history of ischaemic or other significant heart disease, malabsorption syndromes, autoimmune disease
7. Any contraindication to receipt of BHIVA recommended combination antiretrovirals
8. Any contraindication to receipt of the strand-transfer integrase inhibitor (INSTI), raltegravir
9. HIV-2 infection
10. Known HTLV-1 co-infection
11. Prior immunisation with any experimental HIV Immunogens (including any component of the vaccines used in the RIVER protocol; simian or human adenoviral vaccine; other experimental HIV vaccines)
12. Current or planned systemic immunosuppressive therapy (inhaled corticosteroids are allowed)
13. Any history of proven thromboembolism (pulmonary embolism or deep vein thrombosis)
14. Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers, varices
15. Concurrent or planned use of any drugs contraindicated with vorinostat i.e. antiarrhythmics; any other drugs that prolong QTc; warfarin, aspirin, sodium valproate
16. Prior intolerance of any of either the components of the vaccine or HDACi,
17. Uncontrolled diabetes mellitus defined as an HBA1C>7%
18. Any congenital or acquired prolongation of the QTc interval, with normal defined as 0.40s (≤400ms); bradycardia <55 bpm
19. Participation in any other clinical trial of an experimental agent or any non-interventional study where additional blood draws are required; participation in an observational study is permitted
20. Allergy to egg
21. History of anaphylaxis or severe adverse reaction to vaccines
22. Planned receipt of vaccines (including vaccines such as yellow fever; hepatitis B, influenza) within 2 weeks of the first vaccination at week 24 on study
23. Abnormal blood test results at screening including
a. Moderate to severe hepatic impairment as defined by Child-Pugh classification
b. ALT >5xULN
c. Platelets <150x109/L
d. eGFR <90 (b)
e. uPCR >30 mg/mmol
24. Physical and laboratory test findings: Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination and/or vital signs that the investigator believes is a preclusion from enrolment into the study
25. Active alcohol or substance use that, in the Investigator’s opinion, will prevent adequate adherence with study requirements
26. Insufficient venous access that will allow scheduled blood draws as per protocol
(a) defined as any female who has experienced menarche and who has not undergone successful surgical sterilisation (hysterectomy or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhoea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35mIU/mL); NB bilateral tubal ligation is reversible, a women with only tubal ligation who does not meet any of the other criteria is considered a WCBP.
(b)eGFR is calculated by the local labs using CKD-EPI or MDRD, both equations are acceptable. Units ml/min/1.73m2. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary study outcome measure is HIV ‘total’ DNA from CD4 T-cells identified by flow cytometry of peripheral blood mononuclear cells (PBMC). This HIV total DNA from CD4 T-cells – the average at week 40 and 42 - will be compared between the two groups as allocated (intention to treat, ITT) by analysis of covariance with adjustment for week 24 values. The analysis will be performed on all eligible participants randomised. An imputation method will be used to estimate HIV integrated DNA values at weeks 40 and 42 in participants with unobserved values this will be defined in the Statistical Analysis Plan. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoint measures will be carried out at weeks 40 and 42. |
|
| E.5.2 | Secondary end point(s) |
The secondary research questions including the following
1) to describe how safe the approach is for patients. The safety aspects are documented in two ways, using the results of laboratory tests, ECGs (a tracing of the heart) and clinical assessment by the research staff;
2) measuring the HIV reservoir by measuring the amount of HIV DNA (genes) in different types on immune cells circulating in the blood;
3) measuring the amount of circulating HIV virus in the blood using an extra sensitive test called an ultrasensitive viral load assay;
4) looking at the change in the way the immune system is responding to HIV;
5) and assessing how much activity there is in the immune system through looking at the immune cells themselves and some of the proteins (biomarkers) they are making.
|
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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
|
| The end of the interventional phase of the study is defined as being 30 days after LPLV (last participant last visit), after this time the long-term follow-up phase will commence. The study will end after the last participant completes their 5th annual visit after the interventional phase. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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