A Phase 2 interventional study of Stamaril and Imojev in Infectious Disease, Yellow Fever and Japanese Encephalitis, sponsored by Singapore General Hospital. Recruiting at 1 site in Singapore. Open to participants aged 21 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-04-12.
Sponsored by Singapore General Hospital · Phase 2, Interventional, and Basic science
We hypothesize that a high CD4+ and CD8+ T cell count will reduce viremia upon challenge with a structurally heterologous virus, and correspondingly result in reduced magnitude of host response to challenge infection.
Primary Objective: To compare, after challenge with a structurally heterologous vaccine, the differences in levels of viremia between healthy adults who received primary vaccination with either YF17D vaccine, chimeric JE-YF17D vaccine, or inactivated JE vaccine.
58 subjects will be randomised into 1 of 2 arms (Arm B1 and Arm B2) in a 1:1 ratio, in a double-blind fashion. Subjects in Arm B1 will receive JE-YF17D vaccine (Imojev, Sanofi Pasteur) on Day 0 followed by YF17D vaccine (Stamaril, Sanofi Pasteur) on Day 28. Subjects in Arm B2 will receive Stamaril on Day 0 followed by Imojev on Day 28. Arm B3 will be conducted as a separate single-arm open label design in 14 subjects. Subjects in Arm B3 will receive inactivated JE vaccine (Ixiaro, Valneva) on Day 0 followed by Stamaril on Day 28.
The rationale for these three study arms is as follows: Arm B1 will show the impact low levels of viremia, and the resultant low levels of virus-specific CD4+ and CD8+ T cells, would have on YF17D infection. In contrast, YF17D vaccination in Arm B2 would produce high levels of viremia, and in turn high levels virus-specific T cells, thus likely ameliorating JE-YF17D infection. Arm B3 will serve as the control arm, as vaccination with inactivated JE vaccine would not produce any YF17D-specific T cell response. Notably, the first vaccination in Arms B1 and B2 would also provide the viremia response in the absence of virus-specific T cells, which would serve as a reference point to interpret the outcome of the second vaccination.
Criteria for Recruitment and Recruitment Process: Subjects will be recruited from SingHealth Investigational Medicine Unit (IMU) healthy volunteer database and recruitment posters. Subjects will be given a copy of the Participant Information and Informed Consent Form to read upon their arrival. A briefing session on the study will be conducted by the Investigator. Thereafter, subjects will be ushered into a private room where informed consent is obtained and where questions about the study can be asked freely. Subjects will not be rushed into making a decision to participate in the study. They will be encouraged to speak to their family members about participation in the study; and allowed to defer their decision (without any prejudice) to participate till after discussion with their family members.
Screening Visits and Procedures: Subjects will be recruited via the SingHealth Investigational Medicine Unit (IMU). Informed written consent will be sought from subjects who fulfill criteria for enrollment. All consented subjects will undergo screening, which includes physical examination, full blood count, liver function test, anti-dengue antibodies ELISA (Enzyme-Linked Immunosorbent Assay) and urinary pregnancy test (for female subjects of child-bearing potential).
A urine pregnancy test will be performed at screening and on the day of vaccination (day 0 and day 28) for female subjects of child-bearing potential. Only those with a negative urine pregnancy test will be considered to be eligible for the study, provided that other eligibility criteria were fulfilled.
Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) must agree to use adequate and reliable contraceptive measures (e.g. spermicides, condoms, contraceptive pills) or practice abstinence for 10 days after vaccination.
Study Visits and Procedures: 58 subjects will be randomised into 1 of 2 arms (Arm B1 and Arm B2) in a 1:1 ratio, in a double-blind fashion. Subjects in Arm B1 will receive JE-YF17D vaccine (Imojev, Sanofi Pasteur) on Day 0 followed by YF17D vaccine (Stamaril, Sanofi Pasteur) on Day 28. Subjects in Arm B2 will receive Stamaril on Day 0 followed by Imojev on Day 28. Arm B3 will be conducted as a separate single-arm open label design in 14 subjects. Subjects in Arm B3 will receive inactivated JE vaccine (Ixiaro, Valneva) on Day 0 followed by Stamaril on Day 28. Study visits in all arms will occur on Day 0, 4, 7, 10, 14, 28, 29, 32, 35, 38, 42, 58. At each study visit, physical examination, vital signs and research blood sampling will be performed. On Day 0 and Day 28, blood sampling will be performed prior to vaccination.
Final study visit: Last study visit will be on Day 58 post-study vaccination.
Post study follow up and procedures: There is no requirement for post-study follow-up or procedures.
Safety Monitoring Plan: The study may be evaluated by government inspectors/ regulatory authorities who must be allowed access to e-CRFs, source documents, and other study files. The inspectors will review CRFs and compare them with source documents to verify accurate and complete collection of data and confirm that the study is being conducted according to the protocol, ICH Good Clinical Practices (ICH-GCP) and all applicable regulations.
At any time post-vaccination, all subjects will be trained to observe for systemic AEs. A diary will also be given to the subjects to record such events should they occur during this period. Should they develop systemic symptoms that require intervention, they will report to the study site for medical evaluation and receive the appropriate therapy. Duration of symptoms will be recorded. Any concomitant medication use during this period will also be recorded.
During the study, full history taking and physical examination will be performed at both scheduled and unscheduled visits. A full physical examination will only be done at the screening visit, while a brief physical examination will be done for all subsequent visits. The Common Terminology Criteria for Adverse Events (CTCAE), routinely employed in clinical trials, will be used to define AE terminology and severity. Management of AEs is at the discretion of the study team PI and co-Is, guided by severity and clinical indication for intervention. All medication prescribed for the management of AEs will be documented in the medication/concomitant medication clinical record form. Details of AE event terminology, date and time of event start and end, severity, using the CTCAE or treatment given, impact on work and to the continuation of the study, and final outcome of the event will be recorded on the case report until resolution of the event.
Data Quality Assurance: The PI and Co-Is will review the study periodically for data and safety monitoring. Internal quality checks will be performed by two CRCs who are study team members. The data entered by one CRC will be checked by another using the source documents. The study may also be picked for monitoring by SingHealth Office of Research Integrity and Compliance (ORIC) or evaluated by government inspectors/regulatory authorities who must be allowed access to e-CRFs, source documents, and other study files. The monitors/inspectors may review CRFs and compare them with source documents to verify accurate and complete collection of data and confirm that the study is being conducted according to the protocol, ICH-Good Clinical Practices (ICH-GCP) and all applicable regulations.
Data Entry and Storage: All participant's data will be de-identified upon recruitment. Hardcopy research data collection forms such as CRFs, logs and diaries will be kept in the Investigator's Site File and stored in SingHealth IMU under lock and key, accessible only to delegated study team members.
Direct data capture of demographic and clinical data will be captured on source documents. Identifiers will be kept in a separate file in another office and every effort will be made to protect the privacy of the participants. The data to be analysed will contain only de-identified data. An electronic data capture system will be used. All electronic data will be password protected and can only be accessed by study team members. Specimens, test results or pathogen data will be stored at Duke-NUS EID laboratory in a stand-alone PC whereby access is password protected.
Determination of sample size: To detect an effect size of 0.8 SD in mean viremia level on log(10) scale between first and second with the same vaccine - first dose of will be analysed against those who received YF17D after JE-YF17D and vice versa - a sample size of 25 per group will provide 80% power at 5% two-sided type 1 error rate. To allow for 10% early dropouts, a total sample size of 28 per group for Arm B1 and B2 is targeted. For Arm B3, which is the control group, a sample size of 14 will be used.
Statistical and Analytical plan: Distributional diagnostic plots will be used to examine the shape of distributions of T-cell counts immediately before the challenge vaccination and the subsequent vaccine viremia. Parametric (t-test) or non-parametric (Mann-Whitney U) procedures will be used to assess the differences in T-cell counts and the various measured variables such as viremia, antibody titres and cytokine levels. Pearson's or Spearman's correlation coefficients will be used, as appropriate, to examine the association between T-cell levels and these variables.
The frequency of symptoms reported and the type of symptoms will first be analysed by determining the median and the interquartile ranges. We will then analyse how the first vaccination impact the symptomatic outcome of the challenge vaccination using 2x2 tables and chi square analysis or Fisher's exact test, whichever is appropriate. Parametric (t-test) or non-parametric (Mann-Whitney U) procedures will be used to assess the differences in pre-challenge virus-specific T-cell counts among those with symptoms and those without.
Tests which will be performed on the blood samples: DENV IgG ELISA, FBC, Liver Panel, Viremia (NS5 PCR), cytokines, Anti-NS1 Ab, T-cell studies (AIM, ELLISPOT, ELLA), BCR sequencing, PRNT and gene expression.
626 studies on the registry are indexed under Communicable Diseases; 128 are open to participants now.
This study's planned enrollment of 70 is below the median of 89 across 380 interventional studies indexed under Communicable Diseases.
Browse Communicable Diseases studies →Singapore General Hospital is the lead sponsor of 270 studies on the registry; 57 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
28 subjects will receive one dose of the JE-YF17D vaccine (Imojev, Sanofi Pasteur, 0.5mls (4.0 - 5.8 log plaque forming units \[PFU\])) on Day 0 followed by one dose of the YF17D vaccine (Stamaril, Sanofi Pasteur, 0.5mls (3 - 4 log PFU) ) on Day 28.
Biological: Stamaril · Biological: Imojev
28 subjects will receive one dose of the YF17D vaccine (Stamaril, Sanofi Pasteur, 0.5mls (3 - 4 log PFU)) on Day 0 followed by one dose of the JE-YF17D vaccine (Imojev, Sanofi Pasteur, 0.5mls (4.0 - 5.8 log plaque forming units \[PFU\]) on Day 28.
Biological: Stamaril · Biological: Imojev
14 subjects will receive one dose of the inactivated JE vaccine (Ixiaro, Valneva, 0.5mls) on Day 0 followed by one dose of the YF17D vaccine (Stamaril, Sanofi Pasteur, 0.5mls (3 - 4 log PFU)) on Day 28.
Biological: Stamaril · Biological: Ixiaro
Stamaril is licensed by the Health Sciences Authority (HSA), Singapore. The vaccine are manufactured by Sanofi Pasteur and sourced from Sanofi Pasteur's local distributor.
Also known as: YF17D vaccine
Imojev is licensed by the Health Sciences Authority (HSA), Singapore. The vaccine are manufactured by Sanofi Pasteur and sourced from Sanofi Pasteur's local distributor.
Also known as: JE-YF17D vaccine
Ixiaro is licensed by the Health Sciences Authority (HSA), Singapore. The Ixiaro vaccines are manufactured by Valneva and sourced from local distributor, Aenon Pharmaceuticals SEA Pte Ltd.
Also known as: Inactivated Japanese Encephalitis vaccine
Viremia levels after second vaccination
Viremia level (genome copies/ml) after second vaccination with either JE-YF17D or YF17D
Time frame: Day 0 to Day 58
T cell responses after vaccination
Magnitude of antigen-specific T cell responses after vaccination.
Time frame: Day 0 to Day 58
Viremia level after first vaccination
Viremia level after first vaccination with either JE-YF17D or YF17D
Time frame: Day 0 to Day 58
Duration of viremia after second vaccination
Duration (in days) of detectable viremia after second vaccination with either JEYF17D or YF17D.
Time frame: Day 0 to Day 58
Antibody Titres
Neutralising Antibody titres as measured by plaque reduction neutralisation test (PRNT50 and PRNT90) i.e the serum titer required to reduce viral plaques by 50% or 90% respectively, after second vaccination with either YF17D, JEYF17D or inactivated JE-YF17D vaccines.
Time frame: Day 0 to Day 58
Rates of Adverse Events
Rates of adverse events after vaccination with either JE-YF17D or YF17D
Time frame: Day 0 to Day 58
Innate Immune Gene Expression
Levels of innate immune gene expression after vaccination with JE-YF17D, YF17D or inactivated JE vaccine.
Time frame: Day 0 to Day 58
Cytokine levels
Levels of cytokines after vaccination with JE-YF17D, YF17D or inactivated JE vaccine
Time frame: Day 0 to 58
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Studies of the drug tested here: Japanese encephalitis virus strain SA 14-14-2 antigen (formaldehyde inactivated)