Transcript Serious adverse event Diary Case-report forms

Clinical Phase I Trial
Signe Sorup
Alex Chaudhuri
Sandrine Duron
Objectives
• Primary - To assess the safety and tolerability of one
dose of rBCG-Pasteur B vaccine compared to BCG in
healthy adults.
The endpoints will be any local and systemic reactogenicity signs
symptoms, any derangement in laboratory measures or any report of
adverse event during the first 4 weeks after the vaccination.
and
• Secondary - To evaluate the immunogenicity of one
dose of rBCG Pasteur B vaccine compared to BCG.
The endpoints will be measured by intracellular cytokine staining on whole
blood
Design
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Randomised
Double-blinded
BCG controlled (Tice strain)
Dose escalating
Single center
Setting - Denmark (Non-endemic + No
routine BCG last 30 years)
Inclusion criteria
• Healthy adults, 20 - 30 years old on the day of trial
enrollment
• Healthy by medical history + clinical examination
• Women - Non-pregnant, contraception during period of trial
including total period of follow-up ( not to commence new
OCP during trial)
• BMI 18-25
• Written consent
Exclusion criteria
• Evidence / risk of latent TB
o Positive Tuberculin Test or Positive Quantiferon (IGRA)
GOLD
o Prior contact with active pulmonary tuberculosis or in
relevant health care setting
o Abnormal chest X-ray
• Confounders of immunogenicity endpoints
o BCG vaccination history or scar
o Other vaccination within the 4 preceding weeks
• Significant language barrier
Exclusion criteria - 2
• Safety concerns
o HIV positive / other immunosuppression
o High risk behaviour for acute HIV infection
o Illicit drug abuse
o Fever > 37.5 c
o Current or recent (one month) acute illness
o Chronic disease or medication
o Abnormality on Full blood Count/Coagulation/Liver
enzymes
o Abnormal urinary analysis
Advertisement for volunteers
• Focus on students
o Student magazines
o Campuses
o Community center
Method - schedule
rBCG Pasteur B*
Controls (BCG TICE)
Number of
injections
Time of
entry
arm
Number of
subjects
Dose
(CFU)
Number of
subjects
Dose
(CFU)
1
7
5*103
2
5*105
1
Day 0
2
7
5*104
2
5*105
1
Day 40
3
7
5*105
2
5*105
1
Day 80
4
7
5*106
2
5*105
1
Day 120
* TICE BCG strain with overexpression of Ag85A, Ag85B, PPE44 and DA-1
Method - description of the product
• No obvious difference between the rBCG Pasteur B and
BCG
• Reconstituted by the pharmacist
o immediately prior to the injection
o 0.1 ml of neutral solvent
• Route of administration: intra-dermal
Adverse events
Any untoward medical event that occurs after
administration of the injection regardless of
whether it is directly attributable to the
vaccine or not.
Adverse events
• Reactogenicity
o
o
Common adverse events usually observed after immunization
 Local reaction
 Systemic reaction
Usually occur up to 2 - 3 days after immunization
Adverse events
• According to the FDA guidance toxicity grading
scale
o
Mild/moderate/severe/potentially life-threatening AE
• Serious adverse events
o
o
o
o
o
Death
Life threatening adverse events
Hospitalisation or prolonged hospitalisation length
Significant disability or incapacity
Congenital abnormality, birth defect, unintentional fetal loss
Data collection
• Daily diary formated
o
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Solicited and unsolicited adverse events
Filled by the volunteer
• Case report forms (CRF)
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o
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Filled by the physicians (diagnosis/syndroms)
Based on the volunteers diary
Clinical examination
Physician
Pre vaccination
Day 0 (after injection)
 Subjects observation for an hour after the injection
 Vital signs monitoring at 30 and 60 minutes post-injection
 Local reactions evaluation at 60 minutes
o Day 7, 14, 28
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o
o
• Biological tests
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Hematology/ liver enzymes/ renal function
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o
Pre vaccination
Day 0, 7, 14, 28
Serious adverse events declaration
• Dedicated phone number
• Declaration as soon as possible
o to the sponsor
o to the institutional review board (IRB)
• Investigation
• Suspend further vaccine administration if possibly related
to vaccine
Immunogenicity assessment
• Intra cellular cytokine staining (flow cytometry)
o Total cytokine positive CD4 frequency
o expression of IFN gamma, IL-2, TNF alpha singly or
in combination (polyfunctional T cell)
o Same with CD8 T cells
• Whole blood (frozen after stimulation) and PBMC for a
subset of volunteers
Follow-up schedule
Pre-vaccination 0
7
14
28
42
Clinical examination
x
x
x
x
x
Blood sample
10ml
10 ml 10
ml
10
ml
10 ml10
ml
Biological tests for
adverse events
Immunogenicity
x
x
x
x
x
x
x
x
x
84
182
Serious adverse event
Diary
Case-report forms
x
10 ml10
ml
x
x
Endpoints
• Rate of all adverse event
• Rate of adverse events acording to severity
• Rate of AE’s possibly attributable to
vaccine
• Immunological endpoints
Environmental and regulatory challenges
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Comply with local GMO guideline
Biohazard facility
Disposal of residual vaccine as medical waste
Drug sensitivity of the new recombinant BCG
• Choose adults instead of infants
o phase 1 trial : infants
o issue of Informed consent