Transcript HIPvac Trial Human papillomavirus infection: a randomised

ATTIRE Trial
Stage 2 (RCT)
Site Initiation Training Slides
Zainib Shabir, Trial Manager
UCL Comprehensive Clinical Trials Unit (CCTU)
[email protected]
020 3549 5013
Agenda
• Overview: Trial design and Protocol
• Eligibility, Recruitment, Baseline visit and
Randomisation
• Example patient
• Safety Management
• Example SAE
• CRF Completion
• Monitoring
SIV Training Slides v1.0 08Jan2016
Trial Design and Protocol
SIV Training Slides v1.0 08Jan2016
ATTIRE Overview
ATTIRE: A trial to investigate whether giving albumin to patients with advanced
liver cirrhosis will reverse immune suppression and improve outcome from
infection.
Chief Investigator: Dr Alastair O’Brien
Funder: HIC Fund
Sites: Up to 40 sites across the UK (initially 25 sites)
Participants: 946 ( Stage 1: 80 and Stage 2: 866)
SIV Training Slides v1.0 08Jan2016
Trial Objectives
Feasibility Study Primary Objective:
Dose feasibility study – can we increase serum albumin to near normal levels with
daily 20% HAS infusions?
RCT Primary objective:
• This is a trial to verify whether targeting a serum albumin level of >35g/l in
patients admitted with AD using repeated 20% HAS infusions will reduce
incidence of:
1. nosocomial infection
2. organ dysfunction
3. Mortality
for the treatment period compared to standard medical care.
Patients in the RCT will be followed up 3 and 6 months (+/- 1 month) following
discharge from hospital
SIV Training Slides v1.0 08Jan2016
Stage 1 Recruitment Completed
• First Patient in 26 May 2015
• 10 sites activated in August
• Recruited all 80 patients within 6 months
Currently: data entry.
Analysis will be in February with
dissemination of results from March
Trial Design
Interventions
Randomised Control Trial (RCT)
In stage 2 patients will be randomised to either:
the immune restorative albumin protocol 20% HAS
or
standard medical care
for the duration of their admission (max 14 days from trial randomisation).
Suggestive protocol (currently same as feasibility)
a. If serum albumin 30-34g/l give 100mls 20% HAS
b. If serum albumin 26-29g/l, give 200mls 20% HAS
c. If serum albumin 20-25g/l, give 300mls 20% HAS
d. If serum albumin <20g/l, give 400mls 20% HAS
Site Activation
Recruitment at the site can not begin until the Site Activation letter
has been received for Stage 2.
Site will not be activated until the following are in place:
•
All Approvals (MHRA, EC and R&D permissions)
•
Signed training information presented and signed log received
•
Completed Updated site delegation log, with all trial staff approved by the PI
•
Site Specific documents*
•
Site Activation letter received to begin recruitment
*Any site specific documentation should be sent to UCL CCTU prior to site activation
Any Questions?
Eligibility, Recruitment, Baseline visit and
Randomisation
Please refer to ATTIRE Protocol and Participant Management Plan for
further details
Eligibility
Participant Inclusion Criteria
•
All patients admitted to hospital with acute onset or worsening of complications
of cirrhosis
•
At least 18 years of age
•
Predicted hospital admission > 5 days (at trial enrolment), which must be
within 72 hours of admission
•
Serum albumin <30g/l at screening
•
Documents informed consent to participate (or consent given by a legal
representative)
Eligibility
Participant Exclusion Criteria
•
Advanced hepatocellular carcinoma with life expectancy of less than 8 weeks
•
Patients who will receive palliative treatment only during their hospital
admission
•
Pregnancy
•
Known or suspected severe cardiac dysfunction
•
Any clinical condition which the investigator considers would make the patient
unsuitable for the trial
•
The patient has been involved in a clinical trial of Investigational Medicinal
Products (CTIMPs) within the previous 30 days that would impact their
participation in the trial (including re-randomisation into the RCT)
•
Trial investigator unable to identify the patient (by NHS number)
Recruitment- Identification
• Total Recruitment: Stage 2: 866
• All patients considered to be eligible for screening should be entered onto the
Screening Log
Recruitment- Informed Consent
•
If participation is agreed, written consent should be taken.
•
Must be taken by member of team who has been trained and delegated
responsibility by PI (documented on delegation log).
•
Ensure potential participant is aware of:
–
What is expected of them, including number of procedures at baseline
–
Trial risks
–
Importance of attending follow-up appointments
•
Ensure all questions have been answered before consent is taken.
•
Confirm whether it is the patient/legal representative who is providing consent.
•
Two copies of the signed consent should be taken to total three copies:
–
One for the patient notes,
–
The Investigator Site File (ISF) (Original)
–
The patient to take home.
Recruitment- Informed Consent
Informed Consent
• Go through each statement on the
informed consent form
• Special attention should be given
to the required and optional
consent options – different from
stage 1
Recruitment- Informed Consent
Ensure both the participant and person taking consent, print sign and date the
form.
The participant should write their name and the date themselves.
Legal Representative
• A subpopulation of patients may not be able to consent for
themselves, e.g. patients who present with hepatic
encephalopathy.
• These patients should not be excluded from the ATTIRE
trial. If a patient does not have capacity to understand the
aims of and procedures involved in the trial, a legal
representative should be chosen to represent the patient
• Personal vs professional representative
• Once the patient regains capacity, re-consent should
occur.
If unfamiliar with consent in this setting suggest the elearning
module (free): ‘Informed Consent with Adults Lacking
Capacity’ via http://learning.nihr.ac.uk/learning
Screening and Eligibility
•
Many of the procedures that are part of the screening for the ATTIRE trial are
done as standard of care
EXCEPT Pregnancy testing (for patients with child bearing potential in not part of
standard care) this can not be done until consent to take part has been given.
•
•
Complete eligibility CRF once consent has been taken.
Eligibility must be confirmed by a medical doctor (as approved on the
delegation log by the PI) before a participant can be randomised. Once
eligibility has been confirmed, enrolment and randomisation can be
completed.
•
If the participant does not meet all of the inclusion and none of exclusion
criteria, they are not eligible and should not be randomised. This should
be recorded as a screen failure on the screening log.
Enrolment
Once consent is obtained and eligibility has been signed by the doctor,
this should be confirmed and the patient enrolled online in Sealed
Envelope
Sealed Envelope can be access at the following address:
https://www.sealedenvelope.com/redpill/attire/
• Sealed Envelope is an online system to confirm eligibility and enrol
and allocate the patient ID for the Trial
• Anyone who still needs access to the system please contact the
CCTU
• You will then be asked to confirm the eligibility criteria have been
met.
• For randomisation, additional information will be required
Sealed Envelope: Information required
Patient Initials:
Site:
Month and year of birth:
NHS number:
Date of admission:
Serum Albumin Level
AAA or A-A
AAA, e.g. UCH
MMM-YYYY
999 999 9999
DD-MMM-YYYY
g/l
HE Grade
Oxygen Saturation
Supplemental Oxygen (in % e.g. 35%) or mechanical ventilation
Blood Pressure (Systolic and diastolic)
Is the patient on one or more of the following, norepinephrine (noradrenaline),
epinephrine (adrenaline) or dobutamine?
INR
Serum Creatinine (and if undergoing renal replacement therapy)
Serum Bilirubin
Sealed envelope
After entering the information you will receive:
• Patient ID number
XXX- 015-01
• Patients treatment arm
– 20% HAS
– Standard of care
Please see Sealed Envelope Guidance for further details
TREATMENT DAY 1
Once the patient is confirmed as eligible they can be entered on the Trial
Enrolment log
TREATMENT DAY 1
• The baseline measurements will be carried out once the
patient eligibility, patient ID and treatment arm are
confirmed in Sealed envelope
• The blood results can be those used as part of the
screening
• Treatment Day 1 should be within 24 hours of screening
(and 72 hours of admission)
• Prescription of HAS [or usual care for Standard of Care
arm]
• Record all fluid administered since admission and any
deviation from the suggested regimen (including nutritional
support)
• Record all medications on concomitant medication log
Treatment Arms
HAS (Active Arm)
Standard of Care (Control)
As per stage 1 the suggestive
protocol
Whatever would have happened to
the patient should they not have
been in the trial
If serum albumin 30-34g/l give 100mls
20% HAS
If serum albumin 26-29g/l, give 200mls
20% HAS
If serum albumin 20-25g/l, give 300mls
20% HAS
If serum albumin <20g/l, give 400mls
20% HAS
HAS only to be given as per current
established evidence based
guidance:
1.
2.
3.
Reasons for any deviation from the
suggested protocol should be
recorded on the CRF
Large Volume Paracentesis (LVP)
Spontaneous Bacterial Peritonitis
(SBP)
Hepatorenal Syndrome (HRS)
HAS given for any other indication
will be considered a protocol
deviation.
TREATMENT Days 2-15
• Patients will remain in the trial for up to 15 days
(or discharge if prior to day 15)
• Days 1-14 the patients will undergo the following
– Clinical Observations (worst recorded in the last 24hrs)
– Record blood results (as per standard care)
– Dosing (as per randomisation)
• This should be aimed to be completed around a
similar time on a daily basis.
TREATMENT Days 2-15: Infection Diagnosis
TREATMENT Days 2-15: Infection Diagnosis
• New infection diagnosis is essential for primary
composite endpoint
• Often difficult to diagnose
• We are using an accepted criteria for clinical
diagnosis – the infection CRF will capture this
information
• A new diagnosis of infection (often marked by
initiation of antibiotics) should be discussed with
trial doctors if there is ANY uncertainty
TREATMENT Days 2-15
• On Day 15 or discharge no HAS will be prescribed as part
of the trial.
• All other observations will be carried out in the same way
as the other treatment days
• Following day 15/discharge the patient's will receive
questionnaires at 3 and 6 months from Discharge - these
can be done at normal clinical visits (if these fall into the
windows)
• Please note that there is a Discharge CRF which will need
to be completed along with the end of treatment CRF, if
the day of discharge is the same as the end of treatment
Follow up
•
•
•
From the Day 15/discharge the patient's treatment phase
is over and they will be in follow up
Patients will be followed up at 3 and 6 months from
discharge - these can be done at normal clinical visits (if
these fall into the windows)
Active follow up will involve
• Questionnaires
• Details of transplant listing
• recent (standard of care) blood result also required
Health economics and QOL
• CSRI
• EQ-5D-5L
Complete: Baseline & Follow up Complete: Baseline, Discharge, Follow up
Re randomisation
Patients who have been enrolled can be re
randomised IF it is > 30 days after discharge
The patient will go through the same process as before - the patient will
be given the same patient ID – with different numbers at the end
BAS- 001-00 – Stage 1
BAS-001-01 – Stage 2
BAS-001-02 – Stage 2 (re-randomisation)
Concomitant medication Log
The concomitant log should also be completed for the patient for all
medication from enrolment until follow up.
This should be maintained throughout the course of the patients
participation
Example Case
for ATTIRE Stage 2
(RCT)
Mr Brown. 56yo ETOH cirrhosis.
Previous admissions: Variceal bleed 8 months
before, mild-mod ascites then – medical
management.
Referred for admission via A&E on Sunday:
• Intermittent confusion at home
• Renal impairment - ?dehydration ?related to
medications
• Hyponatraemia
Day 1 admission (AMU)
Examination
Clinical Impression
Mild ascites
grade 1/2 encephalopathy
no signs of infection
BNO 5/7
Acute Decompensation
- 2y to medication induced
altered electrolytes/renal
function
- Encephalopathy 2y to
constipation/electrolytes
Bloods
FBC: Plts 70
U&Es: Na 128, K 4.2, Urea 12,
Creat 124
LFTs: Albumin 24
Clotting: INR 1.7 CRP: 6
Imaging
Normal CxR
Management
•
•
•
•
•
•
Diuretics held
IV & oral fluids
Lactulose QDS
Full infection screen
Renal USS
Transfer to Gastro ward
Screening: Monday morning
✔
✔
✔
✔
✔
✔
✔
✔
✔
✔
✔
Consent
• Patient information
– Leaflet
– Verbal explanation
• Does this patient have capacity?
• Consent form and consent CRF
• SEALED ENVELOPE:
– Randomised to treatment arm (albumin)
Treatment Day 1
1. Mr Brown’s reasons for admission & PMH
documented
2. Is there any current infection?
3. Clinical Observations and blood results (as taken
on that day) documented
4. IV fluids since admission documented and
nutritional supplementation
5. Concomitant medication log completed
6. CSRI and EQ-5D-5L questionnaires completed
0
3
0
1
0
6
7
7
4
9
0
2
6
8
0 2 1
0 9 6
0 6 8
NONE
A
1
M
Treatment Days 2-8
Worst recorded
reading in the last
24hrs – highest and
lowest
The lowest systolic
and the paired
diastolic reading
Treatment Days 2-8
Mr Brown: Days 1-6
Day
Serum
albumin (g/L)
HAS 20%
given (mls)
Clinical progress
1
24
300mls
2
29
200mls
Improving renal and
electrolyte function
3
36
0mls
4
36
400mls
LVP – albumin prescribed
Mr Brown: Day 7
Diagnosed with a urinary infection on the basis of an increased CRP (48), low
grade fever and positive urine dip stick on the ward: started on Ciprofloxacin:
Infection CRF & concomitant medication log to be completed
Day
Serum
albumin
HAS 20%
given
7
32
100mls
Clinical progress
✔
✔
✔
Infection CRF
Day 11: Mr Brown is medically fit for
discharge
• Renal function normalised
• Oral antibiotics for home
• Awaiting OT assessment (stairs)
Discharge CRF to be completed – includes EQ-5D-5L questionnaire
Follow up 3 months (2-4 months)
• Routine clinic appointment 12 weeks post
discharge
• Bloods taken as standard of care
• CSRI and EQ-5D-5L questionnaire completed
Patient re admitted at 4 months
• Consents to be re enrolled into ATTIRE RCT
• Randomised to treatment arm this time
• Discharged at 20 days
Follow up:
They will no longer be followed up for the initial
randomisation into the RCT only for the most recent
entry into the ATTIRE trial
Any Questions?
Safety Management
Please refer to ATTIRE Safety Management Plan for full details
Safety
•
•
•
Human Albumin Solution is a marketed product and routinely used in patients
with liver disease.
The safety profile is well known and we therefore expect minimal adverse
reactions to the HAS. Adverse Events (AE’s) will be recorded in the patients
notes as per standard practice, however these do not need to be reported to
the CCTU.
Only Serious Adverse Events (SAE’s) will be reported to the CCTU, these
should be reported immediately
Event Type
Serious Adverse Event
Pregnancies (Notifiable Event)
Pregnancy outcome
Reporting timelines
(to UCL CCTU)
Immediately on SAE/Pregnancy Reporting form
Immediately on SAE/Pregnancy Reporting form
Immediately on pregnancy outcome and as resolution to
the initial pregnancy report.
Immediately on new SAE/Pregnancy Reporting form as
required.
Notification Process
Notify UCL CCTU immediately of any SAEs
SAE form should be completed by PI or clinical delegate- if not available, site
team member should sign and email form. The form should then be checked by
the PI/medical delegate at the earliest opportunity and countersigned for accuracy
The minimum criteria required for reporting an SAE are the
• patient identification number,
• the IMP
• the SAE/SUSAR
Researcher should get the next
available number in the sequential log,
• causality assessment
in section 13.2 of the ISF.
• name of reporting investigator
• SAE event number
Send signed SAE form to UCL CCTU: [email protected]
Safety Reporting
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical trial participant administered a
medicinal product and which does not necessarily have a causal relationship with this
product.
Adverse Reaction
(AR)
Any untoward and unintended response to an investigational medicinal product related to any
dose administered
Unexpected Adverse
Reaction (UAR)
An adverse reaction, the nature or severity of which is not consistent with the applicable product
information (e.g. Investigator’s Brochure for an unauthorised product or summary of product
characteristics (SPC) for an authorised product.)
Serious Adverse
Event (SAE) or
Serious Adverse
Reaction (SAR)
Any AE or AR that at any dose:

results in death

is life threatening*

requires hospitalisation or prolongs existing hospitalisation**

results in persistent or significant disability or incapacity

is a congenital anomaly or birth defect

or is another important medical condition***
Suspected
Unexpected Serious
Adverse Reaction
(SUSAR)
A serious adverse reaction, the nature of severity of which is not consistent with the known
potentially expected events associated with the applicable trial treatment. The event is evaluated
as having a possible, probable or definite relationship to a trial treatment and is unexpected for
that trial treatment.
•
* the term life threatening here refers to an event in which the participant is at risk of death at the time of the event; it does not refer to an event that might hypothetically cause
death if it was more severe (e.g. a silent myocardial infarction)
•
** Hospitalisation is defined as an in-patient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation.
Hospitalisation for pre-existing conditions (including elective procedures that have not worsened) do not constitute an SAE
•
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other situations. Important AEs or ARs that may not be immediately life threatening or
result in death or hospitalisation, but may seriously jeopardise the participant by requiring intervention to prevent one of the other outcomes listed in the table (e.g. a secondary
malignancy, an allergic bronchospasm requiring intensive emergency treatment, seizures or blood dyscrasias that do not require hospitalisation, or development of drug
dependency).
Seriousness assessment
When an AE or AR occurs, or when the site becomes aware, the investigator
responsible for the care of the participant must first assess whether or not the
event is serious using the definition given below.
Serious Adverse Event
(SAE) or Serious Adverse
Reaction (SAR)
Any AE or AR that at any dose:
 results in death
 is life threatening*
 requires hospitalisation or prolongs existing
hospitalisation**
 results in persistent or significant disability or
incapacity
 is a congenital anomaly or birth defect
 or is another important medical condition***
If the event is classified as ‘serious’ then an SAE form must be completed
and UCL CCTU notified immediately.
Expectedness
If there is at least a possible involvement of the trial medication, the site investigator
and UCL CCTU delegated clinician must assess the expectedness of the event.
An unexpected adverse reaction is one that is not reported in the current
SmPCs, or one that is more frequently reported or more severe than
previously reported in the SmPC.
•
•
•
The specific SmPC specific the versions filed or specified by the trial manager
should be used for the expectedness review and can be found in section 2.1 of
the ISF. If you are unsure of the current version, please contact the Trial
Manager.
Any updates to the SmPC will be communicated to site by the trial manager.
UCL CCTU will send any reportable events to MHRA and Research Ethics
Committee (REC). In order to meet these deadlines, it is crucial that events are
reported to [email protected] immediately.
Notification process
Points to remember:
• Send the notification to the stated email only:
[email protected]
• Follow-up SAE forms should be sent as soon as information is
available.
• Do not include identifiers on any correspondence- black out any
identifiers and replace with trial identifiers.
• SAEs will be reviewed by CCTU delegated reviewer within 48 hours
and SARs/SUSARs immediately.
• SARs and SUSARs must be notified to UCL CCTU until trial
closure.
• For the purpose of this trial pregnancy is the only notifiable adverse
event, and should be reported within the same timelines as SAEs.
• Participants should be reminded of the importance of using effective
contraception throughout their time on the trial
PLEASE REPORT SAEs in both arms
e.g. if a patient has suspected fluid overload with
pulmonary oedma in EITHER arm it should be
reported
(don’t just events in the albumin arm as you are
concerned the albumin is causal)
Case example:
ADVERSE EVENT
Mrs Williams. 63yo with NASH cirrhosis
• Admitted 6 days ago with worsening ascites and
poor glucose control
– Diagnosed with SBP on day 1
– Recruited to ATTIRE 2 – standard of care arm
• Day 4 diagnosed with hospital acquired
pneumonia
• Day 5 increasing shortness of breath, hypoxia
Day
Serum albumin
(g/L)
HAS 20%
given (mls)
Other IV fluids
1
24
0
3L
2
26
0
2L
3
28
0
3L
4
28
0
5L
5
28
0
3L
?pulmonary oedma ?ARDS ?bilateral pneumonia
Progressive deterioration – transferred to ITU
Questions
1. Is this an expected event?
2. What are the possibilities with regards to
precipitator for this event?
3. Should this be reported?
4. How should this be reported?
5. Causality?
6. Should the patient be withdrawn from the trial?
7. What follow up would you expect after reporting?
Any Questions?
CRF Completion
Please refer to ATTIRE CRF completion guidelines for full details
CRF Completion
• CRFs will be paper based and entered into a database centrally at
CCTU.
• CRFs are the source document for the trial and all information entered
should be completed as clearly and as accurately as possible
• The questionnaires should be completed by the patient (proxy if
incapacitated) at baseline, discharge and follow up visits
• If this is not done should be marked as not done in the CRF
• All questions should be answered (including ‘Y/N’ or ‘not done’) to
reduce queries
CRF Completion
• Treatment days
- Clinical observation and blood results all part of
standard care – no additional procedures.
- CSRI – baseline and FU – if not done before
randomisation should be done prior to discharge
• EQ-5D-5L – baseline (prior to randomisation). If
unconscious then should be marked as ‘no’ and not done
until discharge and follow up. If conscious but unable to
complete the form then the proxy can be completed.
• Infection CRF only from day 1 onwards
• Conmed log to be completed from Day1 onwards
(including follow up)
Email Documents
Preparing Data
Before scanning the patient study data ready to email please ensure the following:
• If sending CRFs, please check that all fields are completed according the trial specific
CRF completion guidelines and the protocol.
•
Please ensure that no patient identifiable data has been entered (including patient name
or hospital number). All documents should contain the participant ID – all headers and
footers should be completed
•
Please ensure all pages of scanned documents are legible including headers and
footers, where applicable. Check the document thoroughly before sending.
•
Please note that in order to maintain confidentiality, all electronic copies of
completed CRFs/sensitive data to be sent to the CCTU should be encrypted to
ensure security of the data. Please see the encryption guidance below.
CRFs can be emailed to the CCTU at the following email address: [email protected].
Encryption of data to be sent by email
Can be either:
• Via NHSmail encryption- if you have an @nhs.net
email address
or
• 7-zip encryption
For both systems, a test message must be sent to
CCTU before any sensitive documents are sent.
Any Questions?
Monitoring
Monitoring
•
•
•
•
Will be both central and on-site monitoring.
Performed by ATTIRE Trial Team
Please note- All trial files and CRFs need to be store securely.
All trial documentation, procedures and facilities are subject to review at
monitoring visits
Central Monitoring
• Performed remotely:
–
–
–
•
Recruitment update (monthly)
Assessment of data in CRFs from sites
Request and review of logs, such as screening logs and other documentation as requested
Queries will be raised as and when necessary
–
–
Queries relating to CRFs will initially be sent on a data Clarification Request
Queries should be resolved within the given time frames (specified when queries are sent).
Monitoring
On-site Monitoring
•
Will be either planned or triggered, as a result of issues raised during central
monitoring
•
Site team will be notified in advance of which documents will be monitored, for
example:
–
–
–
–
Medical notes
Consent forms
Laboratory records (blood results)
Consent, and eligibility procedures
•
Visit may last for 1-2 days.
•
Feedback will be given after the visit
•
A written report will be sent with actions that will require addressing
Monitoring is designed to be a supportive process.
Document Management
• Site responsibility to maintain the Essential documents at
the site (ISF)
– Delegation log
– Training log
– CV’s and GCP certificates
• All updated documents sent by the ATTIRE team should
be filed in the corresponding section of the master file and
all previous versions marked as superseded
• Confirmation of receipt will be required for an audit trail
Protocol Deviations
• Any deviation from the protocol that is approved by the Research
Ethics committee and the Regulatory Authority (MHRA)
– Deviation from admission to day 1
– Deviation from international guidelines for HAS administration
– SAE reporting (both arms)
• If a protocol deviation occurs at site, the ATTIRE team should be
informed the and deviation noted (this should be within 24hrs of
becoming aware – see CRF completion guidance for further details).
• A Corrective and Preventative Action Plan (CAPA) should be
completed as much as possible and sent to the CCTU.
• Deviations do not include
– Deviation from the treatment dosing regimen (as stated in the protocol)
– Missed bloods or clinical observations (if not required as part of clinical
practice
Serious Breach
Serious Breach of GCP or the protocol:
‘is a deviation from a trial protocol or the principles of GCP
which is likely to effect to a significant degree either:
a) The safety or physical or mental integrity of the subjects of
the trial; or
b) The scientific value of the trial.’
If a deviation is classified as a serious breach this should be reported to the TM with 24hrs.
Onward reporting will be carried out by the ATTIRE Team (REC and MHRA)
Any Questions?
Any questions do not hesitate to contact us 
ALL DOCUMENTS AND GUIDANCE ARE AVAILABLE AT
www.attiretrial.com (password @ttir3)