16.1.1 Adverse Events (AE):
An adverse event (AE) includes any untoward sign, symptom, disease, or condition associated with the use of the study treatment (Vitrectomy or Anti-VEGF) regardless of the suspected cause. Conditions or diseases that are chronic but stable should not be recorded on the CRF.
16.1.2 Adverse Reaction (AR):
Any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject.
This includes medication errors, uses outside of protocol (including misuse and abuse of product)
16.1.3 Serious Adverse Events
An AE should be classified as a serious adverse event (SAE) and reported as such, if it meets one or more of the following criteria:
- It results in death (i.e., the AE actually causes or leads to death)
- It is life threatening (i.e., the AE places the participant at immediate risk of death)
- It results in hospitalization or prolongation of hospitalisation
- It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the participant’s ability to conduct normal life functions)
- It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study treatment
- The investigator considers it an important medical event because, based on medical judgment, it may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above
- It is considered sight-threatening by the investigator.
Hospitalizations for the following reasons will not be recorded as SAEs:
- Hospitalization or prolongation of hospitalization for diagnostic, medical or surgical procedures for pre-existing conditions;
- Hospitalization or prolongation of hospitalization required to allow outcome measurement for the study;
- Hospitalization or prolongation of hospitalization for treatment of the target disease of the study.
16.1.4 Sight threatening events
- An event is considered sight-threatening and should be reported as an SAE if it meets one or more of the following criteria:
- It is associated with a decrease in visual acuity of >30 ETDRS letters (compared with the assessment of visual acuity at the last visit)
- It is associated with a decrease in visual acuity to the level of Light Perception or worse
- It required surgical intervention (e.g., conventional surgery, vitreous tap or biopsy with intravitreal injection of antibiotics, or laser or retinal cryopexy with gas) to prevent permanent loss of sight
- It is associated with severe intraocular inflammation (i.e., 4+ anterior chamber cell/flare or 4+ vitritis)
- In the opinion of the investigator it may require medical or surgical intervention to prevent permanent loss of sight.
16.2 Adverse event assessment
All participants who have been exposed to the study treatment will be evaluated for AEs at each visit. All AEs, regardless of severity or seriousness and whether or not they are ascribed to the study treatment, will be recorded in the source documents and eCRF using standard medical terminology.
All AEs will be evaluated beginning with onset, and evaluation will continue until resolution is noted, or until the investigator determines that the participant’s condition is stable. The investigator will take appropriate and necessary therapeutic measures required for resolution of the AE. Any medication or other intervention necessary for the treatment of an AE must be recorded on the concomitant medication section of the source documents and eCRF.
All AEs will be characterized by the following criteria:
- Event term
- Intensity or severity
- Treatment or action taken.
16.3 Adverse Event Terms
Whenever possible, recognized medical terms should be used when recording AEs. Colloquialisms and/or abbreviations should not be used. Only one medical concept, preferably a diagnosis instead of individual symptoms, should be recorded as the event.
If more than one distinct AE occurs, each event should be recorded separately.
However, if known at the time of reporting, a diagnosis (i.e., disease or syndrome) should be recorded on the eCRF rather than individual signs and symptoms (e.g., record congestive heart failure rather than dyspnoea, rales, and cyanosis). If a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each individual event should be recorded as a separate AE. If a diagnosis is subsequently established, this information should be reported on the source documents and eCRF as follow-up information.
Signs and symptoms that are considered unrelated to an encountered syndrome or disease should be recorded as individual AEs (e.g., if congestive heart failure and severe headache are observed at the same time, each event should be recorded as a separate AE).
AEs occurring secondary to other events (e.g., sequelae) should be identified by the primary cause; a "primary" event, if clearly identifiable, should represent the most accurate clinical term to record as the AE.
If a participant is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, should be recorded as the event. For example, if a participant is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the bypass.
16.4 Adverse Event Intensity/Severity
All AEs should be graded on a three-point scale (mild, moderate, severe) for intensity/severity. Unless otherwise defined in the protocol, these definitions are as follows:
Mild: Transient; no medical intervention/therapy required and does not interfere with daily activities.
Moderate: Low level of concern and only mild to moderate limitation in daily activities; some assistance may be needed; minimal or no medical intervention/therapy required.
Severe: Severe limitation in daily activities, significant assistance required; significant medical intervention/therapy required.
There is a distinction between the severity and the seriousness of an AE. Severity is a measurement of intensity; thus, a severe reaction is not necessarily a serious adverse event (SAE). For example, a headache may be severe in intensity, but would not be serious unless it met one of the criteria for SAEs listed in the section Serious Adverse Events, above.
16.5 Treatment or Action Taken
The intervention taken to treat an AE is defined as:
- Medical intervention
- Surgical intervention
- Other (specify).
16.6 Adverse Event Outcome
The clinical outcome of an AE will be characterized as follows:
- Resolved without sequelae
- Resolved with sequelae (specify)
- Ongoing (i.e. continuing at time of study discontinuation)
16.7 Adverse Event Follow up
All AEs and SAEs will be followed through to resolution or 30 days after the participant terminates from the study, whichever occurs first.
The Sponsor or its designee may follow-up with the site by telephone, fax, email, and/or a monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).
16.8 Reporting Adverse Events
Serious Adverse Events must be reported to the Chief Investigator/Trial Manager within 96 hours of learning of their occurrence.
Immediately after the trial personnel become aware of any SAE the Principal Investigator with responsibility at each research site must report them to the Chief Investigator or the organizing research team on the form specified. The Principal Investigator or his/her research team must also follow all through to outcome, and report to the Chief Investigator, or to the organising research team on the form specified.
In addition, the Investigator should expeditiously notify the Chief Investigator of any of serious adverse events that occurs after a participant has completed or discontinued from study participation.
Contact details for submission to:
Chief Investigator (DAH Laidlaw) or Trial Manager (Eme Chan)
The initial report can be made by completing the SAE form, emailing or faxing to:
Email: [email protected]
A record of this notification (including the date of notification) must be clearly documented to provide an audit trail. In the case of incomplete information at the time of initial reporting, a follow up report should be provided as soon as the information becomes available
16.8.1 Reports to Ethics Committee
Please see Appendix 1 “Information with regards to Safety Reporting in Non-CTIMP Research”
The Chief Investigator will provide an annual report of all SAEs which will be distributed to the Data Monitoring and Ethics Committee (DMEC) or the REC, as appropriate
All AEs will be evaluated as to whether they are expected or unexpected.
Expected (anticipated): An AE is expected if it is identified in the list of expected adverse events below, or in the latest Ranibizumab or Aflibercept Summary of Product Characteristics, or the Patient Information Sheet.
Unexpected (unanticipated): An adverse event is unexpected if it is not identified in the list of adverse events below or in the latest Ranibizumab or Aflibercept Summary of Product Characteristics or the Patient Information Sheet.
16.8.3 Expected (anticipated adverse) events
- Post injection endophthalmitis
- Post vitrectomy endophthalmitis
- Vitreous or choroidal Haemorrhage
- Retinal tear or detachment
- Intraocular pressure of ≥ 45 mmHg
- Worsening of Cystoid Macular Oedema
- acute post injection visual loss ≥ 30 ETDRS letter (post injection here is
defined as within 30 minutes of the injection)sight-threatening adverse event: e.g. central retinal vein occlusion, retinal detachment, sterile endophthalmitis
- Serious adverse events should be assessed in terms of the causality or relatedness to the following events:
- Ranibizumab drug
- Aflibercept drug
- Ranibizumab or Aflibercept injection procedure
- Vitrectomy surgery
- This relationship should be classified as follows:
- Not related
16.10 Trial Steering Committee (if applicable)
Due to the size of the trial and as a small feasibility trial there is no TSC for this study.
16.11 Ethics & Regulatory Approvals
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory requirements including but not limited to the Research Governance Framework and the Medicines for Human Use (Clinical Trial) Regulations 2004, as amended in 2006 and any subsequent amendments.
The Medicines and Healthcare products Regulatory Agency (MHRA) has reviewed the VIDEO protocol. They have determined that the trial is not a Clinical Trial of an Investigational Medicinal Product (CTIMP) as defined by the EU Directive 2001/20/EC and that no submission to the Clinical Trials Unit at the MHRA is required.
The protocol and related documents have been reviewed and approved by a UK Research Ethics Committee (REC) prior to trial commencement. The details of the REC will be provided to participants and study sites by the Sponsor.
Annual progress and safety reports and a final report at the conclusion of the trial will be submitted to the REC within the timelines defined in the Regulations.
Prior to recruitment of any participants into the study at each participating site, Site Specific Approval (SSA) and NHS Research and Development approval must also be obtained.
Any changes to the protocol must be discussed and approved by Sponsor in writing unless the change is made to assure the safety of the participant.
Signed consent forms must remain in each participant’s study file and must be available for verification by study monitors at any time.