Clinical Event Adjudication
Adjudication was facilitated by AWARD-Adjudicator and overseen by the Endpoint Adjudication Committee (EAC). The EAC included the Chairs of nine sub-EACs: Cancer, Cardiac, Clinically Significant Bleeding (CSB), Death, Dementia, Depression, Physical Disability and Stroke. Each sub-EAC was responsible for the adjudication of particular ASPREE endpoints (see Table 1). Please refer to the ASPREE-XT Longitudinal Data Set (XT02) Data Dictionary for all endpoint outcomes.
Table 1. Endpoint type and adjudication outcomes, responsible sub-EAC and Chair of sub-EAC.
|Cancer||Cancer||1. Non-metastatic cancer|
|2. Metastatic cancer|
|3. Not cancer endpoint|
|4. Not cancer endpoint - Carcinoma in situ|
|5. Hematological cancer|
|CSB||CSB||1. Clinically significant bleeding endpoint|
|2. Not clinically significant bleeding endpoint|
|Death (Trajectory)||Death||1. Cancer-related death|
|2. Cardiovascular death|
|3. Clinically significant bleeding death|
|4. Coronary heart disease death|
|5. Stroke death|
|6. Dementia death|
|7. COVID-19 related|
|8. Other death|
|Death (Mode)||1. Cancer (primary tumour)|
|4. Heart failure|
|6. Metastasis to vital organ|
|7. Myocardial infarction|
|10. Toxicity from anti-cancer agent or other drug|
|2. Not dementia endpoint|
|Depression||Depression||1. Hospitalisation for depression|
|2. Not hospitalisation for depression endpoint|
|Hospitalisation for Heart Failure||Cardiac||1. Hospitalisation for heart failure endpoint|
|2. Not hospitalisation for heart failure endpoint|
|Myocardial Infarction||Cardiac||1. MI endpoint (acute, resolving or evolving)|
|2. Established MI|
|3. Not MI endpoint|
|Physical Disability||Physical Disability||1. Persistent physical disability – confirmed by admission to care|
|2. Not physical disability endpoint|
|Stroke||Stroke||1. Ischemic stroke|
|2. Hemorrhagic stroke|
|3. Subarachnoid hemorrhage stroke|
|4. Stroke type uncertain|
|5. Not stroke endpoint|
Each endpoint case was assigned to three adjudicators (with the exception of death and dementia, which were only assigned to two adjudicators during the ASPREE Clinical Trial and the Bridge period) via AWARD-Data. During ASPREE-XT, death endpoints were assigned to three adjudicators. Adjudicators assigned to review an endpoint accessed the case summary document via AWARD-Adjudicator and independently completed a standard adjudication form. Relevant information was displayed on adjudication pages to ensure adjudicators adhered to the decision rules and protocol definitions, to produce standardised adjudication outcomes. If the result of the first two adjudications was discordant, the case was automatically sent to the third adjudicator. Death (during the ASPREE Clinical Trial and the Bridge period only) and dementia (during the ASPREE Clinical Trial, the Bridge period and ASPREE-XT) were exceptions to this rule as discordance was resolved by consensus. Regular sub-EAC teleconferences were held to discuss: a) any ‘three-way’ discordant adjudication cases and b) special cases requested for discussion.
Some events required subclassification, e.g. cancer type for cancer. Subclassification was completed either by the first adjudicator or by the third adjudicator. During ASPREE-XT, cancer type subclassification for both cancer events and cancer-related deaths were completed by two adjudicators. The case was automatically assigned to a third when discordance arose between the first two adjudicators. If discordance could not be resolved before the XT02 data cut, cancer type was excluded from the data set. In addition, deaths from other causes were further subclassified by two adjudicators, with any discordance resolved by a third.
For ASPREE-XT, mode of death was completed by one adjudicator only. Bleeding location for clinically significant bleeding events and stroke sub-type were also only completed by the first adjudicator or by the third.
During ASPREE-XT, AWARD-Adjudicator was improved to streamline adjudication of clinical events. The standard adjudication form linked to each endpoint was upgraded to facilitate appropriate application of individual endpoint criteria in the adjudication process, to attain an appropriate adjudication outcome for each case.
Clinical events that were detected during the ASPREE-XT study were adjudicated using these new adjudication forms, while events that were detected during the ASPREE Clinical Trial and Bridge period were adjudicated using the original ASPREE adjudication forms. As event detection is inherently retrospective, a clinical event that occurred during the ASPREE or Bridge period, but was detected after 31 January 2018, would be adjudicated according to the ASPREE-XT protocol and new adjudication forms. The variable called ‘EventPeriod’ in Section F2 indicates whether the event occurred during the ASPREE Clinical Trial, or post-ASPREE during the observational phase. The variable called ‘EventProtocol’ reports whether the event was adjudicated using the ASPREE or ASPREE-XT adjudication process and forms. Differences between the ASPREE and ASPREE-XT adjudication processes have resulted in misalignment of select event subclassifications that were changed between ASPREE and ASPREE-XT.
Although the primary adjudication outcomes for each event type have remained largely unchanged between ASPREE and ASPREE-XT, there have been several changes to adjudication outcome subclasses and types which are described in the ASPREE-XT Longitudinal Data Set (XT02) Data Dictionary.