Unblinding clinical scenarios and advice
It should be possible to manage most acute clinical situations by assuming a trial participant has been taking either total daily amount of 2000mg of Immediate Release Metformin or 1200mg R/S-Alpha Lipoic Acid and/or by subsequently withholding the trial medication if appropriate.
However, there may be clinical circumstances where knowledge of treatment allocation is essential to guide immediate clinical management. Where unblinding is being considered, ideally the case should be discussed with the local trial Principal Investigator or Octopus Trial team, if required and possible. However This discussion is not mandatory.
IF YOU ARE A MEMBER OF AN OCTOPUS TRIAL TEAM UNBLINDING ONE OF THE PARTICIPANTS AT YOUR SITE, PLEASE ENSURE YOU COMPLETE AN SAE FORM WITHIN 24 HOURS.
Guidance on a number of anticipated scenarios with specific advice about the need to unblind:
Overdose
If the patient is suspected to have overdosed on their IMP, it would be appropriate to first try to gauge how many capsules they have taken. If it’s clinically believed to be sufficient to cause significant symptoms or signs or explain their current clinical picture. If this is thought possible then unblinding is appropriate.
The documented cases in R/S- Alpha Lipoic Acid (R/S-ALA) have included encephalopathy, tachycardia, tachypnoea, metabolic/lactic acidosis, and multiorgan failure.
Metformin overdose is associated with gastrointestinal symptoms, hypotension, and lactic acidosis. Hypoglycaemia is also possible, but this is unlikely to occur without additional anti-diabetic agents.
Significant hypoglycaemia
This is a very rare potential complication of R/S-ALA; if the patient is experiencing significant, otherwise inexplicable hypoglycaemia, then unblinding is appropriate.
It should be noted that a patient cannot be randomised to R/S-ALA if they are on diabetic agents or insulin (this being the highest risk group of developing hypoglycaemia), and metformin without concurrent anti-diabetic agents does not carry the risk of hypoglycaemic episodes.
Evidence of renal impairment with high-grade proteinuria (i.e., nephrotic syndrome)
There is the rare potential side effect of developing a membranous nephropathy with R/S-ALA, and therefore if this develops without a more plausible alternative cause, unblinding would be appropriate.
Evidence of B12 deficiency
This is a rare potential side effect of chronic metformin exposure; in the event of an acute presentation (e.g., subacute combined degeneration of the cord), then unblinding is appropriate. If a more chronic concern is present (e.g., uncomplicated megaloblastic anaemia or a limited polyneuropathy), then referral to the participant’s study hospital site might be more appropriate in the first instance.
Significant hepatic derangement or hepatitis
This is a very rare potential side effect of metformin; If this occurs without a suitable alternative explanation then unblinding is appropriate.
Use of iodinated contrast agents
IV administration of iodinated contrast to patients who are receiving metformin can result in lactic acidosis. For this reason a treatment pause is mandated around contrast administration, as per the study protocol, rather than unblinding. Where possible, prior to receiving iodinated contrast agents, if a participant has an eGFR<60ml/min/1.73m2, then trial treatment should be paused for 24 hours prior to receiving the contrast and then restarted 48 hours post-administration only after eGFR has be confirmed as >30ml min/1.73m2. There is no need to unblind the patient in these scenarios.
