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 1200mg R/S-Alpha Lipoic Acid and/or by subsequently withholding the trial medication if appropriate.
If recruited prior to 15th September 2026, they could also be taking 2000mg of Immediate Release Metformin. This treatment arm was stopped and participants not taking treatment post this date. Scenarios for immediate release metformin have now been removed from this page.
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 the country specific coordinating centre team, if required and possible. However this discussion is not mandatory.
IF YOU ARE A MEMBER OF A 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.
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.
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, they can continue on the current dose and a repeat eGFR is required 4 weeks post test. On repeat, if the result remains between 45 - 59 ml/min/1.73m2; the participant can continue on the current dose and be re-tested at their next in-person visit. There is no need to unblind the patient in these scenarios.
