Risks of running clinical trials without prior mechanistic studies

New research demonstrates risks of running clinical trials without prior mechanistic studies.
Scientists find that acetylcysteine has no mechanistic effect in patients at risk of contrast induced nephropathy.


Summary of findings

New research has underlined the importance of undertaking mechanistic studies in humans before designing clinical trials.


Professor Michael Eddleston's team at the Centre for Cardiovascular Science (the University of Edinburgh) have shown that large amounts of both time and money have been wasted on unnecessary clinical trials exploring whether oral tablets of acetylcysteine – a medication typically used to treat paracetamol overdose – can prevent contrast induced nephropathy.


Contrast induced nephropathy (CIN) occurs when the kidneys are injured by the contrast (dye) given to patients by doctors to allow their blood vessels to be visualised. It is a major problem in patients with chronic kidney disease, resulting in deterioration of kidney function that may result in patients requiring dialysis. 


In 2000, a single small clinical trial involving fewer than 90 patients suggested that acetylcysteine was effective in preventing CIN. However, no mechanistic studies were conducted to determine how acetylcysteine affects healthy or damaged kidneys.


The results of the single trial were however accepted and triggered a wave of over 70 small clinical trials, 23 systematic reviews, and two large clinical trials. These two large clinical trials ultimately showed that acetylcysteine did not work.


Scientists from the University have now undertaken mechanistic studies, which should have been done much earlier, exploring how acetylcysteine affects patients with chronic kidney disease who are at risk of contrast nephropathy.


The research team studied whether acetylcysteine increases blood flow to the kidney (reducing spasm caused by the contrast agent) or reduces damage to tissues caused by reactive oxygen (oxidative stress) in chronic kidney disease patients.


They found that oral tablets of acetylcysteine are poorly absorbed, neither increasing blood flow to the kidneys nor protecting against oxidative stress. It therefore offers no protection to patients at risk of CIN. Giving acetylcysteine by intravenous infusions also offered no benefit to patients with kidney disease.



The study shows the risks of designing clinical trials without clear proof of how an intervention might work.


The study is published in Clinical Pharmacology & Therapeutics.

We have shown here that acetylcysteine could never have benefited patients at risk of CIN, despite 18,000 patients being recruited to trials testing this intervention. This has resulted in an immense waste of time and money, which could have been prevented if the appropriate mechanistic studies had been conducted to begin with.

This story also vividly demonstrates the weaknesses of stand-alone small-scale academic clinical trials. The initial finding was likely a false positive and further trials should not have been allowed to happen.

Professor Michael Eddleston, Personal Chair of Clinical Toxicology


Professor Michael Eddleston

Professor Michael Eddleston's research project to prevent deaths from poisoning