Now available on-line the pilot trial of lactoferrin prophylaxis that I performed at Sainte Justine. (Barrington KJ, Assaad M-A, Janvier A. The Lacuna Trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant. J Perinatol. 2016, on-line).
We randomized 79 very immature babies to have a dose of bovine lactoferrin each day in one of their feeds, compared to no lactoferrin. The pilot was performed to ensure that all of our procedures would work well in a future larger RCT. We used the same dose regime as Paolo Manzoni and his group, that is, 100 mg per day regardless of body weight, this is a bit unusual in neonatology, but in his trial it worked, with a huge decrease in late-onset sepsis, and we didn’t want to try a new dose in such a small pilot. The idea was to ensure we could adequately mask the administration, and at the same time to look at feeding tolerance, as there are potential differences in preparation methods between Dr Manzoni’s lactoferrin and the version we used (donated by AOR Inc, who had nothing else to do with trial design or analysis).
Lactoferrin has a pink colouration which makes it difficult to mask if you just mix it with water, for example, you have to find a placebo with a similar colour which is known to be innocuous in preterm babies. What we did was to mix the lactoferrin with one of the day’s feeds, which was done in a milk kitchen ( le “labo de lait”) which is next to the NICU, and staffed by technicians who prepare the milk, adding fortifier and so on, and put the correct quantity in a syringe for the baby, without other involvement in the care of the baby. We did some preliminary testing and found that even when the milk volume was small, there was enough variation in the colour of breast milk (over 90% of our babies were getting maternal breast milk) that the NICU staff could not tell which milk contained lactoferrin and which did not. At the end of the trial we asked parents which group they thought the baby was in (it was double-blind so the parents weren’t told which group their baby was in) and most of the parents, in both groups, thought their baby was getting lactoferrin, and they all basically thought that the baby tolerated their feeds well.
The study was designed with the primary outcome being time to full feeds, which wasn’t different between groups. Our other important clinical outcomes, including late-onset sepsis, were no different between groups, but the study was vastly underpowered for those outcomes. Which points out an issue that Willam Tarnow-Mordi has addressed recently: sometimes pilot trials are performed to get an idea of the effect size of an intervention, to help in calculating sample size for a future trial. Don’t do this. Our pilot had 7 lactoferrin babies and 8 control babies who had at least one episode of late-onset sepsis, this is about a 15% reduction in the rate sepsis, but the confidence intervals of that difference are huge, from a 75% reduction to a 250% increase, and those confidence intervals overlap withe the data from the Manzoni trial.
Two large multi-center RCTs are underway at present, hopefully we will get better a good answer to the question of the efficacy and safety of lactoferrin soon.