Lactoferrin and sepsis in adults

Talactoferrin alfa is a recombinant form of human lactoferrin, manufactured for clinical use rather than extracted from milk. Two randomized placebo-controlled trials, published in 2013 and 2015, gave it by mouth or feeding tube to 499 adults with severe sepsis. Both used 1.5 g three times a day. Both took all-cause mortality at 28 days as the primary endpoint. They disagreed about which arm died more often.

The two trials side by side

Figures come from each trial's own abstract. The descriptions of design are also taken from each abstract, which is why only the first says double-blind.

Both arms moved between the two trials, and that is the part a summary tends to drop. Mortality on talactoferrin rose from 14.4% to 24.8%. Mortality on placebo fell from 26.9% to 17.8%. Neither arm alone accounts for the reversal.

A primary endpoint reported as met at p = 0.052

The phase 2 paper gives its headline result as a two-sided p of 0.052 and states that this met the protocol-specified primary endpoint. The abstract does not give the threshold the protocol had set, and 0.052 sits above the conventional 0.05. On the stated figures the absolute reduction in 28-day mortality was 12.5 percentage points and the relative reduction 46.5%.

The same abstract reports that reductions in mortality appeared "across a wide spectrum of subgroups" and that the drug was very well tolerated, with a safety profile similar to placebo. The larger trial, reported two years later, found its excess deaths concentrated in a subgroup and was halted partly on safety. Neither of those two reassurances held: consistency across subgroups in 194 patients did not predict the subgroup result of the larger trial, and a clean tolerability profile did not predict its safety stop.

The question was asked in print at the time

The March 2013 issue of Critical Care Medicine carried the phase 2 result and, in the same issue, an editorial by McCulloh and Opal titled "Human recombinant lactoferrin for sepsis: too good to be true?" PubMed holds no abstract for it, so it is cited here for its title and its existence rather than for its contents, the same handling this site gives any record whose text it has not read. What the record establishes is that the question of whether the result would hold was on the table in the same issue that reported it.

What the larger trial found

OASIS enrolled adults over 18 admitted with severe sepsis who were already receiving antimicrobial therapy and could take liquid medication by mouth or feeding tube. It was terminated after 305 patients, 153 on talactoferrin and 152 on placebo, because its Data Safety Monitoring Board identified futility and safety concerns. The abstract records no significant differences between the groups at baseline in age, sex, site of infection or severity scores.

The published report does not give the size the trial was designed to reach, but its registry record does. NCT01273779 lists a planned enrollment of 1,280, so OASIS stopped at under a quarter of its intended size. The same record is still marked suspended and was last updated in February 2012, three years before the result appeared in print, which is one of the examples on the audit of registered lactoferrin clinical trials. That record's official title also describes the trial as double-blind. The abstract's design line does not, so the table above follows the abstract and the word is attributed to the registry rather than to the paper.

The 28-day primary endpoint missed significance at p = 0.117, in the direction of more deaths on talactoferrin. Two later endpoints cleared it: in-hospital mortality at 43/153 against 27/152 (p = 0.037) and three-month mortality at 46/153 against 31/152 (p = 0.036). The gap sat almost entirely in patients with shock, where 33 of 105 died on talactoferrin against 21 of 104 on placebo (p = 0.064); among patients without shock the figures were 5 of 48 and 6 of 48 (p = 0.806). Treatment-related adverse and serious adverse events occurred at similar rates in both groups, so the mortality signal is not accompanied by a particular toxicity. The authors' own conclusion is that oral talactoferrin was not associated with reduced 28-day mortality "and may even be harmful".

One limit applies to every number in that paragraph and cuts both ways. A trial stopped early reports effects that are, on average, further from the truth than those of a completed one, and the exaggeration runs in the direction that prompted the stop. That weakens the two significant mortality figures as measurements of how much harm was done. It equally forbids reading the non-significant 28-day p of 0.117 as reassurance, since the trial was halted before it could measure that endpoint properly either.

Where this sits in critical care

A 2019 systematic review searched MEDLINE from inception to April 2019 for multicenter randomized trials in critically ill adults that reported mortality. It found 212. Twenty-seven of them, 13%, reported a significant reduction in mortality; 16 reported an increase; 170 found no difference. Talactoferrin appears in that review by name, in the list of trials whose positive result was not replicated by a later randomized trial, alongside recombinant activated protein C and interleukin-1 receptor antagonist in sepsis. Its authors concluded that the literature offers no conclusive evidence of any drug that consistently reduces mortality in critically ill patients. Jean-Louis Vincent is an author of both that review and the OASIS trial.

This matters for how the sepsis result should be read. A promising phase 2 in sepsis followed by a failed confirmatory trial is close to the base rate in critical care rather than a surprise specific to lactoferrin.

Sepsis in newborns is a separate question

The adult trials above do not settle the neonatal literature, which is larger, uses the bovine protein rather than the recombinant human one, and asks about prevention in infants who are not yet septic rather than treatment of established sepsis. A Cochrane review covers that question. Pooled estimates there have pointed toward a reduction in late-onset sepsis, and the largest single trial did not, which is set out on the page on lactoferrin and infection in very preterm infants and in the pooled figures gathered under lactoferrin and immune support. The grade on this page applies to the adult claim only.

The molecule itself, and the other trials of the recombinant human form in lung cancer, in preterm infants and on the skin, are covered under human lactoferrin. Of the four populations in which talactoferrin has been tried, sepsis is the only one where a trial was stopped for safety.

Why the grade is Not supported

The claim graded here is that lactoferrin reduces mortality in adults with severe sepsis. It was tested twice, in the same disease, at the same dose, by the same route, with the same primary endpoint, and the larger of the two trials was abandoned because continuing looked both futile and unsafe. That is a tested-and-failed claim rather than an untested one, which is what separates this grade from Insufficient.

The basis is not identical to the other two claims on this site that carry it. The preterm infant claim rests on a completed trial of 2,203 infants with a precise null. The COVID-19 claim rests on a pre-specified blinded trial whose interval straddles no effect. Here the confirmatory trial never reached its planned size, so it delivers no precise estimate of anything. What it delivers instead is a monitoring committee's judgment that the treatment arm was doing worse, reached with the trial's own accumulating data and acted on. For a claim about mortality that is enough to grade, and grading it Insufficient would describe the evidence as absent when a drug development program was stopped on it.

What this page does not say

These were trials of a manufactured drug given to adults in intensive care with organ-threatening infection, at 4.5 g a day by feeding tube. They tested neither lactoferrin in milk nor any supplement taken by a person who is not critically ill, and they say nothing about either. The general picture of what the protein is and does sits on the lactoferrin overview. Nothing here is a reason for anyone taking a lactoferrin product to change what they are doing without asking the clinician who knows their case.