The Lyme Times

The Lyme Times

Continued on page 26

NIH Clinical trials

What we learned from four famous trials funded by the National Institutes of Health

By Brian Fallon, MD, MPH

The groundbreaking clinical trials investigating post-treatment

Lyme disease syndrome (PTLDS) contributed to our knowledge

of tick-borne diseases for several reasons.

All the trials showed that a proportion of patients got better

with time (even without medication), i.e., the placebo response.

That’s good news for patients as it demonstrates that not everyone

needs to receive additional antibiotics to get better.

Response to treatment might not be demonstrated immediately

after treatment. In the Krupp trial, there was no difference in the

percentage of responders to IV ceftriaxone vs IV placebo imme-

diately after treatment; but when these same patients were as-

sessed five months later (off antibiotics), patients receiving IV

ceftriaxone were 3.5 times more likely to have meaningful im-

provement in fatigue compared to those who initially received IV

placebo. While antibiotic retreatment can be effective, the impact

may not be seen immediately. This finding was later demonstrated

again in a European study.

The Krupp trial suggested that a much greater proportion of pa-

tients respond to treatment if they are IgG Western blot positive

at the time. In this trial, the responder rate was 80% for drug-ran-

domized patients who were IgG Western blot positive vs 46% for

those who were not; in other words, patients are almost twice as

likely to respond to retreatment if their serologic tests are positive.

This finding highlights the importance of careful study design.

Had the Krupp trial only recruited individuals who were sero-

negative, that study may not have shown the positive treatment

effect on the primary outcome measure of fatigue observed at six

months.

While some have argued that the beneficial response in the

Krupp trial should be disregarded, our Lyme encephalopathy

clinical trial (analyzed in the same fashion as the Krupp trial)

found nearly identical benefits on the fatigue measure at six

months favoring drug over placebo. Finding a nearly identical

treatment effect from an independent study conducted at a dif-

ferent university is compelling evidence in support of the validity

of the original Krupp results.

Thankfully, the NIH funded these four clinical trials, as without

them much less would be known. The NIH should be encouraged

to support new clinical trials, however, to draw firm and clear con-

clusions about the beneficial effects of antibiotic therapy. It is pre-

mature to draw conclusions from such a small sample of Lyme

patients (37 in the Fallon trial, 55 in Krupp, 51 in Klempner’s se-

ronegative trial, and 78 in Klempner’s seropositive trial).

Significance of study design

To get a meaningful outcome, it is important to en roll indi-

viduals with significant impairment – those who meet a severity

cutoff. Too often this key design feature gets violated. For example,

the Krupp trial recruited patients who met a severity cutoff on

fatigue – and convincingly showed a benefit to drug over placebo.

For the Columbia Encephalopathy trial, only patients who met a

severity cutoff on cognition were allowed to enroll. While we did

not see a sustained improvement in cognition to six months for

drug vs placebo, we did see a significantly greater improvement

at 12 weeks.

A preset severity cutoff ensures that a true treatment effect

can be observed. Simply stating that all who entered the trial re-

ported functional impairment is not the same as saying that all

who entered the trial scored at an “impaired level” on the primary

outcome measure of interest. Understandably researchers face

a huge push to enroll as many people as possible as quickly as

possible because such trials cost a lot of money. For the sake of

drawing meaningful conclusions, however, impairment must

meet a predefined standard.

Among the four NIH trials, the two Klempner studies had the

largest enrollment, (a strong positive) but they were the only trials

without a “severity cutoff ” for enrollment (a striking negative). Al-

though these trials showed no drug-placebo difference, we don’t

know what proportion of enrollees would have met a meaningful

cutoff for impairment at the start of the study. Future trials must

include a severity threshold to maximize the likelihood that their

hypothesis is adequately tested.

Columbia encephalopathy trial

We examined whether certain laboratory biomarkers might

predict good or poor outcomes, including the CD 57 marker,

inflammatory markers (CRP, ESR), and presence of antibodies

against

Babesia

Bartonella

. Unfortunately, none of these

markers proved helpful in predicting treatment response. Inter-

estingly, the only markers associated with treatment response were

clinical markers — not lab test markers. In our trial, we found

that the physical exam was one of the best predictors of treatment

Brian Fallon and a team of researchers at Columbia University Medical

Center conducted one of the four famous NIH clinical trials in 2003:

From left: Dexterrie Ramirez, Kathy Corbera, MD, Megan Romano, and

Iordan Slavov, PhD.