The Lyme Times

2014 Volume 26 Number 2

Clinical trials

Been there, done that

By Daniel Cameron, MD

In this 25

anniversary issue of

The

Lyme Times

, Phyllis Mervine and I can

both say, “Been there, done that,” when

it comes to chronic Lyme disease (CLD)

clinical trials. Phyllis was one of two con-

sumers on a review panel to monitor

the two Klempner National Institutes of

Health (NIH) CLD clinical trials in 1996.

The trials validated the severity of CLD

an average of 4.7 years after onset despite

antibiotic treatment. The Klempner trials

also validated the difficulties designing

CLD clinical trials.

1,2

The Cameron trial

I would like to share my experience as

principal investigator of the only com-

munity-based double-

blind

placebo-con-

trolled clinical trial

of CLD, referred to as

the Cameron trial. I

enrolled 84 patients

making it the largest

clinical trial of CLD.

The Fallon, Krupp, and

two Klempner trials

had previously enrolled

37, 55, 70 and 45 indi-

viduals with CLD re-

spectively.

Two-thirds of the

84 individuals in my

trial were assigned

at random to receive

two 500 mg amoxi-

cillin by mouth three

times a day for three months, plus one-

third placebo. Manifestations of CLD

were as severe as those ill with CLD en-

rolling in the NIH-sponsored trials

3-5

within an average of six months of onset

of their Lyme disease. At least 70% in my

trial presented with fatigue, painful joints,

stiff joints, headaches, poor concentration,

sore muscles, disturbed sleep, memory

loss, tingling/numbness, irritability, and

muscle stiffness.

Individuals randomized to amoxicillin

were more likely to improve than the

placebo patients (46% vs 18%, p=0.007)

on a Short Form-36 (SF-36) measure of

quality of life (QOL). The 46% success rate

for amoxicillin was lower than described

in actual practice due in part to short-

comings of the SF-36 as a measure of clin-

ically meaningful benefits. My trial has

been criticized for failing to adjust the

value for the two outcomes - mental and

physical health.

The higher than expected dropout rate

in my trial offers an insight into the dif-

ficulties individuals with CLD face when

enrolling in placebo-controlled trials. In-

dividuals with CLD were expected to

remain off antibiotics for six months

despite symptoms as severe as those de-

scribed in the Klempner and Fallon trials.

I advised 17 individuals with persistent

severe

symptoms

to leave the pla-

cebo-controlled trial

within three months

to pursue an individ-

ualized treatment. I

advised an additional

six individuals with a

positive IgM Western

blot test to leave the

placebo-controlled

trial to avoid the risk

that an individual

with a persistent in-

fection or reinfection

might be randomized

to placebo for six

months. The decision

to drop individuals

with a persistent positive IgM Western

blot is reinforced by published reports that

a positive IgMWestern blot test can persist

in LD for up to two years.

6-8

Conclusions

I concluded that three months of

amoxicillin can lead to clinically mean-

ingful benefits without serious adverse

events, consistent with the goal of im-

proving patients’ Quality of Life (QOL)

worthy of further study.

In 2012, Fallon

came to a similar conclusion, saying that

“while repeated IV antibiotic therapy can

be effective, safer modes of delivery are

needed.”

Lessons learned

I published the community-based CLD

trial in 2008 despite the higher than ex-

pected dropout rate to offer insights into

designing future innovative compas-

sionate trials. The paper published in the

peer-review journal Medical Minerva re-

flected that goal: “Severity of Lyme disease

with persistent symptoms”

Having been there, done that, I remain

convinced that we can design innovative

trials of CLD to eliminate the design issues

in both the NIH and community-based

trials. It would be helpful if serious dollars

were available to launch such innovative

trials.

Endnotes

1. Delong AK, Blossom B, Maloney EL, Phillips SE.

Antibiotic retreatment of Lyme disease in patients

with persistent symptoms: a biostatistical review of

randomized, placebo-controlled, clinical trials. Con-

temporary clinical trials. Nov 2012;33(6):1132-1142.

2. Fallon BA, Petkova E, Keilp JG, Britton CB.

A reappraisal of the U.S. Clinical trials of post-

treatment Lyme disease syndrome. Open Neurol J.

2012;6:79-87.

3. Krupp LB, Hyman LG, Grimson R, et al., “Study

and treatment of post Lyme disease (STOP-LD): a

randomized double masked clinical trial.”

Neurology

Jun 24 2003;60(12):1923-1930.

4. Fallon BA, Keilp JG, Corbera KM, et al. A ran-

domized, placebo-controlled trial of repeated IV an-

tibiotic therapy for Lyme encephalopathy. Neurology.

Oct 10 2008;70(13):992-1003.

5. Klempner MS. Controlled trials of antibiotic

treatment in patients with post-treatment chronic

Lyme disease. Vector Borne Zoonotic Dis. Winter

2002;2(4):255-263.

6. Steere AC, Hardin JA, Ruddy S, Mummaw

JG, Malawista SE. “Lyme arthritis: correlation of

serum and cryoglobulin IgM with activity, and

serum IgG with remission.”

Arthritis Rheum

, May

1979;.22(5):471-483.

7. Lomholt H, Lebech AM, Hansen K, Brandrup F,

Halkier-Sorensen L., “Long-term serological follow-

up of patients treated for chronic cutaneous bor-

reliosis or culture-positive erythema migrans.”

Acta

Derm Venereol

, Sep.-Oct. 2000;.80(5):362-366.

8. Massarotti EM, Luger SW, Rahn DW, et al.

“Treatment of early Lyme disease.”

Am J Med

., Apr

1992;92(4):396-403.

9. Cameron D., “Severity of Lyme disease with per-

sistent symptoms. Insights from a double-blind pla-

cebo-controlled clinical trial.”

Minerva Med

., Oct.

2008; 99(5):489-496.Dan Cameron currently serves

as president of ILADS.

Daniel Cameron, MD