Re: Controlled trial ABX persistant lyme

From: A_Weisman (a_weisman_at_yahoo.com)
Date: 07/08/04 

Date: 8 Jul 2004 11:45:03 -0700

derdrittemann2003@yahoo.com (derdrittemann) wrote in message news:<f2af2263.0407070622.5531f228@posting.google.com>...
<snip>
 
> I have not seen the study since its original publication...but it was
> my recollection that the largest single group at the time the study
> was prematurely terminated was the group that was taking
> antibiotics...and reported that they were doing better. (Although the
> numerical differences were slight...the study was ceased on the basis
> that the percentage difference could not approach statistical
> signifigance...which is somewhat misleading in and of itself...given
> the very samll numbers).

derdrittemann2003@yahoo.com (derdrittemann) wrote in message news:<f2af2263.0407070622.5531f228@posting.google.com>...
> I have not seen the study since its original publication...but it was
> my recollection that the largest single group at the time the study
> was prematurely terminated was the group that was taking
> antibiotics...and reported that they were doing better. (Although the
> numerical differences were slight...the study was ceased on the basis
> that the percentage difference could not approach statistical
> signifigance...which is somewhat misleading in and of itself...given
> the very samll numbers).
    
FULL TEXT OF THE NEJM article on the Klempner study below.

First I am excerpting two portions. One is the stuff on the DSMB
termination. The other are the names thanked including Karen
Forschner, Carl BRENNER, Phyllis Mervine et al.

1. Excerpt re DSMB Termination:

Results After a planned interim analysis, the data and safety
monitoring
board recommended that the studies be discontinued because data from
the
first 107 patients indicated that it was highly unlikely that a
significant
difference in treatment efficacy between the groups would be observed
with
the planned full enrollment of 260 patients. Base-line assessments
documented severe impairment in the patients' health-related quality
of
life. In intention-to-treat analyses, there were no significant
differences
in the outcomes with prolonged antibiotic treatment as compared with
placebo. Among the seropositive patients who were treated with
antibiotics,
there was improvement in the score on the physical-component summary
scale
of the SF-36, the mental-component summary scale, or both in 37
percent, no
change in 29 percent, and worsening in 34 percent; among seropositive
patients receiving placebo, there was improvement in 40 percent, no
change
in 26 percent, and worsening in 34 percent (P=0.96 for the comparison
between treatment groups). The results were similar for the
seronegative
patients.

2. Names thanked: See CAPS: includes CARL BRENNER, PHYLLIS MERVINE,
KAREN FORSCHNER, JILL AUERBRACH, BETTY GROSS, BRIAN FALLON,M.D. AND
RICHARD HOROWITZ, M.D. AKA THE ENABLERS (WITH RESPECT TO BETTY GROSS,
GOD REST HER SOUL). Yes I am sure they all meant well.

Source Information

>From New England Medical Center and Tufts University School of
Medicine,
Boston (M.S.K., L.T.H., C.H.S., G.M.J., R.P. T., J.M.); Yale–New Haven
Hospital, New Haven, Conn. (J.E., D.W.), New York Medical College,
Valhalla
(D.N., L.L., A.W.); and Quality Metric, Lincoln, R.I. (M.K.). Address
reprint requests to Dr. Klempner at the Department of Medicine, Boston
University School of Medicine, 715 Albany St., Boston, MA 02118, or at
klempner@bu.edu.

Supported by grants (N01-AI-65308 and M01 RR000054) from the National
Institutes of Health. Roche provided the ceftriaxone for the study,
and
Pfizer provided the doxycycline.

We are indebted to Philip J. Baker, Ph.D., Steven P. Heyse, M.D.,
Marilyn
Tuttleman, M.S., Dennis Dixon, Ph.D., and Mark Van Raden, Ph.D., of
the
National Institute of Allergy and Infectious Diseases Lyme Disease
Program;
to Barbara E. Murray, M.D., Robert Edelman, M.D., Frank G. Miller,
Ph.D.,
Donald Rosenstein, M.D., and Barbara Tilley, Ph.D., of the data and
safety
monitoring board; to John E. Edwards, Jr., M.D., CARL BRENNER, J.
Stephen
Dumler, M.D., Fred A. Gill, M.D., PHYLLIS MERVINE, Justin Radolf,
M.D., and
Gregory Owens, Ph.D., of the Scientific Advisory Committee; and to the
following persons who provided helpful services: Rich Noring, Bilaal
McCloud, Bo Lin, Ph.D., Richard Kaplan, Ph.D., David Weld, Roger
D'Entremont, Kitty Mullen, Chris Covington, Vincent DiPaola, Paul
Drouilhet,
David Fletcher, Jerrold Gold, Thomas Hirsch, Clyde Kessel, Keith
Krewson,
Laura Lattanzio, Rebecca Leland, Shawn Lyden, William Macleod, Roy
Matthews,
Peter Morton, Dave Murray, Jim Platz, John Sample, Elliott Schiffman,
Michael Shabazian, Jason Stone, John Taylor, Bradford Von Weise, Frank
Weldon, Larry Camerlin, Raymond Partridge, M.D., Marianna Wilson,
M.S., John
Consoletti, Pharm.D., Cindy Mason, R.N., David Thorpe, Pharm.D., Cindy
Moore, R.N., June Novio, R.N., Eileen Regan, R.N., Andy Dousa,
Pharm.D., Don
Morrison, Pharm.D., Laura Cavagna, Pharm.D., Linda Griffith, Pharm.D.,
Sean
Corbett, Pharm.D., Scott Reid, Pharm.D., Fran Bickert, R.N., John
Opolski,
R.N., Karen Tooker, R.N., Mark Wolff, Ph.D., Phyllis Barr, Ph.D., Anna
Lornell, M.D., Phil Molloy, M.D., KAREN FORSCHNER, Dennis Hoak, M.D.,
David
N. Mesches, M.D., Tim Lepore, M.D., Robina Folland, Robert Lopez, Bai
Margolin, Crystal Sylvester, George Perides, Ph.D., Allen Steere,
M.D.,
Ellen Jamieson, Jim Grayson, Timothy Brauns, Lilla Rogers, Jenn Finn,
R.N.,
Pamela Norton, R.N., Karen Mazzotta, Anh Nguyen, M.D., Eric Logigian,
M.D.,
William Brown, M.D., Anne Donohoe, Sandy Doveikis, Karen Fenicchia,
R.N.,
Hua Wang, R.N., Nancy Zajac, R.N., Jamie Evanowski, David Carlson,
Jason
Hoitt, Carol Bauscher, L.P.N., Teryi Deshefy-Longhi, R.N., M.S., Carl
Henn,
Dee Dee Moss, Glynnis Fisher, Janet Mattson, Rosemary Hammil, Beth
Horrigan,
William Blackwelder, M.D., Frank Cavileri, M.D., John Nowakowski,
M.D.,
Morris Dannon, M.D., Brij Mohan Singh Ahluwalia, M.D., Gary Wormser,
M.D.,
Rhea Dornbush, Ph.D., Catherine Crea, Maria Aguero-Rosenfeld, M.D.,
Alan
Gerber, M.D., Michael Tenner, M.D., Maureen Grix, Ph.D., Lois
Zentmaier,
Denise Cooper, Susan Bittker, Sheila Hughes, R.N., Junius Edlow, Tim
McGarty, Jeffrey Bandola, M.D., Andrew Artenstein, M.D., Nancy Clark,
R.N.,
Jerry Fingerut, M.D., Robert Schoen, M.D., Donna D'Euginio, R.N.,
Linda
Bockenstedt, M.D., Alexia Bellperron, Brad Herskowitz, M.D., George
Rickerson, M.D., LeBraun Paige, M.D., Volker Knappertz, M.D., Kimberly
Stoddard, Ph.D., Ann Sweeney, R.N., Michael Westerveldt, Ph.D.,
Maureen
Tacey, Thomas Rush, M.D., JILL AUERBACH, BETTY GROSS, Manuel DaSilva,
M.D.,
Arthur Rabson, M.D., BRIAN FALLON, M.D., Linda Tanner, RICHARD
HOROWITZ,
M.D., Edmond Yunis, M.D., Paul Alexander, R.N., and Ann Marie McClean,
R.N.

==============================================================================

Search Result 5
From: Rita Stanley (ritastan@worldnet.att.net)
Subject: NIH STUDY! Chronic LD Not Helped by Intensive Antibiotic
Treatment
View: Complete Thread (15 articles)
Original Format
Newsgroups: sci.med.diseases.lyme
Date: 2001-06-12 16:09:22 PST
 

http://www.nih.gov/news/pr/jun2001/niaid-12.htm

NATIONAL INSTITUTES OF HEALTH

National Institute of
Allergy and Infectious Disease

EMBARGOED FOR RELEASE
Tuesday, June 12, 2001

Contact:
Laurie K. Doepel
(301) 402-1663
doepel@nih.gov

Chronic Lyme Disease Symptoms Not Helped by Intensive Antibiotic
Treatment

Results of the first randomized, placebo-controlled, double-blind
trials
testing antibiotics in patients with a stubborn form of Lyme disease —
those
whose symptoms persist after standard courses of antibiotics —
validate that
these patients suffer significant pain and other disabling symptoms.
The two
trials found, however, that a 90-day course of intravenous and oral
antibiotics was no better than placebo at improving these chronic
symptoms.

Because of their potential importance to Lyme disease treatment, The
New
England Journal of Medicine is publishing these findings today online
at
http://www.nejm.org. The report will appear in the July 12th print
edition
of the journal. The studies were funded by a National Institute of
Allergy
and Infectious Diseases (NIAID) contract to Mark S. Klempner, M.D., of
Boston University School of Medicine.

"Our results suggest that we need to define the cause or causes of the
debilitating, persisting symptoms experienced by some patients with
Lyme
disease. Understanding the origin of these symptoms should lead to
more
effective therapeutic approaches to ameliorate these symptoms," says
Dr.
Klempner. "Based on experience with other chronic infectious diseases
caused
by persisting bacteria — syphilis, tuberculosis, and ulcers, for
example —
we think it is unlikely that a longer course of treatment or different
antibiotic combination would result in greater improvement than what
we
found in these studies."

Significantly, more than 700 different blood and cerebrospinal fluid
samples
were collected from the study volunteers. None of the samples showed
evidence of persistent infection with the Lyme agent, Borrelia
burgdorferi.
This suggests, Dr. Klempner says, that researchers should investigate
autoimmune and other processes to determine whether they play a role
in a
least some of the symptoms of chronic Lyme disease. The trials were
carried
out by primary investigators and their staffs at three centers: New
England
Medical Center in Boston (Dr. Klempner's former affiliation); New York
Medical College in Valhalla (Arthur Weinstein, M.D.); and Yale-New
Haven
Hospital in Connecticut (Janine Evans, M.D.) Volunteers were recruited
through hundreds of screening clinics set up in schools, hospitals,
and town
halls located in these areas where Lyme disease is highly endemic.

A total of 129 volunteers enrolled in the two studies. All
participants had
well-documented Lyme disease and had previously received at least one
course
of recommended antibiotics. Despite prior antibiotic treatment, the
volunteers currently suffered from persisting muscle or joint pains
and
complained of memory and thinking problems, often associated with
fatigue.

Although both trials were identical in design, one trial enrolled 78
chronic
Lyme disease patients who tested positive for antibodies to the Lyme
bacterium, while the other trial enrolled 51 people with chronic
symptoms
but no evidence of antibodies.

In each study, volunteers were assigned at random to receive either
antibiotic treatment or an inactive placebo. Treatment consisted of
intravenous ceftriaxone, 2 grams daily, for 30 days, followed by oral
doxycycline, 200 milligrams daily, for 60 days. The investigators
evaluated
symptom improvement based on the patients' responses to a
health-related
quality-of-life questionnaire given 90 days after they completed the
course
of antibiotic treatment or placebo.

An interim data analysis planned into the design of the trials was
carried out last November by a Data and Safety Monitoring Board
(DSMB), an
independent group of doctors and researchers. The DSMB unanimously
recommended that NIAID stop the treatment arm of both trials because
the
data showed no significant difference in the percentage of patients
who
received either antibiotic treatment or placebo who felt their
symptoms had
improved, worsened, or stayed the same: a little more than one-third
felt
better, about one-third felt worse, and slightly less than one-third
felt
the same. The DSMB's review suggested that even with continued accrual
of
another 131 patients, the number needed to reach full enrollment,
there was
only a slight chance a difference between the antibiotic treatment and
placebo groups would be found. NIAID agreed with the DSMB's
recommendation,
as well as their recommendation that the investigators continue to
follow
the patients to monitor them for safety and to learn more about
possible
causes of chronic Lyme disease.

"Although we still have much to learn," says Dr. Klempner, "we know
much
more about chronic Lyme disease now than we did when these studies
began."
Besides the information obtained about the efficacy of intensive
antibiotic
treatment, the investigators found that the impact of Lyme disease on
physical health was at least equal to the disability of patients with
congestive heart failure and osteoarthritis. Some patients were also
found
to have cognitive impairment.

"The antibiotic treatment component is only one piece of NIAID's
comprehensive clinical studies on chronic Lyme disease," adds Phillip
J.
Baker, Ph.D., who oversees NIAID's Lyme disease program. "These
studies have
yielded a considerable amount of new information. We intend to
characterize
the patients enrolled in the study as thoroughly as possible to learn
more
about the mechanisms involved in chronic Lyme disease," Dr. Baker
adds. "The
knowledge obtained from such studies should be of immense value in
developing new, more promising approaches for treating this disease."

NIAID is a component of the National Institutes of Health (NIH). NIAID
supports basic and applied research to prevent, diagnose, and treat
infectious and immune-mediated illnesses, including HIV/AIDS and other
sexually transmitted diseases, tuberculosis, malaria, autoimmune
disorders,
asthma and allergies.

Press releases, fact sheets and other NIAID-related materials are
available
on the NIAID Web site at http://www.niaid.nih.gov/.
The National Institute of Allergy and Infectious Diseases is a
component of
the National Institutes of Health, U.S. Department of Health and Human
Services.

----------------------------------------------------------------------------
Reference: MS Klempner et al. Two controlled trials of antibiotic
treatment
in patients with persistent symptoms and a history of Lyme disease.
New
England Journal of Medicine vol. 345(2), July 12, 2001.
--------------------------------------------------------------------------

The NEMJ article:

http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/0107120
2

Two Controlled Trials of Antibiotic Treatment in Patients with
Persistent
Symptoms and a History of Lyme Disease

Mark S. Klempner, M.D., Linden T. Hu, M.D., Janine Evans, M.D.,
Christopher
H. Schmid, Ph.D., Gary M. Johnson, Richard P. Trevino, B.S., DeLona
Norton,
M.P.H., Lois Levy, M.S.W., Diane Wall, R.N., John McCall, Mark
Kosinski,
M.A., and Arthur Weinstein, M.D.

ABSTRACT

Background It is controversial whether prolonged antibiotic treatment
is
effective for patients in whom symptoms persist after the recommended
antibiotic treatment for acute Lyme disease.

Methods We conducted two randomized trials: one in 78 patients who
were
seropositive for IgG antibodies to Borrelia burgdorferi at the time of
enrollment and the other in 51 patients who were seronegative. The
patients
received either intravenous ceftriaxone, 2 g daily for 30 days,
followed by
oral doxycycline, 200 mg daily for 60 days, or matching intravenous
and oral
placebos. Each patient had well-documented, previously treated Lyme
disease
but had persistent musculoskeletal pain, neurocognitive symptoms, or
dysesthesia, often associated with fatigue. The primary outcome
measures
were improvement on the physical- and mental-health–component summary
scales
of the Medical Outcomes Study 36-item Short-Form General Health Survey
(SF-36) — a scale measuring the health-related quality of life — on
day 180
of the study.

Results After a planned interim analysis, the data and safety
monitoring
board recommended that the studies be discontinued because data from
the
first 107 patients indicated that it was highly unlikely that a
significant
difference in treatment efficacy between the groups would be observed
with
the planned full enrollment of 260 patients. Base-line assessments
documented severe impairment in the patients' health-related quality
of
life. In intention-to-treat analyses, there were no significant
differences
in the outcomes with prolonged antibiotic treatment as compared with
placebo. Among the seropositive patients who were treated with
antibiotics,
there was improvement in the score on the physical-component summary
scale
of the SF-36, the mental-component summary scale, or both in 37
percent, no
change in 29 percent, and worsening in 34 percent; among seropositive
patients receiving placebo, there was improvement in 40 percent, no
change
in 26 percent, and worsening in 34 percent (P=0.96 for the comparison
between treatment groups). The results were similar for the
seronegative
patients.

Conclusions There is considerable impairment of health-related quality
of
life among patients with persistent symptoms despite previous
antibiotic
treatment for acute Lyme disease. However, in these two trials,
treatment
with intravenous and oral antibiotics for 90 days did not improve
symptoms
more than placebo.
----------------------------------------------------------------------------

Notice: Because of their potential importance in the treatment of Lyme
disease, these articles are being published early (on June 12, 2001).
The
final versions will appear in the July 12 issue of the Journal.

---------------------------------------------------------------------------

Antibiotic treatment is highly effective for the acute and late septic
manifestations of Lyme disease, which is caused by the tick-borne
bacterium
Borrelia burgdorferi.1 However, some patients have persistent fatigue,
myalgias, arthralgias without arthritis, dysesthesias or paresthesias,
or
mood and memory disturbances after the standard courses of
antibiotics.2 3
Persistent symptoms have been reported both in patients who are
seropositive
for antibodies against B. burgdorferi and in patients who are
seronegative.
Although the cause of persistent symptoms has not been determined,
their
temporal association with B. burgdorferi infection has led some
physicians
to treat patients with prolonged courses of antibiotics. Case reports
and
uncontrolled trials describe success with prolonged antibiotic
therapy,
often with a recurrence of the symptoms after the discontinuation of
therapy.4 In view of the substantial morbidity and even death5
associated
with prolonged parenteral antibiotic treatment of Lyme disease, it is
important to determine the efficacy of such therapy. We report results
from
randomized, placebo-controlled, double-blind trials of antibiotic
therapy in
seropositive and seronegative patients who had chronic symptoms after
treatment for Lyme disease.

Methods

Patients

Patients were recruited by means of advertisements and referrals from
physicians. Between July 24, 1997, and November 14, 2000, eligible
patients
were enrolled in two double-blind, placebo-controlled trials, each
conducted
at three sites. Patients with a positive Western blot for IgG
antibodies
against B. burgdorferi antigens6 were enrolled in a study of
seropositive
patients, and patients who were seronegative were enrolled in a
separate
study. Seronegative patients were required to have documentation of an
erythema migrans skin lesion provided by an experienced physician. We
initially planned to enroll 260 patients in the studies (194
seropositive
and 66 seronegative patients). Patients were eligible if they were at
least
18 years old, had a history of acute Lyme disease acquired in the
United
States, and had at least one of the following: a history of single or
multiple erythema migrans skin lesions, early neurologic or cardiac
symptoms
attributed to Lyme disease, radiculoneuropathy, or Lyme arthritis.
Documentation by a physician of previous treatment of acute Lyme
disease
with a recommended antibiotic regimen was also required. At the time
of
enrollment, all patients had one or more of the following symptoms
that
interfered with their functioning: widespread musculoskeletal pain,
cognitive impairment, radicular pain, paresthesias, or dysesthesias.
Profound fatigue often accompanied one or more of these symptoms. The
chronic symptoms had to have begun within 6 months after the initial
infection with B. burgdorferi and had to have persisted for at least 6
months but less than 12 years.

Patients were excluded if they had hypersensitivity to the study
medications, had previously received parenteral antibiotic therapy for
60
days or more for their current symptoms, had active inflammatory
synovitis,
had a coexisting condition that could have accounted for their
symptoms, or
were unable to discontinue medications that could interfere with the
evaluation of their response to the treatment regimen (e.g., narcotic
analgesics or prednisone in a dose of 10 mg per day or more). Patients
with
a positive polymerase-chain-reaction (PCR) test for B. burgdorferi DNA
in
plasma or cerebrospinal fluid at base line were also excluded.

Study Protocols

The study protocols were approved by the institutional review boards
for
human investigations at the participating centers, and each patient
gave
written informed consent. A data and safety monitoring board planned
an
interim analysis after at least 110 subjects had been enrolled.
Patients
were randomly assigned in a 1:1 ratio to receive either antibiotics or
placebo. The antibiotic treatment regimen consisted of intravenous
ceftriaxone for 30 consecutive days (2 g per day), followed by oral
doxycycline for 60 consecutive days (100 mg twice daily). The patients
in
the placebo group received an intravenous dextrose solution that was
the
same color as the ceftriaxone solution and oral placebo capsules
identical
in appearance to the doxycycline, both for the same lengths of time as
the
antibiotics were administered. Compliance and safety were monitored by
home
visits by study nurses every other day during the
intravenous-treatment
phase and twice (on days 45 and 75) during the oral-treatment phase.

Clinical and laboratory evaluations were performed at screening, at
base
line, and on days 3, 5, 13, 21, 30, 45, 75, 90, and 180. The base-line
evaluation included a complete medical history taking, a detailed
physical
examination, neuropsychological testing, a lumbar puncture, and
sampling of
peripheral blood.

Clinical Response

The primary outcome was an improvement in the patients' health-related
quality of life, which was measured by means of the Medical Outcomes
Study
(MOS) 36-item Short-Form General Health Survey (SF-36).7 8 Additional
measures of the health-related quality of life included the MOS scales
for
pain, cognition, and role functioning (the ability to participate in
usual
daily activities)9 10 11 and a modified version of the Fibromyalgia
Impact
Questionnaire (FIQ).12 13 Each of the instruments used to measure the
health-related quality of life was administered to study participants
at
base line and at 30, 90, and 180 days. The SF-36 includes eight
multiple-item scales that measure physical functioning, physical
limitations
on usual role-related activities, bodily pain, general health
perceptions,
vitality, social functioning, emotional limitations on usual
role-related
activities, and mental health. These scales provide the basis for
calculating the summary scores on the physical component and the
mental
component of the SF-36.7 8 The scores range from 0 (worst) to 100
(best).
For each of the scales, the mean (±SD) score for members of the
general
population of the United States without chronic conditions was
considered to
be 50±10.

To assess changes in the health-related quality of life over time, a
change
score for each SF-36 summary scale was calculated by subtracting the
base-line score from the scores at 30, 90, and 180 days. With the use
of 2
SE as the criterion,8 14 individual patients were classified into
three
categories of change: those whose follow-up scores did not change more
than
would be expected by chance (unchanged group); those whose follow-up
scores
improved by more than 2 SE (improved group); and those whose follow-up
scores declined by more than 2 SE (worse group). According to previous
studies, a change of 2 SE is 6.5 points on the SF-36 physical-health
summary
scale and 7.9 points on the SF-36 mental-health summary scale.8 14 The
overall change in health status was calculated for each patient.
Patients
were categorized as having improved health status if they had better
scores
on both scales or had a better score on one scale and a score on the
other
scale that was not worse. Patients were categorized as having worsened
health status if they had worse scores on one or both of the scales
and as
having the same health status if their scores on both the physical-
and
mental-component scales were unchanged.

Three additional multiple-item scales from the MOS were used as
secondary
measures of cognitive functioning, pain, and functioning in
role-related
activities.9 10 11 15 Clinical response was also measured with the use
of
the modified version of the FIQ, for which the scores range from 0
(best) to
110 (worst). This version of the FIQ has been validated for patients
who
have persistent symptoms after treatment for Lyme disease.13 In a
control
population without chronic illness, the mean total score on the
modified FIQ
was 14.0, whereas the mean for patients with chronic Lyme disease
after
treatment was 50.2.13 Previous studies have indicted that a change of
16.0
points is clinically meaningful.16 17 18 19

Laboratory Studies

Western blotting for IgG antibodies against B. burgdorferi antigens
was
performed with the IgG MarBlot (MarDx Diagnostics, Carlsbad, Calif.)
according to the manufacturer's instructions.6 The intrathecal
production of
antibodies against B. burgdorferi was measured as previously
described.20
Base-line specimens of cerebrospinal fluid and plasma specimens
obtained at
base line and on days 3, 5, 21, and 45 were tested by PCR for the
presence
of B. burgdorferi DNA, as previously described.21 All samples of
cerebrospinal fluid were cultured in Barbour–Stoenner–Kelly II medium
to
detect B. burgdorferi and were monitored by dark-field microscopy for
six
weeks.22 Some blood samples were cultured for B. burgdorferi in
hypertonic
medium.23

Adverse Events

Adverse events and changes in laboratory values were evaluated and
graded
with the use of scales derived from the Common Toxicity Criteria of
the
National Cancer Institute.

Compliance

Compliance with the regimen of medications was assessed by counts of
both
the number of doses of the intravenous medication the patients
received and
the pills they had remaining. The actual pill counts were compared
with the
number of pills that the patient should have had remaining at the time
of
the home visit by a nurse on day 75.

Statistical Analysis

The primary analysis was an intention-to-treat analysis of all the
patients
enrolled in the studies. The primary clinical end point was the
proportion
of patients whose condition was categorized as improved, unchanged,
and
worse on the basis of the summary scores for the mental and physical
components of the SF-36 at 180 days. Patients who withdrew from the
study
were categorized as having worsened health status on both of these
scales.

The study of seropositive patients was designed to have a power of 90
percent, with a 5 percent level of significance in a two-sided test
and a
sample size of 194, to detect a difference of 25 percent between the
antibiotic group and the placebo group in the proportion of patients
with
improved health status.24 With the enrollment of 66 patients, the
study of
seronegative patients would have 80 percent power, with a 5 percent
level of
significance in a two-sided test, to detect a 35 percent difference
between
the antibiotic group and the placebo group.24

In the interim analysis of the primary outcome, the O'Brien–Fleming
adjustment for multiple testing and the B-value stochastic curtailment
method were used.25 The primary outcome for each trial was analyzed by
the
chi-square test with individual type I error rates of 0.05. The
efficacy of
the treatment in each trial was estimated as the difference in risk
(with 95
percent confidence interval). Secondary outcomes included improvement
or
worsening as measured by the SF-36 at 30 and 90 days, the total FIQ
score,
and the MOS pain, cognition, and role-functioning scores at 30, 90,
and 180
days.

Results

Characteristics of the Patients

A total of 129 patients were enrolled in the studies (78 seropositive
and 51
seronegative). The base-line characteristics of the patients are shown
in
Table 1. A total of 42 (33 percent) of the patients had previously
received
intravenous antibiotic treatment for a mean (±SD) of 30±12 days. All
other
previous treatment consisted of oral antibiotics. There were no
significant
differences between the seropositive patients and the seronegative
patients
other than the presence or absence of serum antibodies to B.
burgdorferi.
All cultures of cerebrospinal fluid in standard Barbour–Stoenner–Kelly
II
medium and of blood in hypertonic medium were negative for B.
burgdorferi.
B. burgdorferi DNA was not detected in any base-line sample of
cerebrospinal
fluid or blood, nor was it detected in any of the blood samples
obtained
during the treatment phase (on days 3, 5, 21, and 45). Given a cutoff
of 1.2
for the ratio of antibody against B. burgdorferi in cerebrospinal
fluid to
antibody in serum, the intrathecal production of antibody was detected
in
eight patients (five in the combined antibiotic groups and three in
the
combined placebo groups).

Treatment was discontinued in 14 patients (8 seropositive and 6
seronegative). The reasons for the discontinuation of treatment were
similar
across the groups of patients. An adverse event was the reason for the
discontinuation of treatment in three of the patients in the combined
antibiotic groups (5 percent) and three of those in the combined
placebo
groups (5 percent). Treatment was discontinued in the other eight
patients
for reasons other than an adverse event.

In the combined population of both studies, the mean base-line summary
score
for the physical component of the SF-36 was approximately 1.5 SD below
that
of age-matched members of the general population of the United States
who
did not have a chronic illness, and the mean base-line summary score
for the
mental component was approximately 0.5 SD below that of such a control
group. Similarly, the base-line FIQ scores were markedly abnormal.

Compliance

All patients who completed 180 days in one of the trials took at least
75
percent of the prescribed medications. There were no differences
between the
treatment groups in either the seropositive or the seronegative study
in
patients' compliance with medication.

Efficacy

The interim analysis was performed with the use of data on 107
patients who
had completed 180 days in one of the trials. This analysis indicated
that
there was a 1.4 percent chance in the seropositive study and a 4.0
percent
chance in the seronegative study that a significant difference in the
efficacy of treatment between the antibiotic group and the placebo
group
would be observed when the full projected enrollment was reached. An
analysis that included the patients in both studies indicated that
there was
a 3.9 percent chance of observing a significant difference at full
enrollment. Because of the lack of efficacy of the antibiotic
treatment at
the time of the interim analysis, the data and safety monitoring board
recommended discontinuation of the active treatment of enrolled
patients and
of further enrollment in the treatment phase of the studies.

The responses of the 115 patients who were enrolled in the studies at
least
180 days before enrollment was stopped are shown in Table 2 and Figure
1.
Intention-to-treat analyses at 30, 90, and 180 days showed no
significant
differences in the measures of the health-related quality of life
between
the patients in the antibiotic groups and those in the placebo groups
in the
seropositive study, the seronegative study, or both studies combined.

In the combined study populations, changes in the score on the
modified FIQ
at 180 days also revealed no significant differences between the
antibiotic
groups and the placebo groups. We defined a decrease of 25 percent
from the
base-line score on the modified FIQ as indicative of clinical
improvement
and an increase of 25 percent as indicative of clinical worsening.
Given
these definitions, 28 of the 51 patients in the combined antibiotic
groups
(55 percent) had improved health status as measured by the FIQ at 180
days,
as compared with 22 of the 53 patients in the combined placebo groups
(42
percent) (P=0.17). Conversely, 14 percent of the patients in the
antibiotic
groups (7 of 51) had worsened health status as measured by the FIQ at
180
days, as compared with 19 percent (10 of 53) in the placebo groups
(P=0.48).
Separate comparisons of the FIQ scores in the antibiotic group and the
placebo group of the seropositive study and of those in the two
treatment
groups in the seronegative study found no statistically significant
differences according to treatment.

Adverse Events

At least one study-related adverse event occurred in 16 of the 64
patients
in the combined antibiotic groups (25 percent) and 11 of the 65
patients in
the combined placebo groups (17 percent). Most of the adverse events
were
minor and resolved without intervention or sequelae. However, the two
patients in whom a study-related serious adverse event occurred were
both in
the antibiotic group. During intravenous treatment, one had a
life-threatening pulmonary embolism and the other had fever, anemia,
and
gastrointestinal bleeding. Although the overall rate of adverse events
was
not significantly different in the two treatment groups, rash,
diarrhea, and
vaginal pruritus occurred more frequently among the patients in the
antibiotic groups (9 of 64 patients) than among those in the placebo
groups
(2 of 65 patients). There were no infections associated with the
intravenous
catheter, and there were no deaths.

Discussion

The primary goals of these studies in patients with symptoms that
persist
after recommended antibiotic treatment for Lyme disease were to
characterize
the impairment in health-related quality of life among such patients
and to
determine the efficacy of prolonged treatment with antibiotics. The
effect
of chronic Lyme disease on the health-related quality of life was
substantial in both seropositive and seronegative patients. The
deficits in
physical health status as measured by the SF-36 were equivalent to
those
observed in patients with congestive heart failure or osteoarthritis
and
were more than 0.5 SD greater than the impairment observed in patients
with
type 2 diabetes or a recent myocardial infarction.7 8 Chronic pain was
an
important contributor to the impairment of physical health and was
similar
to that reported by patients with osteoarthritis.7 8 The impairment of
mental health status was similar to that observed in patients with
subthreshold lifetime depression (a depressive disorder that does not
meet
all of the criteria for major depression of the Diagnostic and
Statistical
Manual of Mental Disorders, third edition).7 8 26 The study patients
also
had some impairment in cognitive functioning. Their base-line FIQ
scores
reflected the impairments in health status that were evident in the
SF-36
scores and were similar to those in previous studies of patients with
fibromyalgia or those with chronic Lyme disease after treatment.8 9 10
11 12
13

The administration of placebo and treatment with a regimen of
parenteral
ceftriaxone for 30 days, followed by oral doxycycline for 60 days, had
similar effects on the patients' health-related quality of life. This
antibiotic-treatment regimen was selected because of the in vitro and
in
vivo activity of both of these antibiotics against B. burgdorferi and
because they are effective for the treatment of neuroborreliosis.1
Experience with other chronic infectious diseases caused by persistent
bacteria (e.g., syphilis, tuberculosis, and helicobacter infection)
suggests
that it is unlikely that more prolonged antibiotic therapy or a
different
combination of antibiotics would result in greater improvement than
was
observed in this study.

Although we used both conventional and hypertonic culture mediums to
isolate
B. burgdorferi in base-line samples of cerebrospinal fluid and blood
and
used PCR to detect B. burgdorferi DNA in base-line samples of blood
and
cerebrospinal fluid as well as samples of blood collected during
treatment,
we did not find evidence of persistent infection with B. burgdorferi
in
these patients. There was no evidence of B. burgdorferi in a total of
more
than 700 different blood and cerebrospinal fluid samples from the 129
patients in these studies.

The placebo groups in these studies provide a view of the natural
history of
symptoms among patients with chronic Lyme disease after treatment.
During
the six-month evaluation period, we observed improvement in health
status in
36 percent of patients, worsening health status in 39 percent, and no
significant change in 25 percent. A similar relation between the
administration of placebo and health-related quality of life has been
reported previously among patients with other rheumatologic diseases
that do
not appear to be related to persistent infection. For example, a
randomized,
placebo-controlled trial in patients with mild-to-moderate rheumatoid
arthritis found an improved clinical response after 48 weeks of
placebo
treatment in 39 to 41 percent of patients, as compared with 54 to 56
percent
of patients treated with minocycline.27

In summary, patients with chronic musculoskeletal pain, neurocognitive
symptoms, or both that persist after antibiotic treatment for
well-documented Lyme disease have considerable impairment in their
health-related quality of life. The patients enrolled in these studies
did
not have evidence of persistent infection by B. burgdorferi, as judged
on
the basis of the available microbiologic and molecular methods of
detection.
There were no significant differences between clinical responses of
patients
who received intravenous and oral antibiotics for 90 days and those of
patients who received placebo.

Source Information

>From New England Medical Center and Tufts University School of
Medicine,
Boston (M.S.K., L.T.H., C.H.S., G.M.J., R.P. T., J.M.); Yale–New Haven
Hospital, New Haven, Conn. (J.E., D.W.), New York Medical College,
Valhalla
(D.N., L.L., A.W.); and Quality Metric, Lincoln, R.I. (M.K.). Address
reprint requests to Dr. Klempner at the Department of Medicine, Boston
University School of Medicine, 715 Albany St., Boston, MA 02118, or at
klempner@bu.edu.

Supported by grants (N01-AI-65308 and M01 RR000054) from the National
Institutes of Health. Roche provided the ceftriaxone for the study,
and
Pfizer provided the doxycycline.

We are indebted to Philip J. Baker, Ph.D., Steven P. Heyse, M.D.,
Marilyn
Tuttleman, M.S., Dennis Dixon, Ph.D., and Mark Van Raden, Ph.D., of
the
National Institute of Allergy and Infectious Diseases Lyme Disease
Program;
to Barbara E. Murray, M.D., Robert Edelman, M.D., Frank G. Miller,
Ph.D.,
Donald Rosenstein, M.D., and Barbara Tilley, Ph.D., of the data and
safety
monitoring board; to John E. Edwards, Jr., M.D., Carl Brenner, J.
Stephen
Dumler, M.D., Fred A. Gill, M.D., Phyllis Mervine, Justin Radolf,
M.D., and
Gregory Owens, Ph.D., of the Scientific Advisory Committee; and to the
following persons who provided helpful services: Rich Noring, Bilaal
McCloud, Bo Lin, Ph.D., Richard Kaplan, Ph.D., David Weld, Roger
D'Entremont, Kitty Mullen, Chris Covington, Vincent DiPaola, Paul
Drouilhet,
David Fletcher, Jerrold Gold, Thomas Hirsch, Clyde Kessel, Keith
Krewson,
Laura Lattanzio, Rebecca Leland, Shawn Lyden, William Macleod, Roy
Matthews,
Peter Morton, Dave Murray, Jim Platz, John Sample, Elliott Schiffman,
Michael Shabazian, Jason Stone, John Taylor, Bradford Von Weise, Frank
Weldon, Larry Camerlin, Raymond Partridge, M.D., Marianna Wilson,
M.S., John
Consoletti, Pharm.D., Cindy Mason, R.N., David Thorpe, Pharm.D., Cindy
Moore, R.N., June Novio, R.N., Eileen Regan, R.N., Andy Dousa,
Pharm.D., Don
Morrison, Pharm.D., Laura Cavagna, Pharm.D., Linda Griffith, Pharm.D.,
Sean
Corbett, Pharm.D., Scott Reid, Pharm.D., Fran Bickert, R.N., John
Opolski,
R.N., Karen Tooker, R.N., Mark Wolff, Ph.D., Phyllis Barr, Ph.D., Anna
Lornell, M.D., Phil Molloy, M.D., Karen Forschner, Dennis Hoak, M.D.,
David
N. Mesches, M.D., Tim Lepore, M.D., Robina Folland, Robert Lopez, Bai
Margolin, Crystal Sylvester, George Perides, Ph.D., Allen Steere,
M.D.,
Ellen Jamieson, Jim Grayson, Timothy Brauns, Lilla Rogers, Jenn Finn,
R.N.,
Pamela Norton, R.N., Karen Mazzotta, Anh Nguyen, M.D., Eric Logigian,
M.D.,
William Brown, M.D., Anne Donohoe, Sandy Doveikis, Karen Fenicchia,
R.N.,
Hua Wang, R.N., Nancy Zajac, R.N., Jamie Evanowski, David Carlson,
Jason
Hoitt, Carol Bauscher, L.P.N., Teryi Deshefy-Longhi, R.N., M.S., Carl
Henn,
Dee Dee Moss, Glynnis Fisher, Janet Mattson, Rosemary Hammil, Beth
Horrigan,
William Blackwelder, M.D., Frank Cavileri, M.D., John Nowakowski,
M.D.,
Morris Dannon, M.D., Brij Mohan Singh Ahluwalia, M.D., Gary Wormser,
M.D.,
Rhea Dornbush, Ph.D., Catherine Crea, Maria Aguero-Rosenfeld, M.D.,
Alan
Gerber, M.D., Michael Tenner, M.D., Maureen Grix, Ph.D., Lois
Zentmaier,
Denise Cooper, Susan Bittker, Sheila Hughes, R.N., Junius Edlow, Tim
McGarty, Jeffrey Bandola, M.D., Andrew Artenstein, M.D., Nancy Clark,
R.N.,
Jerry Fingerut, M.D., Robert Schoen, M.D., Donna D'Euginio, R.N.,
Linda
Bockenstedt, M.D., Alexia Bellperron, Brad Herskowitz, M.D., George
Rickerson, M.D., LeBraun Paige, M.D., Volker Knappertz, M.D., Kimberly
Stoddard, Ph.D., Ann Sweeney, R.N., Michael Westerveldt, Ph.D.,
Maureen
Tacey, Thomas Rush, M.D., Jill Auerbach, Betty Gross, Manuel DaSilva,
M.D.,
Arthur Rabson, M.D., Brian Fallon, M.D., Linda Tanner, Richard
Horowitz,
M.D., Edmond Yunis, M.D., Paul Alexander, R.N., and Ann Marie McClean,
R.N.

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2001 Massachusetts Medical Society. All rights reserved.

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