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CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy.

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CINRG Randomized
Controlled Trial of Creatine
and Glutamine in Duchenne
Muscular Dystrophy
Diana M. Escolar, MD,1 Gunnar Buyse, MD, PhD,2
Erik Henricson, MPH,1 Robert Leshner, MD,3
Julaine Florence, PT, DPT,4 Jill Mayhew, PT,5
Carolina Tesi-Rocha, MD,1 Ksenija Gorni, MD,1
Livia Pasquali, MD,1 Kantilal M. Patel, PhD,1
Robert McCarter, ScD,1 Jennifer Huang, PhD, MPH,1
Thomas Mayhew, PT, PhD,3 Tulio Bertorini, MD,6
Jose Carlo, MD,7 Anne M. Connolly, MD,4
Paula R. Clemens, MD,8,9 Nathalie Goemans, MD,2
Susan T. Iannaccone, MD,10 Masanori Igarashi, MD,6
Yoram Nevo, MD,11 Alan Pestronk, MD,4
S. H. Subramony, MD,12 V. V. Vedanarayanan, MD,12
Henry Wessel, MD,9 and the CINRG Goup
We tested the efficacy and safety of glutamine (0.6gm/kg/
day) and creatine (5gm/day) in 50 ambulant boys with
Duchenne muscular dystrophy in a 6-month, doubleblind, placebo-controlled clinical trial. Drug efficacy was
tested by measuring muscle strength manually (34 muscle
groups) and quantitatively (10 muscle groups). Timed
functional tests, functional parameters, and pulmonary
function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of
creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were
well tolerated.
Ann Neurol 2005;58:151–155
From the 1Children’s National Medical Center, George Washington
University, Washington, DC; 2University Hospitals, KU Leuven,
Leuven, Belgium; 3Virginia Commonwealth University, Richmond,
VA; 4Washington University, St. Louis, MO; 5Children’s Hospital,
Richmond, VA; 6University of Tennessee, Memphis, TN; 7University of Puerto Rico, San Juan, Puerto Rico; 8Neurology Service, Department of Veterans Affairs Medical Center; 9Children’s Hospital
of Pittsburgh, Pittsburgh, PA; 10Texas Scottish Rite Hospital for
Children, Dallas, TX; 11University of Tel Aviv, Tel Aviv, Israel; and
12
University of Mississippi, Jackson, MS.
Received Apr 27, 2004, and in revised form Oct 8 and Apr 20,
2005. Accepted for publication Apr 21, 2005.
Published online Jun 27, 2005 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20523
Members of the CINRG Study Group are listed in the Appendix on
page 153.
Address correspondence to Dr Escolar, Associate Professor of Neurology and Pediatrics, Children’s National Medical Center, Research
Center for Genetic Medicine, 111 Michigan Ave, NW, Washington, DC 20010. E-mail: descolar@cnmcresearch.org
The Cooperative International Neuromuscular Research Group (CINRG) completed a trial of glutamine
and creatine (Cr) in ambulatory Duchenne muscular
dystrophy (DMD) patients based on the drug’s potential to block pathophysiological cascades involved in
DMD and on experimental data in the mdx mouse
model of DMD.1,2
Patients and Methods
This was a randomized, placebo-controlled, double-blind,
three-arm, multicenter study of effects of oral glutamine or
Cr versus placebo in ambulant children with DMD. Enrollees included 50 ambulant steroid-naive DMD boys aged 4 to
10 years. Children with symptomatic cardiomyopathy; ventricular arrhythmias; or recent or current use of glutamine,
Cr, or other supplements were excluded from participating
in the study.
Patients were recruited at 10 CINRG centers with institutional review board approval at each site (see Appendix).
After obtaining assent from patients aged 7 years and older
and consent from parents of all participants, patients underwent two screening visits. If patients met all inclusion criteria, they were enrolled and randomly assigned to either 5gm
daily of Cr (EAS, Golden, CA) powder, 0.3mg/kg glutamine
twice daily (EAS), or placebo for 6 months. Blinding was
achieved according to the “double-dummy technique.” The
drugs and placebo were given as powders of identical color,
texture, and taste, flavored with chocolate (Swiss Miss cocoa
powder) and granulated glucose in predetermined proportions.
An adaptive, biased-coin (urn) randomization technique
was applied by the Biostatistics Center Medical Center Unit
of George Washington University.
Outcome Measures
The primary end point was percentage change in averaged
modified manual muscle testing (MMT) score of 34 muscle
groups. Secondary outcome measures included change in the
following characteristics: (1) quantitative muscle testing
(QMT) of bilateral elbow flexors and extensors, knee flexors
and extensors, and grip; (2) combined QMT arm and leg
scores; (3) time to rise from supine position, to run/walk
10m and to climb four steps; and (4) pulmonary forced vital
capacity and negative inspiratory force.
MMT, QMT, and functional evaluation protocols have
been published elsewhere.3,4 Outcome measures (MMT,
QMT, functional evaluations, pulmonary function tests)
were performed by blinded clinical evaluators who were
trained and shown to be reliable before study start-up.4
Sample Size and Power
Sample size calculations were based on response to the primary outcome measure, the average MMT score. The number of patients needed in a two-sample t test comparing
change in average strength scores in placebo and treated
groups was determined to control the probabilities of type I
error at 0.025 and type II error at 0.20 to achieve statistical
power of 0.80. The type I error was set to 0.025 because we
compared the two active interventions against the placebo.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
151
Table 1. Comparison of Study Groups at Baseline
Baseline
Age (yr)
MMT score (0–10)
QMT score (lb)
QMT (arm) (lb)
QMT (leg) (lb)
Timed stand (sec)
Timed climb (sec)
Timed run (sec)
Placebo
(N ⫽ 16)
Creatine
(N ⫽ 15)
Glutamine
(N ⫽ 19)
6.81 ⫾ 1.33
6.24 ⫾ 0.70
7.46 ⫾ 2.16
6.92 ⫾ 2.52
8.30 ⫾ 1.85
9.21 ⫾ 5.33
7.21 ⫾ 4.17
6.58 ⫾ 1.11
6.67 ⫾ 1.76
6.30 ⫾ 1.27
8.66 ⫾ 3.87
7.21 ⫾ 3.31
10.84 ⫾ 5.74
7.97 ⫾ 4.68
10.92 ⫾ 13.27
8.30 ⫾ 5.79
6.32 ⫾ 1.00
6.61 ⫾ 0.66
8.07 ⫾ 2.47
7.17 ⫾ 2.43
9.43 ⫾ 3.20
9.18 ⫾ 7.55
6.73 ⫾ 3.16
6.86 ⫾ 1.58
There were no significant differences on demographic characteristics, muscle strength (MMT score and QMT measures) or functional scores
among groups at baseline.
MMT ⫽ manual measure of muscle strength; QMT ⫽ quantitative measure of muscle strength.
We were interested in finding an effect size of 1.29 standard
deviations, which is at least as large as that reported from a
previous clinical trial of prednisone in DMD.5 Projected
sample size of 14 per group was increased to 16 patients per
arm to cover the potential need for nonparametric analyses
and for patient attrition or follow-up losses.
Statistical Analysis
We applied an intention-to-treat analysis. We used the Generalized Estimating Equations method based on PROC
Mixed in SAS (SAS Institute, Cary, NC) to handle correlated data and missing values in longitudinal measurements
taken over 6 months in each subject. Data on each subject
were treated as a cluster under the assumption of unstructured covariance. We adjusted baseline strength and function
measures, and generated the growth curves as change in
strength and function for each treatment as adjusted slopes
(trends) over the 6-month follow-up period.
Because there were no statistically significant differences
based on side of the body or muscle group within limb, we
created arm and leg total scores. Because analyses by limb
did not differ by group, we summarized based on total
strength, presented herein as QMT and MMT scores together with timed function tests.
Results
Sixty children were screened at 10 CINRG centers.
Fifty children aged 4 to 10 years were enrolled, 48%
aged 7 years or older. Ten did not meet one or more of
the inclusion criteria because of unconfirmed diagnosis
(n ⫽ 2) or more than 10% variability in MMT score
on screening Visits 1 and 2 (n ⫽ 8). Of 50 enrolled
patients, 45 completed the study. Five patients withdrew (glutamine ⫽ 2; placebo ⫽ 2; Cr ⫽ 1) because
of medication noncompliance (n ⫽ 4) and progressive
muscle weakness (n ⫽ 1, placebo group). Table 1
shows baseline characteristics of the study population.
There were no statistically significant differences in
the primary outcome measure (MMT score) (Table 2)
when the Cr and glutamine groups were compared
with the placebo group.
The Figure shows trends in MMT score, QMT
score, and functional evaluations adjusted for baseline
measures. Interestingly, in accordance with a recent
study of oxandrolone in DMD,6 the placebo group did
not show deterioration of strength measured by MMT
over a 6-month period. This unexpected result reduced
Table 2. Mean Muscle Strength and Function Scores at Baseline and the Mean Changes at Six Months
Placebo
Overall
N
MMT
QMT
QMT arm
QMT leg
Time to stand
Time to climb 4 stairs
Time to run 10 meters
Baseline
6.24 ⫾ 0.70
7.46 ⫾ 2.16
6.92 ⫾ 2.52
8.30 ⫾ 1.85
9.21 ⫾ 5.33
7.21 ⫾ 4.17
6.58 ⫾ 1.11
Creatine
Changes at
Month 6
16
⫺0.08 ⫾ 0.47
⫺0.53 ⫾ 1.86
⫺0.61 ⫾ 2.28
⫺0.51 ⫾ 1.88
4.33 ⫾ 2.38
4.22 ⫾ 5.20
1.41 ⫾ 1.24
Baseline
6.30 ⫾ 1.27
8.66 ⫾ 3.87
7.21 ⫾ 3.31
10.84 ⫾ 5.74
7.97 ⫾ 4.68
10.92 ⫾ 13.27
8.30 ⫾ 5.79
15
Glutamine
Changes at
Month 6
Baseline
0.24 ⫾ 0.55
⫺0.06 ⫾ 1.52
0.28 ⫾ 1.52
⫺0.54 ⫾ 2.47
3.50 ⫾ 5.25
0.85 ⫾ 2.36
0.44 ⫾ 0.36
6.61 ⫾ 0.66
8.07 ⫾ 2.47
7.17 ⫾ 2.43
9.43 ⫾ 3.20
9.18 ⫾ 7.55
6.73 ⫾ 3.16
6.86 ⫾ 1.58
Changes at
Month 6
19
⫺0.07 ⫾ 0.46
⫺0.54 ⫾ 1.79
⫺0.67 ⫾ 1.50
⫺0.66 ⫾ 2.77
3.06 ⫾ 4.08
2.34 ⫾ 3.89
0.60 ⫾ 1.23
Scores are created by adding the individual right and left group muscle values in pounds (QMT) or modified MRC scale (MMT) and dividing
by total number of muscle groups tested in each modality (MMT and QMT). Time function tests are expressed in seconds.
MMT ⫽ manual measure of muscle strength; QMT ⫽ quantitative measure of muscle strength.
152
Annals of Neurology
Vol 58
No 1
July 2005
Fig. Predicted change of muscle strength from baseline after adjustment for baseline measures. Overall, deterioration of muscle
strength over 6 months was demonstrated by quantitative measure of muscle strength (QMT), but not manual measure of muscle
strength (MMT), score. The creatine group showed a smaller strength deterioration over 6 months (p ⫽ 0.07) compared with the
placebo group. On secondary analysis, creatine and glutamine showed significant less deterioration in timed scores compared with
placebo in the younger than 7 years age group, whereas creatine showed a smaller degree of strength deterioration in the equal or
older than 7 years age group. (—䡲—) Creatine; (—●—) glutamine; (—Œ—) placebo.
our statistical power to show groupwise differences.
However, we found strong, consistent, nonstatistically
significant trends. The Cr and glutamine groups had
less deterioration in all outcome measures except for
MMT when compared with the placebo group. The
Cr group showed less strength deterioration ( p ⫽
0.07), as measured by QMT, than those on placebo. In
the timed climbing test, the Cr group did significantly
Escolar et al: Creatine and Glutamine in DMD
153
better than the placebo group over time ( p ⫽ 0.015),
and there was a similar trend for the glutamine group
( p ⬎ 0.05). We observed similar trends with both glutamine and Cr in the timed running test.
We investigated age as a confounding variable because a “honeymoon” period is recognized clinically in
DMD. Our analysis shows that age is a statistical interaction for all measures except MMT (MMT: p ⫽
0.4758; QMT: p ⫽ 0.0050; time to stand: p ⬍
0.0001; time to climb stairs: p ⫽ 0.0139; time to run
10m: p ⫽ 0.028). Strength measured by QMT in the
younger children (⬍7, N ⫽ 26) mildly increased over
the 6-month trial in all groups (slope ⫽ 0.024, 0.020,
and 0.026 for QMT by Cr, glutamine, and placebo
groups, respectively, p ⬎ 0.05), with the Cr and glutamine groups showing improved scores on time to
stand from a supine position ( p ⫽ 0.003 for Cr; p ⬍
0.000 for glutamine) and time to climb four standard
steps ( p ⫽ 0.005 for Cr; p ⫽ 0.002 for glutamine)
when compared with placebo group. Older children
(ⱖ7, n ⫽ 24) showed clear deterioration of strength
measured by QMT over time (slope ⫽ ⫺0.11, ⫺0.14,
and ⫺0.22 for Cr, glutamine, and placebo groups, respectively). However, the Cr group consistently showed
less deterioration compared with the other groups in
QMT arm and leg scores (data not shown), but the
differences between groups did not achieve statistical
significance.
Cr and glutamine were safe and well tolerated at the
doses prescribed with no significant differences in sideeffect profiles among groups.
Discussion
In this study, we did not see the expected strength deterioration in our placebo group. Thus, the study was
underpowered to demonstrate a statistically significant
benefit of glutamine or Cr on strength measured by
MMT and QMT scores in boys with DMD.
However, we found consistent trends in QMT and
secondary outcome measures that are of clinical significance, and that impact the design of future clinical
trials in this population.
Cr treatment reduced deterioration in QMT measures of strength in the older age group, suggesting a
modest mitigation of strength deterioration over time.
However, this modest effect was not reflected in functional measurements in this age group. Despite the apparent lack of effect on strength, both Cr and glutamine appeared to have an effect on functional timed
scores in younger children. The discordance between
measures of function and strength makes it imperative
to consider both outcomes in the design of therapeutic
trials in DMD. Our age-related findings derive from
an unplanned analysis in a small group of patients and
154
Annals of Neurology
Vol 58
No 1
July 2005
must be interpreted with caution. Larger trials that include a priori age stratification and correlation of these
outcome measures with disease-specific quality-of-life
measurements will be useful to better understand these
issues.
The lack of strength deterioration of placebo groups
with MMT in both younger and older groups is in
contrast to published natural history data of DMD.7,8
This changes power calculations from previously proposed methods,8 and makes it important to include a
control group in future studies or to use QMT as a
more sensitive measure of strength for the older children. Finally, we were able to demonstrate muscle
strength deterioration with QMT in the placebo
group, as well as changes in strength that were undetected by MMT in treatment groups. This demonstrates that QMT is a more sensitive and reliable4 measure of strength in DMD.
The age-specific results suggest that drug therapies
in DMD may have different effects depending on the
stage of disease process. Although not surprising, this
has not been emphasized previously in the literature.
An important implication of these findings is that
drug trials in DMD should target specific disease
stages.
Conclusion
Treatment with Cr or glutamine does not improve
strength to the same degree as treatment with prednisone or deflazacort. However, disease-modifying effects of long-term treatment are not excluded. Larger,
age-stratified studies are needed to further test this hypothesis. QMT is a more sensitive primary outcome
measure for such a study.
Appendix
Members of the CINRG Study Group are as follows: Children’s Hospital of Richmond, Richmond, VA: R. Leshner,
B. Grillo, S. Blair, J. Mayhew; Children’s National Medical
Center, Washington, DC: D. Escolar, E. Henricson, M.
Bartczak, K. Parker, R. McCarter, L. Morton, C. Jilles;
Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel: Y.
Nevo, A. Orr, Y. Yaron, S. Katzenelbogen; Texas Scottish
Rite Hospital, Dallas, TX: S. Iannaccone, B. Teitell, H.
Owens, C. Rushing; University Hospital Gasthuisberg,
K.U. Leuven, Leuven, Belgium: G. Buyse, N. Goemans,
M. van den Hauwe; University of Mississippi, Jackson, MS:
S. H. Subramony, V. Vedanaryan, T. O’Connor; University of Pittsburgh, Pittsburgh, PA: P. Clemens, H. Wessel,
C. Belz, K. Tatar; University of Puerto Rico, San Juan,
Puerto Rico: J. Carlo-Izquierdo, E. Ramos-Cortis, D. Molina; University of Tennessee, Memphis, TN: T. Bertorini,
M. Igarashi, H. Rashed, J. Clifft, A. Coleman; Washington
University, St. Louis, MO: A. Connolly, A. Pestronk, C.
Wulf, J. Florence, J. Schierbecker, R. Renna.
This work was supported by the Muscular Dystrophy Association
(2916, D.E.), the General Clinic Research Center (M01RR020359-01, D.E., MO1-RR00084, P.C), NIH (National Center
for Research Resources, K-23 RR16281-01, D.E., RR011126, J.C.),
Deutch Duchenne Parent Project (G.B.) and the Beigian American
Educational Foundation Inc., (G.B.).
We are grateful to Dr E. Hoffman for his support and scientific
contributions, L. Morton for her invaluable coordination role
within CINRG, A. Kennedy for her continuous support and interface with patients, and all parents and patients who participated in
the study.
This study was first presented as Work in Progress abstract at the
128th American Neurological Association Annual Meeting, San
Francisco, CA, 10/19 –10/22/03.
References
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A 10-Item Smell
Identification Scale Related
to Risk for Alzheimer’s
Disease
Matthias H. Tabert, PhD,1–3 Xinhua Liu, PhD,4
Richard L. Doty, PhD,5 Michael Serby, MD,6,7
Diana Zamora, BSc,1 Gregory H. Pelton, MD,1–3,8
Karen Marder, MD,2,3,8,9 Mark W. Albers, MD, PhD,3,8,9
Yaakov Stern, PhD,1,2,3,8,9 and D. P. Devanand, MD1–3,8,9
University of Pennsylvania Smell Identification Test data
from control subjects (n ⴝ 63), patients with mild cognitive impairment (n ⴝ 147), and patients with Alzheimer’s disease (n ⴝ 100) were analyzed to derive an optimal subset of items related to risk for Alzheimer’s
disease (ie, healthy through mild cognitive impairment to
early and moderate disease stages). The derived 10-item
scale performed comparably with the University of Pennsylvania Smell Identification Test in classifying subjects,
and it strongly predicted conversion to Alzheimer’s disease on follow-up evaluation in patients with mild cognitive impairment. Independent replication is needed to
validate these findings.
Ann Neurol 2005;58:155–160
Early in the course of Alzheimer’s disease (AD), neurofibrillary tangles appear in olfactory-related brain regions (eg, anterior olfactory nucleus and entorhinal
cortex).1 Olfactory deficits, which have been observed
consistently in AD,2 occur early,3,4 are predictive of a
future diagnosis of AD,5,6 and increase with disease severity.7,8
The University of Pennsylvania Smell Identification
Test (UPSIT)9 is widely used in research to assess odor
identification deficits,2,10 but it is less widely used in
clinical practice, partly because administration takes 10
From the 1Department of Biological Psychiatry, New York State
Psychiatric Institute; 2Department of Psychiatry and 3Gertrude H.
Sergievsky Center, Columbia University College of Physicians and
Surgeons; 4Department of Biostatistics, Columbia University, New
York, NY; 5The Smell and Taste Center, University of Pennsylvania
School of Medicine, Philadelphia, PA; 6Department of Psychiatry,
Beth Israel Medical Center; 7Albert Einstein College of Medicine;
8
Department of Neurology, Columbia University College of Physicians and Surgeons; and 9Taub Institute for Research in Alzheimer’s
Disease and the Aging Brain, Columbia University, New York, NY.
Received Dec 9, 2004, and in revised form Mar 29, 2005. Accepted
for publication Apr 28, 2005.
Published online Jun 27, 2005 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20533
Address correspondence to Dr Tabert, 1051 Riverside Drive, Unit
126, New York, NY 10032. E-mail: mht35@columbia.edu
Tabert et al: 10-Item Smell Identification Scale
155
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