Using Gadolinium-enhanced Magnetic
`Resonance Imaging Lesions to Monitor
`Disease Activity in Multiple Sclerosis
`
`Henry F. McFarland, MD," Joseph A. Frank, MD,z Paul S. Albert, PhD, Mary E. Smith, MD,*
`Roland Martin, MD,” Jonathan O. Harris, MD,* Nicholas Patronas, MD,+§
`Heidi Maloni, RN,* and Dale E. McFarlin, MD“
`
`
`The highly variable clinical course and the lack of a direct measurementof disease activiry have made evaluation of
`experimental therapies in multiple sclerosis (MS) difficult. Recent studies indicate that clinically silent lesions can be
`demonstrated by magnetic resonance imaging (MRI) in patients with mild relapsing-remicting MS. Thus, MRI may
`provide a means for monitoring therapeutic trials in the early phase of MS, We studied 12 patients longitudinally for
`12 to 21 months with monthly gadolinium (Gd)-enhanced MRIs. The data have been used to identify the most effective
`design ofa clinical trial using Gd-enhanced lesions as the outcome measure. Frequent (> 1/mo) Gd-enhancing lesions
`were observed in 9 of the 12 patients, indicating thac the disease is active even during the early phase of the illness.
`The frequency of the lesions was not constant; there was marked fluctuation in lesion number from month to month.
`However, the magnitudeof che peak number of lesions and the frequency of rhe peaks varied among patients. Because
`of this variability, che most effective use of Gd-enhancing lesions as an outcome measure in a clinical trial was a
`crossover design with study arms of sufficient duration to allow accurate estimation of lesion frequency. Monitoring
`Gd-enhancing lesions may be an effective tool to assist in the assessment of experimental therapies in early MS.
`McFarland HF, Frank JA, AJberc P5, Smith ME, Martin R, Harris JO, Patronas N, Maloni H,
`McFarlin DE. Using gadolinium-enhanced magnetic resonance imaging lesions to monitor
`disease activicy in multiple sclerosis. Ann Neurol 1992;32:758-766
`cePSsPVPTSPSPSPS
`
`‘The clinical variability in multiple sclerosis (MS) has
`cur in the cerebrum in clinically stable patients {9, 10].
`made design and assessment of clinical
`trials difficulr
`In addition, use of gadolinium (Gd) with T1-weighted
`{1}. Although there is increasing interest in treating
`imaging can identify areas of breakdown in the blood-
`patients before significant disabiliry occurs, the inability
`brain barrier. These areas of enhancement seem to rep-
`to predict che furure course of the disease has made
`resent the initial stage of lesion development [12-15]
`assessment of the risk-benefir relationship diffcult.
`and are probably associated with active inflammation
`Some patients will continue to have mild disease
`(14, 16}. Recent studies, including an initial report on
`throughout
`the course of the illness. Treatment of
`G6 of the patients from our present study, indicate that
`these patients early in the course of the disease with
`frequent, new Gd-enhancing lesions occur in patients
`potentially toxic creatments may pose greater risk than
`without corresponding clinical changes [17~19]. These
`the disease. Further complicating clinical trials has been
`findings indicate that MRI paramerers and, in particu-
`the difficulty in measuring disease activity, which is
`jar, Gd-enhancing lesions, should be helpful in moni-
`usually assessed indirectly by measuring disabilicy.
`toring disease activity in patients with MS and may
`Magnetic resonance imaging (MRI) is well established
`provide a suitable tool for assessing the effectiveness
`as the optimal imaging technique for the diagnosis of
`ofclinical crials, particularly in patients with early, mild,
`MS [2—8}, and the presence of disease aczivicy in the
`relapsing-remining MS {1, 20].
`absence of clinical changes has been confirmed by re-
`Ourprevious investigation of patients with MS using
`cent MRI studies [9, 10]. Areas of increased signal
`Gd-enhanced MRI suggested that the occurrence of
`on T2-weighted images, which reflect demyelination,
`enhancing lesions was not constant over time. Because
`inflammation, or edema [11], have been shown to oc-
`the pattern of lesion occurrence affects the usefulness
`
`
`From the *Neuroimmunology Branch and che {Biometry Branch,
`National Institute of Neurological Disease and Stroke, and the #Di-
`agnostic Radiology Department, Clinical Center, National Inssitures
`of Health, Hethesda, MD; and the $Deparrment of Radiology.
`Georgetown University Medical Center, Washington, DC.
`
`758
`
`Page 1 of 10
`
`Received Jan 8, 1992, and in revised form Apr 20 and Jun 24.
`Accepted for publication jun 28, 1992.
`Address correspondence to Dr McFarland, National Insticutes of
`Health, Building 10, Room 5B16, Bethesda, MD 20892,
`
`
`
`Biogen Exhibit 2222
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`IPR 2018-01403
`
`Page 1 of 10
`
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`IPR 2018-01403
`
`

`

`the initial study
`of MRI in monitoring clinical trials,
`has been expanded into an extended longitudinal ex-
`amination of 10 patients with relapsing-remitting MS
`and 2 patients with chronic-progressive MS studied for
`12 to 21 months. The data derived from this study
`have been used to evaluate the optmal design of a
`clinical trial using Gd-enhanced lesions as the primary
`outcome measure.
`
`Materials and Methods
`Patient Selection
`This study was reviewed and approved by the Insticute Clini-
`cal Research Subpanel and informed consent was obtained
`from each patient prior to beginning the study. Twelve pa-
`tients with clinically definite MS were selected for this study.
`Disability was classified according ta the Expanded Disabil-
`ity Status Scale (EDSS) [21]. Ten patients had relapsing-
`remitting MS and 9 of these had mild disabiliry (EDSS
`= 3.5). The tenth patient with relapsing-remitting disease
`had an EDSSscore of 6.5 and required bilateral assistance to
`walk due co corticospinal tract involvement, but her other
`clinical
`findings were mild. Two patients had chronic-
`progressive disease;
`1
`started with a relapsing-remitting
`course, whereas the other (Patient 12) had a chronic-
`progressive course since the onsetof his iliness.
`
`Patient Evaluation
`Patients were imaged and examined monthly. Examination
`consisted of a standardized neurological examination. Pa-
`tients were raced using che functional systems scale and
`EDSS. Exacerbations were defined using a modification of
`the Schumackercriteria [22] and consisted of any new symp-
`tom or worsening of previous symptoms associated with sig-
`nificant changesin signslasting longer than 24 hours.
`
`MRI Scans
`imaging was performed monthly for 12 co 21 months in the
`12 patients. Reproducible head positioning from month to
`month was assured by placing one vitamin E capsule in che
`external ear canal and raping a second to the Jateral canchus
`of the eye. The canthal-mearal line between these capsules
`delineated the plane of each scan. A scout slice was per-
`formed at the start of each study to establish consistent head
`positioning. MRI scans were performed on a General Electric
`Signa 1.5T unic (General Electric, Milwaukee, WH) using a
`T2-weighted spin echo pulse sequence with an echo time
`(TE) of 80 msec, a repetition time (TR) of 2,000 msec, 2
`excitations, a 128 * 256 acquisition matrix, and 3 mm con-
`tiguous interleaved slices. Tl-weighted spin-echo (TR G00/
`TE 20) images of the brain were performed before and ap-
`proximately 5 minutes after Gd (Magnevist, 0.1 mmol/kg;
`Berlex Laboratories, Cedar Knolls, NJ} was administered,
`using 2 excitations, a 192 x 256 acquisition matrix, and
`5 mm contiguous slices. All studies were performed with
`a field of view of 24 cm.
`
`Image Evaluation
`MRIs were evaluated by at least 2 neurologists, and ques-
`tionable lesions were reviewed with a nevroradiologisr. T1-
`
`Page 2 of 10
`
`weighted, Gd-enhanced images were visually compared to
`images taken prior to administration of contrast. Most en-
`hancing lesions were easily recognized as areas of increased
`signal intensity in the white matter. Questionable smail areas
`of enhancementnear the cortical surface were excluded from
`the analysis. Lesions were numbered sequentially, and new
`enhancing lesions were defined as lesions that had not en-
`hanced the previous month. Reenhancement of lesions was
`noted in patients studied for more than 12 months. Because
`reenhancing lesions mayreflect areas of renewed breakdown
`of the blood-brain barrier, they have been considered new
`lesions.
`
`Statistical Analysis
`Inspection of the frequency of lesions indicated that the aum-
`ber oflesions varied from month to month in the same pa-
`tient. Because there was a suggestion of a cyclical trend in
`lesion frequency, new and roral enhanced lesion data were
`examined by fitting the data to Poisson regression models
`{23] with sinusoidal trends. The best fitting sinusoidal curve
`with a frequency becween 2 and 14 months was obtained and
`compared using a chi-square test to the dara firted to a model
`employing a constant mean, Lesions occurring randomly
`would have a best Ht with che model employing a constant
`mean. Such a comparison is particularly sensitive for de-
`tecting a pattern of fluctuations between high and low fre-
`quency. This analysis was done using Poisson regression in
`conjunction with an analytic technique [23] originally pro-
`posed for another application [24]. A p value of 0.01 was
`chosen as the cutoff for statistical significance to accountfor
`multiple comparisons inherent in fitting these models sepa-
`rately to each of rhe 10 parients.
`The data from the 10 patients with relapsing-remitting MS
`were used to calculace sample sizes for various trial designs.
`The sample sizes required to detect a 5096 reduction in le-
`ston frequency due to treatment (alpha = 0.05, power =
`0.8; two-tailed test} were computed for various parallel and
`crossover study designs using variance estimates obtained
`with repeated sampling techniques (the bootstrap analysis)
`{25, 26}. Sample sizes were computed using standard size
`calculations [27}.
`
`Results
`Characteristics of Gd-enbancing Lesions
`The clinical characteristics of the patients are shown in
`Table 1. These patients were studied with monthly
`MRIs,
`including Gd-enhanced images,
`for periods
`ranging from 12 to 21 months. A cotal of 197 MRIs
`were analyzed in this study.
`With the exception of Patient 12, numerous Gd-
`enhancing lesions were observed in each ofthe patients
`(see Table 1). The toral number of enhancing lesions
`was greater than the number of new enhancing lesions
`because some lesions persisted and were observed
`on more chan one sequential examination (data not
`shown), In the majority (689) of new lesions, en-
`hancement was not detected at the next monthly exam-
`ination,
`indicating that the duration of the enhance-
`ment was less than 2 months. This observation is
`
`McFarland et al: MRI Lesions in MS
`
`759
`
`Page 2 of 10
`
`

`

`Table 1, Clinical Parameters af Patients Studied by Serial Gadolinium-enbanced MRI
`
`Years
`Age
`from
`Months
`
`Patient
`(yr)
`Diagnosis
`Course
`Studied
`Start
`End
`Exacerbations
`Toral
`New
`
`EDSS
`
`Average No.
`Gd-enhancing
`Lesions
`
`1
`2
`3
`4
`5
`6
`7
`g
`9
`10
`iH
`12
`
`44
`29
`41
`28
`28
`4]
`38
`31
`38
`28
`43
`60
`
`2
`2
`5
`3
`2.5
`35
`16
`10
`2.5
`6
`9
`i?
`
`R/R
`R/R
`R/R
`R/R
`R/R
`R/R
`R/R-CP
`R/R
`R/R
`R/R
`R/R
`cP
`
`19
`19
`20
`19
`21
`20
`14
`14
`13
`12
`14
`12
`
`1.5
`2.0
`1.5
`1.5
`1.5
`3.5
`5.5
`1.5
`2.0
`6.5
`2.
`6.0
`
`L5
`2.0
`i5
`2.0
`1.5
`2.3
`6.0
`1.5
`2.5
`6.5
`2.0
`6.5
`
`0
`L
`1
`4
`1
`I
`0
`2
`3
`1
`1
`0
`
`3.4
`0.5
`1.6
`5.0
`3.3
`3.6
`1.8
`5.6
`0.9
`8.0
`3,2
`0.1
`
`2.2
`0.2
`1.1
`4.1
`2.4
`3.3
`L.1
`3.5
`0.7
`5.9
`2.1
`0.1
`
`R/R = relapsing-remitting, CP = chronic-progressive.
`
`consistent with previous reports [15, 18]. Twenty-
`eight percent of the lesions were seen on 2 concurrent
`examinations, whereas 59 persisted for 3 months.
`Noneofthelesions persisted for more than 4 months.
`In general, lesions persisting for 2 months or longer
`were observed in patients with a large number of new
`enhancing lesions (Patients 5, 6, 8, and 10). Reen-
`hancement of lesions chat were enhanced previously
`was observed in 5 patients. It is likely that reenhance-
`ment will be observed more frequently as patients are
`followed longer.
`The mean number of Gd-enhancing lesions per
`month varied among the 12 patients. Although 3 of
`the patients with relapsing-remitting disease (Patients
`2, 3, and 9) and both of the patents with chronic-
`progressive disease (Patients 7 and 12) had an average
`of 2 or fewer new lesions per month, 4 of the patients
`with relapsing-remicting disease (Patients 4, 6, 8, and
`10) had an average of 3 or more new lesions per
`month.
`
`Pattern of Lesion Occurrence
`As indicated, inspection of the frequencies of new en-
`hancing lesions indicated that the lesions were not oc-
`cutting at a constant rate but tended to occur in bursts
`of increased lesion frequency. Figure 1 illustrates the
`fluctuating number of Gd-enhancing lesions in Patient
`4. By inspection, the pattern of lesion frequency in this
`patient had a cyclical trend. A suggestion of a similar
`cyclical pattern in lesion frequency was also observed
`in the other patients. Consequently, the likelihood that
`the pattern of lesion occurrence was not random was
`assessed using Poisson regression models as described
`in Marerials and Methods. In 6 of the 10 patients with
`relapsing-remitting MS, the total and new lesion data
`
`fit a mode] employing a sinusoidal mean significantly
`better than a model using a constant mean (p < 0.01)
`(Fig 2). This finding indicates that the mean of the
`lesion frequency was not constant and that the lesions
`were not occurring with random frequency. Although
`not reaching statistical significance, a sinusoidal trend
`in lesion frequency was also observed in 3 of the re-
`maining 4 patients (p < 0.06, 0.12, 0.12). The Poisson
`regression mode] with sinusoidal trends was used only
`as a means to describe the fluctuating nacure of lesion
`frequency over short durations and to test for non-
`constancy in lesion frequency. The model was not in-
`tended as a definitive description of lesion occurrence.
`Using the fitced curves, the period between the peaks
`in lesion frequency varied considerably and ranged
`from 2,1 to 12 months. The mean period between
`peaks in the patients showing a significant fit to a sinu-
`soidal curve was 6.2 and 5.9 monthsforall 10 patients.
`
`Correlations Between Clinical Changes and
`Ga-enbancing Lesions
`the frequency of enhancing
`As reported previously,
`lesions seen on MRI did not necessarily parallel clinical
`changes. Most notable was Patient 12, who despite
`continued clinical progression had only | enhancing
`lesion during 10 months of study. Becausetheclinical
`course demonstrated by Patient 12 may represent a
`unique form of MS (i.e., primary chronic-progressive
`MS) {18, 28, 29], the findings from this patient were
`excluded from the subsequenceanalysis.
`A dissociation berween clinical change and enhanc-
`ing lesions in the cerebrum was observed in the 11
`remaining patients. All had new enhancing lesions,
`often numerous,
`that occurred without new symp-
`coms or abnormalities on neurological examination.
`
`760 Annals of Neurology Vol 32 Ne 6 December 1992
`
`Page 3 of 10
`
`Page 3 of 10
`
`

`

`
`
`Patient 4
`
`<>
`
`~——te—= Total Lesions
`scgeree
`Now Lesions
`
`12
`
`10
`
`a
`
`
`
`NumberofEnhancingLesions
`
`
`Qremisieieren
`
`
`0
`
`2
`
`4
`
`§
`
`8
`
`10
`
`12
`
`4
`
`i6
`
`168
`
`20
`
`Months
`
`
`
`Fig 1, (A) Plactuations in number of total and new Gd-
`enhancing lesions in Patient 4. (B) Tl-weighted postgadolin-
`dum MRI af Patient 4 at month 14. Four representative slices
`
`are shown demonstrating multiple enhancing lesrons. (C) T1-
`weighted postgadolininm MRI at month 15. Four representative
`slices showing reduction in number of enbancing lestons.
`
`McFarland er al: MRI Lesions in MS 76]
`
`Page 4 of 10
`
`Page 4 of 10
`
`

`

`Frequency = 2.1 mo.
`
`
`
`Month
`a a
`
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`ww
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`
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`WY
`Month
`
`%
`
`8
`
`8 2 22
`
`Patient 10
`
`Patient 14
`
`Frequency = 12,0 mo,
`p0.01
`
`2
`
`4
`
`a
`
`8
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`ec 2 «4
`
`«6
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`46
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`
`fk
`
`Frequency * 4.2 mo.
`p< 0.01
`
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`
`Patient 3
`
`Patient 4
`
`p «0.01
`
`Patient 6
`
`Patient 8
`
`6
`
`z
`
`4
`
`a
`
`8
`
`8
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`Month
`
`4
`
`8
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`
`22
`
`Frequency * T.5 mo.
`
`Frequency « 3.2 mo.
`p 0.01
`
`e
`kK
`a
`w
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`t
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`a
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`‘
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`Ww
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`
`Fig 2. The observed number of new lesions and the frequency of
`lesions derivedfrom the bert fitting Porsson regression model with
`Sinusoidal trends, (A) p < 0.01. (B} p > 0.02.
`
`For example, Patient 1, who had a mean of 2.2 new
`Gd-enhancing lesions per month, was clinically stable
`throughout the 19-month study period. Each of the
`remaining 10 patients had one or more exacerbations
`(see Table 1). The clinical
`findings associated with
`these exacerbations could not be explained by the toca-
`tion of the new enhancing lesions in the cerebrum and,
`iN MOSt instances, were consistent with involvement of
`the spinal cord or the brainstem.
`
`762 Annals of Neurology Vol 32 No 6 December 1992
`
`Page 5 of 10
`
`Page 5 of 10
`
`

`

`ttAA
`
`Patient 1
`
`Patient 2
`
`Frequancy » 4.9 mo,
`
`2
`
`6
`
`8 ww
`Month
`
`2022
`
`eagQ-werEsax*® o
`exsc-per£0&
`
`Patient 9
`
`Frequency « 4,0 mo,
`
`wy
`
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`
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`
`4
`
`6
`
`a
`
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`we
`
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`
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`
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`
`
`Frequancy © 6.3 mo.
`
`7
`6 20
`
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`
`
`
`22
`
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`
`6
`
`¢
`
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`
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`hs
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`Frequency = 6.6mo.|
`
`o
`
`2
`
`4
`
`3
`
`8
`
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`ww
`Month
`
`
`Fig 2 (continued)
`
`Trial Design Using Gd-enbancing Lesions as an
`Outcome Measure
`Althoughit is reasonable to consider using Gd-enhanc-
`ing lesions as an outcome measurement in therapeutic
`trials, the fluctuationsin lesion frequency noted herein
`indicate that there are potential difficulties with this
`approach. To explore the usefulness of the approach,
`we assessed the longicudinal MRI dara obtained in chis
`study using a statistical technique termed doetstrap anal-
`sis, which involves repeated random resampling of the
`dara. Using this technique, we calculated the required
`sample sizes for 2 trial designs: a parallel groups design
`and a crossover design. First, the sample sizes required
`to detect a 50% reduction in lesion frequency in a
`therapeutic trial using a parallel groups design was cal-
`culated (Table 2). The number of new lesions, in con-
`trast co che number of total lesions, was chosen as the
`most appropriate measure because an effective trear-
`ment would be more likely to stop new lesion develop-
`ment than to shorten the duration of lesions. The sam-
`ple size estimates for a parallel groups design were very
`high and decreased only slightly when the number of
`MRIs for each individual was increased. The large sarn-
`
`Page 6 of 10
`
`Table 2. Estimated Sample Sizes Requiredfor a Clinital Trial
`in MS Using a Parallel Groups Detign and New
`Gd-enhancing Lesions as the Outcome Meature
`
`No. Monthly MRIs
`
`
` per Subject Sample Size* No. MRIs
`
`
`
`1
`2
`3
`4
`5
`6
`
`165
`114
`192
`94
`90
`90
`
`330
`342
`408
`470
`540
`630
`
`*Sample size required for each of the two groups (a treatment and a
`placebo group) to detece a $096 reduction in lesions/month with a
`power of 0.8 and an alpha = 0.05 (two-tail test).
`
`ple sizes were due largely to the variabiliry among pa-
`tients.
`Because of the large sample sizes required for a par-
`allel groups design, a crossover study design was next
`considered. The boorstrap analysis was used to com-
`pute the sample sizes required to detect a 5096 reduc-
`tion in the number of enhancing lesions due to treat-
`
`McFarland et al: MRI Lesions in MS
`
`763
`
`Page 6 of 10
`
`

`

`
`
`DESIGNS FOR CROSS-OVER STUDY
`
`Baseline
`
`Finding
`
`|
`
`Treatment
`
`Treatment
`Crossover
`Treatment
`Washout
`
`
`
`
`Randomization
`Treatment
`Baseline
`me
`
`Finding
`
`Placebo
`
`Selection
`
`Placebo
`
`a)
`
`b)
`
`c)
`
`Fig 3. Crossover designs using Gd-enbanced MRI lesions as the
`primary outcome variable.
`
`mentfor 3 crossover design variations (Fig 3; Table 3).
`Thefirst 2 crossover designs are similar because both
`compare the frequency of lesions in the treatment ver-
`sus the nontreatment arm. In the open crossover de-
`sign (see Fig 3A), the sample sizes are based on the
`assumption thar patients with relapsing-remitting dis-
`ease would be entered ineo the trial regardless oflesion
`frequency. This design could be easily modifed, how-
`ever, to select for treatment only patients with a prede-
`termined lesion frequency.
`Disadvantages of che open crossover design include
`lack of randomization, difficulty in assessing the MRIs
`in a blinded manner, and a potential bias in the treat-
`ment effect because treatment always follows the non-
`weatment arm.
`In the second crossover design (see
`Fig 3B), patients would be randomized at enery into
`treatment and placebo groups with subsequent cross-
`over. This approach eliminates the disadvantages noted
`with the open crossover design. To avoid a carryover
`effect of the experimental creatment, a 3-month wash-
`
`out period was included in the design. Because an ad-
`ditional MRI would be needed after the washout pe-
`riod to identify new lesions, the number of MRIs was
`greater than in the open crossover design.
`The third crossover design (see Fig 3C) allows for
`the selection of patients with a particular esion fre-
`quency before randomization. This trial design incor-
`porates elements of both parallel groups and crossover
`designs because the outcome analysis would compare
`the changein lesion frequency in the treatment group
`with that of the placebo group. Consequently, rhe sam-
`ple size would be greater than twice that for the open
`crossover design (see Table 3) bur less than chat re-
`quired for the parallel groups design. Because the fluc-
`tuationsin lesion frequency were usually 3 to 7 months
`in duration, an initial assessment period of less than 4
`months was unlikely co provide an accurate estimate
`of the lesion frequency. Thus, sample sizes for shorter
`periods were not calculated.
`
`Discussion
`Although there has been increasing interest in using
`MRI as an outcome measure in assessing efficacy of
`experimental treatments in patients with MS, the ap-
`propriate design of trials incorporating MRI measure-
`ments of disease activicy has only begun to be con-
`sidered [1, 20}. Various MRI parameters,
`including
`new lesions as demonstrated on T2-weighted images,
`changes in the amount (area or volume) of diseased
`tissue identified by increased T2 signal or lesions that
`enhance following administration of Gd could be used
`as aN outcome measure. Because breakdown in the
`blood-brain barrier as reflected by Gd enhancement
`has been shown to usually represent che initial stage in
`lesion development {15} and because Gd-enhancing
`lesions are easily identified, Gd-enhancing lesions rep-
`resent a reasonable choice for monitoring disease activ-
`ity. Before any MRI parameters can be used to moni-
`tor MS, however, the natural history of that parameter
`must be established in patients without rreatment. The
`
`Table 3, Estimated Sample Sizes Requiredfor a Clinical Trial Using
`Crossover Designs and New Gd-enhancing Lesions as the Outcome Measure
`
`Design B
`
`Design C
`
`Design A
`
`No. MRIs
`per Pacient
`
`per Study Arm
`Sample Size*
`No. MRIs
`Sample Size
`No. MRIs*
`Sample Size‘
`No. MRIs
`1
`55
`165
`50
`200
`2
`27
`135
`34
`204
`an
`see
`3
`22
`154
`28
`224
`423
`47
`4
`18
`162
`20
`200
`495
`45
`5
`1?
`187
`17
`204
`
`
`12 156 12 168 316 403
`
`
`
`
`
`*Padents not preselected for lesion frequency.
`‘An additional MRI is required ar che beginning of each arm to identify newlesions.
`‘Patients with 2 or more new enhancing lesions/month. Sample size and number of MRIs does not include patients screened and excluded.
`
`764 Annals of Neurology Vol 32. No 6 December 1992
`
`Page 7 of 10
`
`Page 7 of 10
`
`

`

`longitudinal study of Gd-enhanced MRI le-
`present
`sions was underraken to define the natural history of
`these abnormalities, particularly during the early, re-
`lapsing-remitting phase and, based on this longim-
`dinal data,
`to establish how Gd-enhancing lesions
`could be bese used as an effecrive outcome measure in
`clinical treatment trials.
`The findings described herein confirm previous MRI
`studies [9, 10}, which demonstrated thac MS can be a
`progressive disease even during the early, relapsing-
`remitting phase and that focal disruptions in the blood-
`brain barrier are readily observed during periods of
`clinical remission {17—-19]. Importanely, che tongiradi-
`nal study of the patients in this study showed that the
`frequency of Gd-enhancing lesions is not constant. In
`all patients, the number of Gd-enhancing lesions ffuc-
`tuated; in some patients 4 striking variation in lesion
`frequency was noted to occur, with a suggestion of
`regularicy, The lesion frequency did not appear to oc-
`cur randomly because a better fit of the data was dem-
`onstrated employing a statistical model using a sinusoi-
`dal mean function than with one using a constant mean
`function. We believe it is unlikely that the fluccuations
`in lesion frequency in individual patients will continue
`to occur with a constant periodicity and do not suggest
`that
`the Poisson regression mode! with sinusoidal
`trends provides a definitive description of lesion occur-
`rence over the duration of disease. With extended fol-
`low-up,
`the patrern of lesion frequency in individual
`patients may change and bursts of lesions may occur
`either more or less frequently. However, the cyclical
`trend in lesion frequency represents an important con-
`sideration in the design of clinical trials using Gd-en-
`hancing lesions as an outcome measure. Short periods
`of study could easily fail to identify the crue mean in
`lesion frequency and could lead to incorrect conclu-
`sions. Although additional longimidinal patient data are
`needed, the present findings indicaté that study periods
`of 6 months or longer are probably needed to obrain
`a reasonable measure of the frequency of lesions.
`We examined 2 general approaches for the design
`of a clinical trial using Gd-enhanced lesions as the our-
`come measure and calculated the sample sizes and
`number of MRIs required for the various designs. The
`first approach examined,
`the parallel groups design,
`would require prohibitively large sample sizes and
`MRI resources. Only a small reduction in the sample
`size occurred when the number of MRIs per patient
`was increased, reflecting the large variability among pa-
`tients. Similar sample sizes were recently reported by
`other investigators using data obtained from 17 pa-
`tients with either relapsing-remitting or secondary pro-
`gressive MS followed for 6 months with monthly MRIs
`{20}. On the basis of the frequency of Gd-enhancing
`lesions, 150 patients would be required for a G6-month
`parallel study.
`
`Page 8 of 10
`
`To minimize the effect of variability ammong patients,
`we next examined the use of 3 variations of a crossover
`design. The first employed an initial series of MRIs to
`establish the baseline frequency of enhancing lesions
`in each patient, followed by crossover to a treatment
`group. Not unexpectedly, the required sample sizes
`for this crossover design were substantially smaller
`than for the parallel groups design, and the required
`sample sizes declined as the aumber of MRIs in-
`creased. The reduction in sample size seen when the
`number of monthly MRIs increased from 5 to 6 in
`each arm of the study reflected the frequency of the
`bursts of lesions, which was, on average, approximately
`6 months.
`Disadvantages of the open crossover design include
`lack of randomization and difficuley in assessing the
`Mls in a blinded fashion. A solution would be to
`randomize patients at entry and to incorporate a wash-
`out period at the time ofcrossover to avoid a treatment
`carryover effect. The duration of the washout period
`could be vatied depending on the nature of the treat-
`ment. The randomized crossover design would require
`sample sizes similar to those for the open crossover
`design. Generally, sample sizes are insensitive to small
`changes in the washout period. When the carryover
`effect of a trearment cannot be assessed,
`the open
`crossover design would be preferable ro design 2.
`A concern regarding the randomized crossover de-
`sign is that patients with low frequencies of enhancing
`lesions (e.g., Patient 2, who had fewer than 1 new
`lesion per month) would be included: in fact, the sam-
`ple sizes are calculated on chat basis. The relationship
`berween !esion frequency and eventual disability is un-
`known. However, a recent study demonstrated that
`patients with benign MS have fewer enhancing lesions
`than most patients with relapsing-remitting MS [30].
`Und che relationship berween lesion frequency and
`eventual disability is betrer understood, it would seem
`bese to select patients with frequent lesions for thera-
`peutic trials, particularly if the crreaement has potential
`risks. A third possibilicy (see Fig 3C) represents a
`blending of crossover and parallel groups design. This
`design uses an initial evaluation phase co determine
`lesion frequency and a subsequent randomization to
`treatment and placebo groups. Unfortunately, a sample
`size of 31 patients and more than 400 MRIs would
`be required to conduct this trial. Although chis design
`would seem optimal for treatments other than those
`with only minimal risk,
`the required MRI resources
`are prohibitive unless MRI units dedicated to MS re-
`search are available or che design is used in multicen-
`ter studies. Consequently, the open crossover design,
`which allows selection of patients with sufficient lesion
`frequencies, followed by an open crossover to treat-
`ment represents the sécond choice for testing treat-
`ments with potential risks.
`
`McFarland et al: MRI Lesions in MS
`
`765
`
`Page 8 of 10
`
`

`

`The findings in this and other studies indicate rhat
`MRI can provide a means for assessing one aspect
`of disease activity in patients with early,
`relapsing-
`remitting MS. The results also indicate that monitoring
`lesions by MRI can be an effective outcome measure
`In clinical trials in MS. Evaluation of other MRI param-
`eters, such as the change in che volume of white matter
`lesions with increased signal intensity on T2-weighted
`MRI, also may be helpful in monitoring outcome of
`therapy. The relationship berween frequency of MRI
`lesions as well as other MRI measurements of disease
`and clinical disabilicy awaits longer follow-up of pa-
`tients such as those in this study. Consequently, we
`do not propose that MRI parameters become the sole
`outcome measures in examining cherapeutic effects.
`We do propose that MRI assessment represents a
`means for accurately selecting potentially effective
`treatments that can then be evaluated in more costly
`phase-III clinical trials. This approach will allow the
`diminishing resources available for clinical studies to
`be used with the greatest efficiency.
`
`‘This work was performed in part at the In Vivo Nuclear Magnetic
`Resonance Research Center of the National Jnstirures of Healch,
`Bethesda, MD.
`
`We thank Ms Susan Inscce and Ms Jeanette Black for their excellent
`technical magnetic resonance imaging skills chroughout this study.
`We thank Mrs Irene Naveau for her excellent nursing support during
`the study. We chank ehe patiencs for their cooperation in this seudy.
`
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