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Cumulative effect of a weekly low dose of interferon beta 1a on standard and triple dose contrast-enhanced MRI from multiple sclerosis patients
Journal of the Neurological Sciences 171 (1999) 130–134 www.elsevier.com / locate / jns
Cumulative effect of a weekly low dose of interferon beta 1a on standard and triple dose contrast-enhanced MRI from multiple sclerosis patients Marco Rovaris a , Ruggero Capra b , Vittorio Martinelli c , Claudio Gasperini d , Francesca Prandini e , d c a, Carlo Pozzilli , Giancarlo Comi , Massimo Filippi * a
Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy b Department of Neurology, Spedali Civili, University of Brescia, Brescia, Italy c Clinical Trials Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy d Department of Neurology, Universita` ‘ La Sapienza’, Rome, Italy e Department of Neuroradiology, Spedali Civili, University of Brescia, Brescia, Italy Received 26 May 1999; received in revised form 8 August 1999; accepted 6 October 1999
Abstract In patients with multiple sclerosis (MS), we assessed the short- and long-term effects of a weekly low dose of recombinant human interferon beta 1a (rh-IFN beta 1a) on the development of new magnetic resonance imaging (MRI) lesions enhancing at different gadolinium-DTPA (Gd) doses. Every 4 weeks, standard dose (SD) (0.1 mmol / kg of Gd) and triple dose (TD) (0.3 mmol / kg of Gd) Gd-enhanced brain MRI scans were obtained from 18 patients with relapsing–remitting MS for 3 months before treatment, 4 months after treatment initiation (treatment period [TP] I) and 4 months after 1 year of treatment (TP II) with 44 mg of rh-IFN beta 1a subcutaneously, once a week. The mean numbers of new enhancing lesions / patient / month were 1.4 (baseline), 1.1 (TP I) and 0.7 (TP II) on SD scans and 2.4 (baseline), 1.3 (TP I) and 0.8 (TP II) on TD scans. On average, treatment decreased the rate of new enhancing lesion appearance by 24% (SD scans) and 45% (TD scans) during TP I and by 52% (SD scans) and 66% (TD scans) during TP II. This study indicates that the effect of 44 mg of rh-IFN beta 1a given once a week on MRI-monitored MS activity increases over time. It also suggests that TD MRI is useful in detecting early treatment effect, that would otherwise be missed. 1999 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Interferon beta 1a; Magnetic resonance imaging; Gadolinium enhancement; Standard dose; Triple dose
1. Introduction In patients with relapsing–remitting (RR) multiple sclerosis (MS), treatment with interferon (IFN) beta 1b [1–4] or IFN beta 1a [5–8] results in a significant reduction in the frequency of enhancing lesions on serial T1-weighted magnetic resonance imaging (MRI) obtained after injecting a standard dose (SD) of gadolinium-DTPA (Gd). Several studies have suggested that the effect of IFN *Corresponding author. Tel.: 139-02-2643-3033; fax: 139-02-26433031. E-mail address: [email protected] (M. Filippi)
beta 1a on clinical and MRI activity is dose-related [6,8,9] and that there might even be a paradoxical increase in immunological and MRI activity during the early treatment phases [10]. In these studies, patients were being treated with 30 mg of IFN beta 1a given intramuscularly once a week [5,7,10] or with 22 or 44 mg of IFN beta 1a given subcutaneously three times a week (e.g. with total weekly doses of 66 and 132 mg, respectively) [6,8]. The use of a triple dose (TD) of Gd is the most effective MRI strategy to increase the yield of active MS lesions [11]. Statistical simulations suggest that this strategy reduces the number of scans needed to detect treatment effects in MS clinical trials [11]. TD MRI should, there-
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00265-8
M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
fore, also increase the ability to detect earlier or more subtle treatment effects on MRI activity. With the present baseline versus treatment study, we aimed at investigating the short- and long-term effects of a low dose (e.g. 44 mg) of IFN beta 1a given subcutaneously once a week on the appearance of new enhancing lesions on monthly SD and TD MRI scans from patients with MS.
2. Materials and methods
2.1. Patients Eighteen patients (nine women and nine men) with clinically definite RRMS [12] were studied. At study entry, their mean age was 31 years (range523–43 years), mean disease duration was 5 years (range52–12 years) and median Expanded Disability Status Scale (EDSS) [13] was 1.5 (range51.0–3.5). None of the patients were taking immunosuppressive or immunomodulating treatments for at least 12 months prior to entry to the study. In addition, they had neither relapses nor steroid treatment during the preceding 3 months. Local ethical committee approval at each center and written informed consent from all the patients were obtained before study initiation.
2.2. Study design MRI examinations were performed every 28 (65) days on 12 separate occasions (four at baseline and eight during treatment). Treatment with rh-IFN beta 1a was initiated the day after the fourth MRI session; four sessions were then consecutively performed at the beginning of treatment (treatment period — TP I) and four after 12 months of treatment (TP II). In case of documented clinical relapse, treatment with intravenous methylprednisolone (1 g per day for 3 consecutive days) was allowed. In cases of steroid treatment, MRI was always scheduled either before the start of the treatment or 10 days after the end. No other immunosuppressive or immunomodulating treatment was allowed during the study.
2.3. Treatment Treatment consisted of subcutaneous administration of 44 mg of rh-IFN beta 1a (Rebif , Ares-Serono, Geneva, Switzerland), once a week.
2.4. MRI Scanners operating at 1.5 T were used at all participating centers. On each scanning occasion, the MRI examination was split into two sessions, separated by a 12–24-h interval. During the first session, the following scans were performed: (a) dual echo conventional spin-echo (CSE) (TR52000–2400, TE530–50 / 80–100, number of
131
acquisitions51); (b) pre-contrast T1-weighted CSE (TR5 560–768, TE514–15, number of acquisitions52); (c) post-contrast T1-weighted scans, with the same acquisition parameters as pre-contrast ones, 5 min after the injection of Gd. During the second session, the following were performed with the same parameters as above: (a) pre-contrast T1-weighted scan; (b) post-contrast T1-weighted scans 5 min after the Gd injection. The dose of Gd was randomized, so that in the first session the patient received either an SD (0.1 mmol / kg) or TD (0.3 mmol / kg) of Gd, with the opposite dose given during the second session. For all the scans, 24 contiguous interleaved axial slices were acquired with 5 mm slice thickness, 192–2563256 raw data matrix and 220–250 mm square field-of-view. For follow-up scans, the scan planes were carefully repositioned according to published guidelines [14].
2.5. Image review The numbers of total and new enhancing lesions were assessed by two observers from enhanced T1-weighted scans, in a manner described in previously published studies [11,15].
2.6. Statistical analysis The effect of Gd dose and treatment on the number of new enhancing lesions was evaluated by a Poisson regression model with patients considered as blocks. The number of new enhancing lesions, rather than the number of total enhancing lesions, was chosen as the primary endpoint, because (a) the numbers of new enhancing lesions at each time-point are independent measures and (b) an effective treatment is more likely to stop new enhancing lesion development than to shorten the duration of enhancement.
3. Results During the baseline period, five clinical relapses were documented in five patients; during TP I, seven clinical relapses were documented in six patients, while, during TP II, eight clinical relapses were documented in five patients. Four relapses during the baseline period, six during TP I and six during TP II were treated. At the end of TP II, median patient EDSS score was 1.5 (range50.0–3.5; P5 n.s. versus baseline). The total numbers of enhancing lesions were 145 on 47 / 72 SD scans obtained during the 3-month baseline period, 126 on 46 / 72 SD scans obtained during the 4month TP I, 124 on 34 / 72 SD scans obtained during the 4-month TP II, 278 on 54 / 72 TD scans obtained during the baseline period, 192 on 48 / 72 TD scans obtained during TP I and 166 on 37 / 72 SD scans obtained during TP II. One patient had no enhancing lesions on both SD and TD
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M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
scans during the baseline period. This was the case for three patients during TP I and for six patients during TP II. On SD scans, 78 new enhancing lesions were detected over the 3-month baseline period, 79 over the 4-month TP I and 67 over the 4-month TP II. On TD scans, 132 new enhancing lesions were detected over the baseline period, 96 over TP I and 76 over TP II. Fig. 1 shows the mean numbers of new enhancing lesions per patient per month on SD and TD scans during baseline period, TP I and TP II. In Fig. 2, the numbers of new enhancing lesions per scan from a representative patient are shown. In Table 1, the estimated frequencies of appearance of new enhancing lesion in each of the six experimental conditions are presented. On average, TD detected 69% more new enhancing lesions than SD during the baseline period (95% confidence interval (CI): 128 / 1123%, P5 0.002), 22% more during TP I (95% CI: 210 / 163%, P5n.s.) and 23% more during TP II (95% CI: 221 / 1 92%, P5n.s.). In comparison with the baseline period, the average decrease in the rate of new enhancing lesion appearance was 224% on SD scans (95% CI: 244 / 14%) and 245% on TD scans (95% CI: 258 / 229%) during TP I, 252% on SD scans (95% CI: 268 / 228%) and 266% on TD scans (95% CI: 276 / 251%) during TP II. The effect of treatment on the frequency of new enhancing lesions significantly increased over time on both SD (P5 0.0002) and TD (P,0.0001) scans. The mean number of
new enhancing lesions / patient / month was significantly different during baseline and TP I on TD (P,0.001) but not on SD scans, while it was significantly lower during TP II than during TP I and baseline on both SD (P50.02 and ,0.0001, respectively) and TD (P50.01 and ,0.0001, respectively) scans.
4. Discussion Our data indicate that the early effect on new enhancing MS lesions of 44 mg of rh-IFN beta 1a administered once a week is weaker than that obtained at higher doses and with more frequent administrations [6,8,9]. However, they also show that this effect becomes more evident after 1 year of treatment. The early treatment effect is significantly more pronounced on lesions enhancing only after TD, whose number is already decreased by 50% during TP I. A recent double-blind, placebo-controlled study [8] with two doses of rh-IFN beta 1a (e.g. 22 and 44 mg three times a week) reported an 80–90% reduction in the frequency of active lesions on monthly scans obtained during the first 9 months of treatment. In the same study, the frequencies of patients with inactive scans were 31% and 41% in the two treatment arms. Our results suggest that a lower dose of rh-IFN beta 1a can achieve a significant effect on MRI activity only after a relatively long period of treatment,
Fig. 1. Bar chart of the mean numbers of new enhancing lesions per patient per month on SD (grey bars) and TD (black bars) MRI scans from 18 MS patients, during baseline period, TP I and TP II. For further details, see text.
M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
133
Fig. 2. Bar chart of the numbers of new enhancing lesions per month on SD (grey bars) and TD (black bars) MRI scans from patient [14, during baseline period, TP I and TP II. For further details, see text.
although this effect becomes of the same magnitude as that of higher doses in terms of frequency of inactive patients (33% during TP II in our study). This may also explain why previous reports failed to demonstrate a significant effect of low doses of IFN beta 1a on clinical and MRI MS activity [10], probably owing to the short follow-up duration. TD MRI enabled us to detect the effect of treatment with 44 mg of rh-IFN beta 1a earlier than SD MRI, thus confirming the potential role of the former technique for MRI monitoring of phase II trials [11]. We also found a discrepancy between the treatment efficacy in reducing enhancing lesion frequency and the persistance of clinical relapses. This might be due to the relatively short followup period and the small sample size studied, which might
Table 1 Mean numbers (95% confidence intervals) of new enhancing lesions per patient per month on SD and TD scans during the baseline and the treatment periods, estimated using a Poisson regression model
Baseline period Treatment period I Treatment period II
SD scans
TD scans
1.44 (1.15–1.80) 1.09 (0.88–1.37) 0.68 (0.49–0.96)
2.44 (2.06–2.90) 1.33 (1.09–1.63) 0.84 (0.63–1.14)
have prevented the detection of any treatment effect on MS clinical activity. This confirms that results from MRImonitored preliminary trials have to be interpreted cautiously and need to be confirmed by phase III studies with primary clinical endpoints. The use of TD MRI might, however, significantly reduce the sample size needed and shorten the follow-up periods for conducting exploratory treatment trials [11], thus speeding up the screening of new potential treatments for MS. It is known that MS lesions enhancing only after TD represent a subgroup with less severe tissue damage and milder blood–brain barrier (BBB) disruption than those enhancing after SD [16]. The major treatment effect on MS lesions enhancing only after TD may, therefore, suggest that the efficacy of low doses of IFN is almost immediate in restoring less severe BBB damages, while it takes a longer time to exert a more effective anti-inflammatory activity. This is confirmed by a recent baseline versus treatment study from Kita et al. [17]. Low weekly doses (e.g. 30 mg) of IFN beta 1a significantly reduced the number of newly-formed Gd-enhancing lesions over 6 months after treatment initiation, whilst the severity of tissue disruption within new lesions and normal-appearing white matter (as assessed by means of quantitative MRI measures) was not significantly different between baseline and treatment periods, thus also suggesting that low doses of IFN may first act by preventing MS lesion formation in its earlier stages.
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M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
Acknowledgements The recombinant human interferon beta-1a (REBIF ) was supplied to us at no cost by Serono Pharma (Rome, Italy). The study was supported by the Associazione Italiana Sclerosi Multipla (AISM). We thank Dr Maria Pia Sormani for her help in data statistical analysis.
References [1] Paty DW, Li DKB, UBC MS / MRI Study Group, IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing– remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:662–7. [2] Stone LA, Frank JA, Albert PS et al. The effect of interferon-beta on blood–brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing–remitting multiple sclerosis. Ann Neurol 1995;37:611–9. [3] Stone LA, Frank JA, Albert PS et al. Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure. Neurology 1997;49:862–9. [4] Calabresi P, Stone LA, Bash CN, Frank JA, McFarland HF. Interferon beta results in immediate reduction of contrast-enhanced MRI lesions in multiple sclerosis patients followed by weekly MRI. Neurology 1997;48:1446–8. [5] Jacobs DL, Cookfair DL, Rudick RA et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285–94. [6] Pozzilli C, Bastianello S, Koudriavtseva T et al. Magnetic resonance imaging changes with recombinant human interferon beta-1a: a short term study in relapsing–remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;61:251–8.
[7] Simon JH, Jacobs LD, Campion M et al. Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. Ann Neurol 1998;43:79–87. [8] PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing–remitting multiple sclerosis. Lancet 1998;352:1498–504. [9] Blumhardt LD. Interferon beta-1a in relapsing–remitting multiple sclerosis: a meta-analysis. Neurology 1999;52(Suppl 2):A498, Abstract. [10] Rudge P, Miller D, Crimlisk H, Thorpe J. Does interferon beta cause initial exacerbation of multiple sclerosis? Lancet 1995;345:580. [11] Filippi M, Rovaris M, Capra R et al. A multi-centre longitudinal study comparing the sensitivity of monthly MRI after standard and triple dose gadolinium-DTPA for monitoring disease activity in multiple sclerosis. Implications for phase II clinical trials. Brain 1998;121:2011–20. [12] the National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis, Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996;46:907–11. [13] Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444– 52. [14] Miller DH, Barkhof F, Berry I, Kappos L, Scotti G, Thompson AJ. Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. J Neurol Neurosurg Psychiatry 1991;54:683–8. [15] Barkhof F, Filippi M, van Waesberghe JH et al. Interobserver variation in reporting gadolinium-enhanced MS lesions: consensus rules and effect of training. Neurology 1997;49:1682–8. [16] Filippi M, Rocca MA, Rizzo G et al. Magnetization transfer ratios in multiple sclerosis lesions enhancing after different doses of gadolinium. Neurology 1998;50:1289–93. [17] Kita M, Goodkin DE, Rooney WD et al. Quantitative MR measures in new MS lesions and NAWM before and during interferon beta 1a. Neurology 1999;52(Suppl 2):A496, Abstract.
Cumulative effect of a weekly low dose of interferon beta 1a on standard and triple dose contrast-enhanced MRI from multiple sclerosis patients Marco Rovaris a , Ruggero Capra b , Vittorio Martinelli c , Claudio Gasperini d , Francesca Prandini e , d c a, Carlo Pozzilli , Giancarlo Comi , Massimo Filippi * a
Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy b Department of Neurology, Spedali Civili, University of Brescia, Brescia, Italy c Clinical Trials Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy d Department of Neurology, Universita` ‘ La Sapienza’, Rome, Italy e Department of Neuroradiology, Spedali Civili, University of Brescia, Brescia, Italy Received 26 May 1999; received in revised form 8 August 1999; accepted 6 October 1999
Abstract In patients with multiple sclerosis (MS), we assessed the short- and long-term effects of a weekly low dose of recombinant human interferon beta 1a (rh-IFN beta 1a) on the development of new magnetic resonance imaging (MRI) lesions enhancing at different gadolinium-DTPA (Gd) doses. Every 4 weeks, standard dose (SD) (0.1 mmol / kg of Gd) and triple dose (TD) (0.3 mmol / kg of Gd) Gd-enhanced brain MRI scans were obtained from 18 patients with relapsing–remitting MS for 3 months before treatment, 4 months after treatment initiation (treatment period [TP] I) and 4 months after 1 year of treatment (TP II) with 44 mg of rh-IFN beta 1a subcutaneously, once a week. The mean numbers of new enhancing lesions / patient / month were 1.4 (baseline), 1.1 (TP I) and 0.7 (TP II) on SD scans and 2.4 (baseline), 1.3 (TP I) and 0.8 (TP II) on TD scans. On average, treatment decreased the rate of new enhancing lesion appearance by 24% (SD scans) and 45% (TD scans) during TP I and by 52% (SD scans) and 66% (TD scans) during TP II. This study indicates that the effect of 44 mg of rh-IFN beta 1a given once a week on MRI-monitored MS activity increases over time. It also suggests that TD MRI is useful in detecting early treatment effect, that would otherwise be missed. 1999 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Interferon beta 1a; Magnetic resonance imaging; Gadolinium enhancement; Standard dose; Triple dose
1. Introduction In patients with relapsing–remitting (RR) multiple sclerosis (MS), treatment with interferon (IFN) beta 1b [1–4] or IFN beta 1a [5–8] results in a significant reduction in the frequency of enhancing lesions on serial T1-weighted magnetic resonance imaging (MRI) obtained after injecting a standard dose (SD) of gadolinium-DTPA (Gd). Several studies have suggested that the effect of IFN *Corresponding author. Tel.: 139-02-2643-3033; fax: 139-02-26433031. E-mail address: [email protected] (M. Filippi)
beta 1a on clinical and MRI activity is dose-related [6,8,9] and that there might even be a paradoxical increase in immunological and MRI activity during the early treatment phases [10]. In these studies, patients were being treated with 30 mg of IFN beta 1a given intramuscularly once a week [5,7,10] or with 22 or 44 mg of IFN beta 1a given subcutaneously three times a week (e.g. with total weekly doses of 66 and 132 mg, respectively) [6,8]. The use of a triple dose (TD) of Gd is the most effective MRI strategy to increase the yield of active MS lesions [11]. Statistical simulations suggest that this strategy reduces the number of scans needed to detect treatment effects in MS clinical trials [11]. TD MRI should, there-
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00265-8
M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
fore, also increase the ability to detect earlier or more subtle treatment effects on MRI activity. With the present baseline versus treatment study, we aimed at investigating the short- and long-term effects of a low dose (e.g. 44 mg) of IFN beta 1a given subcutaneously once a week on the appearance of new enhancing lesions on monthly SD and TD MRI scans from patients with MS.
2. Materials and methods
2.1. Patients Eighteen patients (nine women and nine men) with clinically definite RRMS [12] were studied. At study entry, their mean age was 31 years (range523–43 years), mean disease duration was 5 years (range52–12 years) and median Expanded Disability Status Scale (EDSS) [13] was 1.5 (range51.0–3.5). None of the patients were taking immunosuppressive or immunomodulating treatments for at least 12 months prior to entry to the study. In addition, they had neither relapses nor steroid treatment during the preceding 3 months. Local ethical committee approval at each center and written informed consent from all the patients were obtained before study initiation.
2.2. Study design MRI examinations were performed every 28 (65) days on 12 separate occasions (four at baseline and eight during treatment). Treatment with rh-IFN beta 1a was initiated the day after the fourth MRI session; four sessions were then consecutively performed at the beginning of treatment (treatment period — TP I) and four after 12 months of treatment (TP II). In case of documented clinical relapse, treatment with intravenous methylprednisolone (1 g per day for 3 consecutive days) was allowed. In cases of steroid treatment, MRI was always scheduled either before the start of the treatment or 10 days after the end. No other immunosuppressive or immunomodulating treatment was allowed during the study.
2.3. Treatment Treatment consisted of subcutaneous administration of 44 mg of rh-IFN beta 1a (Rebif , Ares-Serono, Geneva, Switzerland), once a week.
2.4. MRI Scanners operating at 1.5 T were used at all participating centers. On each scanning occasion, the MRI examination was split into two sessions, separated by a 12–24-h interval. During the first session, the following scans were performed: (a) dual echo conventional spin-echo (CSE) (TR52000–2400, TE530–50 / 80–100, number of
131
acquisitions51); (b) pre-contrast T1-weighted CSE (TR5 560–768, TE514–15, number of acquisitions52); (c) post-contrast T1-weighted scans, with the same acquisition parameters as pre-contrast ones, 5 min after the injection of Gd. During the second session, the following were performed with the same parameters as above: (a) pre-contrast T1-weighted scan; (b) post-contrast T1-weighted scans 5 min after the Gd injection. The dose of Gd was randomized, so that in the first session the patient received either an SD (0.1 mmol / kg) or TD (0.3 mmol / kg) of Gd, with the opposite dose given during the second session. For all the scans, 24 contiguous interleaved axial slices were acquired with 5 mm slice thickness, 192–2563256 raw data matrix and 220–250 mm square field-of-view. For follow-up scans, the scan planes were carefully repositioned according to published guidelines [14].
2.5. Image review The numbers of total and new enhancing lesions were assessed by two observers from enhanced T1-weighted scans, in a manner described in previously published studies [11,15].
2.6. Statistical analysis The effect of Gd dose and treatment on the number of new enhancing lesions was evaluated by a Poisson regression model with patients considered as blocks. The number of new enhancing lesions, rather than the number of total enhancing lesions, was chosen as the primary endpoint, because (a) the numbers of new enhancing lesions at each time-point are independent measures and (b) an effective treatment is more likely to stop new enhancing lesion development than to shorten the duration of enhancement.
3. Results During the baseline period, five clinical relapses were documented in five patients; during TP I, seven clinical relapses were documented in six patients, while, during TP II, eight clinical relapses were documented in five patients. Four relapses during the baseline period, six during TP I and six during TP II were treated. At the end of TP II, median patient EDSS score was 1.5 (range50.0–3.5; P5 n.s. versus baseline). The total numbers of enhancing lesions were 145 on 47 / 72 SD scans obtained during the 3-month baseline period, 126 on 46 / 72 SD scans obtained during the 4month TP I, 124 on 34 / 72 SD scans obtained during the 4-month TP II, 278 on 54 / 72 TD scans obtained during the baseline period, 192 on 48 / 72 TD scans obtained during TP I and 166 on 37 / 72 SD scans obtained during TP II. One patient had no enhancing lesions on both SD and TD
132
M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
scans during the baseline period. This was the case for three patients during TP I and for six patients during TP II. On SD scans, 78 new enhancing lesions were detected over the 3-month baseline period, 79 over the 4-month TP I and 67 over the 4-month TP II. On TD scans, 132 new enhancing lesions were detected over the baseline period, 96 over TP I and 76 over TP II. Fig. 1 shows the mean numbers of new enhancing lesions per patient per month on SD and TD scans during baseline period, TP I and TP II. In Fig. 2, the numbers of new enhancing lesions per scan from a representative patient are shown. In Table 1, the estimated frequencies of appearance of new enhancing lesion in each of the six experimental conditions are presented. On average, TD detected 69% more new enhancing lesions than SD during the baseline period (95% confidence interval (CI): 128 / 1123%, P5 0.002), 22% more during TP I (95% CI: 210 / 163%, P5n.s.) and 23% more during TP II (95% CI: 221 / 1 92%, P5n.s.). In comparison with the baseline period, the average decrease in the rate of new enhancing lesion appearance was 224% on SD scans (95% CI: 244 / 14%) and 245% on TD scans (95% CI: 258 / 229%) during TP I, 252% on SD scans (95% CI: 268 / 228%) and 266% on TD scans (95% CI: 276 / 251%) during TP II. The effect of treatment on the frequency of new enhancing lesions significantly increased over time on both SD (P5 0.0002) and TD (P,0.0001) scans. The mean number of
new enhancing lesions / patient / month was significantly different during baseline and TP I on TD (P,0.001) but not on SD scans, while it was significantly lower during TP II than during TP I and baseline on both SD (P50.02 and ,0.0001, respectively) and TD (P50.01 and ,0.0001, respectively) scans.
4. Discussion Our data indicate that the early effect on new enhancing MS lesions of 44 mg of rh-IFN beta 1a administered once a week is weaker than that obtained at higher doses and with more frequent administrations [6,8,9]. However, they also show that this effect becomes more evident after 1 year of treatment. The early treatment effect is significantly more pronounced on lesions enhancing only after TD, whose number is already decreased by 50% during TP I. A recent double-blind, placebo-controlled study [8] with two doses of rh-IFN beta 1a (e.g. 22 and 44 mg three times a week) reported an 80–90% reduction in the frequency of active lesions on monthly scans obtained during the first 9 months of treatment. In the same study, the frequencies of patients with inactive scans were 31% and 41% in the two treatment arms. Our results suggest that a lower dose of rh-IFN beta 1a can achieve a significant effect on MRI activity only after a relatively long period of treatment,
Fig. 1. Bar chart of the mean numbers of new enhancing lesions per patient per month on SD (grey bars) and TD (black bars) MRI scans from 18 MS patients, during baseline period, TP I and TP II. For further details, see text.
M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
133
Fig. 2. Bar chart of the numbers of new enhancing lesions per month on SD (grey bars) and TD (black bars) MRI scans from patient [14, during baseline period, TP I and TP II. For further details, see text.
although this effect becomes of the same magnitude as that of higher doses in terms of frequency of inactive patients (33% during TP II in our study). This may also explain why previous reports failed to demonstrate a significant effect of low doses of IFN beta 1a on clinical and MRI MS activity [10], probably owing to the short follow-up duration. TD MRI enabled us to detect the effect of treatment with 44 mg of rh-IFN beta 1a earlier than SD MRI, thus confirming the potential role of the former technique for MRI monitoring of phase II trials [11]. We also found a discrepancy between the treatment efficacy in reducing enhancing lesion frequency and the persistance of clinical relapses. This might be due to the relatively short followup period and the small sample size studied, which might
Table 1 Mean numbers (95% confidence intervals) of new enhancing lesions per patient per month on SD and TD scans during the baseline and the treatment periods, estimated using a Poisson regression model
Baseline period Treatment period I Treatment period II
SD scans
TD scans
1.44 (1.15–1.80) 1.09 (0.88–1.37) 0.68 (0.49–0.96)
2.44 (2.06–2.90) 1.33 (1.09–1.63) 0.84 (0.63–1.14)
have prevented the detection of any treatment effect on MS clinical activity. This confirms that results from MRImonitored preliminary trials have to be interpreted cautiously and need to be confirmed by phase III studies with primary clinical endpoints. The use of TD MRI might, however, significantly reduce the sample size needed and shorten the follow-up periods for conducting exploratory treatment trials [11], thus speeding up the screening of new potential treatments for MS. It is known that MS lesions enhancing only after TD represent a subgroup with less severe tissue damage and milder blood–brain barrier (BBB) disruption than those enhancing after SD [16]. The major treatment effect on MS lesions enhancing only after TD may, therefore, suggest that the efficacy of low doses of IFN is almost immediate in restoring less severe BBB damages, while it takes a longer time to exert a more effective anti-inflammatory activity. This is confirmed by a recent baseline versus treatment study from Kita et al. [17]. Low weekly doses (e.g. 30 mg) of IFN beta 1a significantly reduced the number of newly-formed Gd-enhancing lesions over 6 months after treatment initiation, whilst the severity of tissue disruption within new lesions and normal-appearing white matter (as assessed by means of quantitative MRI measures) was not significantly different between baseline and treatment periods, thus also suggesting that low doses of IFN may first act by preventing MS lesion formation in its earlier stages.
134
M. Rovaris et al. / Journal of the Neurological Sciences 171 (1999) 130 – 134
Acknowledgements The recombinant human interferon beta-1a (REBIF ) was supplied to us at no cost by Serono Pharma (Rome, Italy). The study was supported by the Associazione Italiana Sclerosi Multipla (AISM). We thank Dr Maria Pia Sormani for her help in data statistical analysis.
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