Fingolimod Versus Intramuscular Interferon in Patient Subgroups from TRANSFORMS

Cohen JA et al.

SUPPLEMENTARY MATERIAL

Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS

Jeffrey A Cohen ·FrederikBarkhof· Giancarlo Comi· Guillermo Izquierdo· BhupendraKhatri· Xavier Montalban· Jean Pelletier · Benjamin Eckert · Dieter AHäring· Gordon Francis · on behalf of the TRANSFORMS Study Group

J. A. Cohen (corresponding author)

Mellen Center U-10, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH44195, USA

e-mail: ; phone: 216 445 8110; fax: 216 445 6259

F. Barkhof

Image Analysis Center, VU University Medical Center, Amsterdam, Netherlands

G. Comi

Department of Neurology, Vita-Salute San Raffaele University, Milan, Italy

G. Izquierdo

Department of Neurology, Virgen Macarena University Hospital, Seville, Spain

B. Khatri

St Luke's Medical Center, Milwaukee, WI, USA

X. Montalban

Department of Neurology-Neuroimmunology and Cemcat, Valld’Hebron University Hospital, Barcelona, Spain

J. Pelletier

Department of Neurology and CRMBM CNRS7339, CHU La Timone, Marseille, France

B. Eckert · G. Francis

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

D. A. Häring

Novartis Pharma AG, Basel, Switzerland

METHODS

Study design and oversight. TRANSFORMS adhered to the International Conference on Harmonisation Guidelines for Good Clinical Practice[1] and was conducted in accordance with the Declaration of Helsinki[4]. The protocol was approved by each site’s institutional review board. All patients gave written informed consent. An independent steering committee consisting of academic investigators collaborated with the sponsor (Novartis Pharma AG, Basel, Switzerland) to design the study and monitor its conduct.

Patient eligibility criteria.Eligible patients were 18–55 years of age,had a diagnosis of MS according to the revised McDonald criteria[3],had disease with a relapsing–remitting course,with at least one documented relapse in the previous year or at least two relapses in the previous 2 years, and a score of 0–5.5 on the EDSS[2]. Exclusion criteria were relapse or corticosteroid treatment within 30 days before randomization, active infection, macular edema, immune suppression (drug or disease induced) and clinically significant coexisting systemic disease. Previous recent therapy with any type of interferon beta or glatiramer acetate was not exclusionary.

Study randomization and masking. Randomization for the core phase of TRANSFORMS and re-randomization for the extension phase were performed centrally, with stratification according to site, and a block size of six within each site. An interactive voice-response system was used to perform assignments. Patients, study personnel, MRI evaluators, steering committee members and the study statistician were unaware of treatment assignments during the TRANSFORMS core phase. Blinding was maintained using a double-dummy technique. Capsules, syringes and packaging for active and placebo treatments were indistinguishable. Patientswere instructed to cover injection sites at visits and not todiscuss adverse events with clinical assessors. During the extension phase, patients and investigators were aware that allpatients were receiving fingolimod but the dose remainedmasked. Doses for patients assigned to receive fingolimodin the core phase were unmasked to Novartis personnel,but reassignment remained masked to Novartis personnel for those patients who were randomly reassigned toreceive fingolimod 0.5 mg or fingolimod 1.25 mg after receivinginterferon beta-1a for the first year.

REFERENCES

1.(1996) ICH harmonized tripartite guidelines for good clinical practice. In:

2.Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444-1452

3.Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the 'McDonald Criteria'. Ann Neurol 58:840-846

4.World Medical Association (2004) Declaration of Helsinki: ethical principles for medical research involving human subjects. In, Ferney-Voltaire, France

SUPPLEMENTARY FIGURES

Supplementary Fig. 1 Annualized relapse rate for fingolimod 1.25 mg versus interferon beta-1a over 12months in patient subgroups defined by demographic factors and baseline disease characteristics (intent-to-treat population)

ARRs and ARR ratios estimated using a negative binomial regression model adjusted for treatment, and(for subgroup analyses only) subgroup variable and treatment by subgroup variable interaction; log time on study was used as an offset variable

aPatients were categorized according to whether they were treatment-naïve (had received no form of medication for MS before the study) or had previously received treatment for multiple sclerosis with anymedication at any timebefore study enrollment

bp value for the treatment contrast within the subgroup

cp value for the treatment by subgroup interaction, which evaluates heterogeneity of the treatment effect (see Methods)

EDSSExpanded Disability Status Scale Gdgadolinium IFN interferon MS multiple sclerosisGd gadoliniumRRMSrelapsing–remitting MS

Supplementary Fig. 2 Gd-enhancing T1 lesion counts and ratios over 12 months in patient subgroups defined by demographic factors and baseline disease characteristics (intent-to-treatpopulation)

Gd-enhancing T1 lesion counts were estimated using a negative binomial regression model, log-link, adjusted for treatment for the overall result, and adjusted for treatment subgroup and treatment by subgroup variable interaction for the subgroup analyses. n number of observations included in the analysis (patients with non-missing Gd-enhancing T1 lesion count assessments at month 12; scans obtained 30 days after the last use of steroids to treat MS were excluded from this analysis)

aPatients were categorized according to whether they were treatment-naïve (had received no form of medication for MS before the study) or had previously received treatment for MS with anymedication at any time before study enrollment

bp value for the treatment contrast within the subgroup

cp value for the treatment by subgroup interaction, which evaluates heterogeneity of the treatment effect (see Methods)

EDSS Expanded Disability Status ScaleGd gadolinium MS multiple sclerosis

Supplementary Fig. 3 New/newly enlarging T2 lesion counts andratios over 12 months in patient subgroups defined by demographic factors and baseline disease characteristics (intent-to-treatpopulation)

New/newly enlarged T2 lesion counts were estimated using a negative binomial regression model, log-link, adjusted for treatment for the overall result, and adjusted for treatment subgroup and treatment by subgroup variable interaction for the subgroup analyses. nnumber of observations included in the analysis (patients with non-missing new/newly enlarged T2 lesion count assessments at month 12)

aPatients were categorized according to whether they were treatment-naïve (had received no form of medication for MS before the study) or had previously received treatment for MS with anymedication at any time before study enrollment

bp value for the treatment contrast within the subgroup

cp value for the treatment by subgroup interaction, which evaluates heterogeneity of the treatment effect (see Methods)

EDSS Expanded Disability Status ScaleGd gadolinium MS multiple sclerosis

Supplementary Fig. 4 Percentage change in normalized brain volume over 12 months in patient subgroups defined by demographic factors and baseline disease characteristics (intent-to-treatpopulation)

The percentage change in brain volume was analyzed using an ANOVA model adjusted for treatment for the overall result and for treatment, subgroup, and treatment by subgroup interaction for subgroup analyses.The pvalue for the ANOVA analysis refers to a ttest for the treatment contrast. For the brain volume analyses, n = number of patients in each group with a non-missing assessment of percentage change from baseline in normalized brain volume at month 12

aPatients were categorized according to whether they were treatment-naïve (had received no form of medication for MS before the study) or had previously received treatment for MS with anymedication at any time before study enrollment

bp value for the treatment contrast within the subgroup

cp value for the treatment by subgroup interaction, which evaluates heterogeneity of the treatment effect (see Methods)

ANOVA analysis of varianceEDSS Expanded Disability Status ScaleGdgadolinium LS least-squares
MS multiple sclerosis

Supplementary Fig.5(A) Annualizedrelapse rates, (B) Gd-enhancing T1 lesion count, (C) estimated new/newly enlarged t2 lesion count and (D) brain volume loss for fingolimod 1.25mg versus interferon beta-1a over 12months in previously treated or treatment-naïve patients with highly active disease (intent-to-treat population)

Gd-enhancing T1 and new/newly enlarged T2 lesion counts were estimated using a negative binomial regression model, log-link, adjusted for treatment for the overall result, and adjusted for treatment subgroup and treatment by subgroup variable interaction for the subgroup analyses

Least-squares mean change in brain volume calculated using an ANOVA model adjusted for treatment for the overall result and for treatment, subgroup and treatment by subgroup interaction for subgroup analyses

ap value for the treatment contrast within the subgroup

bp value for the treatment by subgroup interaction, which evaluates heterogeneity of the treatment effect (see Methods)

cn number of observations included in this analysis (patients withnon-missing Gd-enhancing T1 lesion count assessments at month 12; scans obtained 30 days after the last use of steroids to treat MS were excluded from this analysis)

dnnumber of observations included in this analysis (patients withnon-missing new/newly enlarged T2 lesion count assessments at month 12)

en number of patients in each group with a non-missing assessment of percentage change from baseline in normalized brain volume at month 12

ANOVA analysis of variance ARR annualized relapse rate DMT disease-modifying therapy Gd gadolinium IFN interferon MRImagnetic resonance imaging MS multiple sclerosis RES rapidly evolving severe RRMSrelapsing–remitting multiple sclerosis