January 29, 2004
T. Jock Murray
Division of Neurology, Dalhousie MS Research Unit, Queen Elizabeth II, Health Sciences Center, Halifax, Nova Scotia, Canada
From Current Medical Research and Opinion
Curr Med Res Opin 20(1):25-30, 2004
Summary and Introduction
Previous studies comparing the two available interferon beta (IFNß)-1a products, Avonex and Rebif, for the treatment of relapsing-remitting multiple sclerosis (RRMS) have been limited and of short duration. Therefore, the Prospective and Retrospective Observational Study of Avonex and Rebif (PROOF) was designed to provide long-term (up to 5 years) comparative data on the efficacy, safety, and tolerability of these two agents. Patients with RRMS receiving treatment with either Avonex* 30 µg intramuscularly once weekly or Rebifć 44 µg subcutaneously three times weekly from 12 to 24 months are being enrolled and will continue their respective treatments for the 36-month duration of the study. The primary efficacy endpoint will be change in brain parenchymal fraction, which will be evaluated through magnetic resonance imaging scans by blinded radiologists. Secondary endpoints will include the following: relapse rates; intravenous steroid use; the proportion of patients with an increase of >/= 1 point on the Expanded Disability Status Scale (EDSS) and with an increase in EDSS score sustained for 6 months; mean change in EDSS score; cumulative number of new or enlarging T2 lesions; T2 and T1 lesion volumes; gadolinium-enhanced lesion number and volume; and safety and tolerability. The study design of PROOF will permit more meaningful conclusions regarding the optimal IFNß-1a product for the long-term treatment of patients with multiple sclerosis.
Multiple sclerosis (MS) is a lifelong debilitating disease that requires lifelong therapy. Within the last decade, two interferon beta (IFNß)-1a formulations, Avonex* and Rebifć, have emerged as first-line therapies for the treatment of relapsing-remitting MS (RRMS). In the respective phase III clinical studies of each IFNß-1a product, the approved dosages of Avonex (30 µg intramuscular [i.m.] once weekly) and Rebif (44 µg subcutaneous [s.c.] three times weekly) delayed the time to sustained progression in disability, reduced the frequency of exacerbations, and decreased subclinical disease activity as measured by magnetic resonance imaging (MRI) when compared with placebo.[1,2] The phase III trial of Avonex also demonstrated beneficial effects on brain atrophy and cognitive function in patients with MS.[3,4] There are no reports in the literature on the effects of Rebif on cognitive function in MS, and the studies that do exist for brain atrophy are mostly small, retrospective, exploratory analyses in which the effects of treatment are inconclusive.[5-7]
Controversy exists within the MS community regarding whether higher doses of IFNß are more effective than lower doses. Although head-to-head studies can provide valuable information regarding the relative efficacy among IFNß products and doses, no long-term, head-to-head comparison studies have been conducted. A recent study (the EVidence of Interferon Dose-Response: European North American Comparative Efficacy [EVIDENCE] study) compared the effects of Rebif with those of Avonex on the proportion of relapse-free patients after 24 weeks of treatment (the primary endpoint). Results showed that significantly more patients who were treated with Rebif were relapse-free at 24 weeks compared with patients who were treated with Avonex (p < 0.0005). In addition, the mean number of combined unique lesions (the primary endpoint evaluated by MRI scan), T1 lesions, and T2 lesions was significantly lower at 24 weeks in patients treated with Rebif than in those treated with Avonex (p < 0.0001). The incidence of neutralizing antibodies (NAbs) (measured at 48 weeks) was 25% in patients in the Rebif group compared with 2% in the Avonex group (p < 0.001). The EVIDENCE investigators concluded that higher doses of IFNß-1a are more effective than are lower doses. Because MS is a lifelong debilitating disease and NAbs can reduce the clinical efficacy of IFNß starting from 18 to 24 months after treatment initiation,[9,10] however, the EVIDENCE study was not long enough to evaluate the relative efficacy of the two IFNß-1a products. Even in the second 24 weeks of the EVIDENCE study it appears that the advantage of Rebif over Avonex had diminished (not due to NAbs at this point). Unfortunately, no long-term data are available that compare Avonex and Rebif.
Studies conducted to date that have compared IFNß-1a products do not permit definitive conclusions regarding the long-term superiority of one IFNß-1a product over another, nor do they support any conclusion regarding effects on the long-term accumulation of physical disability. The Prospective and Retrospective Observational Study of AVONEX and REBIF (PROOF) was designed to compare the relative long-term (up to 5 years) efficacy and tolerability of Avonex and Rebif. This paper describes the design of PROOF, which is currently enrolling patients.
The study protocol was approved by local institutional review boards
at each study site and is being carried out according to the Declaration
|Table 1. PROOF: Key Inclusion and Exclusion Criteria
Investigators will identify qualified individuals for PROOF by retrospective review of patient charts. To be eligible for study entry, men and women must satisfy the inclusion and exclusion criteria listed in Table 1. Briefly, patients must be from 18 to 50 years of age, have a diagnosis of RRMS, an expanded disability status scale (EDSS) score of 0.0-5.5 (inclusive), and >/= 2 documented relapses during the 3 years before treatment initiation. In addition, patients must have received Avonex 30 µg i.m. once weekly or Rebif 44 µg s.c. three times weekly for >/=12 months and up to 24 months before enrollment. Patients must have remained on the same IFNß-1a treatment since the diagnosis of MS prior to enrollment in PROOF; hence patients were not allowed to have received another IFNß product prior to receiving Avonex or Rebif.
Patients who had received the following therapy prior to enrollment will be excluded from the study: glatiramer acetate (Copaxone, Teva), total lymphoid irradiation, cladribine, or T-cell vaccination at any time; cyclophosphamide or mitoxantrone within 26 weeks; cyclosporine, plasma exchange, intravenous (i.v.) immunoglobulin, azathioprine, or methotrexate within 12 weeks; and corticosteroids within 8 weeks. Patients may have received investigational symptomatic therapy for MS at any time before enrollment. Administration of any of the previously listed agents during the study will result in permanent discontinuation from the study. In the event of a relapse, patients are to be treated for either 3 or 5 days with i.v. methylprednisolone 1000 mg, administered once daily or in divided doses.
All aspects of the study protocol are reviewed with each subject and informed written consent is obtained before enrollment.
PROOF is a prospective and retrospective, double-blind, multicenter, observational study involving 26 sites in Austria, Australia, Canada, and the United States.
Patients will continue with their current MS therapy (Avonex 30 µg i.m. once weekly or Rebif 44 µg s.c. three times weekly) for 3 years. The doses of study drug may be reduced or interrupted in accordance with the clinical judgment of the investigator. Enrollment in the two treatment groups will be balanced across all sites using the method of minimization according to annualized relapse rate and EDSS score before treatment and disease duration. An interactive voice response system (IVRS) will be used to track and control enrollment at each site. The first 100-150 eligible patients will be enrolled in the study without restrictions. For each subsequent patient, IVRS will calculate an imbalance index. The patient will be enrolled only if his or her data do not cause the imbalance index to exceed its prespecified limit. Minimization ensures balance between treatment groups for important patient factors. A placebo control group is not being used because denial of effective therapy in a study of 3 years' duration would present substantial ethical concerns.
Primary Endpoint. The primary objective of PROOF is to compare the long-term efficacy of Avonex with that of Rebif as measured by change in brain parenchymal fraction (BPF). BPF was selected as the primary outcome because this measure is highly reproducible, sensitive to change, and free of bias introduced by clinical examinations and patient reporting (e.g. relapses). Over observation periods of up to 8 years, the degree of brain atrophy has been convincingly shown to be related to level of disability (EDSS and Multiple Sclerosis Functional Composite), as well as to T1, T2, and gadolinium (Gd+)-enhanced lesion volumes. Furthermore, the relationship demonstrated between progression in brain atrophy and subsequent disability status suggests that progression of atrophy during the course of RRMS is clinically relevant.[4,12,13]
Table 2. PROOF: Safety and Tolerability Endpoints
|Safety endpoints||Tolerability endpoints|
|Adverse events and serious adverse events
Hematology and blood chemistry
Incidence of depression using the Beck Depression Inventory-II
Pregnancy testing, if applicable
Severity of injection-site reactions
Incidence of skin necrosis
Duration of flu-like symptoms
Patient global assessment, as measured by a visual analogue scale
Dose reduction rate of i.m. IFNß-1a (Avonex) or s.c. IFNß-1a (Rebif) during the 3-year study
Percentage of patients developing NAbs to IFNß
Effect of NAbs on Gd+ lesions
|Gd+ = gadolinium-enhanced; IFNß = interferon beta; i.m. = intramuscular; NAbs = neutralizing antibodies; PROOF = Prospective and Retrospective Observational Study of Avonex and Rebif; s.c. = subcutaneous.|
Secondary Endpoints. Secondary endpoints of PROOF include the following: the proportion of patients who experience relapses at 6, 12, 24, and 36 months; annualized relapse rate; rate of i.v. steroid use for relapses, the proportion of patients with an increase in EDSS score of >/= 1 point; the mean change in EDSS; and increases in EDSS of >/= 1 point sustained over two consecutive visits. Relapses are defined as new or recurrent neurologic symptoms that are not associated with fever or infection, last >/= 48 hours, and are accompanied by new objective neurologic findings on examination by the investigator. MRI endpoints include the cumulative number of new or enlarging T2 lesions, T2 lesion volume, T1 lesion volume, and Gd+ lesion number and volume. PROOF will also compare the safety and tolerability of the two IFNß-1a formulations (Table 2).
Subjects will be required to visit the clinic at least six times during the study: at screening, baseline (month 0), and at months 6, 12, 24, and 36. In addition, nurse coordinators will conduct monthly telephone interviews with patients using a case report form; patients will be given a copy of the case report form so that they can follow along with the nurse coordinator at each telephone visit. Treating physicians, nurses, and study coordinators are not blinded to treatment assignment. Only the examining physicians and the radiologist who analyzes the MRI scans, as well as the technicians who perform NAb testing at Biogen, are blinded to treatment allocation.
Efficacy. MRI will be performed at months 0, 6, 12, 24, and 36 to quantify BPF and brain lesions. MRI testing also must be performed >/= 4 weeks after treatment with corticosteroids for relapses. MRI scans will be evaluated at a central MRI reading center (Cleveland Clinic Foundation, Cleveland, Ohio, USA) by radiologists who are blinded with respect to treatment.
Each site will designate one primary examining neurologist who is responsible for performing all EDSS evaluations and defining whether changes in clinical signs and symptoms can be qualified as an MS relapse. Examining neurologists will be blinded with respect to study drug. To maintain proper blinding of EDSS analyses and MS relapse confirmations, patients will be instructed not to discuss the MS therapy with the examining neurologist or to mention any skin reactions or therapy side-effects they may experience. Other than performing EDSS evaluations and confirming MS relapses, the examining neurologist is not involved in screening patients and may not be involved with any other aspect of patient care and management.
Safety and Tolerability. Adverse events, including injection-site reactions and flu-like symptoms, will be monitored during all study visits. In addition, during the monthly telephone call, the nurse coordinator will ask patients about any injection-site reactions, drug compliance issues, dose reductions, concomitant therapies, and adverse events. When present, skin necrosis at the injection site will be photographed at each study visit. Physical examinations will be conducted and vital signs recorded at screening and at month 36. Blood samples will be obtained for routine hematology and blood chemistry evaluation at screening and at months 6, 12, 24, and 36; a central laboratory will conduct these analyses. For women who are not postmenopausal or surgically sterile, a serum pregnancy test will be performed at screening and at all study visits.
Serum collected at months 0, 6, 12, 24, and 36 will be tested for the presence of binding antibodies to IFNß using an enzyme-linked immunosorbent assay and for the presence of NAbs to IFNß using a viral cytopathic effect assay. Antibodies to IFNß will be measured at Biogen, Inc., by technicians who will be blinded to the patient's treatment. An assessment of depression will be performed at screening and at months 6, 12, 24, and 36 using the Beck Depression Inventory-II. All patients will complete a patient global assessment, as measured by a visual analogue scale, to rate how they feel on a scale from 0 to 10 at screening and at months 6, 12, 24, and 36, before initiation of any other assessments for that visit.
Patients will record study drug dosing in a diary, which will be reviewed during the monthly telephone call and during all on-therapy study visits. Each patient will be questioned about the use of concomitant therapies at screening, during the monthly telephone call, and during all on-therapy study visits; this information will be recorded in the patient's case report form.
A sample size of 300 patients (150 patients per treatment group) will be required to reject the null hypothesis that Avonex and Rebif are not equivalent (i.e. the difference in mean BPF is -0.01 or farther from zero in the same direction), assuming the expected difference in means is 0.00, 90% power, an overall twosided significance level of 0.05, and a 10% dropout rate. Furthermore, because approximately 80% of subjects might remain matched on BPF at baseline, a total of 374 patients will be enrolled in the study to ensure that the analysis of a subgroup of subjects matched on BPF at baseline will have enough power to detect a difference between treatment groups. All statistical analyses will include all subjects, following the intent-to-treat principle. All reported p-values will be based on twotailed statistical tests, with a significance level of 0.05. Missing value patterns will be investigated, and missing value imputation will be utilized if the missing data appear to cause bias in the results. Stratified analyses will be performed for the primary endpoint, BPF, as well as other MRI endpoints, to account for imbalances that may have been present before treatment initiation. Patients will be stratified according to BPF/MRI quartiles at month 0 (baseline), and a 90% confidence interval (CI) for the mean difference within each stratum will be constructed. The overall 90% CI will be formed by combining the CIs from each stratum. Matched subgroup analyses will also be considered for BPF and other MRI parameters and will include only those patients whose values match at month 0.
Debate continues regarding the relative efficacy of Avonex and Rebif. A number of short-term studies that have compared efficacy among available IFNß products (including the two IFNß-1a products) show no differences in efficacy.[15-18] One recent study suggests greater efficacy with Rebif, but better tolerability with Avonex; however, the short duration of this study (48 weeks) does not allow for definitive conclusions to be drawn regarding the long-term efficacy of these products in MS, which is a lifelong disease. Long-term comparative studies are required to accurately determine the impact of IFNß-1a therapy on sustained progression of disability and the impact of IFNß-1a NAbs on MRI and clinical outcomes. PROOF will provide additional data to determine the comparability of these two agents over the longest treatment duration studied to date (up to 5 years). Therefore, more meaningful conclusions may be reached than those made on the basis of data from shorter-term trials.
This study is sponsored by Biogen, Inc
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