Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Trial of Rebif New Formulation (44 Microgram [Mcg] Three Times Weekly [Tiw] and 44 Mcg Once Weekly [ow]) in Subjects at High Risk of Converting to Multiple Sclerosis (REFLEX)
Brief Summary: The study is a 24 months randomized, double-blind, Placebo-controlled, multi-center clinical trial with an optional 12 months open label extension.

The primary objective of the study is to evaluate the effect of fetal bovine serum \[FBS\]-free/human serum albumin \[HSA\]-free formulation of Interferon \[IFN\] beta-1a (RNF) 44 microgram (three times weekly and once weekly) versus placebo on the time to conversion to McDonald multiple sclerosis (MS) criteria (2005) in subjects with a first clinical demyelinating event at high risk of converting to MS.

The main secondary objective of study is to evaluate the effect of RNF 44 microgram (three times weekly and once weekly) versus placebo on the "Time to conversion to clinically definite MS (CDMS)" in subjects with a first clinical demyelinating event at high risk of converting to MS.

At the end of 24 month double-blind core REFLEX trial, subjects who will not convert to CDMS and decide to receive open-label (OL) treatment will be enrolled into an open-label, 12 month extension period to evaluate the effect of RNF 44 mcg three times weekly treatment on the time to conversion to McDonald MS and time to conversion to CDMS.


Options:
A: Inclusion Criteria:

* Ability to provide written informed consent and to be compliant with the schedule of protocol assessments
* Relapsing-remitting multiple sclerosis (MS)
* Ages 18-55 years inclusive
* For sexually active female and male participants of reproductive potential, use of reliable means of contraception

Exclusion Criteria:

* Secondary or primary progressive multiple sclerosis at screening
* Incompatibility with MRI
* Contra-indications to or intolerance of oral or IV corticosteroids
* Known presence of other neurologic disorders
* Pregnancy or lactation
* Lack of peripheral venous access
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
* Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal
* Congestive heart failure
* Known active bacterial, viral, fungal, mycobacterial infection or other infection or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening
* History or known presence of recurrent or chronic infection
* History of cancer, including solid tumors and hematological malignancies (except basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix of the uterus that have been excised and resolved)
* History of alcohol or drug abuse within 24 weeks prior to randomization
* History of or currently active primary or secondary immunodeficiency
* History of coagulation disorders
* Treatment with any investigational agent within 4 weeks of screening
* Receipt of a live vaccine within 6 weeks prior to randomization
* Incompatibility with Avonex use
* Previous treatment with rituximab
* Previous treatment with lymphocyte-depleting therapies except mitoxantrone
* Treatment with lymphocyte trafficking blockers within 24 weeks prior to randomization
* Treatment with beta interferons, glatiramer acetate, IV immunoglobulin, plasmapheresis, or immunosuppressive therapies within 12 weeks prior to randomization
* Systemic corticosteroid therapy within 4 weeks prior to randomization
B: Inclusion Criteria:

* Male and female patients with clinical-isolated syndrome or multiple sclerosis who have been treated at least once in BENEFIT Study 304747

Exclusion Criteria:

* Patients who, according to the investigator's judgment, have medical, psychiatric, or other conditions that compromise the patient's ability to understand the purpose of the study
C: Inclusion Criteria:

* Single, first clinical event suggestive of MS within 60 days prior to study Day 1, which is the day of randomization (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction
* At least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial
* EDSS 0 - 5.0 at least one time point during the screening period before start of treatment
* 18 and 50 years old, inclusive
* Willing to follow study procedures
* Written informed consent
* If female, subject must:

  * be neither pregnant nor breast-feeding nor attempting to conceive
  * use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (that is \[i.e.\] less than 1 percent \[%\] per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner

Exclusion Criteria:

* Diagnosis of MS (per McDonald criteria 2005)
* Any other disease that could better explain the subject's signs and symptoms
* Complete transverse myelitis or bilateral optic neuritis
* Subject uses or has used any other approved MS disease-modifying drug (DMD)
* Any investigational drug or undergone an experimental procedure within 12 weeks prior to study Day 1
* Oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to study Day 1
* Total bilirubin greater than 2.5 times upper limit of normal (ULN)
* Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN
* Inadequate bone marrow reserve, defined as a total white blood cell count less than 3.0 x 109 per liter (/L), platelet count less than 75 x 109/L, hemoglobin less than 100 gram per liter (g/L)
* Current autoimmune disease
* Major medical or psychiatric illness (including history of or current severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
* History of seizures not adequately controlled by treatment
* Cardiac disease, such as angina, congestive heart failure or arrhythmia
* Known allergy to IFN-beta or the excipient(s) of the study medication
* Any condition that could interfere with the MRI evaluation;
* Known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)
* Previously participated in this study
* Participated in any clinical trial within the past 6 months
* Any immunomodulatory or immunosuppressive therapy at any time prior to enrollment, including, but not limited to, the following products: any IFN, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 \[CD4\]), intravenous, immunoglobulins (Igs), cytokines or anti-cytokine therapy
* Any experimental MS treatment prior to trial entry, including, but not limited to, any statins (if given to prevent MS) and pentoxyfylline
* History of alcohol or drug abuse
* Intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
* Inability to administer subcutaneous injections either by self or by caregiver
* Moderate to severe renal impairment
D: Inclusion Criteria:

* All patients randomized and treated at least once in study 304747

Exclusion Criteria:

* Medical, psychiatric or other conditions that compromise the patient's ability to understand the purpose of the study

Answer: C