Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Open, Parallel Group Study for the Evaluation of an Oral Dose of 100 mg Thalidomide and Subsequent Dose Escalation of 400 mg Thalidomide in Combination With Riluzole in Patients With Amyotrophic Lateral Sclerosis (ALS)
Brief Summary: Neuroinflammation has recently emerged as a significant contributor to motor neuron damage. ALS tissue is characterized by inflammatory changes that are observed in both sporadic and familial ALS and in the ALS superoxide dismutase 1 (SOD1) transgenic mouse model. They include an accumulation of large numbers of activated microglia and astrocytes.

Proinflammatory cytokines, such as tumor necrosis factor (TNF-), are robustly upregulated in ALS. The receptor for tumor necrosis factor- (TNF-R1) is elevated at late presymptomatic as well as symptomatic phases of disease. TNF acts as a principal driver for neuroinflammation in ALS, while several co-stimulating cytokines and chemokines act to potentiate the TNF effects \[4-6\].

We propose an investigational therapy of ALS with oral administration of thalidomide. The rationale for this study is based on the anti-inflammatory properties of thalidomide through the modulation of inflammatory cytokines such as TNF. The primary aim of the trial is to determine whether treatment with thalidomide is safe and well tolerated in conjunction with riluzole and whether patients with ALS can tolerate daily doses of up to 400 mg. The trial is designed as feasibility study in planning for a larger phase IIb/III trial of efficacy.


Options:
A: Inclusion Criteria:

* Definite, probable, or probable-laboratory supported ALS according to the revised El Escorial World Federation of Neurology criteria.
* Intake of riluzole 50 mg twice a day (bid)
* A disease duration at inclusion of more than 6 months and less than 36 months \[inclusive\] (disease onset is defined as the date of first symptoms excluding muscle cramps and fasciculations)
* Vital capacity (VC%) ≥ 70% of normal value (slow expiration, best of a minimum of three and a maximum of five measurements, with a respiratory function validly assessable and a spontaneous, non-assisted ventilation)
* Ages 18 - 85 years (inclusive)
* Capable of thoroughly understanding the trial information given; has signed the informed consent.

Exclusion Criteria:

* Tracheostomy, tracheostomal ventilation of any type, non-invasive ventilation more than 16 hours/ day, or supplemental oxygen during the last three months prior to inclusion.
* Any medical condition or intoxication known to have an association with motor neuron dysfunction, which might confound or obscure the diagnosis of ALS.
* Presence of any concomitant life-threatening disease or any disease or impairment likely to interfere with functional assessment.
* Confirmed hepatic insufficiency or abnormal liver function (ASAT, ALAT greater than twice the upper limit of normal range).
B: Inclusion Criteria:

* patients aged 25 and 80 years
* female patients who are either postmenopausal for at least 24 month or who are willing and able to practice the methods of contraception following the Pharmion-Risk Managment Program (PRMP)
* Male patients who are willing and able to practice the methods of contraception along with their female partners of childbearing potential following the PRMP
* Clinical diagnosis of probable and definite ALS
* Sporadic or familial ALS
* Onset of pareses for no more than 4 years
* Vital capacity equal to or more than 65% of the predicted value
* Treatment with riluzole 100mg/day
* Patients who are willing to give informed consent

Exclusion Criteria:

* pregnancy or breast feeding
* female patients who are unwilling or unable to practice the methods of contraception following the Pharmion-Risk Managment Program (PRMP)
* Male patients who are willing and able to practice the methods of contraception along with their female partners of childbearing potential following the PRMP
* Patients unlikely to comply with the PRMP and other study requirements
* Patients with significant sensory abnormalities, dementia, uncompensated medical illnesses and psychiatric disorders
* Laboratory abnormalities consistent with clinically significant cardiovascular, respiratory, haematological, metabolic, hepatic and renal disease
* Infectious disease including HIV, hepatitis B and C
* monoclonal gammopathy of unknown significance (MGUS)
* History of substance abuse within the past year
* History of recurrent thrombosis
* Continuous non-invasive ventilation (ventilation-free interval equal to or less than 2 hours daily)
* Tracheotomy and invasive ventilation
* Treatment with investigational drug within 3 months prior to screening
* patients with clinically signifikant sensory polyneuropathy (inflammatory neuropathy cause and treatment sensory sum score - ISS ≥ 2)
* patients with sleep disorder (Epworth Sleeping Scale-ESS ≥ 10)
C: Inclusion Criteria:

* Eligible patients should have a diagnosis of definite ALS according to the El Escorial revised criteria with clear clinical upper and lower motor neuron signs.

Exclusion Criteria:

* Contraindications to transcranial magnetic stimulation:

  * Tracheostomy
  * Pace-maker
  * Implanted metallic devices
  * Epilepsy
D: To be eligible for enrollment in this study, subjects must meet the following eligibility criteria within fourteen days prior to randomization:

Inclusion criteria:

* A clinical diagnosis of laboratory-supported probable, probable or definite ALS, according to modified EL Escorial criteria.
* FVC greater or equal to 75% of predicted.
* Onset of weakness within 3 years prior to enrollment.
* If patients are receiving riluzole they must be on a stable dose for at least the past thirty days.
* Women of childbearing age must be non-lactating and surgically sterile or using an effective method of birth control and have a negative pregnancy test (adequate birth control includes use of intra-uterine device or oral contraceptives plus a barrier method, e.g. condom, diaphragm).
* Willing and able to give signed informed consent that has been approved by your Institutional Review Board (IRB).

Exclusion criteria:

* Requirement for tracheotomy ventilation (or non-invasive ventilation \> 23 hours/day).
* Diagnosis of other neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, etc).
* FVC \< 75% of predicted.
* A clinically significant history of unstable medical illness (unstable angina, advanced cancer, etc) over the last 30 days.
* History of renal disease (screening creatinine greater than 1.5).
* History of liver disease (screening alanine aminotransferase greater than 3 times the upper limit of normal).
* History of hematologic disease (screening white blood cell count less than 3,800/mm3).
* History of system lupus erythematosis (or screening ANA of 1:160 or greater).
* Treatment with any medications that may cause lupus-like symptoms within 4 weeks of baseline visit (e.g. procainamide, hydralazine).
* History of vestibular disease (excluding benign position vertigo).
* Pregnancy or lactation.
* Allergy to tetracycline antibiotics.
* Use of minocycline within thirty days of enrollment (baseline visit).
* Use of anti-epileptic medications other than gabapentin.
* Limited mental capacity rendering the subject unable to provide written informed consent or comply with evaluation procedures.
* History of recent alcohol or drug abuse or noncompliance with treatment or other experimental protocols.
* Use of any investigational drug within the past 30 days (Creatine, Vioxx, Celebrex, Topiramate).
* Women with the potential to become pregnant who are not practicing effective birth control.

Answer: B