Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study of L Glutamine Therapy for Sickle Cell Anemia and Sickle ß0-Thalassemia
Brief Summary: The purpose of this research is to evaluate the effects of L-glutamine as a therapy for sickle cell anemia and sickle ß0-thalassemia. as evaluated by the number of occurrences of sickle cell crises.


Options:
A: Inclusion Criteria:

* Established diagnosis of H SS or S-beta thalassemia
* History of at least one vaso-occlusive pain event in the 12 months prior to study entry
* Regular compliance with comprehensive medical care
* In a steady disease state and not in the midst of any acute complication due to SCD at study entry

Exclusion Criteria:

* Inability to take or tolerate oral medications
* Liver dysfunction (i.e., SGPT level greater than or equal to two times the normal limit and albumin level less than or equal to 3.2 g/dL)
* Kidney dysfunction ( i.e., creatinine level greater than or equal to 1.2 mg/dL for children and greater than or equal to 1.4 mg/dL for adults)
* Allergy to arginine
* Pregnant
* Received a blood transfusion within the 90 days prior to study entry
* More than 10 hospital admissions for pain in the 12 months prior to study entry
* Daily use of opioids and experiencing unstable pain that interferes with work or daily routine
* Required more than 3 hospital admissions and more than 10 emergency department/day hospital visits in the 12 months prior to study entry
* Received treatment with hydroxyurea within the 90 days prior to study entry
* Received treatment with any investigational drug in the 90 days prior to study entry
B: Inclusion Criteria:

1. Age 3-21 years of age, inclusive
2. Established diagnosis of sickle cell disease (any genotype)
3. Pain requiring medical care in an acute care setting (emergency department, hospital ward, day hospital, clinic) not attributable to non-sickle cell causes, treated with parenteral opioids

Exclusion Criteria:

1. Responds to 2 doses of IV opioids sufficiently for outpatient management
2. Greater than 12 hours from first dose of intravenous opioids to treat current pain in acute care setting
3. Hemoglobin less than 5 gm/dL or emergent need for red blood cell transfusion for hemodynamically unstable patient
4. Ketamine use in the emergency department for treatment of VOE
5. Glutamine within 30 days
6. New SCD drug use \< 3 months (e.g. Hydroxyurea, voxelotor, crizanlizumab, etc)
7. Acute mental status or neurological changes
8. Acute stroke or clinical concern for stroke
9. Three or more ED visits for sickle cell related pain receiving parenteral opioids in previous 7 days (not including current emergency department visit)
10. Hospital discharge within previous 7 days
11. Hypotension requiring clinical intervention; hemodynamic instability; septic shock
12. Previous randomization in this arginine phase 3 randomized controlled trial
13. Use of inhaled nitric oxide, sildenafil or arginine within the last month
14. Non-English speaking or requires a translator for clinical care
15. Pregnancy
16. Allergy to arginine
17. PI/clinical team concerns for compliance/issues that may adversely impact study participation/outcome
18. Adults 18 years or older who lack medical decision-making capacity to consent
C: Inclusion Criteria:

1. Aged greater than or equal to 5 years and less than or equal to 17 years at screening;
2. Has been diagnosed with SCD that includes the phenotypes HbSS, hemoglobin SC, and HbS/beta-thalassemia. Hemoglobin phenotyping must be previously documented by either hemoglobin high-performance liquid chromatography \[HPLC\] or electrophoresis at time of Screening. If a patient does not have documented hemoglobin phenotyping at the time of Screening, or has received a blood transfusion within the two months prior to the Screening Visit, hemoglobin phenotyping should be documented by hemoglobin HPLC;
3. Has had at least two and no more than ten documented episodes of clinical sickle cell crises within 12 months prior to the Screening Visit. A sickle cell crisis is defined as an episode of vaso-occlusive event:

   * Painful crisis defined as new onset of pain that lasts two or more hours for which there is no explanation other than vaso-occlusion, and which requires therapy with oral or parenteral opioids, non-steroidal anti-inflammatory drugs, or other analgesics prescribed by a healthcare provider in a medical setting such as a hospital, clinic, or emergency room visit, or documented telephone management (Ballas, 2010; Heeney, 2016; Jacob, 2005); and
   * Acute chest syndrome defined as acute illness characterized by a new segmental pulmonary infiltrate on a chest x-ray, and fever (greater than or equal to 38.5°C) or respiratory symptoms such as hypoxia, chest pain, tachypnea, wheezing, or cough (Ballas, 2010);
4. Is either not on hydroxyurea at the Screening Visit and does not plan on receiving it during the course of the first 12 weeks of the study (Part A), or has received hydroxyurea for a minimum of 6 months and, except for safety reasons, will remain on the same weight-based dose of hydroxyurea from screening throughout the duration of Part A of the study;
5. Parent or guardian is able to give written informed consent, and the potential pediatric patient is able to provide assent in a manner approved by the Institutional Review Board (IRB) and comply with the requirements of the study other than for safety reasons; and
6. If sexually active, agrees to use a reliable method of birth control (eg, barrier, birth control pills, abstinence) during the study and for one month following the last dose of study drug.

Exclusion Criteria:

1. Has a significant medical condition that required hospitalization (other than sickle cell crisis) within two months of the Screening Visit;
2. Has a known allergy or hypersensitivity to fish or shellfish;
3. Has a known allergy or hypersensitivity to soy;
4. Is planning to initiate, terminate, or alter the dosing of hydroxyurea during the first 12 weeks of the study, other than for safety reasons;
5. Has chronic daily use (more than 30 consecutive days during the last six months prior to enrollment) of opioid analgesia for any reason;
6. Has a diagnosis of chronic pain or chronic pain syndrome (eg, chronic pain from the repeated vaso-occlusive events, chronic pain from avascular necrosis);
7. Has a history of Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection;
8. Has a history of documented episode(s) of priapism within 12 months of the Screening Visit;
9. Has a history of atrial or ventricular arrhythmia;
10. Has an international normalized ratio (INR) \>2.0, or is on regular anticoagulation therapy, or has a history of a known bleeding diathesis;
11. Has thrombocytopenia (platelets less than 80,000) or is on chronic acetylsalicylic acid therapy;
12. Has increased risk of stroke: documented abnormal or "high conditional" transcranial Doppler (TCD) mean velocity (TCD V) by STOP criteria (Adams, 1998) within the preceding year or has a history of known cerebrovascular disease:

    * "High conditional" = TCD V greater than or equal to 185 to 199 cm/sec, or TCDi V greater than or equal to 170 to 184 cm/sec, or TCD maximum V greater than or equal to 250 cm/sec; or
    * Abnormal = TCD V greater than or equal to 200 cm/sec, or abnormal high TCDi V greater than or equal to 185 cm/sec, or TCD maximum V greater than or equal to 250 cm/sec;
13. Has received a blood transfusion or exchange transfusion in the three months prior to the Screening Visit;
14. Has renal insufficiency (creatinine greater than 1.5 times upper limit of normal \[ULN\], or requiring peritoneal dialysis or hemodialysis);
15. Has liver dysfunction (ALT greater than 2.0 times ULN);
16. Has other concomitant chronic medical or psychiatric condition that, in the opinion of the Investigator, would compromise participation in the study or confound the evaluation of the study outcome;
17. Is pregnant or lactating or has the intention of becoming pregnant during the study (if a female of child-bearing potential or partner of a patient participating in the study);
18. Is currently taking, or has been treated with, any form of omega-3 fatty acid or fish oil supplement within 30 days of the Screening Visit or during the course of the study;
19. Has been treated with an experimental anti-sickling medication/treatment within 30 days of the Screening Visit or during the course of the study;
20. Is currently taking or has been treated with any investigational drug for any disease within 30 days of the Screening Visit or during the course of the study;
21. Is currently enrolled in an investigational drug or device study and/or has participated in such a study within 30 days of the Screening Visit or during the course of the study; or
22. There are factors that would, in the judgment of the Investigator, make it difficult for the patient to comply with the requirements of the study (eg, inability to swallow capsules due to past history of stroke, or poor compliance).
D: Inclusion Criteria:

To be eligible to participate in the study, a patient must meet all of the following inclusion criteria:

* Patient is at least five years of age.
* Patient has been diagnosed with sickle cell anemia or sickle ß0-thalassemia (documented by hemoglobin electrophoresis).
* Patient has had at least two episodes of painful crises within 12 months of the screening visit.
* If the patient has been treated with an anti-sickling agent within three months of the screening visit, the therapy must have been continuous for at least three months with the intent to continue for the next 14 months.
* Patient or the patient's legally authorized representative has given written informed consent.
* If the patient is a female of child-bearing potential, she agrees to practice a recognized form of birth control during the course of the study.

Exclusion Criteria:

If the patient meets any of the following criteria, the patient must not be enrolled:

* Patient has a significant medical condition that required hospitalization (other than sickle painful crisis) within two months of the screening visit.
* Patient has diabetes mellitus with untreated fasting blood sugar \>115 mg/dL.
* Patient has prothrombin time International Normalized Ratio (INR) \> 2.0.
* Patient has serum albumin \< 3.0 g/dl.
* Patient has received any blood products within three weeks of the screening visit.
* Patient has a history of uncontrolled liver disease or renal insufficiency.
* Patient is pregnant or lactating.
* Patient has been treated with an experimental anti-sickling medication/treatment (except hydroxyurea) within 30 days of the screening visit.
* Patient has been treated with an experimental drug within 30 days of the screening visit.
* There are factors that would, in the judgment of the investigator, make it difficult for the patient to comply with the requirements of the study.

Answer: D