A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle βo-thalassemia

• The Number of Hospitalizations for Sickle Cell Pain [ Time Frame: 48 weeks ]
  The number of hospitalizations that occur from Week 0 to Week 48, will be used to evaluate the efficacy of oral L-glutamine as a treatment for sickle cell anemia and beta-0 thalassemia.
• The Number of Emergency Room/Medical Facility Visits for Sickle Cell Pain [ Time Frame: 48 weeks ]
  The number of emergency room visits or medical facility visits that occur from Week 0 to Week 48, will be used to evaluate the efficacy of oral L-glutamine as a treatment for sickle cell anemia and beta-0 thalassemia.
• The Effect of Oral -L-glutamine on Hematological Parameters [ Time Frame: Baseline, Week 4, 24 and 48 ]
  To assess the effect of oral L-glutamine on hematological parameters (hemoglobin), Change from Baseline will be reported at Weeks 4, 24 and 48.
• The Effect of Oral L-glutamine on Vital Signs [ Time Frame: Baseline, Week 4, 24, and 48 ]
  To assess the effect of oral L-glutamine on Vital signs (systolic and diastolic blood pressure). Change from Baseline will be reported at Weeks 4, 24, and 48.
• The Effect of Oral L-glutamine on Hematological Parameters [ Time Frame: Baseline, Week 4, 24 and 48 ]
  To assess the effect of oral L-glutamine on hematological parameters (hematocrit), Change from Baseline will be reported at Weeks 4, 24 and 48.
• The Effect of Oral L-glutamine on Hematological Parameters [ Time Frame: Baseline, Week 4, 24 and 48 ]
  To assess the effect of oral L-glutamine on hematological parameters (reticulocyte count), Change from Baseline will be reported at Weeks 4, 24 and 48.
• The Effect of Oral L-glutamine on Vital Signs [ Time Frame: Baseline, Week 4, Week 24 and Week 48 ]
  To assess the effect of oral L-glutamine on Vital signs (pulse rate). Change from Baseline will be reported at Weeks 4, 24, and 48.
• Effect of Oral L-glutamine on Vital Signs [ Time Frame: Baseline, Week 4, Week 24 and Week 48 ]
  To assess the effect of oral L-glutamine on Vital signs (temperature). Change from Baseline will be reported at Weeks 4, 24, and 48.
• The Effect of Oral L-glutamine on Vital Signs [ Time Frame: Baseline, Week 4, Week 24 and Week 48 ]
  To assess the effect of oral L-glutamine on Vital signs (respiration). Change from Baseline will be reported at Weeks 4, 24, and 48.

Primary objective:

To evaluate the efficacy of oral L-glutamine as a therapy for sickle cell anemia and sickle ß0-thalassemia as evaluated by the number of occurrences of sickle cell crises.

Secondary objectives:

To assess the effect of oral L-glutamine on: (a) frequency of hospitalizations for sickle cell pain; (b) frequency of emergency room/medical facility visits for sickle cell pain; and (c) hematological parameters (hemoglobin, hematocrit, and reticulocyte count); and to assess the safety of L-glutamine as a therapy for sickle cell anemia as evaluated by adverse events, laboratory parameters, and vital signs.

Methodology:

This was a 2:1 randomized, double-blind, placebo-controlled, parallel-group, multicenter study in patients with sickle cell anemia and sickle ß0-thalassemia who were at least 5 years old. Informed consent was obtained up to four weeks prior to Week 0 (Baseline). Screening procedures were performed anytime between the date of consent and Week 0, as long as all eligibility criteria had been confirmed prior to Week 0. At Week 0, patients were randomized (to L-glutamine or placebo) and underwent 48 weeks of treatment (orally BID), with dose calculated according to patient weight. Patient clinic visits occurred every 4 weeks, and phone calls took place between visits to monitor compliance. After 48 weeks of treatment, the dose was tapered to 0 within 3 weeks. A final evaluation visit occurred 2 weeks after last dose for a total of 53 weeks on study.

• Sickle Cell Anemia
• Sickle ß0-Thalassemia

• Drug: L-glutamine
  0.3 g/kg of L-glutamine will be administered twice a day orally to each patient for 48 weeks. The dosage will be in increments of 5 grams based on weight. The upper limit for daily dose of study medication will be set at 30 grams. Patients will be given verbal and written instructions for self-administration of the study medication at the Baseline visit. The powder can be mixed with water or most non-heated beverages other than alcohol, or can be mixed with most non-heated foods such as yogurt, applesauce, or cereal for administration. Mixing L-glutamine with soda or highly acidic juices (such as grapefruit juice or lemonade) is not recommended.
  Other Name: oral L-glutamine
• Drug: Placebo
  0.3 g/kg of placebo (100% maltodextrin) will be administered twice a day orally to each patient for 48 weeks. The dosage will be in increments of 5 grams based on weight. The upper limit for daily dose of study medication will be set at 30 grams. Patients will be given verbal and written instructions for self-administration of the study medication at the Baseline visit. The powder can be mixed with water or most non-heated beverages other than alcohol, or can be mixed with most non-heated foods such as yogurt, applesauce, or cereal for administration.
  Other Name: Maltodextrin

• Experimental: L-glutamine
  Patients will be randomized to receive investigational product, L-Glutamine.
  Intervention: Drug: L-glutamine
• Placebo Comparator: 100% maltodextrin
  Patients will be randomized to receive Placebo.
  Intervention: Drug: Placebo

Inclusion Criteria:

• Patient is at least five years of age.
• Patient has been diagnosed with sickle cell anemia or sickle ß°-thalassemia (documented by hemoglobin electrophoresis).
• Patient has had at least two documented episodes of sickle cell 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 duration of the study.
• 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 avoid pregnancy during the study and is willing and agrees to practice a recognized form of birth control during the course of the study (e.g. barrier, birth control pills, abstinence).

Exclusion Criteria:

• Patient has a significant medical condition that required hospitalization (other than sickle cell crisis) within two months of the screening visit.
• Patient has prothrombin time 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 uncontrolled liver disease or renal insufficiency.
• Patient is pregnant or lactating or has the intention of becoming pregnant during the study (if female and of child-bearing potential).
• Patient is currently taking or has been treated with any form of glutamine supplement within 30 days of the screening visit.
• Patient has been treated with an experimental anti-sickling medication/ treatment within 30 days of the screening visit (with the exception of hydroxyurea in pediatric patients).
• Patient is currently taking or has been treated with an investigational drug within 30 days of the screening visit (with the exception of hydroxyurea in pediatric patients).
• Patient 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.
• 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.