Pulmonary Hypertension, Sickle Cell Disease, Thalassemia
Conditions
Keywords
Pulmonary Hypertension, Sickle Cell Disease, Thalassemia
Brief summary
The primary hypothesis of this study is that glutamine supplementation will improve the erythrocyte glutamine/glutamate ratio, a biomarker of oxidative stress, hemolysis and pulmonary hypertension (PH) in sickle cell disease (SCD) and thalassemia (Thal) patients with PH. PH is defined as a tricuspid regurgitant jet velocity (TRV) on Doppler echocardiography \> 2.5 m/s. We also predict that glutamine therapy will increase arginine bioavailability and subsequently alter sickle red cell endothelial interaction that can be identified using endo-PAT technology through nitric oxide (NO) generation, leading to changes in biological markers, and clinical outcome. Specifically our second hypothesis is that oral glutamine will decrease biomarkers of hemolysis and adhesion molecules, and improve the imbalanced arginine-to-ornithine ratio that occurs in hemolytic anemias, leading to improved arginine bioavailability and clinical endpoints of endothelial dysfunction and PH in patients with SCD and Thal.
Interventions
DRUGL-Glutamine
Oral L-glutamine 10 grams TID or (0.1g/kg TID) for children \< 15 years of age.
Sponsors
Food and Drug Administration (FDA)
UCSF Benioff Children's Hospital Oakland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Established diagnosis of SCD (Hb SS, SC or SBeta- thalassemia) or Thal * PH documented by echocardiography, defined as at TRV greater than 2.5 m/s * Age greater than or equal to 4 years
Exclusion criteria
* Inability to take or tolerate oral medication * Acute crisis or hospitalization within 1 month of enrollment * Hepatic dysfunction (SGPT greater than 3X normal) * Renal dysfunction (Creatinine greater than 2X normal) * Allergy to glutamine * Pregnancy or breastfeeding * Patients on sildenafil (Viagra), calcium channel blockers, or amino acid/protein supplements (other therapies acceptable if stable more than 3 months)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Erythrocyte Glutamine/Glutamate Ratio at 8 Weeks | 8 weeks | Erythrocyte Glutamine/Glutamate Ratio: a novel biomarker of oxidative stress |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glutamine | 8 weeks | — |
| Tricuspid Regurgitant Jet Velocity on Doppler Echocardiography | 8 week | Tricuspid Regurgitant Jet Velocity was measured using Doppler Echocardiography in meters per second. |
| 6 Minute Walk Distance | 8 weeks | The six-minute walk test (6MWT) measures the distance in meters an individual is able to walk over a total of six minutes on a hard, flat surface. |
| Liver Function Tests | 8 weeks | Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) |
| Renal Function Tests | 8 weeks | Creatinine Blood urea nitrogen (BUN) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment: L-glutamine Patients will receive an 8-week course of oral L-glutamine 10 grams TID
L-Glutamine: Oral L-glutamine 10 grams TID or (0.1g/kg TID) for children \< 15 years of age. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Treatment: L-glutamine |
|---|---|
| 6 Minute Walk Distance | 386 Meters STANDARD_DEVIATION 94 |
| Age, Continuous | 45.8 years STANDARD_DEVIATION 13.8 |
| Erythrocyte Glutamine/Glutamate Ratio | 1.75 Ratio STANDARD_DEVIATION 0.6 |
| Liver Function Tests Alanine aminotransferase (ALT) | 40 U/L STANDARD_DEVIATION 42 |
| Liver Function Tests Aspartate aminotransferase (AST) | 73 U/L STANDARD_DEVIATION 40 |
| Plasma Glutamine | 704.5 µmol/L STANDARD_DEVIATION 137 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 13 participants |
| Renal Function Tests Blood urea nitrogen (BUN) | 14 mg/dL STANDARD_DEVIATION 10 |
| Renal Function Tests Creatinine | 0.9 mg/dL STANDARD_DEVIATION 0.4 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 5 Participants |
| Tricuspid Regurgitant Jet Velocity on Doppler Echocardiography | 3.0 Meters per second STANDARD_DEVIATION 0.6 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 13 |
| other Total, other adverse events | 1 / 13 |
| serious Total, serious adverse events | 4 / 13 |
Outcome results
Primary
Erythrocyte Glutamine/Glutamate Ratio at 8 Weeks
Erythrocyte Glutamine/Glutamate Ratio: a novel biomarker of oxidative stress
Time frame: 8 weeks
Population: Blood work only available for N=6 participants, as reported here.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: L-glutamine | Erythrocyte Glutamine/Glutamate Ratio at 8 Weeks | 2.40 Ratio | Standard Deviation 1.6 |
Secondary
6 Minute Walk Distance
The six-minute walk test (6MWT) measures the distance in meters an individual is able to walk over a total of six minutes on a hard, flat surface.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: L-glutamine | 6 Minute Walk Distance | 366 Meters | Standard Deviation 109 |
Secondary
Liver Function Tests
Alanine aminotransferase (ALT) Aspartate aminotransferase (AST)
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment: L-glutamine | Liver Function Tests | ALT | 38 U/L | Standard Deviation 27 |
| Treatment: L-glutamine | Liver Function Tests | AST | 63 U/L | Standard Deviation 26 |
Secondary
Plasma Glutamine
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: L-glutamine | Plasma Glutamine | 685.8 µmol/L | Standard Deviation 139 |
Secondary
Renal Function Tests
Creatinine Blood urea nitrogen (BUN)
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment: L-glutamine | Renal Function Tests | Creatinine | 0.9 mg/dL | Standard Deviation 0.3 |
| Treatment: L-glutamine | Renal Function Tests | BUN | 17 mg/dL | Standard Deviation 7 |
Secondary
Tricuspid Regurgitant Jet Velocity on Doppler Echocardiography
Tricuspid Regurgitant Jet Velocity was measured using Doppler Echocardiography in meters per second.
Time frame: 8 week
Population: Data available for 11 participants only because one patient missed their appointment for their week 8 echocardiogram and was lost to follow up, and another patient died of sepsis before week 8 visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: L-glutamine | Tricuspid Regurgitant Jet Velocity on Doppler Echocardiography | 2.8 Meters per second | Standard Deviation 0.5 |