Sickle Cell Disease Treatment With Arginine Therapy (STArT) Trial
- Conditions
- Sickle Cell Disease
- Interventions
- Other: Normal saline
- Registration Number
- NCT04839354
- Lead Sponsor
- Claudia R. Morris
- Brief Summary
The trial is designed to test intravenous (IV) arginine therapy in children with sickle cell disease (SCD) and vaso-occlusive painful episodes (VOE) to further knowledge on efficacy and safety of this orphan drug.
- Detailed Description
Pain is a clinical hallmark of sickle cell disease (SCD), and a significant problem in emergency medicine. Vaso-occlusive painful episodes (VOE) are common, debilitating, and a medical emergency. VOE are the leading cause of hospitalizations, emergency department (ED) visits, missed school, and are associated with an increased mortality rate. Symptomatic relief with analgesics and hydration are the only currently available treatments, and these have not changed in decades. Episodic periods of severe pain lead to high use of health care resources, with high readmission rates. A 2010 health care utilization report revealed that 20% of patients with SCD experienced ≥3 ED encounters per year. Hospital admission rates for VOE are approximately 60% for children with SCD and VOE. Many children with SCD also live with daily pain to some extent that their families try to control at home through various methods. It is when the pain becomes acutely worse, and unbearable, that they present to the ED in acute distress.
A significant evidence gap exists for best treatment of VOE and novel approaches to SCD/VOE that can be utilized in the ED and hospital ward are critically needed. Interventions that target underlying mechanisms of SCD pain in addition to providing symptomatic relief are worth pursuing.
Vaso-occlusion is believed to be the root cause of sickle cell pain. Nitric oxide (NO) is a free radical and a potent vasodilator that regulates vascular homeostasis and plays a role in SCD vaso-occlusion. NO has properties that can impact every aspect of SCD, and NO dysregulation is a common denominator among varied mechanisms of sickle vasculopathy. NO is produced in the endothelium from its obligate substrate L-arginine, which is converted to citrulline by a family of enzymes, the NO synthases (NOS). Although NOS expression and activity is increased, SCD is characterized by a state of NO resistance, NO inactivation, and impaired NO bioavailability. Under conditions of increased hemolysis, inflammation or oxidative stress, the compensatory upregulation of NO likely becomes overwhelmed and ineffective. Vascular dysfunction is the end result, due to complex and multifactorial interactions.
SCD is an arginine deficiency syndrome. Normal arginine metabolism is impaired for many reasons. Plasma arginine concentration decreases significantly in both adults and children with VOE and is associated with low nitric oxide (NO) and nitrogen dioxide (NO2) levels (NOx). It was observed that lowest arginine levels were found in children requiring admission for VOE, with arginine levels returning to baseline during convalescence in the hospital. Of interest, low plasma arginine concentration alone was a sensitive predictor for admission, while NOx levels were not, suggesting a function for arginine bioavailability in VOE severity that goes beyond NO. Although adults with SCD are arginine deficient at steady-state, children have plasma levels that are similar to normal controls. Alterations in the arginine metabolome differ in children vs. adults. An arginine deficiency develops with age and is influenced by acute events and chronic end organ damage that worsens over time. Children may therefore be more responsive to arginine therapy during an acute pain event compared to adults.
Arginine is a safe nutritional supplement that is FDA approved in parenteral form for growth hormone stimulation testing, with nearly 50 years of safety experience through its common use by endocrinologists. Experience with both oral and parenteral arginine therapy in sickle cell disease is growing. When arginine is given to SCD patients at steady-state, a paradoxical decrease in NOx occurs that is not overcome by higher doses, clearly indicating that arginine is metabolized differently in SCD compared to controls. However when arginine is given during VOE, a robust dose-dependent increase in NOx is observed. This indicates that arginine is also metabolized differently in SCD at steady-state (baseline) compared to times of acute illness including pain. Low dose arginine therapy is likely to be subtherapeutic in SCD; higher levels of plasma arginine are likely needed to overcome multi-factorial effects on global arginine bioavailability, and accelerated arginine consumption during VOE compared to baseline.
The trial is designed as a double-blind, placebo controlled, randomized, phase 3, multi-center trial of IV arginine therapy in children with VOE in SCD to further knowledge on efficacy and safety of the therapy. The exploratory objective is to more fully characterize the arginine metabolome in children with SCD during VOE, and evaluate the effects of arginine therapy on global arginine bioavailability and mitochondrial function together with important clinical outcomes of time to VOE resolution, pain scores, total parenteral opioid use, Patient-Reported Outcomes (PROs), and hospital length of stay in children with SCD and VOE.
Participants are randomized to receive 21 doses of IV arginine or a placebo, administered over 7 to 8 days (depending on what time of day the study drug was first administered on Day 1). Participants will be followed for up to 28 days following hospital discharge.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 271
- Age 3-21 years of age, inclusive
- Established diagnosis of sickle cell disease (any genotype)
- 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
- Responds to 2 doses of IV opioids sufficiently for outpatient management
- Greater than 12 hours from first dose of intravenous opioids to treat current pain in acute care setting
- Hemoglobin less than 5 gm/dL or emergent need for red blood cell transfusion for hemodynamically unstable patient
- Ketamine use in the emergency department for treatment of VOE
- Glutamine within 30 days
- New SCD drug use < 3 months (e.g. Hydroxyurea, voxelotor, crizanlizumab, etc)
- Acute mental status or neurological changes
- Acute stroke or clinical concern for stroke
- Three or more ED visits for sickle cell related pain receiving parenteral opioids in previous 7 days (not including current emergency department visit)
- Hospital discharge within previous 7 days
- Hypotension requiring clinical intervention; hemodynamic instability; septic shock
- Previous randomization in this arginine phase 3 randomized controlled trial
- Use of inhaled nitric oxide, sildenafil or arginine within the last month
- Non-English speaking or requires a translator for clinical care
- Pregnancy
- Allergy to arginine
- PI/clinical team concerns for compliance/issues that may adversely impact study participation/outcome
- Adults 18 years or older who lack medical decision-making capacity to consent
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description L-Arginine Hydrochloride L-Arginine Hydrochloride Participants receiving L-arginine hydrochloride in parenteral form. Participants receive up to 21 doses, with participants who are discharged early receiving fewer doses. Placebo Normal saline Participants receiving normal saline as a placebo for L-arginine hydrochloride for up to 21 doses, with participants who are discharged early receiving fewer doses.
- Primary Outcome Measures
Name Time Method Time-to-crisis Resolution From study drug delivery to last IV opioid treatment (up to 2 months) The time-to-crisis resolution is defined as the time in hours from the date and time of the first study drug delivery to time of the last dose of parenteral opioid delivery.
- Secondary Outcome Measures
Name Time Method Total Parenteral Opioid Use From the time of IV placement throughout opioid treatment (up to 2 months) Total parenteral opioid use is assessed as morphine equivalents in milligrams per kilogram (mg/kg).
Pain Score Time of presentation and on the day of discharge (up to 2 months) Pain is assessed using a scale from 0 to 10, where 10 is the highest pain level. Daily highest and lowest pain scores are recorded.
Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Score Within 12 hours of study drug delivery, and on the day of discharge (up to 2 months) The PROMIS Pain Interference instrument is an 8-item, self-administered survey that assesses the interference of pain on daily activities. Participants are asked to respond to questions regarding the extent of their pain. Responses range from 1 to 5, where 1 represents "not at all" and 5 represents "very much". Total raw scores are converted to T-scores. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. Scores below 50 indicate a lower amount of pain interference compared to the reference population, while scores higher than 50 indicate greater pain interference compared to the reference population.
PROMIS Pain Behavior Score Within 12 hours of study drug delivery, and on the day of discharge (up to 2 months) The PROMIS Pain Behavior instrument is an 8-item, self-administered survey that assesses external manifestations of pain. Participants are asked to respond to questions regarding the extent of their pain. Responses range from 1 to 5, where 1 represents "never" and 5 represents "always". Total raw scores are converted to T-scores. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. Scores below 50 indicate a lower amount of pain behavior compared to the reference population, while scores higher than 50 indicate greater pain behavior compared to the reference population.
PROMIS Fatigue Score Within 12 hours of study drug delivery and on the day of discharge (up to 2 months) The PROMIS Fatigue instrument is an 8-item, self-administered survey that assesses fatigue level within the past seven days. Participants are asked to respond to questions regarding fatigue frequency. Responses range from 1 to 5, where 1 represents "never" and five represents "always". Total raw scores are converted to T-scores. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. Scores below 50 indicate a lower amount of fatigue compared to the reference population, while scores higher than 50 indicate greater fatigue compared to the reference population.
Trial Locations
- Locations (10)
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's Healthcare of Atlanta at Hughes Spalding
🇺🇸Atlanta, Georgia, United States
Children's Healthcare of Atlanta at Egleston
🇺🇸Atlanta, Georgia, United States
Washington University/St. Louis Children's Hospital
🇺🇸Saint Louis, Missouri, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Medical College of Wisconsin/Wisconsin Children's Hospital
🇺🇸Wauwatosa, Wisconsin, United States
UCSF Benioff Children's Hospital
🇺🇸San Francisco, California, United States
Texas Children's Hospital/Baylor College of Medicine
🇺🇸Houston, Texas, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States