Sickle Cell Disease
Conditions
Keywords
Arginine Therapy, Pain management
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.
Interventions
A one-time L-arginine hydrochloride loading dose of 200 mg/kg will be administered intravenously (IV) followed by a standard dose of 100 mg/kg given by IV three times per day (TID).
OTHERNormal saline
A placebo of normal saline will be administered by IV with a loading dose of 2ml/kg followed by 1ml/kg given by IV three times per day (TID).
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Claudia R. Morris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-crisis Resolution | From study drug delivery to last IV opioid treatment (up to 1,724.1 hours) | 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
| Measure | Time frame | Description |
|---|---|---|
| Total Parenteral Opioid Use | From the time of IV placement throughout opioid treatment (up to 1,724.1 hours) | Total parenteral opioid use is assessed as morphine equivalents in milligrams per kilogram (mg/kg). |
| Change in Pain Score | Time of presentation and on the day of discharge (up to 554.8 days) | 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. The change in score is calculated by subtracting the score at discharge from the score at the time of presentation. |
| Change in 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 554.8 days) | 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. The change in score is calculated by subtracting the score at the time of discharge from the score from within 12 hours of study drug delivery. The change in score is calculated by subtracting the score at discharge from the score within 12 hours of study drug delivery. |
| Change in PROMIS Pain Behavior Score | Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days) | 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. The change in score is calculated by subtracting the score at discharge from the score within 12 hours of study drug delivery. |
| Change in PROMIS Fatigue Score | Within 12 hours of study drug delivery and on the day of discharge (up to 554.8 days) | 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. The change in score is calculated by subtracting the score at discharge from the score within 12 hours of study drug delivery. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Medication Quantification Score (MQS) | Pre-dose and on day of discharge (up to 2 months) | Medication Quantification Score (MQS) is a tool to objectively quantify pain. The MQS is a validated score calculated based off of daily doses of pain related medications (including acetaminophen, aspirin, NSAIDs, and antidepressants). The MQS is a single numeric value for a patient's pain medication profile. This number is used to track pain levels through a treatment course. |
| Mitochondrial Function | Pre-Dose, Day 2, after 21 doses (Day 7 or 8) or at discharge (if discharged prior to Dose 21) | Mitochondrial respiratory complex activities are measured to estimate mitochondrial function. |
| Hospital Length of Stay | Up to 6 months | Hospital length of stay in days is recorded. |
| Pediatric PROMIS Score | Within 12 hours of study drug delivery and on the day of discharge (up to 2 months) | The Pediatric PROMIS assesses five domains of health with in a 35-item instrument. The survey is completed by patients ages 8-17 years of age and parents of children ages 5-17 years of age. The domains included are: pain behavior (8 items), pain interference (8 items), pain intensity (1 item), physical stress experiences (8 items), and fatigue (10 items). 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 the concept being measured compared to the reference population, while scores higher than 50 indicate a greater amount of the concept being measured (e.g., more fatigue) compared to the reference population. |
| PedsQL SCD Pain and Hurt Scale Score | Within 12 hours of study drug delivery and on the day of discharge (up to 2 months) | The Pain and Hurt scale of the PedsQL SCD module has 9 items asking how much of a problem each item has been during the past month. Responses to items are given on a 5-point Likert scale where 0 = never a problem and 4 = almost always a problem. Items are reversed and transformed to a scale of 0 to 100 then the mean score for the scale is calculated. The total score for the Pain and Hurt scale ranges from 0 to 100 with higher scores indicating greater quality of life and lower SCD symptoms. |
| PedsQL SCD Pain Impact Scale Score | Within 12 hours of study drug delivery and on the day of discharge (up to 2 months) | The Pain Impact scale of the PedsQL SCD module has 10 items asking how much of a problem each item has been during the past month. Responses to items are given on a 5-point Likert scale where 0 = never a problem and 4 = almost always a problem. Items are reversed and transformed to a scale of 0 to 100 then the mean score for the scale is calculated. The total score for the Pain Impact scale ranges from 0 to 100 with higher scores indicating greater quality of life and lower SCD symptoms. |
| Arginine Bioavailability | Pre-Dose, Day 2, after 21 doses (Day 7 or 8) or at discharge (if discharged prior to Dose 21) | Peak plasma arginine concentration is assessed via pharmacokinetic study. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from ten children's hospitals in the United States. Participant enrollment began June 21, 2021 and all follow-up assessments were completed by July 11, 2024.
Participants by arm
| Arm | Count |
|---|---|
| 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. A one-time L-arginine hydrochloride loading dose of 200 mg/kg is administered intravenously (IV) followed by a standard dose of 100 mg/kg given by IV three times per day (TID). | 129 |
| Placebo 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. A placebo of normal saline is administered by IV with a loading dose of 2ml/kg followed by 1ml/kg given by IV three times per day (TID). | 142 |
| Total | 271 |
Baseline characteristics
| Characteristic | L-Arginine Hydrochloride | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 14.8 years | 15.2 years | 15.1 years |
| Age, Customized 12 to 21 years old | 93 Participants | 100 Participants | 193 Participants |
| Age, Customized Under 12 years old | 36 Participants | 42 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 7 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 115 Participants | 135 Participants | 250 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 115 Participants | 134 Participants | 249 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 8 Participants |
| Region of Enrollment United States | 129 participants | 142 participants | 271 participants |
| Sex: Female, Male Female | 70 Participants | 62 Participants | 132 Participants |
| Sex: Female, Male Male | 59 Participants | 80 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 129 | 0 / 142 |
| other Total, other adverse events | 81 / 129 | 83 / 142 |
| serious Total, serious adverse events | 22 / 129 | 25 / 142 |
Outcome results
Primary
Time-to-crisis Resolution
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.
Time frame: From study drug delivery to last IV opioid treatment (up to 1,724.1 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine Hydrochloride | Time-to-crisis Resolution | 81.5 hours | Standard Deviation 79.6 |
| Placebo | Time-to-crisis Resolution | 88.6 hours | Standard Deviation 152.2 |
Secondary
Change in Pain Score
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. The change in score is calculated by subtracting the score at discharge from the score at the time of presentation.
Time frame: Time of presentation and on the day of discharge (up to 554.8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine Hydrochloride | Change in Pain Score | 3.5 score on a scale | Standard Deviation 3.3 |
| Placebo | Change in Pain Score | 3.7 score on a scale | Standard Deviation 3.3 |
Secondary
Change in Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Score
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. The change in score is calculated by subtracting the score at the time of discharge from the score from within 12 hours of study drug delivery. The change in score is calculated by subtracting the score at discharge from the score within 12 hours of study drug delivery.
Time frame: Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine Hydrochloride | Change in Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Score | 3.5 score on a scale | Standard Deviation 3.3 |
| Placebo | Change in Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Score | 3.7 score on a scale | Standard Deviation 3.3 |
Secondary
Change in PROMIS Fatigue Score
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. The change in score is calculated by subtracting the score at discharge from the score within 12 hours of study drug delivery.
Time frame: Within 12 hours of study drug delivery and on the day of discharge (up to 554.8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine Hydrochloride | Change in PROMIS Fatigue Score | -0.4 score on a scale | Standard Deviation 8.1 |
| Placebo | Change in PROMIS Fatigue Score | 0.1 score on a scale | Standard Deviation 9.1 |
Secondary
Change in PROMIS Pain Behavior Score
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. The change in score is calculated by subtracting the score at discharge from the score within 12 hours of study drug delivery.
Time frame: Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine Hydrochloride | Change in PROMIS Pain Behavior Score | 0.8 score on a scale | Standard Deviation 6.8 |
| Placebo | Change in PROMIS Pain Behavior Score | 1.0 score on a scale | Standard Deviation 7.1 |
Secondary
Total Parenteral Opioid Use
Total parenteral opioid use is assessed as morphine equivalents in milligrams per kilogram (mg/kg).
Time frame: From the time of IV placement throughout opioid treatment (up to 1,724.1 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine Hydrochloride | Total Parenteral Opioid Use | 2.6 milligrams per kilogram (mg/kg) | Standard Deviation 4.5 |
| Placebo | Total Parenteral Opioid Use | 1.9 milligrams per kilogram (mg/kg) | Standard Deviation 2.8 |
Other Pre-specified
Arginine Bioavailability
Peak plasma arginine concentration is assessed via pharmacokinetic study.
Time frame: Pre-Dose, Day 2, after 21 doses (Day 7 or 8) or at discharge (if discharged prior to Dose 21)
Other Pre-specified
Hospital Length of Stay
Hospital length of stay in days is recorded.
Time frame: Up to 6 months
Other Pre-specified
Medication Quantification Score (MQS)
Medication Quantification Score (MQS) is a tool to objectively quantify pain. The MQS is a validated score calculated based off of daily doses of pain related medications (including acetaminophen, aspirin, NSAIDs, and antidepressants). The MQS is a single numeric value for a patient's pain medication profile. This number is used to track pain levels through a treatment course.
Time frame: Pre-dose and on day of discharge (up to 2 months)
Other Pre-specified
Mitochondrial Function
Mitochondrial respiratory complex activities are measured to estimate mitochondrial function.
Time frame: Pre-Dose, Day 2, after 21 doses (Day 7 or 8) or at discharge (if discharged prior to Dose 21)
Other Pre-specified
Pediatric PROMIS Score
The Pediatric PROMIS assesses five domains of health with in a 35-item instrument. The survey is completed by patients ages 8-17 years of age and parents of children ages 5-17 years of age. The domains included are: pain behavior (8 items), pain interference (8 items), pain intensity (1 item), physical stress experiences (8 items), and fatigue (10 items). 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 the concept being measured compared to the reference population, while scores higher than 50 indicate a greater amount of the concept being measured (e.g., more fatigue) compared to the reference population.
Time frame: Within 12 hours of study drug delivery and on the day of discharge (up to 2 months)
Other Pre-specified
PedsQL SCD Pain and Hurt Scale Score
The Pain and Hurt scale of the PedsQL SCD module has 9 items asking how much of a problem each item has been during the past month. Responses to items are given on a 5-point Likert scale where 0 = never a problem and 4 = almost always a problem. Items are reversed and transformed to a scale of 0 to 100 then the mean score for the scale is calculated. The total score for the Pain and Hurt scale ranges from 0 to 100 with higher scores indicating greater quality of life and lower SCD symptoms.
Time frame: Within 12 hours of study drug delivery and on the day of discharge (up to 2 months)
Other Pre-specified
PedsQL SCD Pain Impact Scale Score
The Pain Impact scale of the PedsQL SCD module has 10 items asking how much of a problem each item has been during the past month. Responses to items are given on a 5-point Likert scale where 0 = never a problem and 4 = almost always a problem. Items are reversed and transformed to a scale of 0 to 100 then the mean score for the scale is calculated. The total score for the Pain Impact scale ranges from 0 to 100 with higher scores indicating greater quality of life and lower SCD symptoms.
Time frame: Within 12 hours of study drug delivery and on the day of discharge (up to 2 months)