Sickle Cell DiseasePhase 3STArTNCT04839354
Sickle Cell Disease Treatment With Arginine Therapy (STArT) Trial
A Phase 3 study testing L-Arginine Hydrochloride and Normal saline in people with Sickle Cell Disease, run by Claudia R. Morris at 10 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 3 to 21 years
- Conditions the study is for
- Sickle Cell Disease
- What is being tested?
- L-Arginine Hydrochloride and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 271 participants
- Where
- 10 sitesUnited States
- Study dates
- 21 Jun 2021to 11 Jul 2024
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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)
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- 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
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
Children's Healthcare of Atlanta at Hughes Spalding
Atlanta, Georgia, 03322
Children's Healthcare of Atlanta at Egleston
Atlanta, Georgia, 30322
Nationwide Children's Hospital
Columbus, Ohio, 43205
Texas Children's Hospital/Baylor College of Medicine
Houston, Texas, 77030
Children's Hospital Los Angeles
Los Angeles, California, 90027
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
UCSF Benioff Children's Hospital
San Francisco, California, 94158
Washington University/St. Louis Children's Hospital
St Louis, Missouri, 63110
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Medical College of Wisconsin/Wisconsin Children's Hospital
Wauwatosa, Wisconsin, 53226
About this study
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.
Read the 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.
- Conditions
- Sickle Cell Disease
- Being tested
- L-Arginine Hydrochloride, Normal saline
- Keywords
- Arginine Therapy, Pain management
- Medical subject headings
- Anemia, Sickle Cell, Agnosia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-Arginine HydrochlorideDrug
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).
Normal salineOther
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).
| Study group | Role | What they receive |
|---|---|---|
| L-Arginine Hydrochloride | Experimental | Participants receiving L-arginine hydrochloride in parenteral form. Participants receive up to 21 doses, with participants who are discharged early receiving fewer doses. Receives: Drug: L-Arginine Hydrochloride |
| Placebo | Placebo comparator | 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. Receives: Other: Normal saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From study drug delivery to last IV opioid treatment (up to 1,724.1 hours)
Secondary outcomes (5)
Total Parenteral Opioid Use
Total parenteral opioid use is assessed as morphine equivalents in milligrams per kilogram (mg/kg).
Measured: From the time of IV placement throughout opioid treatment (up to 1,724.1 hours)
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.
Measured: Time of presentation and on the day of discharge (up to 554.8 days)
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.
Measured: Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days)
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.
Measured: Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days)
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.
Measured: Within 12 hours of study drug delivery and on the day of discharge (up to 554.8 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2021
- Study start21 Jun 2021
- Primary completion11 Jul 2024
- Study completion11 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 271 participants (actual)
Sponsor and investigators
- Lead sponsor
- Claudia R. Morris
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor-investigator, Claudia R. Morris, Emory University
- Investigators
- Claudia Morris, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04839354
- Sponsor's protocol ID
- STUDY00002344
- Other IDs
- PECARN Protocol Number 050, UG3HL148560, 2021P003315
- Acronym
- STArT
- Status last verified
- May 2026
- First submitted
- 8 Apr 2021
- Last updated
- 23 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual participant data that underlie the results published for this study will be made available for sharing with other researchers.
Publications
Korman R, Hatabah D, Brown LA, Harris F, Wilkinson H, Rees CA, Bakshi N, Archer DR, Dampier C, Morris CR. Impact of arginine therapy on kyotorphin in children with sickle cell disease and vaso-occlusive pain. Blood Adv. 2024 Jun 25;8(12):3267-3271. doi: 10.1182/bloodadvances.2023012209.
PubMed 38527291Onalo R, Cilliers A, Cooper P, Morris CR. Arginine Therapy and Cardiopulmonary Hemodynamics in Hospitalized Children with Sickle Cell Anemia: A Prospective, Double-blinded, Randomized Placebo-controlled Clinical Trial. Am J Respir Crit Care Med. 2022 Jul 1;206(1):70-80. doi: 10.1164/rccm.202108-1930OC.
PubMed 35426778Reyes LZ, Figueroa J, Leake D, Khemani K, Kumari P, Bakshi N, Lane PA, Dampier C, Morris CR. Safety of intravenous arginine therapy in children with sickle cell disease hospitalized for vaso-occlusive pain: A randomized placebo-controlled trial in progress. Am J Hematol. 2022 Jan 1;97(1):E21-E24. doi: 10.1002/ajh.26396. Epub 2021 Nov 12. No abstract available.
PubMed 34724240Morris CR, Brown LAS, Reynolds M, Dampier CD, Lane PA, Watt A, Kumari P, Harris F, Manoranjithan S, Mendis RD, Figueroa J, Shiva S. Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain. Blood. 2020 Sep 17;136(12):1402-1406. doi: 10.1182/blood.2019003672.
PubMed 32384147Onalo R, Cooper P, Cilliers A, Vorster BC, Uche NA, Oluseyi OO, Onalo VD, Zubairu Y, Ayodele-Kehinde AU, Damilare OM, Figueroa J, Morris CR. Randomized control trial of oral arginine therapy for children with sickle cell anemia hospitalized for pain in Nigeria. Am J Hematol. 2021 Jan;96(1):89-97. doi: 10.1002/ajh.26028. Epub 2020 Nov 20.
PubMed 33075179Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005 Jul 6;294(1):81-90. doi: 10.1001/jama.294.1.81.
PubMed 15998894Morris CR, Kuypers FA, Lavrisha L, Ansari M, Sweeters N, Stewart M, Gildengorin G, Neumayr L, Vichinsky EP. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica. 2013 Sep;98(9):1375-82. doi: 10.3324/haematol.2013.086637. Epub 2013 May 3.
PubMed 23645695Sadeghi A, Taherifard E, Dehdari Ebrahimi N, Rafiei E, Hadianfard F, Taherifard E. Effects of l-arginine supplementation in patients with sickle cell disease: A systematic review and meta-analysis of clinical trials. Health Sci Rep. 2023 Apr 11;6(4):e1167. doi: 10.1002/hsr2.1167. eCollection 2023 Apr.
PubMed 37064309Onalo R, Cilliers A, Cooper P. Impact of oral L-arginine supplementation on blood pressure dynamics in children with severe sickle cell vaso-occlusive crisis. Am J Cardiovasc Dis. 2021 Feb 15;11(1):136-147. eCollection 2021.
PubMed 33815929Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med. 2003 Jul 1;168(1):63-9. doi: 10.1164/rccm.200208-967OC. Epub 2003 Mar 5.
PubMed 12626350Rees CA, Brousseau DC, Cohen DM, Villella A, Dampier C, Brown K, Campbell A, Chumpitazi CE, Airewele G, Chang T, Denton C, Ellison A, Thompson A, Ahmad F, Bakshi N, Coleman KD, Leibovich S, Leake D, Hatabah D, Wilkinson H, Robinson M, Casper TC, Vichinsky E, Morris CR; SCD Arginine Study Group and PECARN. Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial. Trials. 2023 Aug 17;24(1):538. doi: 10.1186/s13063-023-07538-z.
PubMed 37587492Rees CA, Hatabah D, Korman R, Ahmad F, Airewele G, Akinsola B, Alzraikat N, Bakshi N, Brousseau DC, Brown K, Campbell AD, Casper TC, Chang TP, Chumpitazi CE, Cohen D, Coleman KD, Cruz AT, Denton C, Ellison A, Fields ME, Harding M, Leibovich S, Remiker A, Singh NV, Thompson AA, Vichinsky E, Villella A, Wynn B, Dampier C, Morris CR; Pediatric Emergency Care Research Network (PECARN). Hospital Variations in Time-To-Crisis-Resolution Among Children and Adolescents With Sickle Cell Disease. Am J Hematol. 2026 Jan;101(1):206-212. doi: 10.1002/ajh.70129. Epub 2025 Nov 5.
PubMed 41190764Morris CR, Hatabah D, Korman R, Ahmad FA, Airewele G, Akinsola B, Alzraikat N, Bakshi N, Brousseau DC, Brown K, Campbell AD, Casper TC, Chang TP, Chumpitazi CE, Cohen D, Coleman KD, Covelo L, Cruz AT, Denton C, Ellison AM, Fields M, Jensen H, Leibovich S, Rees CA, Remiker A, Singh N, Thompson A, Vichinsky E, Villella A, Wilkinson H, Wynn B, Dampier C; Pediatric Emergency Care Applied Research Network (PECARN). Arginine Therapy for Sickle Cell Disease Acute Pain Episodes: The STArT Randomized Clinical Trial. JAMA. 2026 Aug 19:e2613310. doi: 10.1001/jama.2026.13310. Online ahead of print.
PubMed 42616542Bolarinwa AB, Oduwole O, Okebe J, Ogbenna AA, Otokiti OE, Olatinwo AT. Antioxidant supplementation for sickle cell disease. Cochrane Database Syst Rev. 2024 May 22;5(5):CD013590. doi: 10.1002/14651858.CD013590.pub2.
PubMed 38775255