Sickle Cell Disease Treatment With Arginine Therapy (STArT) Trial

Sickle Cell Disease Clinical Trial

— STArT  

Official title:

Sickle Cell Disease Treatment With Arginine Therapy (STArT) Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04839354
• Other study ID #: STUDY00002344
• Secondary ID: PECARN Protocol
• Status: Recruiting
• Phase: Phase 3
• Start date: June 21, 2021
• Est. completion date: April 2027

Study information

• Verified date: April 2024
• Source: Emory University
• Contact: Claudia Morris, MD
• Phone: 404-785-7141
• Email: claudia.r.morris[@]emory.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial of IV arginine therapy in children with Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) is designed to further knowledge on efficacy and safety of the therapy.

Description:

The trial is designed as a double-blind, placebo controlled, randomized, phase 3, multi-center trial of IV arginine therapy in children with Vaso-occlusive painful episodes (VOE) in sickle cell disease (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 (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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 360
• Est. completion date: April 2027
• Est. primary completion date: April 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 21 Years

Eligibility

Inclusion Criteria:

1. Age 3-21 years of age, inclusive; AND

2. Established diagnosis of sickle cell disease (any genotype); AND

3. Pain requiring medical care in an acute care setting (ED, 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; OR

4. Ketamine use in the emergency department for treatment of VOE; OR

5. Glutamine within 30 days; OR

6. New SCD drug use < 3 months (e.g. Hydroxyurea, voxelotor, crizanlizumab, etc) OR

7. Acute mental status or neurological changes; OR

8. Acute stroke or clinical concern for stroke; OR

9. Three or more ED visits for sickle cell related pain receiving parenteral opioids in previous 7 days (not including current ED visit); OR

10. Hospital discharge within previous 7 days; OR

11. Hypotension requiring clinical intervention; hemodynamic instability; septic shock; OR

12. Previous randomization in this arginine phase 3 RCT; OR

13. Use of inhaled nitric oxide, sildenafil or arginine within the last month; OR

14. Non-English or non-Spanish speaking; OR

15. pregnancy; OR

16. Allergy to arginine; OR

17. PI/clinical team concerns for compliance/issues that may adversely impact study participation/outcome; OR

18. Adults 18 years or older who lack medical decision-making capacity to consent

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Arginine Hydrochloride
One-time L-arginine loading dose (200 mg/kg IV) + standard dose (100 mg/kg IV TID)

Other:
• Normal saline
Placebo (normal saline) loading dose (2ml/kg IV) + 1ml/kg IV TID

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia
United States	Children's Healthcare of Atlanta at Hughes Spalding	Atlanta	Georgia
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Texas Children's Hospital/Baylor College of Medicine	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Washington University/St. Louis Children's Hospital	Saint Louis	Missouri
United States	UCSF Benioff Children's Hospital	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia
United States	Medical College of Wisconsin/Wisconsin Children's Hospital	Wauwatosa	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Claudia R. Morris	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (11)

Korman R, Hatabah D, Brown LA, Harris F, Wilkinson H, Rees CA, Bakshi N, Archer DR, Dampier CD, Morris CR. Impact of Arginine Therapy on Kyotorphin in Children with Sickle Cell Disease and Vasoocclusive Pain. Blood Adv. 2024 Mar 25:bloodadvances.2023012209. doi: 10.1182/bloodadvances.2023012209. Online ahead of print. No abstract available. — View Citation

Morris 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. — View Citation

Morris 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. — View Citation

Morris 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. — View Citation

Morris 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. — View Citation

Onalo 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. — View Citation

Onalo 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. — View Citation

Onalo 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. — View Citation

Rees 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 — View Citation

Reyes 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. — View Citation

Sadeghi 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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Medication Quantification Score (MQS)	Medication Quantification Score (MQS) is a tool to objectively quantify pain. It computes a single numeric value for a patient's pain medication profile. This number is used to track pain levels through a treatment course.	Pre-dose and on day of discharge up to 2 months
Other	Hospital length of stay in children	Hospital length of stay in children (days) will be recorded.	Up to 6 months
Other	Change in Pediatric PROMIS score	Pediatric PROMIS: (35 items) To be completed by patients ages 8-17 years of age and parents of children ages 5-17 years of age: (a)pain behavior (8 items), (b)pain interference (8 items), (c)pain intensity (1 item), (d)physical stress experiences (8 items), (e)fatigue (10 items). PROMIS measures are scored on the T-score metric. High scores mean more of the concept being measured (e.g., more fatigue).	Within 12 hours of study drug delivery, and on the day of discharge up to 2 months
Other	Change in Pediatric QL SCD score	Peds QL SCD module (19 items) to be completed by children ages 5-17 years of age and parents of children ages 3-17 years of age: (a)Pain and Hurt (9 items), (b)Pain Impact (10 items)	Within 12 hours of study drug delivery, and on the day of discharge up to 2 months
Other	Change in Arginine bioavailability	Pharmacokinetic study will measure peak plasma arginine concentration	Prior to study drug delivery (pre-Dose), on day 2 and prior to discharge up to 2 months
Other	Change in mitochondrial function	Mitochondrial respiratory complex activities will be measured to estimate mitochondrial function	Prior to study drug delivery (pre-Dose), on day 2 and prior to discharge up to 2 months
Primary	Change in time-to-crisis resolution	Time in hours from study drug delivery to time of last dose of parenteral opioid delivery	Date and time of first study drug administration and last IV opioid treatment - up to 2 months
Secondary	Change in total parenteral opioid use	Total parenteral opioid use (morphine equivalents, mg/kg)	Time of IV placement, opioid monitoring up to 2 months
Secondary	Change in pain scores	Daily highest and lowest pain scores will be recorded. 0-10 scale, 10 is strongest pain	Time of IV placement, and on the day of discharge up to 2 months
Secondary	Change in PROMIS Pain Interference score	PROMIS: pain Interference (8 items). PROMIS measures are scored on the T-score metric. High scores mean more of the concept being measured (e.g., more pain).	Within 12 hours of study drug delivery, and on the day of discharge up to 2 months
Secondary	Change in PROMIS Pain Behavior score	PROMIS: pain behavior (8 items). PROMIS measures are scored on the T-score metric. High scores mean more of the concept being measured (e.g., more pain)	Within 12 hours of study drug delivery, and on the day of discharge up to 2 months
Secondary	Change in PROMIS Fatigue score	PROMIS: fatigue (8 items). PROMIS measures are scored on the T-score metric. High scores mean more of the concept being measured (e.g., more fatigue).	Within 12 hours of study drug delivery, and on the day of discharge up to 2 months