Safety and Efficacy of Sodium Nitrite in Sickle Cell Disease

NCT01033227 | Terminated Phase 1 Results DMC

• 1 other identifier: SN-SC-02-01
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This study will determine if administration of sodium nitrite is safe and can improve small vessel blood flow and tissue oxygenation when given as an additional treatment in patients with acute vaso-occlusive crisis (pain crisis) associated with sickle cell disease.

Conditions

Sickle Cell Disease

Keywords

sickle cell disease; sickle cell anemia; pain crisis; nitric oxide; nitrite; vaso occlusive crisis; pain medication; sickled cells; blood flow; microcirculation

Outcome Measures

Primary Outcomes (1)

• 48 Hour Sodium Nitrite Infusion Safety as Determined by Number of Participants With No Adverse Events

  The primary end points will be to determine if a) a 48-hour sodium nitrite infusion is tolerated without a decrease in mean arterial blood pressure by 15mmHg for greater than 2 hours or development of methemoglobin greater than 5% and b) a 48-hour sodium nitrite infusion is safe as determined by monitoring for adverse events

  48 hours from start of infusion

Secondary Outcomes (1)

• Secondary End Point

  48 hours

Study Arms (2)

No drug

NO INTERVENTION

No study drug administered

Sodium nitrite injection, USP

EXPERIMENTAL

Administration if sodium nitrite injection, USP

Drug: sodium nitrite injection, usp

Interventions

sodium nitrite injection, usp DRUG

Sodium nitrite injection, USP will be administered in blocks of six subjects (3 sodium nitrite and 3 no drug). A total of five dose levels are planned, pending safety starting. Drug will be given by continuous infusion infusion for 48 hours starting at 6 nmol/min/kg (10% of the maximal tolerated dose).

Also known as: sodium nitrite

Sodium nitrite injection, USP

Eligibility Criteria

• Age: 8 Years - 23 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subjects meeting all of the following criteria will be considered for admission to the study:
• Male or female subject aged between 8 and 23 years of age; only patients up to the age of 23 will be studied at Childrens Hospital Los Angeles
• Electrophoretic diagnosis of sickle cell disease;
• Sudden onset of acute pain involving \>=1 sites typical of vaso-occlusive crisis (Vaso-occlusive crisis is defined as acute, severe pain in the extremities, chest, abdomen, or back that can not be explained by other complications of sickle cell disease or by a cause other than sickle cell disease.);
• Severe pain requiring parenteral analgesics and hospitalization.
• Informed consent obtained from a legal representative or from subjects 18 years of age or older before enrollment;
• Being willing and able to be followed for at least 30 days for evaluation.

You may not qualify if:

• Subjects presenting with any of the following will not be included in the study:
• Clinically significant bleeding;
• Current drug abuse or participation in methadone program;
• Episode of pain requiring hospitalization within 2 weeks prior to current admission;
• Other complications of sickle cell disease including cerebrovascular accident, pulmonary hypertension, or seizure;
• Pregnancy (confirmed by a serum human chorionic gonadotropin pregnancy test) or breast feeding;
• Blood pressure less than 25th percentile for the subject's age and sex on admission or at the time of screening;
• Methemoglobinemia \>3%;
• Anemia with hemoglobin level less than 6 g/dL;
• Red blood cell G6PD deficiency, by laboratory testing prior to enrollment;
• History of allergy to nitrites or allergy to other substances characterized by dyspnea and cyanosis;
• Treatment with allopurinol, a medication that could interfere with nitrite metabolism, within the past 30 days before screening;
• Treatment with any investigational drug within the past 30 days;
• Significant acute or chronic concomitant diseases (including renal, hepatic, cardiovascular, pulmonary, or oncologic disease, sepsis, pulmonary edema, pulmonary embolism) that would be inconsistent with survival for at least 6 months;
• Any subject judged by the clinical investigator or study manager to be inappropriate for the study.

Sponsors & Collaborators

• Children's Hospital Los Angeles: lead
• Hope Pharmaceuticals: collaborator

Study Sites (1)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Related Publications (15)

• Wood KC, Hsu LL, Gladwin MT. Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radic Biol Med. 2008 Apr 15;44(8):1506-28. doi: 10.1016/j.freeradbiomed.2008.01.008. Epub 2008 Jan 26.

  PMID: 18261470 BACKGROUND

• Mack AK, McGowan Ii VR, Tremonti CK, Ackah D, Barnett C, Machado RF, Gladwin MT, Kato GJ. Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study. Br J Haematol. 2008 Sep;142(6):971-8. doi: 10.1111/j.1365-2141.2008.07259.x. Epub 2008 Jul 11.

  PMID: 18671702 BACKGROUND

• Lundberg JO, Weitzberg E. Nitrite reduction to nitric oxide in the vasculature. Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H477-8. doi: 10.1152/ajpheart.00611.2008. Epub 2008 Jun 27. No abstract available.

  PMID: 18586886 BACKGROUND

• Hachiya T, Blaber AP, Saito M. Near-infrared spectroscopy provides an index of blood flow and vasoconstriction in calf skeletal muscle during lower body negative pressure. Acta Physiol (Oxf). 2008 Jun;193(2):117-27. doi: 10.1111/j.1748-1716.2007.01827.x. Epub 2007 Dec 19.

  PMID: 18162057 BACKGROUND

• Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008 Jan 5;371(9606):64-74. doi: 10.1016/S0140-6736(08)60073-2.

  PMID: 18177777 BACKGROUND

• Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood. 2007 Sep 15;110(6):2166-72. doi: 10.1182/blood-2006-12-061697. Epub 2007 May 29.

  PMID: 17536019 BACKGROUND

• Vanin AF, Bevers LM, Slama-Schwok A, van Faassen EE. Nitric oxide synthase reduces nitrite to NO under anoxia. Cell Mol Life Sci. 2007 Jan;64(1):96-103. doi: 10.1007/s00018-006-6374-2.

  PMID: 17160351 BACKGROUND

• Kato GJ, McGowan V, Machado RF, Little JA, Taylor J 6th, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006 Mar 15;107(6):2279-85. doi: 10.1182/blood-2005-06-2373. Epub 2005 Nov 15.

  PMID: 16291595 BACKGROUND

• Ferreira LF, Harper AJ, Townsend DK, Lutjemeier BJ, Barstow TJ. Kinetics of estimated human muscle capillary blood flow during recovery from exercise. Exp Physiol. 2005 Sep;90(5):715-26. doi: 10.1113/expphysiol.2005.030189. Epub 2005 May 20.

  PMID: 15908509 BACKGROUND

• Raj A, Bertolone SJ, Mangold S, Edmonds HL Jr. Assessment of cerebral tissue oxygenation in patients with sickle cell disease: effect of transfusion therapy. J Pediatr Hematol Oncol. 2004 May;26(5):279-83. doi: 10.1097/00043426-200405000-00004.

  PMID: 15111778 BACKGROUND

• Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic Biol Med. 2004 Mar 15;36(6):707-17. doi: 10.1016/j.freeradbiomed.2003.11.032.

  PMID: 14990351 BACKGROUND

• Gladwin MT, Lancaster JR Jr, Freeman BA, Schechter AN. Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med. 2003 May;9(5):496-500. doi: 10.1038/nm0503-496. No abstract available.

  PMID: 12724752 BACKGROUND

• Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003 Dec;9(12):1498-505. doi: 10.1038/nm954. Epub 2003 Nov 2.

  PMID: 14595407 BACKGROUND

• Gladwin MT, Schechter AN, Shelhamer JH, Ognibene FP. The acute chest syndrome in sickle cell disease. Possible role of nitric oxide in its pathophysiology and treatment. Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1368-76. doi: 10.1164/ajrccm.159.5.9810094. No abstract available.

  PMID: 10228097 BACKGROUND

• Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, Cabrales P, Fago A, Feelisch M, Ford PC, Freeman BA, Frenneaux M, Friedman J, Kelm M, Kevil CG, Kim-Shapiro DB, Kozlov AV, Lancaster JR Jr, Lefer DJ, McColl K, McCurry K, Patel RP, Petersson J, Rassaf T, Reutov VP, Richter-Addo GB, Schechter A, Shiva S, Tsuchiya K, van Faassen EE, Webb AJ, Zuckerbraun BS, Zweier JL, Weitzberg E. Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol. 2009 Dec;5(12):865-9. doi: 10.1038/nchembio.260.

  PMID: 19915529 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Vaso-Occlusive Crises

Interventions

Sodium Nitrite

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Nitrites; Nitrous Acid; Nitrogen Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Dr. Thomas Coates
• Organization: Children's Hospital Los Angeles

TCoates@chla.usc.edu

323 361 3841

Study Officials

• Thomas Coates, MD

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hematology Division Head

Study Record Dates

• First Submitted: December 15, 2009
• First Posted: December 16, 2009
• Study Start: December 1, 2009
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: October 17, 2017
• Results First Posted: February 8, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)