Safety and Efficacy of Sodium Nitrite in Sickle Cell Disease

Sickle Cell Disease Clinical Trial

Official title:

A Safety and Efficacy Evaluation of Sodium Nitrite Injection for the Treatment of Vaso-Occlusive Crisis Associated With Sickle Cell Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01033227
• Other study ID #: SN-SC-02-01
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: December 15, 2009
• Last updated: September 15, 2017
• Start date: December 2009
• Est. completion date: June 2012

Study information

• Verified date: September 2017
• Source: Children's Hospital Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Nitric oxide (NO) is a naturally occuring chemical that relaxes blood vessels and helps improve blood flow.

The pain associated with vaso-occlusive crisis (pain crisis) in sickle cell disease is caused in part by lack of oxygen and increased tissue acid because blood flow is blocked by stiff sickle red cells. Administration of sodium nitrite should generate nitric oxide in this area of hypoxia and acidosis and improve blood flow.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 23 Years

Eligibility

Inclusion Criteria:

Subjects meeting all of the following criteria will be considered for admission to the study:

1. 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

2. Electrophoretic diagnosis of sickle cell disease;

3. 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.);

4. Severe pain requiring parenteral analgesics and hospitalization.

5. Informed consent obtained from a legal representative or from subjects 18 years of age or older before enrollment;

6. Being willing and able to be followed for at least 30 days for evaluation.

Exclusion Criteria:

Subjects presenting with any of the following will not be included in the study:

1. Clinically significant bleeding;

2. Current drug abuse or participation in methadone program;

3. Episode of pain requiring hospitalization within 2 weeks prior to current admission;

4. Other complications of sickle cell disease including cerebrovascular accident, pulmonary hypertension, or seizure;

5. Pregnancy (confirmed by a serum human chorionic gonadotropin pregnancy test) or breast feeding;

6. Blood pressure less than 25th percentile for the subject's age and sex on admission or at the time of screening;

7. Methemoglobinemia >3%;

8. Anemia with hemoglobin level less than 6 g/dL;

9. Red blood cell G6PD deficiency, by laboratory testing prior to enrollment;

10. History of allergy to nitrites or allergy to other substances characterized by dyspnea and cyanosis;

11. Treatment with allopurinol, a medication that could interfere with nitrite metabolism, within the past 30 days before screening;

12. Treatment with any investigational drug within the past 30 days;

13. 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;

14. Any subject judged by the clinical investigator or study manager to be inappropriate for the study.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• sodium nitrite injection, usp
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).

Locations

Country	Name	City	State
United States	Childrens Hospital Los Angeles	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital Los Angeles	Hope Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (15)

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. Review. — View Citation

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. Epub 2003 Nov 2. — View Citation

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. Epub 2005 May 20. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Epub 2007 Dec 19. — View Citation

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. Epub 2005 Nov 15. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2007 May 29. — View Citation

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. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Secondary End Point	a) reduced the duration and intensity of pain; b) reduced total narcotic analgesic consumption; and c) reduced length of hospitalization.	48 hours