Pilot Phase I/II Study of Amino Acid Leucine in Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia

Diamond Blackfan Anemia Clinical Trial

— LeucineDBA  

Official title:

The Use of Novel Therapies to Reconstitute Blood Cell Production and Promote Organ Performance Using Bone Marrow Failure as a Model: a Pilot, Phase I/II Study of the Amino Acid Leucine in the Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01362595
• Other study ID #: 12-375B
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 2013
• Est. completion date: November 30, 2020

Study information

• Verified date: November 2022
• Source: Northwell Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will determine the safety and possibility of giving the amino acid, leucine, in patients with Diamond Blackfan anemia(DBA)who are on dependent on red blood cell transfusions. The leucine is expected to produce a response in patients with DBA to the point where red blood cell production is increased. Red cell transfusions can then be less frequent or possibly discontinued. The investigators will study the side effects, if any, of giving leucine to DBA patients. Leucine levels of leucine will be obtained at baseline and during the study. The drug leucine will be provided in capsule form and taken 3 times a day for a total of 9 months.

Description:

Leucine will be provided to participants in the form of a capsule and will be taken three times daily. Blood hemoglobin levels will be monitored every 3-4 weeks for 9 months. The entire study will last 12-15 months in length. Subjects must be two years of age or older and on transfusion for more than six months prior to enrollment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: November 30, 2020
• Est. primary completion date: June 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

Inclusion Criteria:

• diagnosed with Diamond Blackfan anemia as published in British Journal of Hematology
• transfusion dependent
• age 2 years and older
• adequate renal function
• adequate liver function
• negative B-HCG if patient is a menstruating female and documentation of adequate contraception
• signed informed consent

Exclusion Criteria:

• Known hypersensitivity to branched chain amino acids
• Diagnosis of an inborn error of amino acid metabolism disorder
• Prior hematopoietic stem cell transplantation
• Pregnancy, or plans to become pregnant during duration of trial

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Anemia, Diamond-Blackfan
• Blackfan Diamond Syndrome
• Congenital Hypoplastic Anemia
• DBA
• Diamond Blackfan Anemia
• Pure Red Cell Aplasia
• Red-Cell Aplasia, Pure

Intervention

Drug:
• leucine
Dosage of leucine will be dependent on body surface area (BSA): leucine 700 mg/m2/dose by mouth three times a day

Locations

Country	Name	City	State
United States	University of Michigan C.S. Mott Children's Hospital	Ann Arbor	Michigan
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of Missouri-Columbia Women's and Children's Hospital	Columbia	Missouri
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Children's Specialty Center of Nevada	Las Vegas	Nevada
United States	University of Louisville	Louisville	Kentucky
United States	Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Stanford University Medical Center	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Northwell Health

Country where clinical trial is conducted

United States, 

References & Publications (56)

Abkowitz JL, Powell JS, Nakamura JM, Kadin ME, Adamson JW. Pure red cell aplasia: response to therapy with anti-thymocyte globulin. Am J Hematol. 1986 Dec;23(4):363-71. doi: 10.1002/ajh.2830230408. — View Citation

Abkowitz JL, Schaison G, Boulad F, Brown DL, Buchanan GR, Johnson CA, Murray JC, Sabo KM. Response of Diamond-Blackfan anemia to metoclopramide: evidence for a role for prolactin in erythropoiesis. Blood. 2002 Oct 15;100(8):2687-91. doi: 10.1182/blood.V100.8.2687. — View Citation

Akiyama M, Yanagisawa T, Yuza Y, Yokoi K, Ariga M, Fujisawa K, Hoshi Y, Eto Y. Successful treatment of Diamond-Blackfan anemia with metoclopramide. Am J Hematol. 2005 Apr;78(4):295-8. doi: 10.1002/ajh.20278. — View Citation

Alessandri AJ, Rogers PC, Wadsworth LD, Davis JH. Diamond-blackfan anemia and cyclosporine therapy revisited. J Pediatr Hematol Oncol. 2000 Mar-Apr;22(2):176-9. doi: 10.1097/00043426-200003000-00020. — View Citation

AMA Department of Drugs; AMA Drug Evaluations, 6th ed. American Medical Association, Chicago, IL,1986.

Ball SE, Tchernia G, Wranne L, Bastion Y, Bekassy NA, Bordigoni P, Debre M, Elinder G, Kamps WA, Lanning M, et al. Is there a role for interleukin-3 in Diamond-Blackfan anaemia? Results of a European multicentre study. Br J Haematol. 1995 Oct;91(2):313-8. doi: 10.1111/j.1365-2141.1995.tb05295.x. — View Citation

Bastion Y, Bordigoni P, Debre M, Girault D, Leblanc T, Tchernia G, Ball S, McGuckin C, Gordon-Smith EC, Bekassy A, et al. Sustained response after recombinant interleukin-3 in diamond blackfan anemia. Blood. 1994 Jan 15;83(2):617-8. No abstract available. — View Citation

Bejaoui M, Fitouri Z, Sfar MT, Lakhoua R. Failure of immunosuppressive therapy and high-dose intravenous immunoglobulins in four transfusion-dependent, steroid-unresponsive Blackfan-Diamond anemia patients. Haematologica. 1993 Jan-Feb;78(1):38-9. — View Citation

Bernardini P, Fischer JE. Amino acid imbalance and hepatic encephalopathy. Annu Rev Nutr. 1982;2:419-54. doi: 10.1146/annurev.nu.02.070182.002223. No abstract available. — View Citation

Bernini JC, Carrillo JM, Buchanan GR. High-dose intravenous methylprednisolone therapy for patients with Diamond-Blackfan anemia refractory to conventional doses of prednisone. J Pediatr. 1995 Oct;127(4):654-9. doi: 10.1016/s0022-3476(95)70134-6. — View Citation

Bobey NA, Carcao M, Dror Y, Freedman MH, Dahl N, Woodman RC. Sustained cyclosporine-induced erythropoietic response in identical male twins with diamond-blackfan anemia. J Pediatr Hematol Oncol. 2003 Nov;25(11):914-8. doi: 10.1097/00043426-200311000-00018. — View Citation

Braverman ER. The Healing Nutrients Within. New Canaan, CT: Keats Publishing, Inc. 1997; 339

Buchanan GR; International Diamond-Blackfan Anemia Study Group. Oral megadose methylprednisolone therapy for refractory Diamond-Blackfan anemia. International Diamond-Blackfan Anemia Study Group. J Pediatr Hematol Oncol. 2001 Aug-Sep;23(6):353-6. doi: 10.1097/00043426-200108000-00006. — View Citation

Choudry HA, Pan M, Karinch AM, Souba WW. Branched-chain amino acid-enriched nutritional support in surgical and cancer patients. J Nutr. 2006 Jan;136(1 Suppl):314S-8S. doi: 10.1093/jn/136.1.314S. — View Citation

Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D. Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat. 2007 Dec;28(12):1178-82. doi: 10.1002/humu.20608. — View Citation

Cmejlova J, Dolezalova L, Pospisilova D, Petrtylova K, Petrak J, Cmejla R. Translational efficiency in patients with Diamond-Blackfan anemia. Haematologica. 2006 Nov;91(11):1456-64. — View Citation

Cynober L, Harris RA. Symposium on branched-chain amino acids: conference summary. J Nutr. 2006 Jan;136(1 Suppl):333S-6S. doi: 10.1093/jn/136.1.333S. No abstract available. — View Citation

Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999 Feb;21(2):169-75. doi: 10.1038/5951. — View Citation

Dunbar CE, Smith DA, Kimball J, Garrison L, Nienhuis AW, Young NS. Treatment of Diamond-Blackfan anaemia with haematopoietic growth factors, granulocyte-macrophage colony stimulating factor and interleukin 3: sustained remissions following IL-3. Br J Haematol. 1991 Oct;79(2):316-21. doi: 10.1111/j.1365-2141.1991.tb04540.x. — View Citation

Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, Talbot CC Jr, Meltzer P, Esposito D, Beggs AH, Schneider HE, Grabowska A, Ball SE, Niewiadomska E, Sieff CA, Vlachos A, Atsidaftos E, Ellis SR, Lipton JM, Gazda HT, Arceci RJ. Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood. 2008 Sep 1;112(5):1582-92. doi: 10.1182/blood-2008-02-140012. Epub 2008 Jun 5. — View Citation

Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, Vlachos A, Atsidaftos E, Ball SE, Orfali KA, Niewiadomska E, Da Costa L, Tchernia G, Niemeyer C, Meerpohl JJ, Stahl J, Schratt G, Glader B, Backer K, Wong C, Nathan DG, Beggs AH, Sieff CA. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2006 Dec;79(6):1110-8. doi: 10.1086/510020. Epub 2006 Nov 2. — View Citation

Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. doi: 10.1016/j.ajhg.2008.11.004. — View Citation

Gillio AP, Faulkner LB, Alter BP, Reilly L, Klafter R, Heller G, Young DC, Lipton JM, Moore MA, O'Reilly RJ. Successful treatment of Diamond-Blackfan anemia with interleukin 3. Stem Cells. 1993 Jul;11 Suppl 2:123-30. doi: 10.1002/stem.5530110820. — View Citation

Gillio AP, Faulkner LB, Alter BP, Reilly L, Klafter R, Heller G, Young DC, Lipton JM, Moore MA, O'Reilly RJ. Treatment of Diamond-Blackfan anemia with recombinant human interleukin-3. Blood. 1993 Aug 1;82(3):744-51. — View Citation

Gilman AG, Rall JW, Nies AD et al (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. Pergamon Press, New York, NY, 1990.

Halperin DS, Estrov Z, Freedman MH. Diamond-Blackfan anemia: promotion of marrow erythropoiesis in vitro by recombinant interleukin-3. Blood. 1989 Apr;73(5):1168-74. — View Citation

Harris SI, Weinberg JB. Treatment of red cell aplasia with antithymocyte globulin: repeated inductions of complete remissions in two patients. Am J Hematol. 1985 Oct;20(2):183-6. doi: 10.1002/ajh.2830200212. — View Citation

Henry JB: Clinical Diagnosis and Management by Laboratory Methods, 20th ed. Saunders 2001.

Hutson SM, Sweatt AJ, Lanoue KF. Branched-chain [corrected] amino acid metabolism: implications for establishing safe intakes. J Nutr. 2005 Jun;135(6 Suppl):1557S-64S. doi: 10.1093/jn/135.6.1557S. Erratum In: J Nutr. 2005 Aug;135(8):2009. — View Citation

Jellin JM, Gregory P, Batz F. Pharmacist's letter/ Prescriber's Letter Natural Medicines Comprehensive Database, 3rd ed, Therapeutic Research Faculty, Stockton, CA, 2000.

Kimball SR, Jefferson LS. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr. 2006 Jan;136(1 Suppl):227S-31S. doi: 10.1093/jn/136.1.227S. — View Citation

Lab Advisor(TM); Leucine Measurements in Micromedex (R) Healthcare Series. 2010Thomson Reuters

Leblanc TM, Da Costa L, Marie I, Demolis P, Tchernia G. Metoclopramide treatment in DBA patients: no complete response in a French prospective study. Blood. 2007 Mar 1;109(5):2266-7. doi: 10.1182/blood-2006-08-039545. No abstract available. — View Citation

Leonard EM, Raefsky E, Griffith P, Kimball J, Nienhuis AW, Young NS. Cyclosporine therapy of aplastic anaemia, congenital and acquired red cell aplasia. Br J Haematol. 1989 Jun;72(2):278-84. doi: 10.1111/j.1365-2141.1989.tb07695.x. — View Citation

Lipton JM, Atsidaftos E, Zyskind I, Vlachos A. Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan Anemia Registry. Pediatr Blood Cancer. 2006 May 1;46(5):558-64. doi: 10.1002/pbc.20642. — View Citation

McGuire WA, Yang HH, Bruno E, Brandt J, Briddell R, Coates TD, Hoffman R. Treatment of antibody-mediated pure red-cell aplasia with high-dose intravenous gamma globulin. N Engl J Med. 1987 Oct 15;317(16):1004-8. doi: 10.1056/NEJM198710153171606. No abstract available. — View Citation

Miceli Sopo S, Pesaresi MA, Pastore M, Stabile A. Intravenous immunoglobulin in Diamond-Blackfan anaemia. Eur J Pediatr. 1990 Aug;149(11):779-80. doi: 10.1007/BF01957279. — View Citation

Monteserin MC, Garcia Vela JA, Ona F, Lastra AM. Cyclosporin A for Diamond-Blackfan anemia: a new case. Am J Hematol. 1993 Apr;42(4):406-7. doi: 10.1002/ajh.2830420419. No abstract available. — View Citation

Olivieri NF, Feig SA, Valentino L, Berriman AM, Shore R, Freedman MH. Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia. Blood. 1994 May 1;83(9):2444-50. — View Citation

Ozsoylu S. Oral megadose methylprednisolone for Diamond-Blackfan anemia. Blood. 1994 Nov 1;84(9):3245-7. No abstract available. — View Citation

Pass KA, Lane PA, Fernhoff PM, Hinton CF, Panny SR, Parks JS, Pelias MZ, Rhead WJ, Ross SI, Wethers DL, Elsas LJ 2nd. US newborn screening system guidelines II: follow-up of children, diagnosis, management, and evaluation. Statement of the Council of Regional Networks for Genetic Services (CORN). J Pediatr. 2000 Oct;137(4 Suppl):S1-46. doi: 10.1067/mpd.2000.109437. No abstract available. — View Citation

Pencharz PB, Ball RO. Amino acid needs for early growth and development. J Nutr. 2004 Jun;134(6 Suppl):1566S-1568S. doi: 10.1093/jn/134.6.1566S. — View Citation

Plaitakis A, Smith J, Mandeli J, Yahr MD. Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet. 1988 May 7;1(8593):1015-8. doi: 10.1016/s0140-6736(88)91841-7. — View Citation

Poon RT, Yu WC, Fan ST, Wong J. Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment Pharmacol Ther. 2004 Apr 1;19(7):779-88. doi: 10.1111/j.1365-2036.2004.01920.x. — View Citation

Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R. Successful treatment of a Diamond-Blackfan anemia patient with amino acid leucine. Haematologica. 2007 May;92(5):e66-7. doi: 10.3324/haematol.11498. No abstract available. — View Citation

Roychowdhury DF, Linker CA. Pure red cell aplasia complicating an ABO-compatible allogeneic bone marrow transplantation, treated successfully with antithymocyte globulin. Bone Marrow Transplant. 1995 Sep;16(3):471-2. — View Citation

Sax HC, Talamini MA, Fischer JE. Clinical use of branched-chain amino acids in liver disease, sepsis, trauma, and burns. Arch Surg. 1986 Mar;121(3):358-66. doi: 10.1001/archsurg.1986.01400030120019. — View Citation

Seip M, Zanussi GF. Cyclosporine in steroid-resistant Diamond-Blackfan anaemia. Acta Paediatr Scand. 1988 May;77(3):464-6. doi: 10.1111/j.1651-2227.1988.tb10682.x. — View Citation

Splain J, Berman BW. Cyclosporin A treatment for Diamond-Blackfan anemia. Am J Hematol. 1992 Mar;39(3):208-11. doi: 10.1002/ajh.2830390310. — View Citation

Sumimoto S, Kawai M, Kasajima Y, Hamamoto T. Intravenous gamma-globulin therapy in Diamond-Blackfan anemia. Acta Paediatr Jpn. 1992 Apr;34(2):179-80. doi: 10.1111/j.1442-200x.1992.tb00947.x. — View Citation

Tietz NE (Ed); Clinical Guide to Laboratory Tests, 3rd ed W. B. Saunders, Philadelphia, PA, 1995.

Totterman TH, Nisell J, Killander A, Gahrton G, Lonnqvist B. Successful treatment of pure red-cell aplasia with cyclosporin. Lancet. 1984 Sep 22;2(8404):693. doi: 10.1016/s0140-6736(84)91245-5. No abstract available. — View Citation

Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM; Participants of Sixth Annual Daniella Maria Arturi International Consensus Conference. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol. 2008 Sep;142(6):859-76. doi: 10.1111/j.1365-2141.2008.07269.x. Epub 2008 Jul 30. — View Citation

Vlachos A, Federman N, Reyes-Haley C, Abramson J, Lipton JM. Hematopoietic stem cell transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Bone Marrow Transplant. 2001 Feb;27(4):381-6. doi: 10.1038/sj.bmt.1702784. — View Citation

Vlachos A, Klein GW, Lipton JM. The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond-Blackfan anemia. J Pediatr Hematol Oncol. 2001 Aug-Sep;23(6):377-82. doi: 10.1097/00043426-200108000-00015. — View Citation

Williams DL, Mageed AS, Findley H, Ragab AH. Cyclosporine in the treatment of red cell aplasia. Am J Pediatr Hematol Oncol. 1987 Winter;9(4):314-6. doi: 10.1097/00043426-198724000-00007. — View Citation

* Note: There are 56 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response to Leucine in Transfusion Dependent Patients With Diamond Blackfan Anemia	The primary outcome is the type of response observed at 9 months. Response to treatment can be one of the following: Complete response (CR): Hb > 9 gm/dL and transfusion-independence as defined in DBA; Partial response (PR): Hb < 9 gm/dL and increased reticulocyte count to greater than baseline.; No response (NR): no change in transfusion requirements and no significant change reticulocyte count from baseline; Progression: worsening of disease as defined by the need for more frequent transfusions	9 Months
Secondary	Severe Adverse Events Attributable to Leucine	Adverse events occurring while participants were on Leucine	9 months

External Links

•   Daniella Maria Arturi Foundation is a family sponsored group which facilitates research for DBA.
•   Diamond Blackfan Anemia Registry - a registry for patients with DBA in North America
•   The DBA foundation is a family sponsored organization who raise funds for research and provides emotional support to families.