Effect of Deferiprone on Oxidative-Stress and Iron-Overload in Low Risk Transfusion-Dependent MDS Patients

NCT02477631 | Completed Phase 2

• 1 other identifier: SHEBA-15-1908-DM-CTIL
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

The effect oral iron chelator Deferiprone on the Oxidative stress and on Iron Overload status in transfusion dependent, iron-overloaded low risk MDS patients; Primary Objective:

• To evaluate the effect of Deferiprone on oxidative stress parameter - Reactive oxygen species (ROS). Secondary Objectives:
• To evaluate the effect of Deferiprone on other oxidative stress parameters
• Reduced glutathione
• Membrane lipid peroxidation
• External phosphatidylserine
• To evaluate the change from baseline to last visit in parameters of iron load.
• Serum ferritin (despite ongoing RBC transfusions during the study period).
• LIP
• LPI
• serum hepcidin
• To evaluate the change from one month preceding baseline visit to last month on study in transfusion requirements.
• To monitor safety measures:
• Adverse events (AEs).
• Number of discontinuations due to AEs

Conditions

Myelodysplastic Syndrome With Low-grade Lesions; Iron Overload Due to Repeated Red Blood Cell Transfusions

Keywords

Myelodysplastic syndrome; oxidative stress; labile plasma iron

Outcome Measures

Primary Outcomes (1)

• To evaluate the effect of deferiprone on oxidative stress parameter ROS in iron overloaded and blood dependent patients with MDS.

  The change from baseline to end of study in ROS

  4 months

Secondary Outcomes (8)

• To evaluate the effect of Deferiprone on other oxidative stress parameters-Reduced glutathione

  4 months

• To evaluate the effect of Deferiprone on other oxidative stress-Membrane lipid peroxidation

  4 months

• To evaluate the effect of Deferiprone on other oxidative stress parameters - External phosphatidylserine

  4 months

• To evaluate the change from baseline to last visit in parameters of iron load-serum ferritin levels (despite ongoing RBC transfusions during the study period).

  4 months

• To evaluate the change from baseline to last visit in parameters of iron load- LIP

  4 months

Other Outcomes (1)

• Adverse events (AEs)

  4 months

Study Arms (1)

Deferiprone

EXPERIMENTAL

patient treated with study drug

Drug: Deferiprone

Interventions

Deferiprone DRUG

This is a single-arm, open-label, multi-center study in 20 patients with MDS. All participants will be treated with deferiprone for up to 4 months.

Also known as: L1, Ferriprox

Deferiprone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged ≥ 18 years
• Have a documented diagnosis of MDS according to WHO 2008 classification (see appendix I), with an International Prognostic Scoring System (IPSS-R) (see Appendix II) of very low, low or intermediate risk.
• Life expectancy of at least 1 year
• Serum ferritin level \> 1000 ng/mL
• Prior receipt of ≥20 RBC units
• Females of childbearing potential must have a negative pregnancy test result month prior to start of dosing, In addition, if applicable, they must:
• Use an effective method of contraception according to local requirements, during the study and within 30 days following their last dose of study medication, OR
• Have had a tubal ligation (supporting evidence required), OR
• Have had a hysterectomy (supporting evidence required), OR
• Participate in a non-heterosexual lifestyle, OR
• Have a male sexual partner who has been sterilized (supporting evidence required)
• Non-sterilized heterosexual males and/or their partners must agree to use an effective method of contraception during the study and for 30 days following their last dose of study medication
• All patients and/or their authorized legal representatives must provide signed and dated written informed consent prior to the first study intervention, and patients must be able to adhere to study restrictions, appointments, and evaluation schedules

You may not qualify if:

• IPSS-R prognosis of high and very high risk (to avoid the confounding influence of a high blast count)
• Unable or unwilling to undergo a 7-day washout period if currently being treated with deferoxamine or deferasirox
• Evidence of abnormal liver function (serum ALT level \> 5 times upper limit of normal or creatinine level \>2 times upper limit of normal)
• A serious, unstable illness, as judged by the investigator, during the past 3 months before screening, including but not limited to: hepatic, renal, gastro-enterologic, respiratory, cardiovascular, endocrinologic, neurologic, or immunologic disease
• Myocardial infarction, cardiac arrest, or cardiac failure within 1 year before screening
• QT interval prolongation on ECG
• Occurrences of severe neutropenia/agranulocytosis (absolute neutrophil count \< 0.5 x 109/L
• History of allergy or sensitivity to deferiprone or related compounds or to other components of the formulation
• Receipt of any investigational products within the past 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication
• Participation in any investigational clinical study, other than observational, within the past 30 days; or plans to participate in such a study at any time from the day of enrollment until 30 days post-treatment in the current study
• History of drug or alcohol abuse within the last 6 months
• Presence of any medical, psychological, or psychiatric condition which in the opinion of the investigator would cause participation in the study to be unwise
• Pregnant, breastfeeding, or planning to become pregnant during the study period.
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication
• Identified as an investigator or other site staff directly affiliated with this study, or an immediate family member (spouse, parent, child, or sibling, whether biological or legally adopted) of either of the above

Sponsors & Collaborators

• Sheba Medical Center: lead
• Hadassah Medical Organization: collaborator
• Tel Aviv Medical Center: collaborator
• Kaplan Medical Center: collaborator
• Ziv Medical Center: collaborator

Study Sites (1)

Chim Sheba Medical Center

Tel Litwinsky, 52621, Israel

Location

Related Publications (15)

• Greenberg PL, Young NS, Gattermann N. Myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2002:136-61. doi: 10.1182/asheducation-2002.1.136.

  PMID: 12446422 BACKGROUND

• Hellstrom-Lindberg E. Management of anemia associated with myelodysplastic syndrome. Semin Hematol. 2005 Apr;42(2 Suppl 1):S10-3. doi: 10.1053/j.seminhematol.2005.01.002. No abstract available.

  PMID: 15846579 BACKGROUND

• Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann N Y Acad Sci. 1998 Jun 30;850:191-201. doi: 10.1111/j.1749-6632.1998.tb10475.x.

  PMID: 9668540 BACKGROUND

• Farquhar MJ, Bowen DT. Oxidative stress and the myelodysplastic syndromes. Int J Hematol. 2003 May;77(4):342-50. doi: 10.1007/BF02982641.

  PMID: 12774921 BACKGROUND

• Choi SO, Cho YS, Kim HL, Park JW. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun. 2007 Apr 27;356(1):312-7. doi: 10.1016/j.bbrc.2007.02.137. Epub 2007 Mar 5.

  PMID: 17349976 BACKGROUND

• Gattermann N, Rachmilewitz EA. Iron overload in MDS-pathophysiology, diagnosis, and complications. Ann Hematol. 2011 Jan;90(1):1-10. doi: 10.1007/s00277-010-1091-1. Epub 2010 Oct 12.

  PMID: 20938663 RESULT

• Ghoti H, Amer J, Winder A, Rachmilewitz E, Fibach E. Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome. Eur J Haematol. 2007 Dec;79(6):463-7. doi: 10.1111/j.1600-0609.2007.00972.x. Epub 2007 Nov 1.

  PMID: 17976187 RESULT

• Smeets ME, Vreugdenhil G, Holdrinet RS. Improvement of erythropoiesis during treatment with deferiprone in a patient with myelofibrosis and transfusional hemosiderosis. Am J Hematol. 1996 Mar;51(3):243-4. doi: 10.1002/(SICI)1096-8652(199603)51:33.0.CO;2-H. No abstract available.

  PMID: 8619408 RESULT

• Cermak J. Erythropoietin administration may potentiate mobilization of storage iron in patients on oral iron chelation therapy. Hemoglobin. 2006;30(1):105-12. doi: 10.1080/03630260500455375.

  PMID: 16540422 RESULT

• Payne KA, Rofail D, Baladi JF, Viala M, Abetz L, Desrosiers MP, Lordan N, Ishak K, Proskorovsky I. Iron chelation therapy: clinical effectiveness, economic burden and quality of life in patients with iron overload. Adv Ther. 2008 Aug;25(8):725-42. doi: 10.1007/s12325-008-0085-z.

  PMID: 18704280 RESULT

• Cermak J, Jonasova A, Vondrakova J, Walterova L, Hochova I, Siskova M, Neuwirtova R. Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome. Hemoglobin. 2011;35(3):217-27. doi: 10.3109/03630269.2011.578515.

  PMID: 21599434 RESULT

• Cermak J, Jonasova A, Vondrakova J, Cervinek L, Belohlavkova P, Neuwirtova R. A comparative study of deferasirox and deferiprone in the treatment of iron overload in patients with myelodysplastic syndromes. Leuk Res. 2013 Dec;37(12):1612-5. doi: 10.1016/j.leukres.2013.07.021. Epub 2013 Aug 9.

  PMID: 23937987 RESULT

• Kersten MJ, Lange R, Smeets ME, Vreugdenhil G, Roozendaal KJ, Lameijer W, Goudsmit R. Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. Ann Hematol. 1996 Nov;73(5):247-52. doi: 10.1007/s002770050236.

  PMID: 8959943 RESULT

• Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol. 2000 Sep;110(4):971-7. doi: 10.1046/j.1365-2141.2000.02298.x.

  PMID: 11054091 RESULT

• Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, Martin M, Koren G, Cohen AR. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994 Sep 1;331(9):574-8. doi: 10.1056/NEJM199409013310903.

  PMID: 8047081 RESULT

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Deferiprone; Long Interspersed Nucleotide Elements

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Pyridones; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Retroelements; Interspersed Repetitive Sequences; Repetitive Sequences, Nucleic Acid; Base Sequence; Molecular Structure; Biochemical Phenomena; Chemical Phenomena; Genetic Structures; Genetic Phenomena; Genome Components; Genome

Study Officials

• Drorit Merkel, MD

  Sheba Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior physician in the Hematology wing

Study Record Dates

• First Submitted: May 11, 2015
• First Posted: June 23, 2015
• Study Start: February 1, 2016
• Primary Completion: May 1, 2017
• Study Completion: June 1, 2018
• Last Updated: November 1, 2018

Record last verified: 2018-10

Locations

IL (1)