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出境医 / 临床实验 / Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
Study Description
Brief Summary:
The scientific rationale for this study is the evolving understanding that iron-induced tissue damage is not only a process of progressive bulking of organs through high-volumes iron deposition, but also a reactive iron species related "toxic" damage.
Iron mediated damage can occur prior reaching high iron storage thresholds derived from thalassemia major setting, free toxic iron species being already present when transferrin saturation >60-70% (25); therefore a timely early adoption of iron chelation may be of benefit before overt iron overload is seen.
Our hypothesis is that early and low dose DFX-FCT is better tolerated and is able to prevent iron accumulation and consequently tissue iron related damage, by consistently suppressing iron reactive oxygen species (NTBI and LPI).
If this hypothesis is confirmed this approach could contribute to an improvement of clinical practice of patients managements. Additionally this approach might also be a contribute in preventing future iron overloaded related complication, in this already frail and co-treated patient population.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Myelodysplastic Syndromes | Drug: Deferasirox | Phase 2 |
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 60 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Intervention Model Description: | This is an open-label, single arm, phase II, study designed to look whether early intervention with low dose DFX improves clinical outcome of patients with MDS. |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS |
| Estimated Study Start Date : | July 2019 |
| Estimated Primary Completion Date : | January 2021 |
| Estimated Study Completion Date : | January 2021 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Deferasirox
patients will be assigned to a fixed dose of 3.5 mg/kg/day of DFX FCT.
|
Drug: Deferasirox
Fixed dose of 3.5 mg/kg/day of DFX FCT
Other Name: Exjade
|
Outcome Measures
Primary Outcome Measures :
- Change of hepatic iron [ Time Frame: 1 year ]Change of hepatic iron from the baseline according to baseline hepatic iron level: For patients with baseline LIC ≤5 mg/g dry weight (dw) ± 1.5 mg/g dw. For patients with baseline LIC >5 mg/g dw ±20%
Secondary Outcome Measures :
- Definition of iron overload [ Time Frame: 1 year ]
The baseline iron status of MDS patients at the beginning of their transfusion story is today unknown. This study is the first unbiased and direct measurement of iron stress and oxidative stress in MDS patients at the beginning of the transfusion story.
Baseline iron status will be described by classical iron markers:
serum ferritin (ng/ml), transferritin saturation (%), liver and pancreas iron concentration by MRI (mg/g dry weight). Total body iron stores will be calculated (mg/kg) with the published formula (N Engl J Med 2000; 343:327-331).
Tissue reactive oxygen species will be measured in the patient's plasma as follows:
non-transferrin bound iron= micromoles/L, Labile Plasma Iron= micromoles/L. Oxidative stress will be measured by Malonildialdehyde (MDA). Levels in plasmas= micromoles/L.
- Efficacy of treatment [ Time Frame: 1 year ]Absolute change in hepatic iron concentration EOS versus baseline.
- Evolution of iron overload serologic markers [ Time Frame: 1 year ]Absolute and relative changes in serum ferritin and transferrin saturation from baseline to every visit during the whole treatment period
- Evolution of toxic serum iron forms [ Time Frame: 1 year ]Presence and quantitative evolution of toxic serum iron forms (iron tissue reactive species) under low dose DFX therapy
- Relationship between NTBI and LPI with serum ferritin and liver and pancreas iron overload [ Time Frame: 1 year ]
Prevention of iron overload will be studied by the difference iron parameters end of therapy - baseline by liver iron concentration (mg/g dry weight), pancreas iron concentration (mg/g dry weight), total body iron stores (mg/kg) calculated the N Engl J med 2000 343:327-331 formula = liver iron concentration x 10.6.
Serum ferritin = ng/ml.
Relationship between suppression of tissue iron species and prevention of iron accumulation (observational study) will be measured by the:
NTBI/LPI values (micromoles/L), Differences end of study - baseline quantitative parameters of iron loading (liver and pancreas iron concentration and total body iron stores).
- Overall safety of deferasirox [ Time Frame: 1 year ]Evaluate the overall safety of deferasirox FCT formulation in patients with lower risk MDS at the beginning of their transfusional history
- Leukemic transformation [ Time Frame: 1 year ]Leukemic transformation (progression to leukemia or higher rIPSS scores)
- Hemopoietic response [ Time Frame: 1 year ]Percentage of patients with hematologic improvements in term of erythroid response following IWG 2006 criteria.
- Costs analysis [ Time Frame: 1 year ]Treatment cost will be compared with standard approach cost (14 mg/kg/day. DFX-FCT after 20 units of packed red cells units and serum ferritin> 1000 ng/ml over one year of treatment). For comparison literature and matched FISM registry data will be used. Unit of measurement will be 2019 USD and Euros.
- Study of biological cellular damage [ Time Frame: 1 year ]Biological cellular damage will be measured by presence and level of oxidative stress determined at baseline, during and at end of study and compared with ongoing treatment by: Malonildialdehyde (MDA) plasma levels (micromoles/L).
Eligibility Criteria
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Diagnosis: Adult Myelodysplastic Syndrome (≥18 years).
- Revised IPSS: very low. low - intermediate
- Having received 5-20 packed red blood cell units
- Serum ferritin ≥300 ng/ml
- Transferrin saturation ≥ 60%
- Chelation naïve
- Capability to provide informed consent
Exclusion Criteria:
- Patients aged <18 years old
- Higher risk (revised IPSS) MDS (Intermediate 2, high)
- Cumulative transfusion story of > 20 packed red cell units
- Creatinine Clearance (CrCL): <60 ml/min. Patients with CrCl of 40-60ml/min will be included only individually if no other renal risk factors are present.
- Serum creatinine >2 x ULN at screening. If borderline serum creatinine will be measured within 7-10 days and the mean value will be used for eligibility criteria.
- Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void urine sample (or alternatively in two of three samples obtained for screening).
- ECOG performance status >2.
- Left ventricular ejection fraction < 50% by echocardiography
- A history of repeated hospitalization for congestive heart failure.
- Systemic diseases that would prevent study treatment (e.g. uncontrolled hypertension, cardiovascular, renal, hepatic, metabolic, etc.)
- Clinical or laboratory evidence of chronic Hepatitis B or Hepatitis C (definition of chronic hepatitis follows EASL 2017 criteria).
- History of HIV positive test result (ELISA or Western blot).
- Treatment with systemic investigational drug within 4 weeks or topical investigational drug within 7 days of study start.
- ALT or AST over 3 times superior to ULN at screening.
- ANC < 500/ microL
- Platelets transfusion dependency
- Total bilirubin over 1.5 times superior to ULN at screening (patients with Gilbert syndrome are allowed to enter the study)
- Diagnosis of Child score C liver cirrhosis.
- Patients participating in another clinical trial other than an observational registry study.
- Patients with a history of another malignancy within the past 3 years, with the exception of basal skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ.
- History of non-compliance to medical regimens, or patients who are considered potentially unreliable and/or not cooperative.
- Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug.
- Pregnant, intending-to-become pregnant, or breast-feeding patients.
- Women of potential maternity age who do not agree to practice effective contraceptive methods fo the entire study duration.
- History of drug or alcohol abuse within the 12 months prior to enrollment.
- Hypersensitivity to the active substance or to any of the excipients.
- Inability to provide a valid informed consent
Contacts and Locations
Contacts
| Contact: Emanuele Angelucci | +39 010 5553651 | emanuele.angelucci@hsanmartino.it | |
| Contact: SEGRETERIA FISM | +39 0131 206066 | segreteria@fismonlus.it |
Locations
| Italy | |
| S.O.D. Ematologia Policlino Careggi | Not yet recruiting |
| Firenze, FI, Italy, 50134 | |
| Principal Investigator: Valeria Santini, Prof. | |
| Medicina Interna II Divisione di Ematologia, Ospedale S. Luigi Gonzaga | Not yet recruiting |
| Orbassano, TO, Italy, 10043 | |
| Contact: Daniela Cilloni, MD +39 011-9026709 daniela.cilloni@unito.it | |
| Principal Investigator: Daniela Cilloni, MD | |
| Ematologia - Spedali Civili | Not yet recruiting |
| Brescia, Italy, 25100 | |
| Principal Investigator: Giuseppe Rossi, MD | |
| Ospedale Businco | Not yet recruiting |
| Cagliari, Italy | |
| Principal Investigator: Federica Pilo, MD | |
| Ospedale San Martino | Recruiting |
| Genova, Italy | |
| Principal Investigator: Emanuele Angelucci, MD | |
| Ospedale Niguarda | Not yet recruiting |
| Milano, Italy | |
| Principal Investigator: Marta Riva, MD | |
| Azienda Ospedaliera di Padova | Not yet recruiting |
| Padova, Italy, 35128 | |
| Principal Investigator: Gianni Binotto, MD | |
| AO Bianchi Melacrino Morelli | Not yet recruiting |
| Reggio Calabria, Italy, 89125 | |
| Principal Investigator: Ester Oliva, MD | |
| Ospedale S. Eugenio | Not yet recruiting |
| Roma, Italy | |
| Principal Investigator: Pasquale Niscola, MD | |
| Istituto clinico Humanitas | Not yet recruiting |
| Rozzano (MI), Italy | |
| Principal Investigator: Matteo Della Porta, Prof. | |
Sponsors and Collaborators
Fondazione Italiana Sindromi Mielodisplastiche-ETS
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | December 14, 2018 | ||||
| First Posted Date ICMJE | April 19, 2019 | ||||
| Last Update Posted Date | July 17, 2019 | ||||
| Estimated Study Start Date ICMJE | July 2019 | ||||
| Estimated Primary Completion Date | January 2021 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
Change of hepatic iron [ Time Frame: 1 year ] Change of hepatic iron from the baseline according to baseline hepatic iron level: For patients with baseline LIC ≤5 mg/g dry weight (dw) ± 1.5 mg/g dw. For patients with baseline LIC >5 mg/g dw ±20%
|
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
|
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS | ||||
| Official Title ICMJE | Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS | ||||
| Brief Summary |
The scientific rationale for this study is the evolving understanding that iron-induced tissue damage is not only a process of progressive bulking of organs through high-volumes iron deposition, but also a reactive iron species related "toxic" damage. Iron mediated damage can occur prior reaching high iron storage thresholds derived from thalassemia major setting, free toxic iron species being already present when transferrin saturation >60-70% (25); therefore a timely early adoption of iron chelation may be of benefit before overt iron overload is seen. Our hypothesis is that early and low dose DFX-FCT is better tolerated and is able to prevent iron accumulation and consequently tissue iron related damage, by consistently suppressing iron reactive oxygen species (NTBI and LPI). If this hypothesis is confirmed this approach could contribute to an improvement of clinical practice of patients managements. Additionally this approach might also be a contribute in preventing future iron overloaded related complication, in this already frail and co-treated patient population. |
||||
| Detailed Description | Not Provided | ||||
| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 2 | ||||
| Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Intervention Model Description: This is an open-label, single arm, phase II, study designed to look whether early intervention with low dose DFX improves clinical outcome of patients with MDS. Masking: None (Open Label)Primary Purpose: Treatment |
||||
| Condition ICMJE | Myelodysplastic Syndromes | ||||
| Intervention ICMJE | Drug: Deferasirox
Fixed dose of 3.5 mg/kg/day of DFX FCT
Other Name: Exjade
|
||||
| Study Arms ICMJE | Experimental: Deferasirox
patients will be assigned to a fixed dose of 3.5 mg/kg/day of DFX FCT.
Intervention: Drug: Deferasirox
|
||||
| Publications * | Not Provided | ||||
|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Unknown status | ||||
| Estimated Enrollment ICMJE |
60 | ||||
| Original Estimated Enrollment ICMJE | Same as current | ||||
| Estimated Study Completion Date ICMJE | January 2021 | ||||
| Estimated Primary Completion Date | January 2021 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
|
||||
| Sex/Gender ICMJE |
|
||||
| Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | Italy | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT03920657 | ||||
| Other Study ID Numbers ICMJE | FISM_IRON-MDS | ||||
| Has Data Monitoring Committee | Yes | ||||
| U.S. FDA-regulated Product |
|
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| IPD Sharing Statement ICMJE |
|
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| Responsible Party | Fondazione Italiana Sindromi Mielodisplastiche-ETS | ||||
| Study Sponsor ICMJE | Fondazione Italiana Sindromi Mielodisplastiche-ETS | ||||
| Collaborators ICMJE | Not Provided | ||||
| Investigators ICMJE | Not Provided | ||||
| PRS Account | Fondazione Italiana Sindromi Mielodisplastiche-ETS | ||||
| Verification Date | April 2019 | ||||
|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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