Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy Study (TELESTO)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00940602
First received: July 15, 2009
Last updated: August 21, 2014
Last verified: August 2014
  Purpose

The primary purpose of this study is to prospectively assess the efficacy and safety of iron chelation therapy with deferasirox compared to placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload.


Condition Intervention Phase
Myelodysplastic Syndromes
Drug: Deferasirox
Drug: Deferasirox placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Trial of Deferasirox in Patients With Myelodysplastic Syndromes (Low/Int-1 Risk) and Transfusional Iron Overload

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • To compare deferasirox to placebo with regard to event-free survival (a composite primary endpoint including death and non-fatal events related to cardiac and liver function) in low and int-1 risk MDS patient with transfusional iron overload. [ Time Frame: From date of Randomization Up to 5 years1 year - 5 years ] [ Designated as safety issue: No ]
    The composite primary endpoint (event-free survival) consists of both death and non-fatal events. Non-fatal events include worsening cardiac function based on echocardiographic evidence, hospitalization for congestive heart failure, liver function impairment reflected by elevated ALT or AST and bilirubin values, confirmed liver cirrhosis, and transformation to AML. The composite primary endpoint is defined as time from date of randomization to date when death (irrespective of cause) or any of the non-fatal events has been reached (whatever occurred first). Time is measured in days and is defined as date of event minus date of randomization plus 1.


Secondary Outcome Measures:
  • Hematologic improvement in terms of erythroid responses during treatment will be assessed [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]
    The variable used in the analysis of HI will be the proportion of patients who satisfy the erythroid response criteria, namely • Hemoglobin increase of ≥ 1.5 g/dL OR • Reduction of ≥ 4 RBC transfusions/8 weeks in comparison to pre-treatment values and lasting at least 8 weeks. According to IWG criteria, HI is measured in patients with pre-treatment hemoglobin levels of less than 11 g/dL or RBC transfusion dependence.

  • Overall survival [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]
    Overall survival (OS) will be evaluated in patients treated with either deferasirox or placebo. The variable used in the analysis of overall survival is time to death measured in days. It is defined as date of death (irrespective of cause) minus date of randomization plus 1.

  • Proportion of patients with hypothyroidism [ Time Frame: Annually ] [ Designated as safety issue: No ]

    Hypothyroidism will be evaluated by the annual measurement of TSH and free T4. The proportion of patients with normal thyroid function, primary hypothyroidism, secondary hypothyroidism or subclinical hypothyroidism will be determined at each time point (i.e. 1, 2, years after randomization).

    Definitions:

    • normal thyroid function: serum TSH and free T4 within normal limits;
    • primary hypothyroidism: serum TSH >ULN and free T4 <LLN;
    • secondary hypothyroidism: serum TSH <ULN and free T4 <LLN;
    • subclinical hypothyroidism: TSH >ULN and a free T4 within normal limits.

  • Proportion of patients with worsening of glucose metabolism [ Time Frame: Annually ] [ Designated as safety issue: No ]
    An annual oral glucose tolerance test will be carried out to evaluate changes of glucose metabolism compared to the baseline status. The proportion of patients with an increase in glucose metabolism category (normal, impaired glucose metabolism, diabetes mellitus) based on the American Diabetes Association criteria (American Diabetes Association 2009) compared to their baseline result will be determined at each timepoint, i.e. 1, 2, years after randomization. For this classification, fasting and 2-hour post-prandial plasma glucose levels will be measured.

  • Disease progression [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]
    An evaluation of the time from randomization to either MDS progression or progression to AML in the treatment groups will be done based on date of diagnosis of MDS progression or date of first diagnosis of AML minus date of randomization plus 1. MDS progression will be defined as a transition into a higher MDS risk group based on IPSS scoring. Progression to AML will be defined based upon the most current classification guidelines (Vardiman 2009), as 20% or more blasts seen in the bone marrow.

  • Time to first occurrence of serum ferritin > 2 times the baseline value [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]
    An evaluation of the time from randomization to the first occurrence of serum ferritin > 2 times the baseline value at two consecutive assessments (at least two weeks apart) will be performed per treatment group based on the following variable: • date of the first of the two consecutive laboratory assessment fulfilling the criterion of SF > 2 × baseline value minus date of randomization plus 1.

  • Time to at least a 10% increase from baseline in LVIDD [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]
    An evaluation of the time from randomization to the first occurrence of an increase of at least 10% from the baseline value of LVIDD will be performed based on the following variable: • date of echocardiography assessment where a minimum of 10% increase first occurred minus date of randomization plus 1.

  • Time to at least a 10% increase from baseline in LVISD [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]

    An evaluation of the time from randomization to the first occurrence of an increase of at least 10% from the baseline value of LVISD will be performed based on the following variable:

    • date of echocardiography assessment where a minimum of 10% increase first occurred minus date of randomization plus 1.


  • Infections [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: No ]
    Infections requiring intravenous antimicrobials during the treatment period (until the 28 day follow-up visit) will be evaluated separately for each treatment group. Infections will be determined from the reported adverse events with system organ class "Infections and infestations" and action taken "Concomitant medication taken". The total number of infections will be counted and summarized per treatment group. For this number one patient can contribute more than one infection event. To account for different lengths of observation time in the two groups, the rate of infections will be calculated based on patient-years of follow-up. The relative risk of infection will be calculated as the rate of infection in the treatment group compared with the rate in the placebo group.

  • Proportion of patients with significant renal dysfunction [ Time Frame: Annually ] [ Designated as safety issue: Yes ]
    Treatment groups will be evaluated regarding the proportion of patients experiencing a significant renal dysfunction. This is defined as a serum creatinine value ≥ 2 times ULN at two consecutive assessments. The two assessments need to be at least 7 days a part.

  • Proportion of patients with severe neutropenia or thrombocytopenia [ Time Frame: Annually ] [ Designated as safety issue: Yes ]
    Proportion of patients with newly occurring CTCAE grade 4 neutropenia or thrombocytopenia will be displayed by treatment group. Results will also be provided for annual time intervals.

  • Proportion of patients with major gastrointestinal bleeding [ Time Frame: Annually ] [ Designated as safety issue: Yes ]

    An evaluation of the proportion of patients with major gastrointestinal bleeding will be performed. Major gastrointestinal bleeding is defined as an AE that may include one of the following MedDRA preferred terms:

    Gastric haemorrhage Gastrointestinal haemorrhage Small intestinal haemorrhage Oesophageal haemorrhage Large intestinal haemorrhage Rectal haemorrhage Melaena Duodenal ulcer haemorrhage Gastric ulcer haemorrhage Peptic ulcer haemorrhage Large intestinal ulcer haemorrhage Oesophageal ulcer haemorrhage Haematochezia Frequency tables will be prepared by treatment group. Results will also be provided for annual time intervals.

    In addition, a statistical analysis of the multivariate (recurrent) major gastrointestinal bleeding data will be performed.


  • Time to study drug discontinuation due to an AE or laboratory abnormality [ Time Frame: From date of Randomization Up to 5 years ] [ Designated as safety issue: Yes ]

    An evaluation of the time from randomization to study drug discontinuation due to an AE or laboratory abnormality will be performed. The variable will be based on the date and reason given on the Study Treatment Completion eCRF page. Only patients for whom the reason for stopping study medication was entered as AE or laboratory abnormality will be considered.

    The definition of the variable is:

    • date of study drug discontinuation due to an AE or laboratory abnormality minus date of randomization plus 1.



Estimated Enrollment: 210
Study Start Date: March 2010
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Deferasirox, iron chelator
At least 210 male or female patients, ≥ 18 years of age with low/int-1 MDS, as determined by IPSS score, who have serum ferritin >1000 mcg/L at screening. will be assigned to one of the two arms in a ratio of 2:1, deferasirox or matching placebo.
Drug: Deferasirox
Deferasirox will be provided as 125 mg, 250 mg, and 500 mg dispersible tablets packaged in bulk high density polyethylene (HDPE) bottles with induction seals and child resistant closures.
Other Name: ICL670, Exjade®
Placebo Comparator: Placebo
Matching placebo will be administered orally
Drug: Deferasirox placebo
Placebo will be formulated and packaged to be indistinguishable from the 125 mg, 250 mg, and 500 mg tablets of deferasirox.
Other Name: Placebo

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or females ≥ 18 years of age
  • Patients must weigh between 35-135 kg MDS low -int-1 risk as determined by IPSS score and confirmed by bone marrow examination within 6 months prior to study entry
  • Ferritin> 1000 mcg/L at screening
  • History of 15 to 75 PRBC transfusions
  • Anticipated to be transfused at least 8 times annually during the study

Exclusion Criteria:

  • More than 6 months of cumulative iron-chelation therapy (such as daily deferasirox (Exjade) or deferiprone or 5x/week deferosamine). intermittent deferoxamine doses in association with blood transfusions are not exclusionary regardless of duration of such treatment.

    -- More than 3 years since patient began receiving regular transfusions (2 units per 8 weeks or 4 units received in a 3 month period).

  • Creatinine clearance < 40 ml/min
  • Serum creatinine >1.5x ULN at screening
  • Significant proteinuria: urinary protein/creatinine ratio >0.5 mg/mg in a non first void urine sample
  • ECOG performance status > 2
  • Left ventricular ejection fraction < 55% by ECHO
  • History of hospitalization for Congestive Heart Failure
  • Systemic disease that would prevent study treatment (uncontrolled hypertension, cardiovascular renal, hepatic or metabolic disease)
  • Hepatitis B or C (HBsAg in the absences or HBsAB or HCV Ab positive with HCV RNA positive)
  • History of HIV positivity by (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 > 3.5 x ULN at screening
  • Total bilirubin > 1.5 x ULN at screening
  • Diagnosis of liver cirrhosis
  • Patient participating in another clinical trial or receiving an investigational drug
  • History of another malignancy within the past five 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 with medical regimen, or patients potentially unreliable and/or not cooperative
  • Presence of surgical or medical condition which might significantly alter the absorption, distribution , metabolism or excretion of study drug
  • Pregnant or intending to become pregnant or breast-feeding patents
  • History of drug or alcohol abuse within the 12 months prior to enrollment.
  • Other protocol-defined inclusion/exclusion criteria may apply
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00940602

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 191 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00940602     History of Changes
Other Study ID Numbers: CICL670A2302, 2009-012418-38
Study First Received: July 15, 2009
Last Updated: August 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
TELESTO
MDS Study
Myelodysplastic Syndromes
Myelodysplastic Syndromes (low-int-1 risk)

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Syndrome
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Disease
Pathologic Processes
Deferasirox
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014