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

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ClinicalTrials.gov Identifier: NCT00940602
Recruitment Status : Completed
First Posted : July 16, 2009
Last Update Posted : December 17, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this study was to evaluate deferasirox and placebo with regard to event-free survival (EFS) (a composite primary endpoint including death and non-fatal events related to cardiac and liver function and transformation to AML) in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Drug: Deferasirox Drug: Placebo Phase 2

Detailed Description:

A screening period lasting up to 35 days with two screening visits (Visit 1 and Visit 2 - at least 14 days apart) was used to assess patient eligibility. Eligible patients were randomized in a 2:1 ratio in deferasirox and placebo arms respectively. All patients who were randomized in this study started study treatment at 10 mg/kg/day and could be titrated up to 40 mg/kg/day based on dose modification guidelines.

Patients who met a non-fatal event, as specified in the protocol, discontinued from the study treatment and were followed for safety (28 days) and then evaluated with visits every three months if they agreed to move into the post treatment evaluation phase. Subsequent to the evaluation period, or at the end of treatment if a patient and treating physician decided that a patient would not participate in the evaluation period, patients were followed by phone monitoring every six months for their need for iron chelation therapy (ICT) and survival follow-up (OS) until study end.

Patients who did not meet a non-fatal event continued study treatment as long as the patient and the treating physician felt it was in the best interest for the patient or until the study terminated. After termination of study treatment, all patients continued to be followed for safety and endpoints during the evaluation period at visits occurring every three months. Subsequent to the evaluation period, or at the end of treatment if a patient and treating physician decided that a patient would not participate in the evaluation period, patients were followed every 6 months for ICTs and OS.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 224 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Patients, investigator staff, persons performing the assessments, and data analysts remained blind to the identity of the study treatment from the time of randomization until database lock.
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
Actual Study Start Date : March 22, 2010
Actual Primary Completion Date : February 27, 2018
Actual Study Completion Date : February 27, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Deferasirox

Arm Intervention/treatment
Experimental: Deferasirox
10 mg/kg/day (once daily) for the first 2 weeks of treatment, followed by 20 mg/kg/day (once daily) from Week 2 to End of Treatment. After 3 months of treatment at 20 mg/kg/day, the dose was allowed to be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin responses. When a target serum ferritin level was reached (usually between 500 and 1000 µg/L), the dose could be reduced by 50% to maintain the serum ferritin within the target range.
Drug: Deferasirox
Deferasirox provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use
Other Name: ICL670, Exjade®

Placebo Comparator: Placebo
10 mg/kg/day (once daily) for the first 2 weeks of treatment, followed by 20 mg/kg/day (once daily) from Week 2 to End of Treatment. After 3 months of treatment at 20 mg/kg/day, the dose was allowed to be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin responses. When a target serum ferritin level was reached (usually between 500 and 1000 µg/L), the dose could be reduced by 50% to maintain the serum ferritin within the target range.
Drug: Placebo
Inactive ingredients used as a placebo comparator, provided as 125 mg, 250 mg, and 500 mg dispersible tablets for oral use




Primary Outcome Measures :
  1. Event-free Survival [ Time Frame: Time to event (Up to Year 5) ]
    Event-free survival is defined as the time from date of randomization to date of death or any of the non-fatal events as specified in the protocol.


Secondary Outcome Measures :
  1. Proportion of patients with hematologic improvement in terms of erythroid response [ Time Frame: Baseline up to Year 5 ]
    Improvement is defined as a hemoglobin increase of ≥ 1.5 g/dL, or a reduction of ≥ 4 RBC transfusions/8 weeks in comparison to pre-treatment values and lasting at least 8 weeks. This outcome measure was pre-specified for patients with pre-treatment hemoglobin levels of less than 11 g/dL or RBC transfusion dependence.

  2. Overall survival (days) [ Time Frame: Time to event (Up to Year 5) ]
    Overall survival was calculated as the date of death (irrespective of cause) minus date of randomization plus 1.

  3. Proportion of patients with hypothyroidism [ Time Frame: Up to Year 5 ]

    As assessed by annual measurement of TSH and free T4. Hypothyroidism is defned as follows:

    • 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.

  4. Proportion of patients with worsening of glucose metabolism [ Time Frame: Baseline up to Year 5 ]
    An annual oral glucose tolerance test (OGTT) was carried out. 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 was determined. Fasting and 2-hour post-prandial plasma glucose levels were measured.

  5. Time to disease progression [ Time Frame: Time to event (Baseline up to Year 5) ]
    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.

  6. Time to first occurrence of serum ferritin > 2 times the baseline value [ Time Frame: Time to event (Baseline up to Year 5) ]
    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.

  7. Time to at least a 10% increase from baseline in left ventricular end-diastolic internal (LVIDD) at two consecutive assessments at least two weeks apart [ Time Frame: Time to event (Baseline up to Year 5) ]
    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.

  8. Time to at least a 10% increase from baseline in LVISD [ Time Frame: Time to event (Baseline up to Year 5) ]

    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.


  9. Rate of infections requiring intravenous antimicrobials [ Time Frame: Up to Year 5 ]
    Infections were determined from the reported adverse events with system organ class "Infections and infestations" and action taken "Concomitant medication taken." One patient could contribute more than one infection event. To account for different lengths of observation time in the two groups, the rate of infections was calculated based on patient-years of follow-up.

  10. Proportion of patients with significant renal dysfunction [ Time Frame: Up to Year 5 ]
    Significant renal dysfunction is defined as a serum creatinine value ≥ 2 times ULN at two consecutive assessments at least 7 days apart.

  11. Proportion of patients with severe neutropenia or thrombocytopenia [ Time Frame: Up to Year 5 ]
    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.

  12. Proportion of patients with major gastrointestinal bleeding [ Time Frame: Up to Year 5 ]
    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

  13. Time to study drug discontinuation due to an AE or laboratory abnormality [ Time Frame: Time to event (Up to Year 5) ]
    Calculated as the date of study drug discontinuation due to an AE or laboratory abnormality minus the date of randomization plus 1.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Weigh between 35-135 kilograms
  • Low or int-1 risk MDS
  • Ferritin >1000 micrograms/liter at screening
  • History of transfusion of 15 to 75 Packed Red Blood Cells (PRBC) units
  • Anticipated to be transfused with at least 8 units of PRBCs annually during the study
  • Women of child-bearing potential using effective methods of contraception during dosing of study treatment

Exclusion Criteria:

  • More than 6 months of cumulative ICT (such as daily deferasirox (Exjade®) or deferiprone or 5×/week deferoxamine)
  • More than 3 years since patient began receiving regular transfusions (2 units per 8 weeks or 4 units received in a 3 month period)
  • Significant proteinuria
  • History of hospitalization for congestive heart failure; other heart conditions as specified in the protocol
  • Systemic diseases which would prevent study treatment
  • Hepatitis B; Hepatitis C; HIV
  • Liver cirrhosis
  • Pregnant, or breast-feeding patients, or patients of child-bearing potential not employing an effective method of birth control
  • History of drug or alcohol abuse within the 12 months prior to enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00940602


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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00940602     History of Changes
Other Study ID Numbers: CICL670A2302
2009-012418-38 ( EudraCT Number )
First Posted: July 16, 2009    Key Record Dates
Last Update Posted: December 17, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

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

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