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

• ClinicalTrials.gov Identifier: NCT00940602
• Recruitment Status: Completed
• First Posted: July 16, 2009
• Results First Posted: November 23, 2020
• Last Update Posted: November 23, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This was a randomized, double-blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload .The trial was conducted in 17 countries, started in 2010 and ended in 2018.

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

Detailed Description:

This randomized, double blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload consisted of four periods, a screening period, a treatment period, a post treatment follow-up period and a survival period. The trial recruitment period lasted until December 2014 and the trial continued for three years from the date the last patient enrolled until February 2018 (last patient last visit date).

Screening period:

The screening period lasting up to 35 days with two screening visits, at least 14 days apart, used to assess patient eligibility. Eligible patients with low or int-1 risk myelodysplastic syndromes (MDS) with transfusional iron overload were randomized in a 2:1 ratio to deferasirox or placebo respectively. Randomization was also stratified using the International prognostic scoring system of low or int-1 MDS and by geographical region (Asian vs non-Asian countries) since the Asian population has been reported to have a longer survival.

The following concomitant medications could be permitted for use while the patient was on study, and information outlining start date(s) and end date(s) of each medication taken were to be recorded on the appropriate eCRF: Erythropoietin (growth factor), G-CSF (growth factor), GM-CSF growth factor), Azacitidine, Thalidomide, Arsenic trioxide, Lenalidomide, Decitabine, Cyclosporine A, Vitamin C supplements (≤ 200 mg/day)

Treatment period:

The dosing schedule was 10 mg/kg/day (once daily) for the first 2 weeks, followed by 20 mg/kg/day (once daily). After 3 months of treatment at the dose of 20mg/kg/day, the dose could be adjusted by 5 or 10 mg/kg/day up to 40 mg/kg/day based on the serum ferritin response. Placebo matching to each strength of the active deferasirox was utilized to maintain the double-blind trial design.

During the treatment period patients returned to the investigational site every four weeks for routine procedures and to monitor safety, efficacy and compliance to treatment.

An external Data Monitoring Committee (DMC) monitored patient safety and trial conduct and received a blinded summary of serious adverse events.

All suspected endpoint events were reviewed and adjudicated by the Endpoint Adjudication Committee (EAC) to ensure that all events that were reported were judged uniformly using the same criteria. The first confirmed suspected endpoint event for a patient was counted for the trial's composite primary endpoint, "event free survival". The composite primary endpoint, "event free survival," was defined for a patient as the date randomized to trial treatment to the date of the first documented non-fatal event, related to cardiac and liver function, transformation to AML, or death due to any cause.

When a patient had a non-fatal event, related to cardiac and liver function, and transformation to AML, the trial treatment (deferasirox or placebo) was discontinued. After trial treatment was discontinued, a 28 days post treatment safety assessment for AEs and SAEs was completed. Any patient who died during the treatment or 28 day post treatment safety assessment is represented in the all-cause mortality table in the safety section of this result. After trial treatment was discontinued for a patient, their treatment was un-blinded. Subsequent iron chelation treatment was subject to the patient's and investigator's decision. Patients continued to be followed during the post-treatment evaluation or survival follow up period, depending on their choice.

For patients who did not meet a non-fatal event, study treatment was continued as long as the patient and the treating physician felt it was in the best interest for the patient or until the trial terminated/completed. There was no un-blinding of the trial treatment for patients who terminated trial treatment without meeting a non-fatal event. Patients continued to be followed during the post-treatment evaluation or survival follow up period, depending on their choice.

A patient who discontinued study treatment without meeting a non-fatal component of the composite primary endpoint continued to be evaluated every 3 months. Once a patient stopped study evaluations they were followed for at least every 6 months for overall survival and any iron chelation therapies they are receiving up to the end of study.

Post-treatment evaluation period:

For patients who had a non-fatal event: After treatment termination, all patients 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.

For patients who did not meet a non-fatal event: After termination of study treatment, if a patient and investigator chose the post-treatment evaluation period, the patient was followed for safety and endpoints at visits occurring every three months.

Survival Follow Up period:

Subsequent to the post treatment evaluation period, or at the end of treatment period, if a patient and treating physician decided that the patient would not participate in the post treatment evaluation period, the patient was followed every 6 months for overall survival and iron chelation therapies.

The end of the study was defined as three years from the date the last patient was enrolled (last patient first visit).

The sample size of 210 patients did not provide sufficient power for testing statistical hypotheses. The statistical analysis was revised accordingly to concentrate on evaluating the treatment effect of deferasirox relative to placebo, and the study phase designation was changed from Phase lll to Phase II. Amendment 4 of the study adjusted the sample size, statistical analysis, and duration of the study and added two secondary endpoints: Hematologic improvement (HI) in terms of erythroid response and Frequency and rate of infections requiring intravenous (IV) antimicrobials. Upon approval of the amendment, patients signed a new consent form and continued the appropriate visit schedule.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 225 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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Event-free Survival [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
   Event-free survival was defined as the time from the date of randomization to the date of the first documented non-fatal event (worsening cardiac function, hospitalization for congestive heart failure, liver function impairment, liver cirrhosis, transformation to AML, as defined in the protocol), or death, whichever occurred first. Participants who did not experience a non-fatal event as of the time of data cut-off (end of study), as well as participants who did not experience a non-fatal event and stopped study participation before the data cut-off, were censored as specified in the protocol.

Secondary Outcome Measures :

1. Percentage of Participants With Hematologic Improvement (HI) in Terms of Erythroid Response [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]

   HI in terms of erythroid responses was assessed based on International Working Group (IWG) criteria, with improvement defined as follows:

   • 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. The last hemoglobin value measured prior to randomization was used as the pre-treatment value. The last available lab assessment date was used as the cut-off date for the analysis.
2. Overall Survival [ Time Frame: Day 1 to end of treatment period, approx. 7.4 years ]
   Overall survival was calculated as the date of death (irrespective of cause) minus date of randomization plus 1.
3. Percentage of Participants With Newly Occurring Hypothyroidism Compared to Baseline [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]

   As assessed by annual measurement of Thyroid Stimulating Hormone (TSH) and free T4. Hypothyroidism was defined as follows and is inclusive of:

   • Primary hypothyroidism: serum TSH >upper limit of normal (ULN) and free T4 <lower limit of normal (LLN);
   • Secondary hypothyroidism: serum TSH <ULN and free T4 <lower limit of normal;
   • Subclinical hypothyroidism: TSH >ULN and a free T4 within normal limits. The last available lab assessment date was used as the cut-off date for the analysis.
4. Percentage of Participants With Worsening Glucose Metabolism Compared to Baseline [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
   As assessed by an annual glucose tolerance test (OGTT). Worsening glucose metabolism was defined as 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 the baseline result. The last available lab assessment date was used as the cut-off date for the analysis.
5. Time to Disease Progression [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]

   Disease progression was defined as follows:

   • MDS progression: Transition into a higher MDS risk group based on IPSS scoring
   • Progression to AML: 20 percent or more blasts seen in the bone marrow collected by biopsy or aspirate.

   Disease progression was calculated as follows: Date of diagnosis of MDS progression or date of first diagnosis of AML, minus date of randomization plus 1. Participants who neither experienced MDS progression nor progression to AML were censored at the last contact date.

6. Time to First Occurrence of Serum Ferritin Level >2 Times the Baseline Value at Two Consecutive Assessments (at Least Two Weeks Apart) [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
   Assessed by blood draw and calculated as follows: Date of first occurrence of serum ferritin >2 times the baseline value at two consecutive assessments (at least two weeks apart), minus date of randomization plus 1. Participants who did not experience such an increase were censored at the last date when serum ferritin was available.
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: Day 1 to end of treatment period, approx. 7 years ]
   Assessed by echocardiography and calculated as follows: Date of echocardiography assessment where a minimum of 10% increase of LVIDD first occurred, minus date of randomization plus 1. Participants who did not experience such an increase were censored at the last date when LVIDD was available.
8. Time to at Least a 10% Increase From Baseline in Left Ventricular Internal Systolic Diameter (LVISD) at Two Consecutive Assessments at Least Two Weeks Apart [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
   Assessed by echocardiography and calculated as follows: Date of echocardiography assessment where a minimum of 10% increase of LVISD first occurred, minus date of randomization plus 1. Participants who did not experience such an increase were censored at the last date when LVISD was available.
9. Total Number of Infections Requiring Intravenous Antimicrobials [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
   The total number of infections were counted and summarized per treatment group. For this number, one participant can contribute more than one infection event. Infections were determined from the reported AEs with system organ class "Infections and infestations" and action taken "Concomitant medication taken." Antimicrobial therapy was determined from the reported concomitant medications for participants who had an infection AE. The route of administration needed to be specified as "intravenous (i.v.)". End of treatment period was defined as the treatment period plus 28 days.
10. Percentage of Participants With Major Gastrointestinal Bleeding [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
    Major gastrointestinal bleeding was defined as an AE that could include one of the following MedDRA preferred terms: gastric hemorrhage, gastrointestinal hemorrhage, small intestinal hemorrhage, esophageal hemorrhage, large intestinal hemorrhage, rectal hemorrhage, melaena, duodenal ulcer hemorrhage, gastric ulcer hemorrhage, peptic ulcer hemorrhage, large intestinal ulcer hemorrhage, esophageal ulcer hemorrhage, and hematochezia. The end of treatment period was defined as the treatment period plus 28 days.
11. Percentage of Participants With Significant Renal Dysfunction [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
    Significant renal dysfunction was defined as a serum creatinine value ≥ 2 times upper limit of normal (ULN) at two consecutive assessments at least 7 days apart
12. Percentage of Participants With Newly Occurring Moderate or Severe Neutropenia [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
    Moderate or severe neutropenia was defined as neutrophil counts less than 1.0×10E9/L.
13. Percentage of Participants With Newly Occurring Severe Thrombocytopenia [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
    Severe thrombocytopenia was defined as platelets counts less than 50×10E9/L.
14. Time to Study Drug Discontinuation Due to an AE or Laboratory Abnormality [ Time Frame: Day 1 to end of treatment period, approx. 7 years ]
    As recorded on the Study Treatment Completion electronic Case Report Form (eCRF), date and reason given.Only participants for whom the reason for stopping study medication was entered as AE or laboratory abnormality were considered. This time to event endpoint was calculated as the date of study drug discontinuation due to an AE or laboratory abnormality minus date of randomization plus 1. Participants who did not discontinue study medication due to an AE or laboratory abnormality were censored at the date of study drug discontinuation.

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:

• 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

Contacts and Locations

Locations

United States, California

Pacific Cancer Medical Center, Inc. PAC Center

Anaheim, California, United States, 92801

United States, Colorado

Rocky Mountain Cancer Centers RMCC

Greenwood Village, Colorado, United States

United States, Louisiana

Willis-Knighton Cancer Center Dept of Onc

Shreveport, Louisiana, United States, 71103

United States, Michigan

Henry Ford Hospital Henry Ford

Detroit, Michigan, United States, 48202

United States, Missouri

Midwest Cancer Care Physicians MMCC

Kansas City, Missouri, United States, 64131

Mercy Medical Research Institute SC

Manchester, Missouri, United States, 63021

United States, Montana

Glacier View Research Institute - Cancer SC

Kalispell, Montana, United States, 59901

United States, New Jersey

Hackensack University Medical Center Department of Research

Hackensack, New Jersey, United States, 07601

United States, Texas

University of Texas MD Anderson Cancer Center Dept of MD Anderson (16)

Houston, Texas, United States, 77030

Cancer Care Centers of South Texas HOAST CCC of So.TX- MedicalCenter(2)

San Antonio, Texas, United States, 78229

United States, Washington

Swedish Cancer Institute Ballard Campus

Seattle, Washington, United States, 98107

Australia, Queensland

Novartis Investigative Site

Herston, Queensland, Australia, 4029

Bulgaria

Novartis Investigative Site

Plovdiv, Bulgaria, 4002

Novartis Investigative Site

Sofia, Bulgaria, 1407

Novartis Investigative Site

Varna, Bulgaria, 9010

Canada, Alberta

Novartis Investigative Site

Edmonton, Alberta, Canada, T6G 2B7

Canada, Manitoba

Novartis Investigative Site

Winnipeg, Manitoba, Canada, R3E 0V9

Canada, Ontario

Novartis Investigative Site

Brampton, Ontario, Canada, L6R 3J7

Novartis Investigative Site

St. Catharines, Ontario, Canada, L2S 0A9

Canada, Quebec

Novartis Investigative Site

Québec, Quebec, Canada, G1J 1Z4

China, Guangdong

Novartis Investigative Site

Guangzhou, Guangdong, China, 51000

China, Hubei

Novartis Investigative Site

Wuhan, Hubei, China, 430022

China, Jiangsu

Novartis Investigative Site

Nanjing, Jiangsu, China, 210029

Novartis Investigative Site

Suzhou, Jiangsu, China, 215006

China, Shanghai

Novartis Investigative Site

Shanghai, Shanghai, China, 200437

China, Tianjin

Novartis Investigative Site

Tianjin, Tianjin, China, 300020

China, Zhejiang

Novartis Investigative Site

Hangzhou, Zhejiang, China, 310003

China

Novartis Investigative Site

Beijing, China, 100044

Novartis Investigative Site

Jinan, China, 250012

Novartis Investigative Site

Shanghai, China, 200025

Novartis Investigative Site

Shanghai, China, 200233

Denmark

Novartis Investigative Site

Copenhagen, Denmark, DK-2100

Novartis Investigative Site

Herlev, Denmark, DK 2730

Greece

Novartis Investigative Site

Athens, GR, Greece, 115 27

Novartis Investigative Site

Ioannina, GR, Greece, 455 00

Novartis Investigative Site

Athens, Greece, 115 27

Novartis Investigative Site

Patras, Greece, 265 00

Hong Kong

Novartis Investigative Site

Hong Kong, Hong Kong

Novartis Investigative Site

Shatin, New Territories, Hong Kong

Italy

Novartis Investigative Site

Bologna, BO, Italy, 40138

Novartis Investigative Site

Cagliari, CA, Italy, 09126

Novartis Investigative Site

San Giovanni Rotondo, FG, Italy, 71013

Novartis Investigative Site

Firenze, FI, Italy, 50134

Novartis Investigative Site

Messina, ME, Italy, 98125

Novartis Investigative Site

Pescara, PE, Italy, 65124

Novartis Investigative Site

Reggio Calabria, RC, Italy, 89124

Novartis Investigative Site

Orbassano, TO, Italy, 10043

Malaysia

Novartis Investigative Site

Kuching, Sarawak, Malaysia, 93586

Novartis Investigative Site

Selangor, Malaysia, 68000

Mexico

Novartis Investigative Site

Mexico, Distrito Federal, Mexico, 06726

Novartis Investigative Site

México, Distrito Federal, Mexico, 02990

New Zealand

Novartis Investigative Site

Auckland 6, New Zealand

Novartis Investigative Site

Auckland, New Zealand, 1309

Novartis Investigative Site

Auckland, New Zealand

Novartis Investigative Site

Christchurch, New Zealand, 8001

Russian Federation

Novartis Investigative Site

Moscow, Russian Federation, 125167

Novartis Investigative Site

Rostov on Don, Russian Federation, 344022

Switzerland

Novartis Investigative Site

Basel, Switzerland, 4031

Novartis Investigative Site

Zurich, Switzerland, 8091

Thailand

Novartis Investigative Site

Khon Kaen, THA, Thailand, 40002

Novartis Investigative Site

Bangkok, Thailand, 10330

Novartis Investigative Site

Bangkok, Thailand, 10400

Novartis Investigative Site

Chiang Mai, Thailand, 50200

United Kingdom

Novartis Investigative Site

Glasgow, Scotland, United Kingdom, G12 0YN

Novartis Investigative Site

Birmingham, United Kingdom, B15 2TH

Novartis Investigative Site

Bournemouth, United Kingdom, BH7 7DW

Novartis Investigative Site

Cardiff, United Kingdom, CF14 4XW

Novartis Investigative Site

Exeter, United Kingdom, EX2 5DW

Novartis Investigative Site

Kent, United Kingdom, DA2 8DA

Novartis Investigative Site

Macclesfield, United Kingdom, SK10 3BL

Novartis Investigative Site

Nottingham, United Kingdom, NG5 1PB

Novartis Investigative Site

Oxford, United Kingdom, OX3 7LJ

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Statistical Analysis Plan  [PDF] April 19, 2018

Study Protocol  [PDF] September 22, 2014

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Angelucci E, Li J, Greenberg P, Wu D, Hou M, Montano Figueroa EH, Rodriguez MG, Dong X, Ghosh J, Izquierdo M, Garcia-Manero G; TELESTO Study Investigators. Iron Chelation in Transfusion-Dependent Patients With Low- to Intermediate-1-Risk Myelodysplastic Syndromes: A Randomized Trial. Ann Intern Med. 2020 Apr 21;172(8):513-522. doi: 10.7326/M19-0916. Epub 2020 Mar 24.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00940602
• Other Study ID Numbers: CICL670A2302; 2009-012418-38 ( EudraCT Number )
• First Posted: July 16, 2009
• Results First Posted: November 23, 2020
• Last Update Posted: November 23, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• URL: http://www.clinicalstudydatarequest.com

• 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:

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