ENESTfreedom: Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT01784068
Collaborator
(none)
215
Enrollment
114
Locations
1
Arm
143.6
Anticipated Duration (Months)
1.9
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of the study was to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Nilotinib followed by treatment-free
Phase 2

Detailed Description

The Primary objective of this study was to determine the percentage of patients who were in MMR at 48 weeks after starting the TFR phase (patients who required re-initiation of treatment were considered as non-responders).

Nilotinib treatment consolidation phase (NTCS): Patients who satisfied all inclusion/exclusion criteria were enrolled in the consolidation phase and continued to receive nilotinib for 52 weeks. All patients were treated with the planned nilotinib dose 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of toxicity). In order for patients to be eligible for the TFR phase, they had to fulfill the protocol specific definition of durable MRD. The four last quarterly performed PCR assessments must have fulfilled the following criteria:

  • The last assessment was MR4.5 (BCR-ABL ≤ 0.0032% IS)

  • No assessment worse than MR4.0 (BCR-ABL >0.01% IS) and

  • No more than two assessments between MR4.0 and MR4.5 (0.0032% IS<BCR-ABL ≤ 0.01% IS)

Nilotinib TFR phase: Patients who were eligible to enter in the TFR phase after completing the 52 weeks consolidation phase, stopped taking nilotinib on the first day of the TFR phase. Duration of this phase was up to 10 years after the last patient enters in the TFR phase. BCR-ABL levels were monitored every four weeks during the first 48 weeks, every six weeks for the following 48 weeks and every 12 weeks during the last period.

Nilotinib treatment re-initiation (NTRI) phase: If a patient had a loss of MMR (BCR-ABL >0.1% IS) in the TFR phase, the patient restarted nilotinib treatment. Patients were on nilotinib treatment for up to 10 years after the last patient entered the nilotinib TFR phase. Patients who required re-initiation of nilotinib treatment were monitored for the BCR-ABL level every four weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR. The frequency of BCR-ABL monitoring in patients not regaining MMR within the first 24 weeks after re-initiation of treatment was at least every 12 weeks or more frequently as clinically indicated.

Study Design

Study Type:
Interventional
Actual Enrollment :
215 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Single-arm, Multicenter, Nilotinib Treatment-free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment.
Actual Study Start Date :
Mar 4, 2013
Actual Primary Completion Date :
May 31, 2016
Anticipated Study Completion Date :
Feb 20, 2025

Arms and Interventions

ArmIntervention/Treatment
Experimental: Nilotinib followed by treatment-free

Patients who received a minimum of 2 years of first line nilotinib treatment and with pre-screen PCR results in ≥ MR4.5 entered the consolidation phase of the study (52 weeks - nilotinib 300 mg BID). Patients with Minimal Residual Disease (MRD) at the end of this phase entered the Treatment-Free Remission (TFR) phase where no treatment was given. Non eligible patients will enter the continuation phase of the study. Patients with MRD at the end of the continuation phase will enter the TFR-2 phase of the study where no treatment is given. Non eligible patients will enter the prolonged continuation phase of the study. If at any time during TFR or TFR-2 the patient loses MMR, nilotinib treatment will be immediately re-initiated (nilotinib 300 mg BID).

Drug: Nilotinib followed by treatment-free
Nilotinib is being used as commercial available capsules (except in Japan where clinical supplies is used) of 150 mg and 200 mg strength. Treatment occurs during consolidation, continuation, prolonged continuation, re-initiation and re-initiation-2 phases of the study.
Other Names:
  • AMN107
  • Outcome Measures

    Primary Outcome Measures

    1. Percentage of Patients Who Are in MMR (Major Molecular Response) at 48 Weeks After Starting the Treatment-free Remission (TFR) Phase [48 weeks]

      Primary endpoint was the percentage of participants who were in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment were considered as non-responders.

    Secondary Outcome Measures

    1. Percentage of Patients Who Are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 Weeks After Starting the TFR Phase [48 weeks]

      Proportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.

    2. Percentage of Patients Who Are in MMR at 96, 144,192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase [96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years]

      Proportion of patients who are in MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

    3. Percentage of Patients Who Are in MR4.5 at 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase [96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years]

      Proportion of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

    4. Percentage of Patients in MMR at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib [48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years]

      Proportion of patients who are in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis

    5. Percentage of Patients in MR4.5 at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib [48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years]

      Proportion of patients who are in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis

    6. Percentage of Patients Who Achieve MMR Within 12 Weeks of Re-treatment With Nilotinib [12 weeks]

      Proportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks

    7. Kinetics of BCR-ABL Transcript After Re-start of Nilotinib Therapy [Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after last patient has entered the TFR]

      Descriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 528 weks after the last patient has entered TFR

    8. Duration of Re-initiated Treatment Required to Regain MMR After Loss of MMR [Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR]

      Defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment

    9. Duration of Re-initiated Treatment Required to Regain MR4.5 After Loss of MMR [Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR]

      Defined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4.5. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment

    10. Treatment-free Survival (TFS) After the Start of the TFR Phase [Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 432 weeks of the TFR]

      TFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.

    11. Progression-free Survival (PFS) After the Start of the TFR Phase [Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR]

      PFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up

    12. Overall Survival (OS) After the Start of the TFR Phase [Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR]

      OS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up

    13. Safety Profile During the Nilotinib Treatment Consolidation Phase, During the TFR Phase and During Re-initiation Treatment With Nilotinib [Every 4 weeks in treatment consolidation and during the first 24 weeks of the re-initiation phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 432 weeks of the TFR]

      Safety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib

    14. Proportion of Patients Who Develop T3151, E255K/V, Y253H, F359V/C/I Mutations on Study or Any Other BCR-ABL Mutations in Patients Who Lost MMR After Nilotinib Suspension [Every 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)]

      Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR

    15. Percentage of Patients Who Are in Stable Response (MMR and MR4.5) After Achievement of That Response in Nilotinib Re-initiation Phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 Weeks, Based on Availability of Appropriate Data [48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks]

      Proportion of patients who are in stable MMR/MR4.5 after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data, is calculated by dividing the number of patients achieving MMR/MR4.5 any time during the nilotinib re-initiation phase and having the same response 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks after the first achievement of MMR/MR4.5, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR/MR4.5 at any time during the nilotinib re-initiation phase

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Male or female patients ≥ 18 years of age

    • Minimum of 2 calendar years of nilotinib treatment with at least the last 12 months of nilotinib treatment prior to pre-screening at approved total daily dose of 600 mg BID or at a reduced dose of 400 mg QD if required from the perspective of tolerance for BCR-ABL positive CML in documented chronic phase at the time of diagnosis

    • Evidence of typical BCR-ABL transcripts (b3a2 and/or b2a2) at the time of CML-CP diagnosis i.e. prior to first start of TKI treatment which are amenable to standardized RT-PCR quantification"

    • Patient in MR4.5 at prescreening at Novartis designated lab

    • ECOG performance status of 0-2

    • Adequate end organ function as defined by:

    • Direct bilirubin ≤ 1.5 x ULN except for i) patients with documented Gilbert's syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range).

    • SGOT(AST) and SGPT(ALT) ≤ 3 x ULN i.e. equivalent to ≤ Grade 1 NCI-CTCAE v.4.03

    • Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03

    • Alkaline phosphatase ≤ 2.5 x ULN

    • Serum creatinine < 1.5 x ULN

    • Patients must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication:

    • Potassium (suggested keep to prevent issues with QT and/or rhythm abnormalities)

    • Magnesium (suggested keep to prevent issues with QT and/or rhythm abnormalities)

    • Total calcium (corrected for serum albumin)

    • Patients must have normal marrow function as defined:

    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L

    • Hemoglobin ≥ 9.0 g/dL

    • Platelets ≥ 100 x 10E9/L

    • Documented chronic phase CML must meet all the criteria defined by:

    • < 15% blasts in peripheral blood and bone marrow,

    • < 30% blasts plus promyelocytes in peripheral blood and bone marrow,

    • < 20% basophils in the peripheral blood,

    • ≥ 100 x 109/L (≥ 100,000/mm3) platelets,

    • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly

    • Patients must tolerate a minimum total daily dose of nilotinib of 400 mg

    Exclusion Criteria:
    • Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total cumulative duration of 4 weeks

    • Previous treatment with alpha-interferon of any duration

    • Previous anticancer agents for CML other than nilotinib except for cytoreduction after CML diagnosis until up to 4 weeks after first dose of nilotinib

    • Known second chronic phase of CML after previous progression to AP/BC

    • Poorly controlled diabetes mellitus (defined as HbA1c > 9%)

    • Impaired cardiac function including any one of the following:

    • LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher)

    • Inability to determine the QT interval on ECG, except for patients with evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality.

    • Complete left bundle branch block

    • Right bundle branch block plus left anterior or posterior hemiblock

    • Use of a ventricular-paced pacemaker

    • Congenital long QT syndrome or a known family history of long QT syndrome

    • History of or presence of clinically significant ventricular or atrial tachyarrhythmias

    • Clinically significant resting bradycardia

    • QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula). If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-tested for QTc.This exclusion criterion is not applicable for patients with non-measurable QT interval who have evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality.

    • History or clinical signs of myocardial infarction within 1 year of study entry

    • History of unstable angina within 1 year of study entry

    • Other clinically significant heart disease (e.g. congestive heart failure, cardiomyopathy or uncontrolled hypertension)

    • History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis

    • Known presence of significant congenital or acquired bleeding disorder unrelated to cancer

    • Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, uncontrolled infection)

    • History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively

    • Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1

    • Patients who have not recovered from prior surgery

    • Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.

    • Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.

    • Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug. (see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval)

    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)

    • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

    • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 14 days after the final dose of nilotinib. Highly effective contraception is defined as either:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

    • Male sterilization (at least 6 months prior to enrolling). For female patients on the study the vasectomized male partner should be the sole partner for that patient.

    • Use of a combination of any two of the following:

    1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

    In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

    If a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of nilotinib, the Study Doctor needs to be informed immediately and ongoing study treatment with nilotinib has to be stopped immediately.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Florida Cancer Specialists FL Cancer SpecialistsFort MyersFloridaUnited States33901
    2Lakes Research SCMiami LakesFloridaUnited States33014
    3H Lee Moffitt Cancer Center and Research Institute SC - 5TampaFloridaUnited States33612
    4Cancer Center of Kansas SCWichitaKansasUnited States67214-3728
    5Dana Farber Cancer Institute SC - 8BostonMassachusettsUnited States02215
    6Memorial Sloan Kettering SCNew YorkNew YorkUnited States10017
    7Oregon Health and Science University SC-6PortlandOregonUnited States97239
    8Cancer Centers of the Carolinas Cancer Centers of Carolinas (3GreenvilleSouth CarolinaUnited States29605
    9Sarah Cannon Research Institute Sarah Cannon ResearchNashvilleTennesseeUnited States37203
    10Community Cancer Trials of UtahOgdenUtahUnited States84405
    11Novartis Investigative SiteBuenos AiresArgentinaC1114AAN
    12Novartis Investigative SiteGrazAustriaA-8036
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    91Novartis Investigative SiteShinjuku-kuTokyoJapan160-0023
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    114Novartis Investigative SiteOxfordUnited KingdomOX3 7LJ

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01784068
    Other Study ID Numbers:
    • CAMN107I2201
    • 2012-004092-40
    First Posted:
    Feb 5, 2013
    Last Update Posted:
    Nov 12, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details215 patients were actually enrolled in the NTCS (nilotinib treatment consolidation) phase. 190 of the 215 patients completed 52 weeks of nilotinib treatment in the NTCS phase and entered the treatment-free remission (TFR) phase.
    Pre-assignment DetailApproximately 175 patients were planned to be enrolled into the study.
    Arm/Group TitleNTCS PhaseTFR Phase
    Arm/Group DescriptionPatients who received a minimum of two years of first line nilotinib treatment and with BCR-ABL1 transcript level of MR4.5 entered consolidation phase of the study (52 weeks of nilotinib 300 mg BID)Patients with Minimal Residual Disease (MRD) at the end of consolidation phase entered the Treatment-Free Remission (TFR) phase where no treatment was given
    Period Title: NTCS Phase
    STARTED2150
    NTRI Phase860
    NTCT Phase130
    TFR-2 Phase80
    NTCT-P Phase20
    NTRI-200
    COMPLETED00
    NOT COMPLETED2150
    Period Title: NTCS Phase
    STARTED0190
    COMPLETED097
    NOT COMPLETED093

    Baseline Characteristics

    Arm/Group TitleNTCS Phase
    Arm/Group DescriptionPatients who received a minimum of two years of first line nilotinib treatment and with BCR-ABL1 transcript level of MR4.5 entered consolidation phase of the study (52 weeks of nilotinib 300 mg BID)
    Overall Participants215
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    54.0
    Sex: Female, Male (Count of Participants)
    Female
    102
    47.4%
    Male
    113
    52.6%
    Race/Ethnicity, Customized (participants) [Number]
    Caucasian
    189
    87.9%
    Asian
    20
    9.3%
    Unknown
    3
    1.4%
    Native American
    1
    0.5%
    Other
    2
    0.9%

    Outcome Measures

    1. Primary Outcome
    TitlePercentage of Patients Who Are in MMR (Major Molecular Response) at 48 Weeks After Starting the Treatment-free Remission (TFR) Phase
    DescriptionPrimary endpoint was the percentage of participants who were in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment were considered as non-responders.
    Time Frame48 weeks

    Outcome Measure Data

    Analysis Population Description
    FAS: The FAS included the 190 patients who completed 52 weeks of nilotinib treatment in the NTCS phase and entered TFR phase
    Arm/Group TitleTFR Phase
    Arm/Group DescriptionPatients with Minimal Residual Disease (MRD) at the end of consolidation phase entered the Treatment-Free Remission (TFR) phase where no treatment was given
    Measure Participants190
    Number (95% Confidence Interval) [Percentage of participants]
    51.6
    24%
    2. Secondary Outcome
    TitlePercentage of Patients Who Are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 Weeks After Starting the TFR Phase
    DescriptionProportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.
    Time Frame48 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    3. Secondary Outcome
    TitlePercentage of Patients Who Are in MMR at 96, 144,192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase
    DescriptionProportion of patients who are in MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders
    Time Frame96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    TitlePercentage of Patients Who Are in MR4.5 at 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase
    DescriptionProportion of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders
    Time Frame96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    TitlePercentage of Patients in MMR at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib
    DescriptionProportion of patients who are in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis
    Time Frame48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    TitlePercentage of Patients in MR4.5 at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib
    DescriptionProportion of patients who are in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis
    Time Frame48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Secondary Outcome
    TitlePercentage of Patients Who Achieve MMR Within 12 Weeks of Re-treatment With Nilotinib
    DescriptionProportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks
    Time Frame12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    TitleKinetics of BCR-ABL Transcript After Re-start of Nilotinib Therapy
    DescriptionDescriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 528 weks after the last patient has entered TFR
    Time FrameEvery 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after last patient has entered the TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Secondary Outcome
    TitleDuration of Re-initiated Treatment Required to Regain MMR After Loss of MMR
    DescriptionDefined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment
    Time FrameEvery 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    TitleDuration of Re-initiated Treatment Required to Regain MR4.5 After Loss of MMR
    DescriptionDefined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4.5. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment
    Time FrameEvery 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    TitleTreatment-free Survival (TFS) After the Start of the TFR Phase
    DescriptionTFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.
    Time FrameEvery 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 432 weeks of the TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Secondary Outcome
    TitleProgression-free Survival (PFS) After the Start of the TFR Phase
    DescriptionPFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up
    Time FrameEvery 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Secondary Outcome
    TitleOverall Survival (OS) After the Start of the TFR Phase
    DescriptionOS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up
    Time FrameEvery 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 432 weeks of the TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Secondary Outcome
    TitleSafety Profile During the Nilotinib Treatment Consolidation Phase, During the TFR Phase and During Re-initiation Treatment With Nilotinib
    DescriptionSafety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib
    Time FrameEvery 4 weeks in treatment consolidation and during the first 24 weeks of the re-initiation phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 432 weeks of the TFR

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    15. Secondary Outcome
    TitleProportion of Patients Who Develop T3151, E255K/V, Y253H, F359V/C/I Mutations on Study or Any Other BCR-ABL Mutations in Patients Who Lost MMR After Nilotinib Suspension
    DescriptionProportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR
    Time FrameEvery 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    16. Secondary Outcome
    TitlePercentage of Patients Who Are in Stable Response (MMR and MR4.5) After Achievement of That Response in Nilotinib Re-initiation Phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 Weeks, Based on Availability of Appropriate Data
    DescriptionProportion of patients who are in stable MMR/MR4.5 after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data, is calculated by dividing the number of patients achieving MMR/MR4.5 any time during the nilotinib re-initiation phase and having the same response 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks after the first achievement of MMR/MR4.5, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR/MR4.5 at any time during the nilotinib re-initiation phase
    Time Frame48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time FrameAdverse events were collected from first dose of study treatment until 30 days after the last dose of study treatment or the last day in the TFR/TFR-2 phase for approx. 26 months.
    Adverse Event Reporting Description Any sign or symptom that occurs during the study treatment plus 30 days post treatment.
    Arm/Group TitleNTCS PhaseTFR PhaseNTRI PhaseNTCT PhaseTFR-2 PhaseNTRI-2 PhaseNTCT-P PhaseAll Patients
    Arm/Group DescriptionPatients who received a minimum of two years of first line nilotinib treatment and with BCR-ABL1 transcript level of MR4.5 entered consolidation phase of the study (52 weeks of nilotinib 300 mg BID)Patients with Minimal Residual Disease (MRD) at the end of consolidation phase entered the Treatment-Free Remission (TFR) phase where no treatment was givenIf at any time during TFR phase the patient lost MMR, nilotinib treatment was to be immediately re-initiated (nilotinib 300 mg BID)Patients with no MRD at the end of consolidation phase entered the continuation phase of the study and continue with nilotinib 300 mg BIDPatients with MRD at the end of the continuation phase entered the TFR-2 phase of the study where no treatment was givenIf at any time during TFR phase or TFR-2 phase the patient lost MMR, nilotinib treatment was to be immediately re-initiated (nilotinib 300 mg BID)Patients with no MRD at the end of continuation phase entered the prolonged continuation phase of the studyAll patients enrolled in the study
    All Cause Mortality
    NTCS PhaseTFR PhaseNTRI PhaseNTCT PhaseTFR-2 PhaseNTRI-2 PhaseNTCT-P PhaseAll Patients
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total2/215 (0.9%) 1/190 (0.5%) 2/86 (2.3%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 5/215 (2.3%)
    Serious Adverse Events
    NTCS PhaseTFR PhaseNTRI PhaseNTCT PhaseTFR-2 PhaseNTRI-2 PhaseNTCT-P PhaseAll Patients
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total20/215 (9.3%) 15/190 (7.9%) 11/86 (12.8%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 40/215 (18.6%)
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION0/215 (0%) 1/190 (0.5%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    ANGINA PECTORIS0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    CARDIAC ARREST1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    CARDIAC FAILURE CONGESTIVE0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    CORONARY ARTERY DISEASE0/215 (0%) 0/190 (0%) 2/86 (2.3%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    MYOCARDIAL INFARCTION1/215 (0.5%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    Eye disorders
    IRIS NEOVASCULARISATION1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Gastrointestinal disorders
    ABDOMINAL PAIN1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    ABDOMINAL PAIN UPPER0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    ASCITES0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    GASTRIC ULCER1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    HAEMORRHOIDS0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    INGUINAL HERNIA2/215 (0.9%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 3/215 (1.4%)
    NAUSEA0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    PANCREATITIS2/215 (0.9%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    General disorders
    CHEST PAIN0/215 (0%) 0/190 (0%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    DEATH0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    GENERALISED OEDEMA0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Hepatobiliary disorders
    CHOLELITHIASIS0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    HEPATOMEGALY0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Immune system disorders
    CONTRAST MEDIA ALLERGY1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    DRUG HYPERSENSITIVITY1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Infections and infestations
    DACRYOCYSTITIS1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    HERPES ZOSTER1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    PHARYNGEAL ABSCESS1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    RESPIRATORY TRACT INFECTION0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Injury, poisoning and procedural complications
    ANKLE FRACTURE0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Metabolism and nutrition disorders
    TYPE 2 DIABETES MELLITUS0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Musculoskeletal and connective tissue disorders
    BACK PAIN0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    CHONDROPATHY0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    INTERVERTEBRAL DISC PROTRUSION2/215 (0.9%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 3/215 (1.4%)
    ROTATOR CUFF SYNDROME0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    BREAST CANCER0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    BREAST CANCER IN SITU1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    MALIGNANT MELANOMA1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    MESOTHELIOMA0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    RECTAL CANCER0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    THYROID NEOPLASM1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    TRANSITIONAL CELL CARCINOMA0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Nervous system disorders
    CEREBRAL INFARCTION0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    CEREBROVASCULAR ACCIDENT1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    DIZZINESS1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    HEADACHE1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    MULTIPLE SCLEROSIS RELAPSE1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    SCIATICA1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    SYNCOPE0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    TRANSIENT ISCHAEMIC ATTACK1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Psychiatric disorders
    COMPLETED SUICIDE1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Renal and urinary disorders
    HAEMORRHAGE URINARY TRACT0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    RENAL COLIC0/215 (0%) 0/190 (0%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    URINARY INCONTINENCE1/215 (0.5%) 0/190 (0%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    PLEURAL EFFUSION0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    PNEUMONIA ASPIRATION0/215 (0%) 1/190 (0.5%) 0/86 (0%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Vascular disorders
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE2/215 (0.9%) 2/190 (1.1%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 4/215 (1.9%)
    Other (Not Including Serious) Adverse Events
    NTCS PhaseTFR PhaseNTRI PhaseNTCT PhaseTFR-2 PhaseNTRI-2 PhaseNTCT-P PhaseAll Patients
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total136/215 (63.3%) 91/190 (47.9%) 49/86 (57%) 10/13 (76.9%) 1/8 (12.5%) 0/0 (NaN) 0/2 (0%) 171/215 (79.5%)
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER9/215 (4.2%) 6/190 (3.2%) 3/86 (3.5%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 15/215 (7%)
    DIARRHOEA12/215 (5.6%) 9/190 (4.7%) 2/86 (2.3%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 22/215 (10.2%)
    NAUSEA7/215 (3.3%) 2/190 (1.1%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 10/215 (4.7%)
    VOMITING6/215 (2.8%) 5/190 (2.6%) 1/86 (1.2%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 11/215 (5.1%)
    General disorders
    FATIGUE9/215 (4.2%) 6/190 (3.2%) 4/86 (4.7%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 18/215 (8.4%)
    INFLUENZA LIKE ILLNESS3/215 (1.4%) 2/190 (1.1%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 6/215 (2.8%)
    LOCALISED OEDEMA0/215 (0%) 1/190 (0.5%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    Infections and infestations
    GASTROENTERITIS3/215 (1.4%) 1/190 (0.5%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 8/215 (3.7%)
    INFLUENZA7/215 (3.3%) 4/190 (2.1%) 2/86 (2.3%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 11/215 (5.1%)
    LARYNGITIS1/215 (0.5%) 1/190 (0.5%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 4/215 (1.9%)
    NASOPHARYNGITIS22/215 (10.2%) 17/190 (8.9%) 7/86 (8.1%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 36/215 (16.7%)
    PHARYNGITIS2/215 (0.9%) 1/190 (0.5%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 6/215 (2.8%)
    UPPER RESPIRATORY TRACT INFECTION7/215 (3.3%) 9/190 (4.7%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 16/215 (7.4%)
    Injury, poisoning and procedural complications
    FALL5/215 (2.3%) 0/190 (0%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 7/215 (3.3%)
    LIGAMENT SPRAIN1/215 (0.5%) 0/190 (0%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    LIP INJURY0/215 (0%) 0/190 (0%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    Investigations
    BLOOD CHOLESTEROL INCREASED6/215 (2.8%) 4/190 (2.1%) 5/86 (5.8%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 14/215 (6.5%)
    BLOOD CREATININE INCREASED1/215 (0.5%) 1/190 (0.5%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 3/215 (1.4%)
    LIPASE INCREASED8/215 (3.7%) 2/190 (1.1%) 7/86 (8.1%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 15/215 (7%)
    Metabolism and nutrition disorders
    DECREASED APPETITE2/215 (0.9%) 2/190 (1.1%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 6/215 (2.8%)
    HYPERCHOLESTEROLAEMIA2/215 (0.9%) 3/190 (1.6%) 7/86 (8.1%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 10/215 (4.7%)
    HYPERTRIGLYCERIDAEMIA1/215 (0.5%) 0/190 (0%) 1/86 (1.2%) 3/13 (23.1%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 4/215 (1.9%)
    HYPOPHOSPHATAEMIA16/215 (7.4%) 2/190 (1.1%) 5/86 (5.8%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 17/215 (7.9%)
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA17/215 (7.9%) 23/190 (12.1%) 4/86 (4.7%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 39/215 (18.1%)
    ARTHRITIS1/215 (0.5%) 1/190 (0.5%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 3/215 (1.4%)
    BACK PAIN9/215 (4.2%) 7/190 (3.7%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 19/215 (8.8%)
    BONE PAIN4/215 (1.9%) 9/190 (4.7%) 2/86 (2.3%) 0/13 (0%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 13/215 (6%)
    MUSCLE SPASMS7/215 (3.3%) 4/190 (2.1%) 4/86 (4.7%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 14/215 (6.5%)
    MUSCULOSKELETAL PAIN6/215 (2.8%) 7/190 (3.7%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 14/215 (6.5%)
    MYALGIA3/215 (1.4%) 9/190 (4.7%) 3/86 (3.5%) 1/13 (7.7%) 1/8 (12.5%) 0/0 (NaN) 0/2 (0%) 15/215 (7%)
    PAIN IN EXTREMITY8/215 (3.7%) 13/190 (6.8%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 22/215 (10.2%)
    ROTATOR CUFF SYNDROME0/215 (0%) 2/190 (1.1%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 3/215 (1.4%)
    Nervous system disorders
    AMNESIA0/215 (0%) 0/190 (0%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    HEADACHE9/215 (4.2%) 11/190 (5.8%) 6/86 (7%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 24/215 (11.2%)
    Psychiatric disorders
    ANXIETY1/215 (0.5%) 3/190 (1.6%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 4/215 (1.9%)
    DEPRESSION3/215 (1.4%) 1/190 (0.5%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 5/215 (2.3%)
    Reproductive system and breast disorders
    MENSTRUATION IRREGULAR1/215 (0.5%) 0/190 (0%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 2/215 (0.9%)
    Respiratory, thoracic and mediastinal disorders
    COUGH7/215 (3.3%) 1/190 (0.5%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 10/215 (4.7%)
    DYSPHONIA0/215 (0%) 0/190 (0%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 1/215 (0.5%)
    DYSPNOEA6/215 (2.8%) 1/190 (0.5%) 1/86 (1.2%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 8/215 (3.7%)
    OROPHARYNGEAL PAIN4/215 (1.9%) 1/190 (0.5%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 9/215 (4.2%)
    Skin and subcutaneous tissue disorders
    DRY SKIN5/215 (2.3%) 1/190 (0.5%) 0/86 (0%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 7/215 (3.3%)
    PRURITUS4/215 (1.9%) 2/190 (1.1%) 8/86 (9.3%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 15/215 (7%)
    RASH7/215 (3.3%) 1/190 (0.5%) 3/86 (3.5%) 2/13 (15.4%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 13/215 (6%)
    Vascular disorders
    HYPERTENSION16/215 (7.4%) 7/190 (3.7%) 3/86 (3.5%) 1/13 (7.7%) 0/8 (0%) 0/0 (NaN) 0/2 (0%) 24/215 (11.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial.

    Results Point of Contact

    Name/TitleStudy Director
    OrganizationNovartis Pharmaceuticals
    Phone862-778-8300
    Emailnovartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01784068
    Other Study ID Numbers:
    • CAMN107I2201
    • 2012-004092-40
    First Posted:
    Feb 5, 2013
    Last Update Posted:
    Nov 12, 2021
    Last Verified:
    Nov 1, 2021