E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic syndrome (MDS) |
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E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndrome (MDS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part 1: To evaluate the efficacy and safety of imetelstat in transfusion dependent subjects with low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment.
Part 2: To compare the efficacy, in terms of RBC TI, of imetelstat to placebo in transfusion dependent subjects with low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment. |
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E.2.2 | Secondary objectives of the trial |
- To assess the safety of imetelstat in subjects with MDS
- To assess the time to RBC TI and duration of RBC TI
- To assess the rate of hematologic improvement
- To assess the rates of CR, PR or marrow complete remission (mCR)
- To assess OS
- To assess progression free survival (PFS)
- To assess time to progression to AML
- To assess the rate and amount of supportive care, including transfusions and myeloid growth factors (Part 2 only)
- To evaluate the pharmacokinetics and immunogenicity of imetelstat in subjects with MDS
- To assess the effect of imetelstat treatment on patient reported outcomes (PROs)
- To assess the effect of treatment on medical resource utilization (Part 2 only)
- To assess the effect of imetelstat on QTc interval in a subset of subjects (Part 2 only) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Amendment: 31 August 2017 Attachment 11: Ventricular Repolarization Substudy at Selected Sites Study Objectives To evaluate the effect of imetelstat on ventricular repolarization in a subset of subjects in Part 2 from selected clinical sites:
- The primary objective of this substudy is to determine the relationship between the plasma concentrations of imetelstat and QTc interval changes.
- The secondary objectives of this substudy are as follows:
1) To evaluate the effects of imetelstat on ventricular repolarization Fridericia's correction method [QTcF]) by using time-matched ECGs at baseline and on study drug versus placebo
2) To investigate the effect of imetelstat on the following ECG parameters: PR, RR, QRS, QT, QTcB (Bazett's correction method), and TWave morphology by using time-matched ECGs at baseline and on study drug versus placebo
3) To evaluate the pharmacokinetics of imetelstat
Safety will be assessed as part of the main study. At the time of the analysis of this substudy, all safety data from the main study will be provided along with data specific to this subset of subjects. In particular, any cardiac-related adverse events will be summarized in both main study and substudy populations. |
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E.3 | Principal inclusion criteria |
1. Man or woman ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place);
2. Criterion modified per Amendment 1.
2.1. Criterion modified per Amendment 2.
2.2. Criterion modified per Amendment 3.
2.3 In part 1, diagnosis of MDS according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1. A local laboratory report from this diagnostic bone marrow aspirate and biopsy must be reviewed and approved by the sponsor (Attachment 1). In Part 2, diagnosis of MDS according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to Study Entry (Attachment 1). A sample of the baseline bone marrow aspirate and biopsy must be submitted to the Independent Central Pathology Reviewer for diagnostic confirmation. Central laboratory review is required to confirm diagnosis prior to randomization.
3. IPSS low Risk or intermediate-1 risk MDS (Attachment 3);
4. Criterion modified per Amendment 1.
4.1. RBC transfusion dependent, defined as requiring at least 4 RBC units transfused over
an 8-week period during the 16 weeks prior to C1D1 (Part 1) or Randomization (Part 2)(defined in Section 3.1); pre-transfusion Hb should be ≤9.0 g/dL to count towards the 4 units total;
5. Has MDS that is relapsed/refractory to ESA treatment; as defined by meeting any one of the
criteria below:
5.1. Received at least 8 weeks of treatment with a minimum weekly dose of epoetin alfa
40,000 U, epoetin beta 30,000 U or darbepoetin alfa 150 mcg (or equivalent agent/dose), without having achieved a Hb rise ≥1.5 g/dL or decreased RBC transfusion requirement by at least 4 units over 8 weeks
5.2.1 Transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic improvement from at least 8 weeks of treatment with therapies outlined in inclusion criteria 5.1, in the absence of another explanation.
5.4. Endogenous serum EPO level >500 mU/mL;
...
More details see protocol |
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E.4 | Principal exclusion criteria |
1. Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer to the IB 25)
2. Subject has received an experimental or investigational drug or used an invasive investigational medical device within 30 days prior to C1D1 (Part 1) or Randomization (Part 2) (defined in Section 3.1) or is currently enrolled in an investigational study;
3.Prior treatment with imetelstat;
4. Criterion modified per Amendment 2
4.1 Have received corticosteroids > 30 mg/day prednisone or equivalent, or growth factor treatment within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2)
5. Criterion modified per Amendment 2.
5.2 Criterion 5.2 replaced by criterion 5.2.1 per Amendment 5.
5.2.1 Prior treatment with lenalidomide, thalidomide, or other thalidomide analogues;
5.3 Criterion 5.3 replaced by criterion 5.3.1 per Amendment 5.
5.3.1 Has received an ESA or any anti-MDS therapy, chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2) (8 weeks for long-acting ESAs);
6. Prior history of hematopoietic stem cell transplant;
7. Anemia attributed to factors other than MDS (including hemolysis, chronic renal failure, hepatitis, gastrointestinal bleeding);
8. Major surgery within 4 weeks prior to C1D1 (Part 1) or Randomization (Part 2)(excluding the placement of vascular access and other minor surgical procedures);
9. Diagnosed or treated for malignancy other than MDS, except:
9.1. Malignancy treated with curative intent and with no known active disease present for ≥3 years before C1D1 (Part 1) or Randomization (Part 2)
9.2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
9.3. Adequately treated cervical carcinoma in situ without evidence of disease;
10. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of C1D1 (Part 1) or Randomization (Part 2), or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification;
...
More details see protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage of participants without any red blood cell (RBC) transfusion during any consecutive 8 week period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. - Safety profiles of imetelstat in subjects with MDS (eg, incidence, intensity, and type of adverse events, vital signs measurements, clinical laboratory values, ECGs, and deaths);
2. - 24-week RBC TI rate, defined as the proportion of subjects without any RBC transfusion during any consecutive 24 weeks (168 days) starting from Study Day 1;
3. - Time to the 8-week RBC TI, defined as the interval from Study Day 1 to the first day of the first 8-week RBC TI period;
4. - Duration of RBC TI, defined as the first day of the first 8-week RBC TI period to the date of the first RBC transfusion after the TI period;
5. - Rate of hematologic improvement, including HI-E, per IWG 2006;
6. OS, defined as the interval from Study Day 1 to death from any cause.
Survival time of living subjects will be censored on the last date a subject is known to be alive or lost to follow-up;
7. Progression free survival, defined as the time interval from Study Day 1 to the first date of disease progression or death from any cause, whichever occurs first. For subjects who do not have documented disease progression and who are still alive at the end of the study or clinical cutoff will be censored at the last disease evaluation date.
8. Time to progression to AML, defined as the interval from Study Day 1 to the date of AML diagnosis. For subjects who have not progressed to AML and are still alive at the cutoff date for the analysis or who withdraw from the study (withdrawal of consent or lost to follow-up), data will be censored at the date of the last disease evaluation;
9. Amount and relative change in RBC transfusions;
10. Rate of myeloid growth factors usage, defined as the proportion of subjects receive any myeloid growth factors starting from Study Day 1; duration of myeloid growth factor administered starting from Study Day 1;
11. Assessment of QUALMS, FACT-An, and EQ-5D-5L;
12. Pharmacokinetic parameters (eg, Cmax, AUC0-t), and immunogenicity of imetelstat (eg, antibodies to imetelstat);
13. Medical resource utilization data including hospitalization, emergency room visits, and hematology specialist visits (Part 2 only);
14. ECG parameters including change in QT interval by Fridericia's correction method (ΔQTcF) (Part 2 only). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/ up to follow-up (30 days posttreatment [approximately 2 years])
2-5/ up to 2 years after enrollment of the last participant
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Russian Federation |
Spain |
Switzerland |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The End of the Study is defined as 2 years after Study Entry of the last subject or anytime the sponsor terminates the study, whichever comes first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 22 |