Myelodysplastic Syndromes
Conditions
Keywords
Myelodysplastic Syndromes, Imetelstat Sodium, GRN163L, Relapsed/refractory to ESAs, Transfusion dependent, IMerge
Brief summary
The purpose of this study is to evaluate the efficacy and safety of imetelstat sodium in transfusion-dependent participants with low or intermediate-1 risk myelodysplastic syndrome (MDS) that is relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment in Phase 2 study and to compare the efficacy, in terms of red blood cell (RBC) transfusion independence (TI), of imetelstat sodium to placebo in transfusion-dependent participants with low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment in Phase 3 study. A separate Ventricular Repolarization Substudy (QTc Substudy) will evaluate the effect of imetelstat sodium on ventricular repolarization. An Extension Phase has been included to allow continued treatment for those participants who are benefitting from imetelstat sodium and to continue to evaluate the long-term safety, overall survival (OS), and disease progression, including progression to acute myeloid leukemia (AML) in transfusion-dependent participants with low or immediate-1 risk MDS that is relapsed/refractory to ESA treatment.
Detailed description
This is a Phase 2/3, multicenter study of imetelstat sodium in which 289 participants were enrolled. * Phase 2 is an open-label, single-arm design to assess the efficacy and safety of imetelstat sodium. A total of 57 participants were enrolled in Phase 2, including the expansion cohort. * Phase 3 is a double-blind, randomized design to compare the efficacy of imetelstat sodium with placebo. In the Phase 3 study, 178 participants were enrolled and randomized in a 2:1 ratio to receive either imetelstat sodium or placebo, respectively. * In a separate Ventricular Repolarization (VR) Substudy (QTc Substudy), 54 participants were enrolled and randomized 2:1 to receive either imetelstat sodium or placebo. If after a minimum of 2 treatment cycles in the VR substudy, a participant has no significant change to packed red blood cell (pRBC) transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant may be unblinded. If the participant was on placebo treatment, he/she may be permitted to start treatment with imetelstat sodium. The Extension Phase was initiated at the end of the Phase 3 study (24 months after the last participant was randomized in the Phase 3) and will continue until participants who entered Phase 3 study participated in the study for up to 5 years from the first dose of imetelstat sodium (including treatment and follow-up), or 3 years of post-treatment follow-up from the last dose of study treatment, whichever occurs later, or until death, withdrawal of consent, study termination, or until a participant is lost to follow-up. Participants ongoing on imetelstat sodium and considered to be benefiting from treatment per Investigator in the Phase 3 Study or Ventricular Repolarization Substudy, have the option to continue receiving imetelstat sodium in the Extension Phase. Participants in the follow-up phase for the Phase 3 study or Ventricular Repolarization Substudy have the option to continue the follow-up in the Extension Phase. The Phase 2, Phase 3, and VR Substudy all consist of 3 phases: a Screening phase (up to 28 days); a treatment phase; and a post-treatment follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first). The Extension Phase of the study will consist of an extended treatment phase and an extended follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first).
Interventions
Imetelstat sodium IV infusion.
DRUGPlacebo
Imetelstat sodium-matching placebo IV infusion.
Sponsors
Geron Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Man or woman greater than or equal to (≥) 18 years of age * Diagnosis of myelodysplastic syndrome (MDS) according to World Health Organization (WHO) criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to Cycle 1 Day 1 (C1D1) (Phase 2) or randomization (Phase 3). In Ventricular Repolarization Substudy, diagnosis of MDS or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1 * International Prognostic Scoring System (IPSS) low Risk or intermediate-1 risk MDS * Red blood cell (RBC) transfusion dependent, defined as requiring at least 4 RBC units transfused over an 8-week period during the 16 weeks prior to Study Entry; pre-transfusion hemoglobin (Hb) should be less than or equal to (≤) 9.0 gram per deciliter (g/dL) to count towards the 4 units total * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
Exclusion criteria
* Participant has known allergies, hypersensitivity, or intolerance to imetelstat sodium or its excipients * Participant has received an investigational drug or used an invasive investigational medical device within 30 days prior to Study Entry or is currently enrolled in an investigational study * Prior treatment with imetelstat sodium * Have received corticosteroids greater than (\>) 30 milligram per day (mg/day) prednisone or equivalent, or growth factor treatment within 4 weeks prior to study entry * Has received an erythropoiesis-stimulating agent (ESA) or any chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to study entry (8 weeks for long-acting ESAs) * Phase 3: a) Prior treatment with a hypomethylating agent (example \[eg\], azacitidine, decitabine); b) Prior treatment with lenalidomide Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Percentage of Participants Without Any Red Blood Cell (RBC) Transfusion During Any Consecutive 8-Weeks Period (All Participants) | Up to 5 years in Phase 2 | Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place. |
| Phase 2: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period in Target Population | Up to 5 years in Phase 2 | Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place. |
| Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period | Up to 3.7 years in Phase 3 | Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Adverse events: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3; Deaths: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 | TEAEs were defined as those events that 1) occurred after the first dose of study drug, through the treatment phase, and for 30 days following the last dose of study drug or until subsequent anti-cancer therapy if earlier; 2) any event that was considered study drug-related regardless of the start date of the event; or 3) any event that was presented at baseline but worsened in severity or was subsequently considered drug-related by the investigator. Serious TEAEs are any TEAEs that result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product, is medically important. Any clinically significant vital sign measurements, clinical laboratory values, and electrocardiogram (ECG) findings were reported as TEAEs. TEAEs included both serious and non-serious TEAEs. |
| Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Percentage of participants without any RBC transfusion during any consecutive 24 weeks (168 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2 and the day of randomization for participants enrolled in Phase 3. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place. |
| Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI) | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Time to 8-week RBC TI was defined as the interval from Study Day 1 to the first day of the first 8-week RBC TI period. |
| Phase 2 and Phase 3: Time to the 24-Weeks RBC TI | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Time to 24-week RBC TI was defined as the interval from Study Day 1 to the first day of the first 24-weeks RBC TI period. |
| Phase 2 and Phase 3: Duration of RBC TI | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Duration of RBC TI was defined as the first day of the longest RBC TI period to the date of the first RBC transfusion after the TI period started. The 95% CI was based on Kaplan-Meier product limit estimates. |
| Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006 | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | As per IWG Response Criteria 2006: HI-E was defined as a hemoglobin (Hb) increase by greater than or equal to (≥)1.5 grams per deciliter (g/dL) relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusion units/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of less than or equal to (≤)9 g/dL pretreatment were counted in the RBC transfusion response evaluation. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place. |
| Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator | Up to 5 years in Phase 2 | As per the IWG Response Criteria 2006, CR was defined as Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood (PB): Hb ≥11 g/dL; platelets ≥100 x 10\^9/dL; neutrophils ≥1.0 x 10\^9/liter; blasts: 0%. PR was defined as Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment; cellularity and morphology not relevant. mCR was defined as Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pre-treatment PB. Percentages were rounded off to the nearest single decimal place. All participants in Phase 2 were evaluated by the Investigator for CR/PR/mCR regardless of bone marrow blasts at baseline. |
| Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Up to 3.7 years in Phase 3 | As per the IWG Response Criteria 2006, CR was defined as Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; PB: Hb ≥11 g/dL; platelets ≥100 x 10\^9/dL; neutrophils ≥1.0 x 10\^9/liter; blasts: 0%. PR was defined as Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment; cellularity and morphology not relevant. mCR was defined as Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pre-treatment PB. CR, PR and mCR were assessed by IRC in Phase 3 and participants were required to fit at least one of the following criteria (participants with \>5% baseline blasts per central pathology reviewer assessment; participants with CR, PR, mCR, or cytogenetic response as assessed by the investigator) and have at least one post-baseline assessment. |
| Phase 2 and Phase 3: Overall Survival (OS) | Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 | OS was defined as the interval from Study Day 1 to death from any cause. Survival time of living participants was censored on the last date a participant is known to be alive or lost to follow-up. The Kaplan-Meier method was used to estimate overall survival. |
| Phase 2 and Phase 3: Progression Free Survival (PFS) | Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 | Progression free survival was defined as the time interval from study Day 1 to the first date of disease progression or death from any cause, whichever occurs first. Disease progression as per IWG criteria was defined as: at least one of the following: at least 50 % decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by ≥1.5 g/dL; transfusion dependence. |
| Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML) | Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 | Time to progression to AML was defined as the interval from Study Day 1 to the date of AML diagnosis. Participants who did not progress to AML and were still alive at the cutoff date for the analysis or who withdrew from the study (withdrawal of consent or lost to follow-up), data was censored at the date of the last disease evaluation. |
| Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Amount of RBC transfusions for 8-week interval was defined as the total number of RBC transfusion units in a given 8-week interval during study. The best 8-week interval is a post-baseline 8-week interval where the participant had the fewest post-Study Day 1 RBC transfusion units. A valid 8-week period must start before the date of last dose of study drug + 30 days or end of treatment (EOT) visit whichever occurs first and ends before the first transfusion in post-treatment follow-up or the first day of subsequent anti-cancer therapy whichever occurs first. |
| Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Relative percent change in RBC transfusions per 8-week = (amount of RBC transfusions per 8-week - prior RBC transfusion burden) / prior RBC transfusion burden multiplied by 100%. Prior RBC transfusion burden was defined as the maximum number of RBC units transfused over any consecutive 8 weeks prior to study entry. |
| Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Percentage of participants who received any myeloid growth factors starting from Study Day 1 were reported. Percentages were rounded off to the nearest single decimal place. |
| Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration | Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 | Duration of myeloid growth factor administered starting from Study Day 1 was reported. |
| Phase 2 and Phase 3: Maximum Observed Plasma Concentration (Cmax) | Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days) | As pre-specified in the statistical analysis plan (SAP), participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for pharmacokinetic (PK) data collection and analyses in this outcome measure. PK parameters were determined by population PK model. |
| Phase 2 and Phase 3: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Time 28 Days (AUC0-28d) | Cycle 1 (Days 1 to 28) (Cycle duration= 28 days) | As pre-specified in the statistical analysis plan (SAP), participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for PK data collection and analyses in this outcome measure. PK parameters were determined by population PK model. |
| Phase 2 and Phase 3: Percentage of Participants With Anti-drug Antibodies (ADA) to Imetelstat Sodium | Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days) | As pre-specified in the SAP, participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for immunogenicity data collection and analyses in this outcome measure. Percentages were rounded off to the nearest single decimal place. |
| Phase 3: Medical Resource Utilization Assessed Based on Percentage of Participants With Outpatient Medical Encounters | Up to 3.7 years in Phase 3 | Outpatient medical encounters included various sites of care: a) emergency room (ER) visits, b) hospital outpatient visits, c) home care visit, d) visit to lab, e) visit to doctor's office, f) other visits. Percentages were rounded off to the nearest single decimal place. |
| Phase 3: Medical Resource Utilization Assessed Based on Duration of Hospitalization | Up to 3.7 years in Phase 3 | Hospitalization included any medical encounter defined as hospice, hospital inpatient department, and intensive care unit (ICU). Hospitalizations without end dates were not counted in the calculation of length of stay. If any participant had multiple readmissions, duration was calculated as the sum of all hospital stays. |
| QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Baseline, Cycle 1, Day 1: 0.5, 1, 2, 4, 6, and 8 hours post-dose (cycle length= 28 days) | Baseline was defined as the mean of the measured ECG intervals collected at 3 time points (-1 hour, -0.5 hour, and 0 hour) prior to treatment administration on Cycle 1 Day 1 (Cycle length= 28 days) |
Countries
Belgium, Canada, Czechia, France, Germany, Israel, Italy, Netherlands, Poland, Russia, South Korea, Spain, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORTymara Berry, MD
Geron Corporation
Participant flow
Recruitment details
Participants were enrolled in Phase 2 at 48 study sites and in the Phase 3 Study at 77 study sites. Data is reported for the Phase 2, Phase 3 and QTc substudy up to the primary completion date (PCD) of 13 October 2023. Enrolment in Extension phase started after October 2023 and analyses for the participants in extension phase is still ongoing, hence data for extension phase will be reported at study completion date in 2026.
Pre-assignment details
57 participants with MDS received Imetelstat Sodium in Phase 2, followed by Phase 3 where 178 participants were randomized to receive either Imetelstat Sodium or Imetelstat sodium-matching placebo. 54 participants enrolled in QTc Substudy to receive either Imetelstat Sodium or Imetelstat sodium-matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Phase 2: Imetelstat Sodium Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. Dose escalation to 9.4 mg/kg was allowed before Protocol Amendment 2. | 57 |
| Phase 3: Imetelstat Sodium Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. | 118 |
| Phase 3: Placebo Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. | 60 |
| QTc Substudy: Imetelstat Sodium Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. | 35 |
| QTc Substudy: Placebo Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. If after a minimum of 2 treatment cycles a participant has no significant change to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant, he/she may be permitted to start treatment with imetelstat sodium. | 18 |
| Total | 288 |
Baseline characteristics
| Characteristic | Phase 2: Imetelstat Sodium | Phase 3: Imetelstat Sodium | Phase 3: Placebo | QTc Substudy: Imetelstat Sodium | QTc Substudy: Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 70.1 years | 70.4 years | 71.7 years | 69.7 years | 67.8 years | 69.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 5 Participants | 0 Participants | 0 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 100 Participants | 48 Participants | 29 Participants | 15 Participants | 240 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 12 Participants | 7 Participants | 6 Participants | 3 Participants | 36 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 8 Participants | 2 Participants | 3 Participants | 0 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 14 Participants | 8 Participants | 2 Participants | 2 Participants | 34 Participants |
| Race (NIH/OMB) White | 46 Participants | 95 Participants | 48 Participants | 29 Participants | 15 Participants | 233 Participants |
| Sex: Female, Male Female | 25 Participants | 47 Participants | 20 Participants | 8 Participants | 2 Participants | 102 Participants |
| Sex: Female, Male Male | 32 Participants | 71 Participants | 40 Participants | 27 Participants | 16 Participants | 186 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 24 / 50 | 3 / 7 | 35 / 118 | 15 / 59 | 1 / 35 | 0 / 14 | 0 / 18 |
| other Total, other adverse events | 50 / 50 | 6 / 7 | 117 / 118 | 58 / 59 | 33 / 35 | 12 / 14 | 13 / 18 |
| serious Total, serious adverse events | 26 / 50 | 1 / 7 | 41 / 118 | 13 / 59 | 8 / 35 | 3 / 14 | 0 / 18 |
Outcome results
Primary
Phase 2: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period in Target Population
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 5 years in Phase 2
Population: Phase 2: Target Population included participants without prior hypomethylating agent (HMA) or lenalidomide use and non del(5q) in karyotype at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period in Target Population | 42.1 percentage of participants |
Primary
Phase 2: Percentage of Participants Without Any Red Blood Cell (RBC) Transfusion During Any Consecutive 8-Weeks Period (All Participants)
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 5 years in Phase 2
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2: Percentage of Participants Without Any Red Blood Cell (RBC) Transfusion During Any Consecutive 8-Weeks Period (All Participants) | 36.8 percentage of participants |
Primary
Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 3.7 years in Phase 3
Population: Phase 3: The ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period | 39.8 percentage of participants |
| Phase 3: Placebo | Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period | 15.0 percentage of participants |
p-value: <0.00195% CI: [9.9, 36.89]Cochran-Mantel-Haenszel
Secondary
Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval
Amount of RBC transfusions for 8-week interval was defined as the total number of RBC transfusion units in a given 8-week interval during study. The best 8-week interval is a post-baseline 8-week interval where the participant had the fewest post-Study Day 1 RBC transfusion units. A valid 8-week period must start before the date of last dose of study drug + 30 days or end of treatment (EOT) visit whichever occurs first and ends before the first transfusion in post-treatment follow-up or the first day of subsequent anti-cancer therapy whichever occurs first.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval | 3.0 number of RBC transfusions units | Standard Deviation 3.48 |
| Phase 3: Placebo | Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval | 3.1 number of RBC transfusions units | Standard Deviation 3.62 |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval | 3.4 number of RBC transfusions units | Standard Deviation 2.13 |
Secondary
Phase 2 and Phase 3: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Time 28 Days (AUC0-28d)
As pre-specified in the statistical analysis plan (SAP), participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for PK data collection and analyses in this outcome measure. PK parameters were determined by population PK model.
Time frame: Cycle 1 (Days 1 to 28) (Cycle duration= 28 days)
Population: PK Parameter Analysis Set included all densely, and sparsely sampled participants who had received at least 1 dose of imetelstat sodium and who had sufficient data to calculate PK parameters for plasma imetelstat sodium. Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Time 28 Days (AUC0-28d) | 559 hour*micrograms per milliliter(h*mcg/mL) | Standard Deviation 43.2 |
Secondary
Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration
Duration of myeloid growth factor administered starting from Study Day 1 was reported.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study. Overall number of participants analyzed is the number of participants who had at least 1 dose of myeloid growth factors in Phase 2 and Phase 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration | 1.43 weeks |
| Phase 3: Placebo | Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration | 0.71 weeks |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration | 3.14 weeks |
Secondary
Phase 2 and Phase 3: Duration of RBC TI
Duration of RBC TI was defined as the first day of the longest RBC TI period to the date of the first RBC transfusion after the TI period started. The 95% CI was based on Kaplan-Meier product limit estimates.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated 8-week TI Responder Analysis Set included participants in the All Treated Analysis Set who achieved 8-week RBC TI.~Phase 3: ITT 8-week TI Responder Analysis Set included all participants in the ITT Analysis Set who achieved 8-week RBC TI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Duration of RBC TI | 69.6 weeks |
| Phase 3: Placebo | Phase 2 and Phase 3: Duration of RBC TI | 51.6 weeks |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Duration of RBC TI | 13.3 weeks |
p-value: <0.00195% CI: [0.105, 0.586]Log Rank
Secondary
Phase 2 and Phase 3: Maximum Observed Plasma Concentration (Cmax)
As pre-specified in the statistical analysis plan (SAP), participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for pharmacokinetic (PK) data collection and analyses in this outcome measure. PK parameters were determined by population PK model.
Time frame: Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days)
Population: PK Parameter Analysis Set included all densely, and sparsely sampled participants who had received at least 1 dose of imetelstat sodium and who had sufficient data to calculate PK parameters for plasma imetelstat sodium. Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Maximum Observed Plasma Concentration (Cmax) | 89.5 micrograms per milliliter (mcg/mL) | Standard Deviation 27.3 |
Secondary
Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths
TEAEs were defined as those events that 1) occurred after the first dose of study drug, through the treatment phase, and for 30 days following the last dose of study drug or until subsequent anti-cancer therapy if earlier; 2) any event that was considered study drug-related regardless of the start date of the event; or 3) any event that was presented at baseline but worsened in severity or was subsequently considered drug-related by the investigator. Serious TEAEs are any TEAEs that result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product, is medically important. Any clinically significant vital sign measurements, clinical laboratory values, and electrocardiogram (ECG) findings were reported as TEAEs. TEAEs included both serious and non-serious TEAEs.
Time frame: Adverse events: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3; Deaths: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3
Population: Phase 2 and Phase 3: Safety Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants with AEs | 50 Participants |
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants who died | 24 Participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants who died | 3 Participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants with AEs | 6 Participants |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants with AEs | 117 Participants |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants who died | 35 Participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants with AEs | 59 Participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths | Participants who died | 15 Participants |
Secondary
Phase 2 and Phase 3: Overall Survival (OS)
OS was defined as the interval from Study Day 1 to death from any cause. Survival time of living participants was censored on the last date a participant is known to be alive or lost to follow-up. The Kaplan-Meier method was used to estimate overall survival.
Time frame: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Overall Survival (OS) | 55.3 months |
| Phase 3: Placebo | Phase 2 and Phase 3: Overall Survival (OS) | 40.4 months |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Overall Survival (OS) | NA months |
p-value: 0.94995% CI: [0.526, 1.823]Log Rank
Secondary
Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors
Percentage of participants who received any myeloid growth factors starting from Study Day 1 were reported. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors | 33 percentage of participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors | 35.6 percentage of participants |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors | 5.0 percentage of participants |
Secondary
Phase 2 and Phase 3: Percentage of Participants With Anti-drug Antibodies (ADA) to Imetelstat Sodium
As pre-specified in the SAP, participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for immunogenicity data collection and analyses in this outcome measure. Percentages were rounded off to the nearest single decimal place.
Time frame: Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days)
Population: The Pharmacodynamic (PD) Analysis Set included all participants who had at least one quantifiable post-dose determination on biomarker, efficacy or safety parameters as defined in the related Pharmacodynamics analysis plan. Overall number of participants analysed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants With Anti-drug Antibodies (ADA) to Imetelstat Sodium | 16.9 percentage of participants |
Secondary
Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006
As per IWG Response Criteria 2006: HI-E was defined as a hemoglobin (Hb) increase by greater than or equal to (≥)1.5 grams per deciliter (g/dL) relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusion units/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of less than or equal to (≤)9 g/dL pretreatment were counted in the RBC transfusion response evaluation. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006 | 61.4 percentage of participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006 | 63.6 percentage of participants |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006 | 51.7 percentage of participants |
p-value: 0.11295% CI: [-4.1, 27.56]Cochran-Mantel-Haenszel
Secondary
Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period
Percentage of participants without any RBC transfusion during any consecutive 24 weeks (168 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2 and the day of randomization for participants enrolled in Phase 3. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug. Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period | 24.6 percentage of participants |
| Phase 3: Placebo | Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period | 28.0 percentage of participants |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period | 3.3 percentage of participants |
p-value: <0.00195% CI: [12.64, 34.18]Cochran-Mantel-Haenszel
Secondary
Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden
Relative percent change in RBC transfusions per 8-week = (amount of RBC transfusions per 8-week - prior RBC transfusion burden) / prior RBC transfusion burden multiplied by 100%. Prior RBC transfusion burden was defined as the maximum number of RBC units transfused over any consecutive 8 weeks prior to study entry.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden | -62.5 percent change | Standard Deviation 38.36 |
| Phase 3: Placebo | Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden | -57.75 percent change | Standard Deviation 50.22 |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden | -51.01 percent change | Standard Deviation 31.606 |
Secondary
Phase 2 and Phase 3: Progression Free Survival (PFS)
Progression free survival was defined as the time interval from study Day 1 to the first date of disease progression or death from any cause, whichever occurs first. Disease progression as per IWG criteria was defined as: at least one of the following: at least 50 % decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by ≥1.5 g/dL; transfusion dependence.
Time frame: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Progression Free Survival (PFS) | 34.2 months |
| Phase 3: Placebo | Phase 2 and Phase 3: Progression Free Survival (PFS) | NA months |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Progression Free Survival (PFS) | NA months |
Secondary
Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML)
Time to progression to AML was defined as the interval from Study Day 1 to the date of AML diagnosis. Participants who did not progress to AML and were still alive at the cutoff date for the analysis or who withdrew from the study (withdrawal of consent or lost to follow-up), data was censored at the date of the last disease evaluation.
Time frame: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.~Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML) | NA months |
| Phase 3: Placebo | Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML) | NA months |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML) | NA months |
Secondary
Phase 2 and Phase 3: Time to the 24-Weeks RBC TI
Time to 24-week RBC TI was defined as the interval from Study Day 1 to the first day of the first 24-weeks RBC TI period.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated 24-week TI Responder Analysis Set included participants in the All Treated Analysis Set who achieved 24-week RBC TI.~Phase 3: ITT 24-week TI Responder Analysis Set included all participants in the ITT Analysis Set who achieved 24-week RBC TI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Time to the 24-Weeks RBC TI | 8.79 weeks |
| Phase 3: Placebo | Phase 2 and Phase 3: Time to the 24-Weeks RBC TI | 8.43 weeks |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Time to the 24-Weeks RBC TI | 3.79 weeks |
Secondary
Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI)
Time to 8-week RBC TI was defined as the interval from Study Day 1 to the first day of the first 8-week RBC TI period.
Time frame: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3
Population: Phase 2: All Treated 8-week TI Responder Analysis Set included participants in the All Treated Analysis Set who achieved 8-week RBC TI.~Phase 3: ITT 8-week TI Responder Analysis Set included all participants in the ITT Analysis Set who achieved 8-week RBC TI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI) | 8.29 weeks |
| Phase 3: Placebo | Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI) | 9.29 weeks |
| Phase 3: Imetelstat Sodium | Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI) | 8.29 weeks |
Secondary
Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator
As per the IWG Response Criteria 2006, CR was defined as Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood (PB): Hb ≥11 g/dL; platelets ≥100 x 10\^9/dL; neutrophils ≥1.0 x 10\^9/liter; blasts: 0%. PR was defined as Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment; cellularity and morphology not relevant. mCR was defined as Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pre-treatment PB. Percentages were rounded off to the nearest single decimal place. All participants in Phase 2 were evaluated by the Investigator for CR/PR/mCR regardless of bone marrow blasts at baseline.
Time frame: Up to 5 years in Phase 2
Population: Phase 2: All Treated Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator | Percentage of participants with CR | 8.8 percentage of participants |
| Phase 2: Imetelstat Sodium | Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator | Percentage of participants with PR | 0 percentage of participants |
| Phase 2: Imetelstat Sodium | Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator | Percentage of participants with mCR | 12.3 percentage of participants |
Secondary
Phase 3: Medical Resource Utilization Assessed Based on Duration of Hospitalization
Hospitalization included any medical encounter defined as hospice, hospital inpatient department, and intensive care unit (ICU). Hospitalizations without end dates were not counted in the calculation of length of stay. If any participant had multiple readmissions, duration was calculated as the sum of all hospital stays.
Time frame: Up to 3.7 years in Phase 3
Population: Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study. Overall number of participants analyzed is the number of participants who were hospitalized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 3: Medical Resource Utilization Assessed Based on Duration of Hospitalization | 8.0 days |
| Phase 3: Placebo | Phase 3: Medical Resource Utilization Assessed Based on Duration of Hospitalization | 16.5 days |
Secondary
Phase 3: Medical Resource Utilization Assessed Based on Percentage of Participants With Outpatient Medical Encounters
Outpatient medical encounters included various sites of care: a) emergency room (ER) visits, b) hospital outpatient visits, c) home care visit, d) visit to lab, e) visit to doctor's office, f) other visits. Percentages were rounded off to the nearest single decimal place.
Time frame: Up to 3.7 years in Phase 3
Population: Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 3: Medical Resource Utilization Assessed Based on Percentage of Participants With Outpatient Medical Encounters | 39.0 percentage of participants |
| Phase 3: Placebo | Phase 3: Medical Resource Utilization Assessed Based on Percentage of Participants With Outpatient Medical Encounters | 38.3 percentage of participants |
Secondary
Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC)
As per the IWG Response Criteria 2006, CR was defined as Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; PB: Hb ≥11 g/dL; platelets ≥100 x 10\^9/dL; neutrophils ≥1.0 x 10\^9/liter; blasts: 0%. PR was defined as Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment; cellularity and morphology not relevant. mCR was defined as Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pre-treatment PB. CR, PR and mCR were assessed by IRC in Phase 3 and participants were required to fit at least one of the following criteria (participants with \>5% baseline blasts per central pathology reviewer assessment; participants with CR, PR, mCR, or cytogenetic response as assessed by the investigator) and have at least one post-baseline assessment.
Time frame: Up to 3.7 years in Phase 3
Population: Phase 3: ITT Analysis Set included all participants randomized into the Phase 3 study. Overall number of participants analyzed is the number of participants with \>5% baseline bone marrow aspirate blasts per central pathology reviewer's assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: Imetelstat Sodium | Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Percentage of participants with CR | 0 percentage of participants |
| Phase 2: Imetelstat Sodium | Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Percentage of participants with PR | 0 percentage of participants |
| Phase 2: Imetelstat Sodium | Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Percentage of participants with mCR | 0 percentage of participants |
| Phase 3: Placebo | Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Percentage of participants with CR | 0 percentage of participants |
| Phase 3: Placebo | Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Percentage of participants with PR | 0 percentage of participants |
| Phase 3: Placebo | Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) | Percentage of participants with mCR | 0 percentage of participants |
Secondary
QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF)
Baseline was defined as the mean of the measured ECG intervals collected at 3 time points (-1 hour, -0.5 hour, and 0 hour) prior to treatment administration on Cycle 1 Day 1 (Cycle length= 28 days)
Time frame: Baseline, Cycle 1, Day 1: 0.5, 1, 2, 4, 6, and 8 hours post-dose (cycle length= 28 days)
Population: The QTc substudy analysis set included all participants who participated in QTc substudy and received at least one dose of study drug, with measurements at baseline as well as on-treatment with at least 1 post-dose time point with a ΔQTcF value. By-time Point Analysis Set included each post-baseline time point that had a non-missing change-from-baseline observation. Number analysed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Imetelstat Sodium | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 0.5 hr post-dose | 4.2 milliseconds (ms) | Standard Error 1.54 |
| Phase 2: Imetelstat Sodium | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 1 hr post-dose | 5.4 milliseconds (ms) | Standard Error 1.47 |
| Phase 2: Imetelstat Sodium | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 2 hr post-dose | 5.5 milliseconds (ms) | Standard Error 1.56 |
| Phase 2: Imetelstat Sodium | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 4 hr post-dose | 1.8 milliseconds (ms) | Standard Error 2.43 |
| Phase 2: Imetelstat Sodium | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 6 hr post-dose | 1.7 milliseconds (ms) | Standard Error 2.37 |
| Phase 2: Imetelstat Sodium | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 8 hr post-dose | 2.3 milliseconds (ms) | Standard Error 2.53 |
| Phase 3: Placebo | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 6 hr post-dose | -1.1 milliseconds (ms) | Standard Error 3.12 |
| Phase 3: Placebo | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 0.5 hr post-dose | 1.9 milliseconds (ms) | Standard Error 2.09 |
| Phase 3: Placebo | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 4 hr post-dose | 1.1 milliseconds (ms) | Standard Error 3.28 |
| Phase 3: Placebo | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 1 hr post-dose | 0.4 milliseconds (ms) | Standard Error 2 |
| Phase 3: Placebo | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 8 hr post-dose | -3.4 milliseconds (ms) | Standard Error 3.36 |
| Phase 3: Placebo | QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) | Change at 2 hr post-dose | 3.7 milliseconds (ms) | Standard Error 2.12 |
Other Pre-specified
Extension Phase: Number of Participants With AEs
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal product. An AE does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that medicinal product. AEs included clinically significant vital signs measurements, clinical laboratory values and electrocardiograms (ECGs) changes.
Time frame: Up to approximately 3 years in the extension phase
Other Pre-specified
Extension Phase: Overall Survival
Time frame: Up to approximately 3 years in the extension phase
Other Pre-specified
Extension Phase: Progression Free Survival (PFS) Survival
Progression free survival will be assessed as the time interval from the end of the Phase 3 study until death, withdrawal of consent, study termination, or until a subject is lost to follow-up. As per IWG criteria disease progression is defined as: at least one of the following: at least 50 percent (%) decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by greater than or equal to ≥1.5 g/dL; transfusion dependence.
Time frame: Up to approximately 3 years in the extension phase