Anemia
Conditions
Keywords
End-Stage Renal Disease, Anemia, Hemodialysis, Renal Anemia, ESRD
Brief summary
This is the first study in hemodialysis subjects with anemia to evaluate the pharmacokinetics, safety, efficacy, tolerability, and pharmacodynamics of sotatercept (ACE-011)
Detailed description
Part 1: Approximately 8 subjects will be randomized to receive either a single 0.1 mg/kg subcutaneous dose of sotatercept or matching placebo in a 3:1 ratio Part 2: Approximately 8 subjects will be randomized to each of the 3 sequential dose groups (0.3mg/kg or 0.5mg/kg or 0.7 mg/kg) with a 3:1 ratio of sotatercept or placebo (6 subjects in the sotatercept arm and 2 in the placebo arm). A total of 24-36 subjects may be randomized in the 3 dose groups.
Interventions
BIOLOGICALSotatercept
Part 1: Sotatercept single dose 0.1mg/kg subcutaneous Part 2: Sotatercept starting dose groups of 0.3mg/kg, 0.5mg/kg or 0.7 mg/kg in a sequential design, dosed subcutaneously every 28 days for up to 8 doses
BIOLOGICALPlacebo
Placebo
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females ≥18 years of age. * Subjects on hemodialysis for at least 12 weeks before screening * Subjects on a stable dose of Erythrocyte Stimulating Agents product to maintain Hemoglobin (Hb) for at least 6 weeks prior to screening. * 3 consecutive pre-dialysis Hb concentrations with a mean ≥10 to ≤ 12 g/dL (≥100 to ≤120 g/L) at screening and one pre-dialysis Hb concentration ≥8 to \< 10 g/dL (≥ 80 to \< 100 g/L) before randomization. * Adequate iron status defined as serum transferrin saturation ≥ 20% before randomization.
Exclusion criteria
* Non renal causes of anemia. * Subjects on peritoneal dialysis. * Systemic hematological disease * High sensitivity C-reactive protein \>50mg/L at screening. * Alanine transaminase (ALT) or aspartate transaminase (AST) laboratory values \> 2 times the upper limit of normal (ULN) at screening. * Uncontrolled diabetes mellitus (HbA1c \> 9) at screening. * Uncontrolled hypertension. * Red Blood Count (RBC) transfusions within 8 weeks prior to screening. * Active serious infection or history of recurrent serious infection likely to recur during the study * History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product or to the iron products needed to normalize iron levels for subjects. * Subjects that received treatment with another investigational drug or device within 28 days prior to Day 1 * Pregnant or lactating females.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Observed Maximum Concentration (Cmax) | From first dose up to Day 28 | Cmax is a pharmacokinetic parameter defined as the observed maximum concentration of the study drug in the serum and/or blood. Cmax will be estimated from the sotatercept concentration versus time data using noncompartmental method. |
| Time to Maximum Concentration (Tmax) | From first dose up to Day 28 | Time to observed maximum concentration (Tmax) is defined as the amount of time in days for a drug to reach the maximum concentration after administration. |
| Area Under Curve (AUC)-28 Days | From first dose up to Day 28 | AUC-28 days is defined as area under the concentration-time curve over the first 28-day dosing interval |
| AUCinf: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity | From first dose up to Day 28 | Area under the concentration-time curve from time zero extrapolated to infinity. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint. |
| Apparent Total Clearance (CL/F) | From first dose up to Day 28 | Apparent Total Clearance (CL/F) is defined as the volume of plasma from which the study drug is completely removed per unit of time. It is equal to the drug dose divided by the area-under-the-curve. |
| Apparent Volume of Distribution Based on Terminal Phase (Vz/F) | From first dose up to Day 28 | Apparent volume of distribution based on terminal phase (Vz/F) is defined as the apparent volume in which the current amount of drug in the body must be dispersed in order to give the current plasma concentration. Apparent volume of distribution is important for determining the dose required to produce a desired plasma concentration of the drug. |
| Terminal Half-Life (t1/2,z) | Days 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 22, 29, 43, 57, 85 and 113 | Terminal plasma half-life (t1/2,z) is the time taken for concentration of the study drug to decrease from its maximum concentration (Cmax) to half of Cmax in the blood plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL | Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309 | Number of participants with Hemoglobin \> 10g/dL and a change from in hemoglobin values ≥ 1g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered. |
| The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | From first dose up to 115 days post last dose | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. |
| Change From Baseline in Hemoglobin Values | From first dose up to Day 225 | Dose Cycle 1 is defined as the first 28 days of treatment for Dose Groups 0.3 mg/kg, 0.5 mg/kg, and 0.7 mg/kg and the first 14 days of treatment for Dose Group 0.7/0.4 mg/kg. End of the Treatment Period is defined as the day before the follow-up phase started. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered. |
| Length of Time to Rescue Therapy | From first dose up to blood transfusion or ESA therapy, up to approximately 209 days | The length of time in days that participants who were rescued received treatment. When applicable, participants were rescued for anemia. During the rescue, participants discontinued sotatercept and were unblinded to the study treatment. Participants who were rescued continued in the treatment phase of 200 days and a follow-up phase of 112 days after the treatment phase. Rescue is defined as the need for a blood transfusion or Erythropoiesis-stimulating agent (ESA) therapy. |
| Number of Participants With Hemoglobin > 12g/dL | Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309 | Number of participants with hemoglobin \> 12g/dL including Hb values obtained after first study drug dose and before any rescue. |
| Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309 | Proportion of participants with rise in hemoglobin (Hb) \> 2 g/dL during a 4-week period including Hb values obtained after first study drug dose and before any rescue. |
| Blood Pressure Changes From Baseline | From pre-dose up to the final visit 112 days after last dose (up to 225 days) | Blood pressure was generally recorded on the day of dialysis and represent pre-dialysis values. Baseline is defined as blood pressure measurements recorded on Day 1 of the first dose administered. |
| Changes in Follicle Stimulating Hormone (FSH) | Day 1 (baseline), Day 15, Day 29, and Day 113 | The change in follicle stimulating measured at pre-specified timepoints throughout the treatment period. |
| Number of Participants With Hemoglobin > 10g/dL | Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309 | Number of participants with hemoglobin \> 10g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered. |
| Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL | Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309 | Number of participants with a change from in hemoglobin values ≥ 1g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1-Placebo Participants received a single subcutaneous dose of placebo prior to dialysis on Day 1 via an IVRS. | 1 |
| Part 1-ACE-011 0.1 mg/kg Participants received a single subcutaneous dose of sotatercept (0.1 mg/kg) prior to dialysis on Day 1 via an IVRS | 6 |
| Part 2- Placebo Participants received a single subcutaneous dose of placebo | 11 |
| Part 2-0.3 mg/kg Participants received a single subcutaneous dose of 0.3 mg/kg sotatercept every 28 days for up to 8 doses | 9 |
| Part 2-0.5 mg/kg Participants received a single subcutaneous dose of 0.5 mg/kg sotatercept every 28 days for up to 8 doses | 8 |
| Part 2-0.7 mg/kg Participants received a single subcutaneous dose of 0.7 mg/kg sotatercept every 28 days for up to 8 doses | 9 |
| Part 2-0.7/0.4 mg/kg Participants received a subcutaneous dose of 0.7 mg/kg sotatercept loading followed by a subcutaneous dose of 0.4 mg/kg sotatercept every 14 days for up to 15 doses | 6 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Kidney transplant | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Other reasons | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrew consent | 0 | 0 | 1 | 1 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Part 2-0.7/0.4 mg/kg | Total | Part 1-Placebo | Part 1-ACE-011 0.1 mg/kg | Part 2- Placebo | Part 2-0.3 mg/kg | Part 2-0.5 mg/kg | Part 2-0.7 mg/kg |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 13 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 37 Participants | 1 Participants | 5 Participants | 9 Participants | 7 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 11 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 39 Participants | 1 Participants | 5 Participants | 10 Participants | 7 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 24 Participants | 0 Participants | 3 Participants | 6 Participants | 6 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 22 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 21 Participants | 1 Participants | 1 Participants | 4 Participants | 6 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 29 Participants | 0 Participants | 5 Participants | 7 Participants | 3 Participants | 7 Participants | 2 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 | 0 / 1 | 1 / 6 | 2 / 11 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 6 |
| other Total, other adverse events | 1 / 1 | 6 / 6 | 6 / 11 | 8 / 9 | 6 / 8 | 8 / 9 | 4 / 6 |
| serious Total, serious adverse events | 0 / 1 | 2 / 6 | 3 / 11 | 4 / 9 | 0 / 8 | 5 / 9 | 1 / 6 |
Outcome results
Primary
Apparent Total Clearance (CL/F)
Apparent Total Clearance (CL/F) is defined as the volume of plasma from which the study drug is completely removed per unit of time. It is equal to the drug dose divided by the area-under-the-curve.
Time frame: From first dose up to Day 28
Population: Participants with evaluable pharmacokinetic data. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | Apparent Total Clearance (CL/F) | 3.22 L/day | Standard Deviation 1.2 |
| Part 2-0.3 mg/kg | Apparent Total Clearance (CL/F) | 0.255 L/day | Standard Deviation 0.068 |
| Part 2-0.5 mg/kg | Apparent Total Clearance (CL/F) | 0.261 L/day | Standard Deviation 0.075 |
| Part 2-0.7 mg/kg | Apparent Total Clearance (CL/F) | 0.532 L/day | Standard Deviation 0.654 |
| Part 2-0.7/0.4 mg/kg | Apparent Total Clearance (CL/F) | 0.298 L/day | Standard Deviation 0.112 |
Primary
Apparent Volume of Distribution Based on Terminal Phase (Vz/F)
Apparent volume of distribution based on terminal phase (Vz/F) is defined as the apparent volume in which the current amount of drug in the body must be dispersed in order to give the current plasma concentration. Apparent volume of distribution is important for determining the dose required to produce a desired plasma concentration of the drug.
Time frame: From first dose up to Day 28
Population: Pre-specified in the protocol to be collected in Part 1 pharmacokinetic evaluable participants only. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | Apparent Volume of Distribution Based on Terminal Phase (Vz/F) | 98 mL/kg | Standard Deviation 38 |
Primary
Area Under Curve (AUC)-28 Days
AUC-28 days is defined as area under the concentration-time curve over the first 28-day dosing interval
Time frame: From first dose up to Day 28
Population: Participants with evaluable pharmacokinetic data. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | Area Under Curve (AUC)-28 Days | 20.6 ug·day/mL | Standard Deviation 11.4 |
| Part 2-0.3 mg/kg | Area Under Curve (AUC)-28 Days | 50.64 ug·day/mL | Standard Deviation 17.67 |
| Part 2-0.5 mg/kg | Area Under Curve (AUC)-28 Days | 78.03 ug·day/mL | Standard Deviation 13.34 |
| Part 2-0.7 mg/kg | Area Under Curve (AUC)-28 Days | 87.51 ug·day/mL | Standard Deviation 36.68 |
| Part 2-0.7/0.4 mg/kg | Area Under Curve (AUC)-28 Days | 126.96 ug·day/mL | Standard Deviation 20.75 |
Primary
AUCinf: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity
Area under the concentration-time curve from time zero extrapolated to infinity. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint.
Time frame: From first dose up to Day 28
Population: Pre-specified in the protocol to be collected in Part 1 pharmacokinetic evaluable participants only. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | AUCinf: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity | 35.8 ug·day/mL | Standard Deviation 17.4 |
Primary
Observed Maximum Concentration (Cmax)
Cmax is a pharmacokinetic parameter defined as the observed maximum concentration of the study drug in the serum and/or blood. Cmax will be estimated from the sotatercept concentration versus time data using noncompartmental method.
Time frame: From first dose up to Day 28
Population: Participants with evaluable pharmacokinetic data. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | Observed Maximum Concentration (Cmax) | 1.022 ug/mL | Standard Deviation 0.576 |
| Part 2-0.3 mg/kg | Observed Maximum Concentration (Cmax) | 2.40 ug/mL | Standard Deviation 0.96 |
| Part 2-0.5 mg/kg | Observed Maximum Concentration (Cmax) | 3.66 ug/mL | Standard Deviation 0.67 |
| Part 2-0.7 mg/kg | Observed Maximum Concentration (Cmax) | 3.97 ug/mL | Standard Deviation 1.64 |
| Part 2-0.7/0.4 mg/kg | Observed Maximum Concentration (Cmax) | 7.71 ug/mL | Standard Deviation 1.97 |
Primary
Terminal Half-Life (t1/2,z)
Terminal plasma half-life (t1/2,z) is the time taken for concentration of the study drug to decrease from its maximum concentration (Cmax) to half of Cmax in the blood plasma.
Time frame: Days 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 22, 29, 43, 57, 85 and 113
Population: Participants with evaluable pharmacokinetic data. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | Terminal Half-Life (t1/2,z) | 21.1 Day | Standard Deviation 3.9 |
| Part 2-0.3 mg/kg | Terminal Half-Life (t1/2,z) | 24.3 Day | Standard Deviation 3.28 |
| Part 2-0.5 mg/kg | Terminal Half-Life (t1/2,z) | 32.1 Day | Standard Deviation 19.9 |
| Part 2-0.7 mg/kg | Terminal Half-Life (t1/2,z) | 22.2 Day | Standard Deviation 7 |
| Part 2-0.7/0.4 mg/kg | Terminal Half-Life (t1/2,z) | 19.6 Day | Standard Deviation 2.91 |
Primary
Time to Maximum Concentration (Tmax)
Time to observed maximum concentration (Tmax) is defined as the amount of time in days for a drug to reach the maximum concentration after administration.
Time frame: From first dose up to Day 28
Population: Participants with evaluable pharmacokinetic data. Pharmacokinetic data was not recorded for participants who received placebo because no study drug was administered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1-ACE-011 0.1 mg/kg | Time to Maximum Concentration (Tmax) | 6 Days |
| Part 2-0.3 mg/kg | Time to Maximum Concentration (Tmax) | 7 Days |
| Part 2-0.5 mg/kg | Time to Maximum Concentration (Tmax) | 8 Days |
| Part 2-0.7 mg/kg | Time to Maximum Concentration (Tmax) | 7 Days |
| Part 2-0.7/0.4 mg/kg | Time to Maximum Concentration (Tmax) | 5 Days |
Secondary
Blood Pressure Changes From Baseline
Blood pressure was generally recorded on the day of dialysis and represent pre-dialysis values. Baseline is defined as blood pressure measurements recorded on Day 1 of the first dose administered.
Time frame: From pre-dose up to the final visit 112 days after last dose (up to 225 days)
Population: Safety population- all randomized participant who received at least 1 dose of sotatercept and had evaluable safety data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1-Placebo | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 75.0 mmHg | — |
| Part 1-Placebo | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 163.0 mmHg | — |
| Part 1-Placebo | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 151.0 mmHg | — |
| Part 1-Placebo | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 83.0 mmHg | — |
| Part 1-ACE-011 0.1 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 134.6 mmHg | Standard Deviation 6.95 |
| Part 1-ACE-011 0.1 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 142.8 mmHg | Standard Deviation 13.11 |
| Part 1-ACE-011 0.1 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 81.5 mmHg | Standard Deviation 7.56 |
| Part 1-ACE-011 0.1 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 86.2 mmHg | Standard Deviation 15.93 |
| Part 2- Placebo | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 71.6 mmHg | Standard Deviation 13.42 |
| Part 2- Placebo | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 145.0 mmHg | Standard Deviation 26.91 |
| Part 2- Placebo | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 79.7 mmHg | Standard Deviation 15.53 |
| Part 2- Placebo | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 129.4 mmHg | Standard Deviation 27.99 |
| Part 2-0.3 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 85.2 mmHg | Standard Deviation 9.83 |
| Part 2-0.3 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 78.2 mmHg | Standard Deviation 12.45 |
| Part 2-0.3 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 167.0 mmHg | Standard Deviation 12.81 |
| Part 2-0.3 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 145.9 mmHg | Standard Deviation 9.75 |
| Part 2-0.5 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 141.4 mmHg | Standard Deviation 18.72 |
| Part 2-0.5 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 154.0 mmHg | Standard Deviation 34.47 |
| Part 2-0.5 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 74.3 mmHg | Standard Deviation 8.41 |
| Part 2-0.5 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 83.6 mmHg | Standard Deviation 18.98 |
| Part 2-0.7 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 64.6 mmHg | Standard Deviation 13.33 |
| Part 2-0.7 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 75.3 mmHg | Standard Deviation 9.19 |
| Part 2-0.7 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 154.3 mmHg | Standard Deviation 22.93 |
| Part 2-0.7 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 139.9 mmHg | Standard Deviation 29.25 |
| Part 2-0.7/0.4 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Baseline Day 1 | 72.0 mmHg | Standard Deviation 16.1 |
| Part 2-0.7/0.4 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Baseline Day 1 | 135.0 mmHg | Standard Deviation 25.09 |
| Part 2-0.7/0.4 mg/kg | Blood Pressure Changes From Baseline | Diastolic Blood Pressure Final Visit | 71.6 mmHg | Standard Deviation 10.01 |
| Part 2-0.7/0.4 mg/kg | Blood Pressure Changes From Baseline | Systolic Blood Pressure Final Visit | 131.8 mmHg | Standard Deviation 12.79 |
Secondary
Change From Baseline in Hemoglobin Values
Dose Cycle 1 is defined as the first 28 days of treatment for Dose Groups 0.3 mg/kg, 0.5 mg/kg, and 0.7 mg/kg and the first 14 days of treatment for Dose Group 0.7/0.4 mg/kg. End of the Treatment Period is defined as the day before the follow-up phase started. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Time frame: From first dose up to Day 225
Population: All randomized participants in Part 2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1-Placebo | Change From Baseline in Hemoglobin Values | End of Dose Cycle 1 | -3.3 g/L | Standard Deviation 7.57 |
| Part 1-Placebo | Change From Baseline in Hemoglobin Values | End of Treatment Period | 12.5 g/L | Standard Deviation 12.42 |
| Part 1-Placebo | Change From Baseline in Hemoglobin Values | Peak Value During Dose Cycle 1 | -0.9 g/L | Standard Deviation 7.08 |
| Part 1-ACE-011 0.1 mg/kg | Change From Baseline in Hemoglobin Values | Peak Value During Dose Cycle 1 | 5.2 g/L | Standard Deviation 8.24 |
| Part 1-ACE-011 0.1 mg/kg | Change From Baseline in Hemoglobin Values | End of Dose Cycle 1 | -6.9 g/L | Standard Deviation 6.94 |
| Part 1-ACE-011 0.1 mg/kg | Change From Baseline in Hemoglobin Values | End of Treatment Period | 12.8 g/L | Standard Deviation 13.75 |
| Part 2- Placebo | Change From Baseline in Hemoglobin Values | Peak Value During Dose Cycle 1 | 7.1 g/L | Standard Deviation 3.98 |
| Part 2- Placebo | Change From Baseline in Hemoglobin Values | End of Dose Cycle 1 | -2.9 g/L | Standard Deviation 8.18 |
| Part 2- Placebo | Change From Baseline in Hemoglobin Values | End of Treatment Period | 15.3 g/L | Standard Deviation 8.22 |
| Part 2-0.3 mg/kg | Change From Baseline in Hemoglobin Values | End of Dose Cycle 1 | 0.8 g/L | Standard Deviation 5.85 |
| Part 2-0.3 mg/kg | Change From Baseline in Hemoglobin Values | End of Treatment Period | 15.0 g/L | Standard Deviation 12.11 |
| Part 2-0.3 mg/kg | Change From Baseline in Hemoglobin Values | Peak Value During Dose Cycle 1 | 8.4 g/L | Standard Deviation 3.75 |
| Part 2-0.5 mg/kg | Change From Baseline in Hemoglobin Values | Peak Value During Dose Cycle 1 | 5.4 g/L | Standard Deviation 4.1 |
| Part 2-0.5 mg/kg | Change From Baseline in Hemoglobin Values | End of Dose Cycle 1 | 1.0 g/L | Standard Deviation 2.45 |
| Part 2-0.5 mg/kg | Change From Baseline in Hemoglobin Values | End of Treatment Period | 2.8 g/L | Standard Deviation 6.91 |
Secondary
Changes in Follicle Stimulating Hormone (FSH)
The change in follicle stimulating measured at pre-specified timepoints throughout the treatment period.
Time frame: Day 1 (baseline), Day 15, Day 29, and Day 113
Population: All randomized participants in Part 1
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1-Placebo | Changes in Follicle Stimulating Hormone (FSH) | Day 1 (baseline) | 23.5 IU/L | — |
| Part 1-Placebo | Changes in Follicle Stimulating Hormone (FSH) | Day 15 | 17.1 IU/L | — |
| Part 1-Placebo | Changes in Follicle Stimulating Hormone (FSH) | Day 29 | 17.5 IU/L | — |
| Part 1-Placebo | Changes in Follicle Stimulating Hormone (FSH) | Day 113 | 11.8 IU/L | — |
| Part 1-ACE-011 0.1 mg/kg | Changes in Follicle Stimulating Hormone (FSH) | Day 113 | 48.2 IU/L | Standard Deviation 78.81 |
| Part 1-ACE-011 0.1 mg/kg | Changes in Follicle Stimulating Hormone (FSH) | Day 1 (baseline) | 36.9 IU/L | Standard Deviation 67.65 |
| Part 1-ACE-011 0.1 mg/kg | Changes in Follicle Stimulating Hormone (FSH) | Day 29 | 37.4 IU/L | Standard Deviation 67.69 |
| Part 1-ACE-011 0.1 mg/kg | Changes in Follicle Stimulating Hormone (FSH) | Day 15 | 51.8 IU/L | Standard Deviation 80.76 |
Secondary
Length of Time to Rescue Therapy
The length of time in days that participants who were rescued received treatment. When applicable, participants were rescued for anemia. During the rescue, participants discontinued sotatercept and were unblinded to the study treatment. Participants who were rescued continued in the treatment phase of 200 days and a follow-up phase of 112 days after the treatment phase. Rescue is defined as the need for a blood transfusion or Erythropoiesis-stimulating agent (ESA) therapy.
Time frame: From first dose up to blood transfusion or ESA therapy, up to approximately 209 days
Population: Participants in Part 2 who received rescue therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1-Placebo | Length of Time to Rescue Therapy | 44.8 Days | Standard Deviation 43.96 |
| Part 1-ACE-011 0.1 mg/kg | Length of Time to Rescue Therapy | 69.8 Days | Standard Deviation 59.12 |
| Part 2- Placebo | Length of Time to Rescue Therapy | 47.4 Days | Standard Deviation 32.86 |
| Part 2-0.3 mg/kg | Length of Time to Rescue Therapy | 100.4 Days | Standard Deviation 55.73 |
| Part 2-0.5 mg/kg | Length of Time to Rescue Therapy | 117.5 Days | Standard Deviation 73.37 |
Secondary
Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL
Number of participants with a change from in hemoglobin values ≥ 1g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Time frame: Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309
Population: All randomized participants in Part 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1-Placebo | Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL | 2 Participants |
| Part 1-ACE-011 0.1 mg/kg | Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL | 3 Participants |
| Part 2- Placebo | Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL | 4 Participants |
| Part 2-0.3 mg/kg | Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL | 7 Participants |
| Part 2-0.5 mg/kg | Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL | 2 Participants |
Secondary
Number of Participants With Hemoglobin > 10g/dL
Number of participants with hemoglobin \> 10g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Time frame: Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309
Population: All randomized participants in Part 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1-Placebo | Number of Participants With Hemoglobin > 10g/dL | 3 Participants |
| Part 1-ACE-011 0.1 mg/kg | Number of Participants With Hemoglobin > 10g/dL | 3 Participants |
| Part 2- Placebo | Number of Participants With Hemoglobin > 10g/dL | 5 Participants |
| Part 2-0.3 mg/kg | Number of Participants With Hemoglobin > 10g/dL | 7 Participants |
| Part 2-0.5 mg/kg | Number of Participants With Hemoglobin > 10g/dL | 2 Participants |
Secondary
Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL
Number of participants with Hemoglobin \> 10g/dL and a change from in hemoglobin values ≥ 1g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Time frame: Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309
Population: All randomized participants in Part 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1-Placebo | Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL | 2 Participants |
| Part 1-ACE-011 0.1 mg/kg | Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL | 2 Participants |
| Part 2- Placebo | Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL | 4 Participants |
| Part 2-0.3 mg/kg | Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL | 6 Participants |
| Part 2-0.5 mg/kg | Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL | 2 Participants |
Secondary
Number of Participants With Hemoglobin > 12g/dL
Number of participants with hemoglobin \> 12g/dL including Hb values obtained after first study drug dose and before any rescue.
Time frame: Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1-Placebo | Number of Participants With Hemoglobin > 12g/dL | 0 Participants |
| Part 1-ACE-011 0.1 mg/kg | Number of Participants With Hemoglobin > 12g/dL | 0 Participants |
| Part 2- Placebo | Number of Participants With Hemoglobin > 12g/dL | 0 Participants |
| Part 2-0.3 mg/kg | Number of Participants With Hemoglobin > 12g/dL | 0 Participants |
| Part 2-0.5 mg/kg | Number of Participants With Hemoglobin > 12g/dL | 0 Participants |
| Part 2-0.7 mg/kg | Number of Participants With Hemoglobin > 12g/dL | 1 Participants |
| Part 2-0.7/0.4 mg/kg | Number of Participants With Hemoglobin > 12g/dL | 0 Participants |
Secondary
Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period
Proportion of participants with rise in hemoglobin (Hb) \> 2 g/dL during a 4-week period including Hb values obtained after first study drug dose and before any rescue.
Time frame: Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1-Placebo | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 0 Participants |
| Part 1-ACE-011 0.1 mg/kg | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 0 Participants |
| Part 2- Placebo | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 0 Participants |
| Part 2-0.3 mg/kg | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 0 Participants |
| Part 2-0.5 mg/kg | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 1 Participants |
| Part 2-0.7 mg/kg | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 0 Participants |
| Part 2-0.7/0.4 mg/kg | Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period | 0 Participants |
Secondary
The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
Time frame: From first dose up to 115 days post last dose
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1-Placebo | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
| Part 1-ACE-011 0.1 mg/kg | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Part 2- Placebo | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Part 2-0.3 mg/kg | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 8 Participants |
| Part 2-0.5 mg/kg | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Part 2-0.7 mg/kg | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 8 Participants |
| Part 2-0.7/0.4 mg/kg | The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 4 Participants |