Cervical Cancer
Conditions
Keywords
Advanced cervical cancer, Bintrafusp alfa, M7824, INTR@PID, Transforming growth factor-beta, Programmed death-ligand 1
Brief summary
This study was to evaluate the safety and tolerability of bintrafusp alfa in combination with other anti-cancer therapies in participants with locally advanced or advanced cervical cancer.
Interventions
DRUGM7824
Participants received bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).
DRUGCarboplatin
Carboplatin was administered intravenously as per standard of care.
DRUGPaclitaxel
Paclitaxel was administered intravenously as per standard of care.
DRUGBevacizumab
Bevacizumab was administrated as indicated for standard of care.
DRUGCisplatin
Cisplatin was administered intravenously as per standard of care.
RADIATIONRadiotherapy
Participants received radiotherapy as per standard of care.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria for participants enrolling into Cohort 1: * Study participants had documented persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix * Study participants had not been treated with systemic chemotherapy and were not amenable to curative treatment * Prior radiation with or without radio-sensitizing chemotherapy was allowed * Inclusion Criteria for participants enrolling into Cohort 2: * Participants had documented evidence of cervical adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma International Federation of Gynecology and Obstetrics (FIGO) 2018 Stages 1B2 to 4A * Participants had not received prior chemotherapy or radiotherapy for cervical cancer * Inclusion Criteria for all participants: * Archival tumor tissue sample or newly obtained core or excisional biopsy was required * Participants who had Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 1 were eligible * Participants had a life expectancy greater than or equal to 12 weeks * Participants had adequate hematological, hepatic, renal, and coagulation function as defined in the protocol * Participants with known Human immunodeficiency virus (HIV) infections were eligible if the criteria described in the protocol were met * Participants with Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) infections were eligible if the criteria described in the protocol were met * Other protocol defined inclusion criteria could apply
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) | Up to 4 weeks after first administration of study intervention | DLT was defined as Adverse Events (AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to (\>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting \>= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for \>= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (\<) 1,000/mm3 with a temperature of \> 38.3 degree Celsius (°C); grade 4 is defined as ANC \< 1,000/mm3 with a temperature of \> 38.3°C, with life-threatening consequences; Thrombocytopenia \< 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events \>= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay (\> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Time from first treatment assessed up to approximately 20 months | Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Treatment-Emergent Adverse Events (TEAEs) were defined as events with onset date or worsening during the on-treatment period. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs included serious TEAEs and non-serious TEAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Bintrafusp Alfa | Pre-dose Up to 20 months | The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Bintrafusp Alfa | Pre-dose Up to 20 months | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. |
| Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa | Pre-dose Up to 20 months | Cmax was obtained directly from the concentration versus time curve. |
| Time to Reach Maximum Serum Concentration (Tmax) of Bintrafusp Alfa | Pre-dose Up to 20 months | The time to reach the maximum observed concentration collected during a dosing interval. Tmax was obtained directly from the concentration versus time curve. |
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa | Pre-dose Up to 20 months | Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Bintrafusp Alfa concentration-time data. |
| Number of Participants With Positive Anti-Drug Antibody (ADA) of Bintrafusp Alfa | Pre-dose Up to 20 months | A validated method was applied to detect ADAs in the presence of drug in human serum. The ADA titers of positive samples were determined. |
| Number of Japanese Participants With Dose-Limiting Toxicities (DLTs) | Up to 4 weeks after first administration of study intervention | DLT was defined as Adverse Events (AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to (\>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting \>= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for \>= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (\<) 1,000/mm3 with a temperature of \> 38.3 degree Celsius (°C); grade 4 is defined as ANC \< 1,000/mm3 with a temperature of \> 38.3°C, with life-threatening consequences; Thrombocytopenia \< 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events \>= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay (\> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity. |
| Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Time from first treatment assessed up to approximately 20 months | Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Treatment-Emergent Adverse Events (TEAEs) were defined as events with onset date or worsening during the on-treatment period. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. |
| Terminal Elimination Half-Life (T1/2) of Bintrafusp Alfa | Pre-dose Up to 20 months | Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. Elimination half-life determined as 0.693/ Lamda z(λz), λz=terminal first order (elimination) rate constant. |
| Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa | Pre-dose Up to 20 months | Ctrough was the serum concentration observed immediately before next dosing. |
Countries
Japan, Spain, United States
Participant flow
Pre-assignment details
A total of 28 participants were screened out of which 25 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab Participants received 2400 miligrams (mg) Bintrafusp alfa along with 50 milligram per square meter (mg/m\^2) Cisplatin or Carboplatin, Paclitaxel and 15 milligram per kilogram (mg/kg) Bevacizumab every 3 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death. | 8 |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel Participants received 2400 mg Bintrafusp alfa along with 50 mg/m\^2 Cisplatin or Carboplatin, 175 mg/m\^2 Paclitaxel every 3 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death. | 9 |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy Participants received 2400 mg Bintrafusp alfa once every 3 weeks along with 40 mg/m\^2 Cisplatin weekly for 5 weeks followed by radiotherapy as per standard care. | 8 |
| Total | 25 |
Baseline characteristics
| Characteristic | Total | Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab |
|---|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 10 | 49 years STANDARD_DEVIATION 13.1 | 47 years STANDARD_DEVIATION 8.3 | 44 years STANDARD_DEVIATION 9 |
| Ethnicity Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity Missing | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity Not Hispanic or Latino | 23 Participants | 8 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 13 Participants | 3 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Female | 25 Participants | 8 Participants | 9 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 2 / 9 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 9 / 9 | 8 / 8 |
| serious Total, serious adverse events | 7 / 8 | 4 / 9 | 6 / 8 |
Outcome results
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs)
DLT was defined as Adverse Events (AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to (\>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting \>= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for \>= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (\<) 1,000/mm3 with a temperature of \> 38.3 degree Celsius (°C); grade 4 is defined as ANC \< 1,000/mm3 with a temperature of \> 38.3°C, with life-threatening consequences; Thrombocytopenia \< 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events \>= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay (\> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity.
Time frame: Up to 4 weeks after first administration of study intervention
Population: Dose-Limiting Toxicity Analysis (DLT) Set included all participants who completed the DLT period (within 4 weeks after first administration of study intervention) with at least 80 Percent (%) of the planned cumulative dose received during this period for each study intervention and/or who experienced at least one DLT during the DLT period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Number of Participants With Dose-Limiting Toxicities (DLTs) | 2 Participants |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Treatment-Emergent Adverse Events (TEAEs) were defined as events with onset date or worsening during the on-treatment period. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs included serious TEAEs and non-serious TEAEs.
Time frame: Time from first treatment assessed up to approximately 20 months
Population: The safety (SAF) analysis set included all participants who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 8 Participants |
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Serious TEAEs | 7 Participants |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 9 Participants |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Serious TEAEs | 4 Participants |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 8 Participants |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Serious TEAEs | 6 Participants |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Bintrafusp Alfa
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
Area Under the Serum Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Bintrafusp Alfa
The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa
Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Bintrafusp Alfa concentration-time data.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
Number of Japanese Participants With Dose-Limiting Toxicities (DLTs)
DLT was defined as Adverse Events (AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to (\>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting \>= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for \>= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (\<) 1,000/mm3 with a temperature of \> 38.3 degree Celsius (°C); grade 4 is defined as ANC \< 1,000/mm3 with a temperature of \> 38.3°C, with life-threatening consequences; Thrombocytopenia \< 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events \>= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay (\> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity.
Time frame: Up to 4 weeks after first administration of study intervention
Population: Dose-Limiting Toxicity Analysis (DLT) Set included all participants who completed the DLT period (within 4 weeks after first administration of study intervention) with at least 80 Percent (%) of the planned cumulative dose received during this period for each study intervention and/or who experienced at least one DLT during the DLT period. Number of Participants Analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab | Number of Japanese Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Number of Japanese Participants With Dose-Limiting Toxicities (DLTs) | 2 Participants |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Number of Japanese Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Treatment-Emergent Adverse Events (TEAEs) were defined as events with onset date or worsening during the on-treatment period. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.
Time frame: Time from first treatment assessed up to approximately 20 months
Population: The safety (SAF) analysis set included all participants who were administered any dose of any study intervention. Number of Participants Analyzed=participants evaluable for this outcome.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab | Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 3 Participants |
| Cohort 1A: Bintrafusp Alfa +Cisplatin/Carboplatin+Paclitaxel+Bevacizumab | Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Serious TEAEs | 3 Participants |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 3 Participants |
| Cohort1B: Bintrafusp Alfa +Cisplatin or Carboplatin+Paclitaxel | Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Serious TEAEs | 3 Participants |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 3 Participants |
| Cohort 2: Bintrafusp Alfa + Cisplatin+ Radiotherapy | Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Serious TEAEs | 3 Participants |
Secondary
Number of Participants With Positive Anti-Drug Antibody (ADA) of Bintrafusp Alfa
A validated method was applied to detect ADAs in the presence of drug in human serum. The ADA titers of positive samples were determined.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to immunogenicity were not assessed.
Secondary
Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa
Ctrough was the serum concentration observed immediately before next dosing.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
Terminal Elimination Half-Life (T1/2) of Bintrafusp Alfa
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. Elimination half-life determined as 0.693/ Lamda z(λz), λz=terminal first order (elimination) rate constant.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
Time to Reach Maximum Serum Concentration (Tmax) of Bintrafusp Alfa
The time to reach the maximum observed concentration collected during a dosing interval. Tmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose Up to 20 months
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.