Chronic Hepatic Impairment
Conditions
Keywords
Parkinson disease
Brief summary
The purpose of this study is to compare the pharmacokinetics (PK) of preladenant after administration of a single 5 mg oral dose of preladenant in participants with hepatic impairment and healthy volunteers. Part 1 of this study compares healthy volunteers with participants with mild hepatic impairment. Part 2 compares healthy volunteers with participants with moderate hepatic impairment. Healthy volunteers in each part of this study are to be matched with participants with hepatic impairment by race, age, gender, and body mass index (BMI). The primary hypotheses are that in participants with mild or moderate HI, the area under the concentration-time curve from time 0 extrapolated to time of the last quantifiable concentration (AUC0-t) of preladenant is similar to that observed in matched healthy volunteers, so that the mean ratio of hepatic impaired/healthy is contained within the interval \[0.50, 2.00\].
Interventions
DRUGPreladenant
After at least an 8 hours overnight fast, one 5-mg preladenant tablet, is administered orally, on Day 1.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria for Healthy Participants Groups: * Must be healthy with normal hepatic function and be free of any clinically significant disease or condition that requires a physician's care and/or would interfere with study evaluations or procedures. Key Inclusion Criteria for Hepatic Impaired Groups: * Must have mild or moderate hepatic impairment. * Must have a diagnosis of chronic liver disease for \>6 months. * Clinical laboratory tests, physical examination, and electrocardiographs must be clinically acceptable to the investigator and sponsor. * Must be free, other than chronic liver disease, of significant medical conditions unrelated to their hepatic disorder except for conditions that in the opinion of the investigator may not interfere with the study evaluations, procedures or participation. Key
Exclusion criteria
* Must not be on any prohibited medications for entry into the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Time of the Last Quantifiable Concentration (AUC 0-t) of Preladenant After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of preladenant. |
| Maximum Observed Plasma Concentration (Cmax) of Preladenant After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of preladenant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC 0-t of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of SCH 446637. |
| Cmax of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of SCH 446637. |
| AUC 0-t of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of SCH 434748. |
| Cmax of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of preladenant calculated using free drug concentration. |
| AUC 0-t of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of preladenant calculated using free drug concentration. |
| Cmax of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | Pre-dose up to 72 hours postdose | For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of SCH 434748. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mild Hepatic Impaired (HI) Part 1 Participants with mild chronic liver disease enrolled in Part 1 received one 5-mg preladenant tablet, orally, on Day 1. | 12 |
| Healthy to Match Mild HI Part 1 Healthy volunteers with normal hepatic function matched to participants with mild chronic liver disease by race, age, BMI, and gender, enrolled in Part 1 received one 5-mg preladenant tablet, orally, on Day 1. | 12 |
| Moderate HI Part 2 Participants with moderate chronic liver disease enrolled in Part 2 one 5-mg preladenant tablet, orally, on Day 1. | 9 |
| Healthy to Match Moderate HI Part 2 Healthy volunteers with normal hepatic function matched to participants with moderate chronic liver disease by race, age, BMI, and gender, enrolled in Part 2 received one 5-mg preladenant tablet, orally, on Day 1. | 9 |
| Total | 42 |
Baseline characteristics
| Characteristic | Mild Hepatic Impaired (HI) Part 1 | Healthy to Match Mild HI Part 1 | Moderate HI Part 2 | Healthy to Match Moderate HI Part 2 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 6.5 | 52.3 Years STANDARD_DEVIATION 7.1 | 52.2 Years STANDARD_DEVIATION 4.8 | 50.1 Years STANDARD_DEVIATION 3.3 | 52.7 Years STANDARD_DEVIATION 5.9 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 5 Participants | 5 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 0 / 12 | 1 / 9 | 1 / 9 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Time of the Last Quantifiable Concentration (AUC 0-t) of Preladenant After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of preladenant.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Time of the Last Quantifiable Concentration (AUC 0-t) of Preladenant After a Single Dose of Preladenant | 97.864 hr*ng/mL |
| Healthy to Match Mild HI Part 1 | Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Time of the Last Quantifiable Concentration (AUC 0-t) of Preladenant After a Single Dose of Preladenant | 91.014 hr*ng/mL |
| Moderate HI Part 2 | Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Time of the Last Quantifiable Concentration (AUC 0-t) of Preladenant After a Single Dose of Preladenant | 300.667 hr*ng/mL |
| Healthy to Match Moderate HI Part 2 | Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Time of the Last Quantifiable Concentration (AUC 0-t) of Preladenant After a Single Dose of Preladenant | 115.715 hr*ng/mL |
Comparison: The analysis was performed using an analysis of covariance (ANCOVA) model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, Body Mass Index (BMI) and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.695, 1.662]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [1.334, 5.06]
Primary
Maximum Observed Plasma Concentration (Cmax) of Preladenant After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of preladenant.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | Maximum Observed Plasma Concentration (Cmax) of Preladenant After a Single Dose of Preladenant | 39.380 ng/mL |
| Healthy to Match Mild HI Part 1 | Maximum Observed Plasma Concentration (Cmax) of Preladenant After a Single Dose of Preladenant | 30.171 ng/mL |
| Moderate HI Part 2 | Maximum Observed Plasma Concentration (Cmax) of Preladenant After a Single Dose of Preladenant | 56.997 ng/mL |
| Healthy to Match Moderate HI Part 2 | Maximum Observed Plasma Concentration (Cmax) of Preladenant After a Single Dose of Preladenant | 39.735 ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.84, 2.027]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [0.643, 3.198]
Secondary
AUC 0-t of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of preladenant calculated using free drug concentration.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | AUC 0-t of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 1.605 hr*ng/mL |
| Healthy to Match Mild HI Part 1 | AUC 0-t of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 1.211 hr*ng/mL |
| Moderate HI Part 2 | AUC 0-t of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 6.792 hr*ng/mL |
| Healthy to Match Moderate HI Part 2 | AUC 0-t of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 1.681 hr*ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.749, 2.348]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [1.46, 11.187]
Secondary
AUC 0-t of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of SCH 434748.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | AUC 0-t of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 28.505 hr*ng/mL |
| Healthy to Match Mild HI Part 1 | AUC 0-t of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 15.395 hr*ng/mL |
| Moderate HI Part 2 | AUC 0-t of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 60.486 hr*ng/mL |
| Healthy to Match Moderate HI Part 2 | AUC 0-t of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 25.288 hr*ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.81, 4.234]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [1.306, 4.382]
Secondary
AUC 0-t of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the AUC 0-t of SCH 446637.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | AUC 0-t of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 38.262 hr*ng/mL |
| Healthy to Match Mild HI Part 1 | AUC 0-t of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 24.612 hr*ng/mL |
| Moderate HI Part 2 | AUC 0-t of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 170.215 hr*ng/mL |
| Healthy to Match Moderate HI Part 2 | AUC 0-t of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 35.421 hr*ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.617, 3.917]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [2.77, 8.335]
Secondary
Cmax of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of preladenant calculated using free drug concentration.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | Cmax of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 0.646 ng/mL |
| Healthy to Match Mild HI Part 1 | Cmax of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 0.401 ng/mL |
| Moderate HI Part 2 | Cmax of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 1.288 ng/mL |
| Healthy to Match Moderate HI Part 2 | Cmax of Preladenant Calculated Using Free Drug Concentration After a Single Dose of Preladenant | 0.577 ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [1.007, 2.572]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [0.844, 5.896]
Secondary
Cmax of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of SCH 434748.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | Cmax of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 10.503 ng/mL |
| Healthy to Match Mild HI Part 1 | Cmax of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 6.784 ng/mL |
| Moderate HI Part 2 | Cmax of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 13.983 ng/mL |
| Healthy to Match Moderate HI Part 2 | Cmax of Preladenant Metabolite SCH 434748 After a Single Dose of Preladenant | 9.936 ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.918, 2.61]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [0.72, 2.75]
Secondary
Cmax of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant
For healthy and HI participants blood samples were collected at pre-dose (0 hour) and at 0.50, 1, 2, 4, 6, 12, 16, 24, 30, 36, and 48 hours postdose. Blood samples were also collected for HI participants only at 60 and 72 hours postdose in order to determine the Cmax of SCH 446637.
Time frame: Pre-dose up to 72 hours postdose
Population: All participants who received an oral dose of preladenant and for whom at least one pharmacokinetic parameter can be calculated for the treatment phase according to the protocol and who did not have any protocol deviation interfering with pharmacokinetics.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mild Hepatic Impaired (HI) Part 1 | Cmax of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 12.691 ng/mL |
| Healthy to Match Mild HI Part 1 | Cmax of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 10.004 ng/mL |
| Moderate HI Part 2 | Cmax of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 21.761 ng/mL |
| Healthy to Match Moderate HI Part 2 | Cmax of Preladenant Metabolite SCH 446637 After a Single Dose of Preladenant | 10.993 ng/mL |
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was excluded from Part 1 analysis.90% CI: [0.703, 2.288]
Comparison: The analysis was performed using an ANCOVA model. Parameters were log-transformed (using the natural logarithm) prior to analysis. Study population (i.e., HI or Healthy) was included as a fixed effect with continuous covariates age, BMI and a categorical covariate, gender. Gender was included from Part 2 analysis.90% CI: [1.316, 2.977]