Healthy Volunteers
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of MLN3126 when administered as a single dose of tablets at escalating dose levels in healthy participants.
Detailed description
The drug tested in this study is called MLN3126. The study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and the potential effect of food on the PK of MLN3126 and its M-I metabolite following single oral dose administrations. This study planned to enroll approximately 48 healthy participants, who were to be enrolled in 1 of the 6 dose cohorts or matching placebo in an ascending fashion. Participants were randomly assigned to MLN3126 or placebo within each cohort- which remained undisclosed to the participant and study doctor during the study (unless there was an urgent medical need): * Cohort 1 - MLN3126 300 mg or matching placebo * Cohort 2 - MLN3126 600 mg or matching placebo * Cohort 3 - MLN3126 1000 mg or matching placebo * Cohort 3 - MLN3126 1000 mg or matching placebo (fed regimen) * Cohort 4 - MLN3126 1500 mg or matching placebo * Cohort 5 - MLN3126 2000 mg or matching placebo * Cohort 6 - Did not taken place due to termination of the study All participants were asked to take the required tablets at the same time throughout the study. This single-centre trial was conducted in The United States. Participants were confined to the clinic for 5 days, and were contacted by telephone on day 14 (±2days) for a follow-up assessment. This study was terminated after completion of Cohort 5 due to findings of study site non-compliance to Good Clinical Practice (GCP) regarding study documentation. There were no safety concerns.
Interventions
DRUGMLN3126
MLN3126 tablets
DRUGMLN3126 Placebo
MLN3126 placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. In the opinion of the investigator, the participant was capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signed and dated a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Is a male or female adult, aged 18 to 55 years, inclusive, at the time of informed consent and study drug dosing. 4. Is a healthy adult male or female subject as evidenced by their medical history, complete physical examination, vital signs, ECG, and safety laboratory evaluations. 5. Weighed at least 45 kg (99 lbs) and had a body mass index (BMI) between 18 and 30.0 kg/m2 inclusive at Screening. 6. A male participant who was nonsterilized and sexually active with a female partner of childbearing potential agreed to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. In addition, participants were advised not to donate sperm during this period. 7. A female participant of childbearing potential who was sexually active with a nonsterilized male partner agreed to use routinely adequate contraception from signing of informed consent throughout the duration of the study to their next postconfinement menstruation. In addition participants were advised not to donate ova during this period.
Exclusion criteria
Any participant who meets any of the following criteria will not qualify for entry into the study: 1. Has received any investigational compound within 30 days prior to the first dose of study medication. 2. Is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 3. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, GI, or endocrine disease or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results. 4. Has a known hypersensitivity to any component of the formulation of MLN3126. 5. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1). 6. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as 4 alcoholic beverages per day) within 1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. 7. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products section of the protocol. 8. If female, the participant is pregnant or lactating or intending to become pregnant, or intending to donate ova, before or during, the study; including the timeframe to participant's next postconfinement menstruation after participating in this study. 9. If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter. 10. Has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contra indicate taking MLN3126 or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias. 11. Has current or recent (within 6 months) GI disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention known to impact absorption \[eg, bariatric surgery or bowel resection\], esophageal reflux, peptic ulcer disease, erosive esophagitis or frequent \[more than once per week\] occurrence of heartburn). 12. Has a history of cancer or other malignancy, except basal cell carcinoma that has been in remission for at least 5 years prior to Day 1. 13. Has a positive test result for hepatitis B surface antigen, antibody to hepatitis C virus, at Screening or a known history of human immunodeficiency virus infection. 14. Has used nicotine-containing products (this includes, but is not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in Day -1. Cotinine test is positive at Screening or Check-in (Day -1). 15. Has poor peripheral venous access. 16. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 45 days prior to Day 1. 17. Has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry of any subject with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator or medically qualified subinvestigator. 18. Has abnormal Screening or Check-in (Day -1) laboratory values that suggest a clinically significant underlying disease or participant with the following laboratory abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>1.5×ULN. 19. Has QT interval with Fridericia correction method (QTcF) \>430 ms for men and \>450 ms for women or PR outside the range of 120 to 220 ms confirmed upon repeat testing within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | Up to Day 22 | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. |
| Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | Up to Day 16 | Clinical safety laboratory tests included clinical chemistry, hematology and urinalysis. The percentage of participants with any markedly abnormal laboratory finding during the study. |
| Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Up to Day 16 | Vital signs included oral body temperature measurement, blood pressure, respiration rate, and pulse rate \[beats per minute (bpm) or heart rate\]. The percentage of participant with markedly abnormal vital signs findings during the study. OBP=Orthostatic Blood Pressure. All OBP measurements were standing. |
| Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Up to Day 16 | A standard 12-lead ECG was performed. The percentage of participants with markedly abnormal electrocardiogram (ECG) findings during the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | AUC(0-inf) is measure of area under the curve from time 0 to infinity. |
| CL/F: Oral Clearance of MLN3126 | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | CL/F is apparent clearance of the drug from the plasma, after extravascular administration. |
| Renal Clearance (CLr) of MLN3126 and Metabolite M-I | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | Renal clearance was calculated as CLr=Ae(0-96)/AUC (0-96). |
| Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | Ae (0-96) is the total amount of drug excreted in urine from time 0 to time 96 hours. |
| Fe: Fraction of MLN3126 Excreted in the Urine | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | Fe is the Fraction of drug excreted in urine, calculated as Fe=(Ae\[0-t\]/dose)×100. |
| T ½: Half-life of MLN3126 and Metabolite M-I | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. |
| Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | Tmax is the time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. |
| AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | Pre-dose and multiple timepoints post-dose (Up to 96 Hours) | AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]). |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in the United States from 19 August 2013 (first participant signed informed consent form) to 05 February 2014.
Pre-assignment details
Healthy volunteers were enrolled in 1 of 5 MLN3126 ascending dose treatment groups: once a day 300 mg, 600 mg, 1000 mg under fed or fasting conditions,1500 mg or 2000 mg OR once a day placebo.
Participants by arm
| Arm | Count |
|---|---|
| MLN3126 300 mg MLN3126 300 mg tablets, orally, fasting, once on Day 1. | 5 |
| MLN3126 600 mg MLN3126 600 mg tablets, orally, fasting, once on Day 1. | 6 |
| MLN3126 1000 mg MLN3126 1000 mg tablets, orally, fasting, once on Day 1. Participants returned to the clinic then received MLN3126 1000 mg tablets, orally, fed (30 minutes after the start of a high-fat breakfast), once on Day 1. | 6 |
| MLN3126 1500 mg MLN3126 1500 mg tablets, orally, fasting, once on Day 1. | 6 |
| MLN3126 2000 mg MLN3126 2000 mg tablets, orally, fasting once on Day 1. | 6 |
| Placebo Placebo-matching MLN3126 tablets, orally, fasting, once on Day 1. | 10 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Other | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MLN3126 300 mg | MLN3126 600 mg | MLN3126 1000 mg | MLN3126 1500 mg | MLN3126 2000 mg | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 36.8 Years STANDARD_DEVIATION 10.43 | 30.3 Years STANDARD_DEVIATION 6.5 | 41.2 Years STANDARD_DEVIATION 10.42 | 32.3 Years STANDARD_DEVIATION 11.78 | 30.0 Years STANDARD_DEVIATION 8.39 | 32.8 Years STANDARD_DEVIATION 6.32 | 33.7 Years STANDARD_DEVIATION 9.1 |
| Body Mass Index (BMI) | 26.65 kg/m^2 STANDARD_DEVIATION 2.643 | 27.56 kg/m^2 STANDARD_DEVIATION 2.127 | 27.18 kg/m^2 STANDARD_DEVIATION 2.293 | 25.01 kg/m^2 STANDARD_DEVIATION 1.811 | 25.16 kg/m^2 STANDARD_DEVIATION 2.329 | 27.22 kg/m^2 STANDARD_DEVIATION 3.251 | 26.54 kg/m^2 STANDARD_DEVIATION 2.587 |
| Caffeine Consumption No | 4 participants | 5 participants | 4 participants | 3 participants | 6 participants | 7 participants | 29 participants |
| Caffeine Consumption Yes | 1 participants | 1 participants | 2 participants | 3 participants | 0 participants | 3 participants | 10 participants |
| Height | 170.8 cm STANDARD_DEVIATION 10.64 | 172.3 cm STANDARD_DEVIATION 5.47 | 174.7 cm STANDARD_DEVIATION 10.42 | 169.8 cm STANDARD_DEVIATION 5.71 | 173.3 cm STANDARD_DEVIATION 6.09 | 174.9 cm STANDARD_DEVIATION 13.08 | 172.9 cm STANDARD_DEVIATION 9.14 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 6 participants | 3 participants | 5 participants | 5 participants | 7 participants | 28 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 0 participants | 2 participants | 2 participants | 1 participants | 3 participants | 10 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 3 participants | 6 participants | 4 participants | 4 participants | 5 participants | 7 participants | 29 participants |
| Race/Ethnicity, Customized White | 2 participants | 0 participants | 3 participants | 1 participants | 1 participants | 3 participants | 10 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 5 Participants | 7 Participants | 24 Participants |
| Smoking Classification Current smoker | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Smoking Classification Ex-smoker | 0 participants | 0 participants | 2 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Smoking Classification Never smoked | 5 participants | 6 participants | 4 participants | 6 participants | 6 participants | 10 participants | 37 participants |
| Weight | 78.00 kg STANDARD_DEVIATION 12.9 | 81.98 kg STANDARD_DEVIATION 8.538 | 83.67 kg STANDARD_DEVIATION 15.871 | 72.22 kg STANDARD_DEVIATION 7.165 | 75.87 kg STANDARD_DEVIATION 10.016 | 82.58 kg STANDARD_DEVIATION 7.42 | 79.44 kg STANDARD_DEVIATION 10.498 |
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 | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 5 | 0 / 6 | 1 / 6 | 0 / 6 | 1 / 6 | 1 / 10 | 1 / 5 | 0 / 2 |
| serious Total, serious adverse events | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 5 | 0 / 2 |
Outcome results
Primary
Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: Up to Day 22
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN3126 300 mg | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 1 Participants |
| MLN3126 600 mg | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 0 Participants |
| MLN3126 1000 mg | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 1 Participants |
| MLN3126 1500 mg | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 0 Participants |
| MLN3126 2000 mg | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 1 Participants |
| Placebo | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 1 Participants |
| MLN3126 1000 mg (Fed) | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 1 Participants |
| Placebo (Fed) | Number of Participants That Experience At Least One Treatment-Emergent Adverse Event (TEAE) Post-Dose | 0 Participants |
Primary
Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose
Clinical safety laboratory tests included clinical chemistry, hematology and urinalysis. The percentage of participants with any markedly abnormal laboratory finding during the study.
Time frame: Up to Day 16
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Clinical Laboratory Results Post-Dose | 0 Percentage of Participants |
Primary
Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose
A standard 12-lead ECG was performed. The percentage of participants with markedly abnormal electrocardiogram (ECG) findings during the study.
Time frame: Up to Day 16
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 16.7 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 16.7 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 33.3 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 33.3 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 33.3 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 10.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 10.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 20.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 40.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc Interval | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QTc - Fredericia's | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | Heart Rate | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | QRS Interval | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings Post-Dose | PR Interval | 0 Percentage of Participants |
Primary
Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose
Vital signs included oral body temperature measurement, blood pressure, respiration rate, and pulse rate \[beats per minute (bpm) or heart rate\]. The percentage of participant with markedly abnormal vital signs findings during the study. OBP=Orthostatic Blood Pressure. All OBP measurements were standing.
Time frame: Up to Day 16
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 20.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 40.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 20.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 20.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 40.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 40.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 20.0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 0 Percentage of Participants |
| MLN3126 300 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 33.3 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 33.3 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 16.7 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 50.0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 50.0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 600 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 33.3 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 33.3 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 16.7 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 33.3 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 33.3 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 1000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 33.3 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 33.3 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 16.7 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 50.0 Percentage of Participants |
| MLN3126 1500 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 16.7 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 16.7 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 33.3 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 16.7 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 16.7 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 33.3 Percentage of Participants |
| MLN3126 2000 mg | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 33.3 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 20.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 10.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 20.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 50.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 20.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 40.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 40.0 Percentage of Participants |
| Placebo | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 30.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 40.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 40.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 20.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 20.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 40.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 40.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 20.0 Percentage of Participants |
| MLN3126 1000 mg (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 20.0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 3 minutes | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 1 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 3 minutes | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 3 minutes (Decrease >20 mmHg) | 50.0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 3 minutes | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - supine | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - supine | 50.0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Diastolic blood pressure - standing 1 minute | 50.0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP diastolic - 1 minutes (Decrease >20 mmHg) | 100.0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | OBP systolic - 3 minutes (Decrease of >40 mmHg) | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure - standing 1 minute | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Pulse - standing 1 minute | 0 Percentage of Participants |
| Placebo (Fed) | Percentage of Participants With Markedly Abnormal Vital Signs Post-Dose | Systolic Blood pressure (BP) - supine | 0 Percentage of Participants |
Secondary
Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine
Ae (0-96) is the total amount of drug excreted in urine from time 0 to time 96 hours.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK urine concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 | 65864.50 ng | Standard Deviation 13803.378 |
| MLN3126 300 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 M-I Metabolite | 1606271.00 ng | Standard Deviation 661316.505 |
| MLN3126 600 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 | 128194.87 ng | Standard Deviation 41264.086 |
| MLN3126 600 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 M-I Metabolite | 3785848.92 ng | Standard Deviation 1487530.534 |
| MLN3126 1000 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 M-I Metabolite | 3669719.92 ng | Standard Deviation 3805989.87 |
| MLN3126 1000 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 | 115101.67 ng | Standard Deviation 101342.371 |
| MLN3126 1500 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 | 115443.11 ng | Standard Deviation 45489.137 |
| MLN3126 1500 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 M-I Metabolite | 3042712.33 ng | Standard Deviation 1087430.529 |
| MLN3126 2000 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 | 179199.95 ng | Standard Deviation 94480.203 |
| MLN3126 2000 mg | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 M-I Metabolite | 4934093.92 ng | Standard Deviation 2367261.267 |
| Placebo | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 M-I Metabolite | 7969436.83 ng | Standard Deviation 9141564.346 |
| Placebo | Ae (0-96): Total Amount of MLN3126 and Metabolite M-I Excreted in the Urine | MLN3126 | 216883.09 ng | Standard Deviation 193535.668 |
Secondary
AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity
AUC(0-inf) is measure of area under the curve from time 0 to infinity.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK plasma concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 | 41765.17 ng*hr/mL | Standard Deviation 7549.827 |
| MLN3126 300 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 M-I Metabolite | 1993.65 ng*hr/mL | Standard Deviation 1099.291 |
| MLN3126 600 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 | 63508.18 ng*hr/mL | Standard Deviation 26520.426 |
| MLN3126 600 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 M-I Metabolite | 4132.89 ng*hr/mL | Standard Deviation 2266.377 |
| MLN3126 1000 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 | 78964.45 ng*hr/mL | Standard Deviation 40182.582 |
| MLN3126 1000 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 M-I Metabolite | 6668.14 ng*hr/mL | Standard Deviation 7725.447 |
| MLN3126 1500 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 | 110437.12 ng*hr/mL | Standard Deviation 20911.078 |
| MLN3126 1500 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 M-I Metabolite | 6949.52 ng*hr/mL | Standard Deviation 2129.918 |
| MLN3126 2000 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 | 134119.22 ng*hr/mL | Standard Deviation 45470.528 |
| MLN3126 2000 mg | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 M-I Metabolite | 6177.45 ng*hr/mL | Standard Deviation 1977.067 |
| Placebo | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 | 250789.67 ng*hr/mL | Standard Deviation 73569.482 |
| Placebo | AUC(0-inf): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to Infinity | MLN3126 M-I Metabolite | 12068.75 ng*hr/mL | Standard Deviation 10609.268 |
Secondary
AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration
AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK plasma concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 | 41480.14 ng*hr/mL | Standard Deviation 7541.025 |
| MLN3126 300 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 M-I Metabolite | 1961.73 ng*hr/mL | Standard Deviation 1106.451 |
| MLN3126 600 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 | 63117.71 ng*hr/mL | Standard Deviation 26292.596 |
| MLN3126 600 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 M-I Metabolite | 4096.06 ng*hr/mL | Standard Deviation 2261.405 |
| MLN3126 1000 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 | 73474.61 ng*hr/mL | Standard Deviation 29655.501 |
| MLN3126 1000 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 M-I Metabolite | 5550.19 ng*hr/mL | Standard Deviation 5139.476 |
| MLN3126 1500 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 | 108475.58 ng*hr/mL | Standard Deviation 20425.152 |
| MLN3126 1500 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 M-I Metabolite | 6724.92 ng*hr/mL | Standard Deviation 2067.765 |
| MLN3126 2000 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 | 133029.91 ng*hr/mL | Standard Deviation 44849.002 |
| MLN3126 2000 mg | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 M-I Metabolite | 6110.64 ng*hr/mL | Standard Deviation 1936.969 |
| Placebo | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 | 248462.35 ng*hr/mL | Standard Deviation 72106.157 |
| Placebo | AUC(0-tlqc): Area Under the Plasma Concentration Time Curve of MLN3126 and Metabolite M-I From Time 0 to the Last Quantifiable Concentration | MLN3126 M-I Metabolite | 11989.43 ng*hr/mL | Standard Deviation 10546.217 |
Secondary
CL/F: Oral Clearance of MLN3126
CL/F is apparent clearance of the drug from the plasma, after extravascular administration.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MLN3126 300 mg | CL/F: Oral Clearance of MLN3126 | 7.39 L/hr | Standard Deviation 1.457 |
| MLN3126 600 mg | CL/F: Oral Clearance of MLN3126 | 11.34 L/hr | Standard Deviation 5.934 |
| MLN3126 1000 mg | CL/F: Oral Clearance of MLN3126 | 15.12 L/hr | Standard Deviation 6.345 |
| MLN3126 1500 mg | CL/F: Oral Clearance of MLN3126 | 13.97 L/hr | Standard Deviation 2.473 |
| MLN3126 2000 mg | CL/F: Oral Clearance of MLN3126 | 16.76 L/hr | Standard Deviation 6.656 |
| Placebo | CL/F: Oral Clearance of MLN3126 | 4.23 L/hr | Standard Deviation 1.066 |
Secondary
Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: Pharmacokinetic (PK) analysis set included all participants who received study drug and who had at least 1 measurable PK plasma concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 125.26 ng/mL | Standard Deviation 44.94 |
| MLN3126 300 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 2466.00 ng/mL | Standard Deviation 387.208 |
| MLN3126 600 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 238.17 ng/mL | Standard Deviation 101.275 |
| MLN3126 600 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 3605.00 ng/mL | Standard Deviation 920.885 |
| MLN3126 1000 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 4061.67 ng/mL | Standard Deviation 1192.299 |
| MLN3126 1000 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 278.17 ng/mL | Standard Deviation 176.552 |
| MLN3126 1500 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 5490.00 ng/mL | Standard Deviation 1110.531 |
| MLN3126 1500 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 374.00 ng/mL | Standard Deviation 78.908 |
| MLN3126 2000 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 8200.00 ng/mL | Standard Deviation 1937.431 |
| MLN3126 2000 mg | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 424.83 ng/mL | Standard Deviation 131.574 |
| Placebo | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 684.40 ng/mL | Standard Deviation 556.234 |
| Placebo | Cmax: Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 9444.00 ng/mL | Standard Deviation 1929.632 |
Secondary
Fe: Fraction of MLN3126 Excreted in the Urine
Fe is the Fraction of drug excreted in urine, calculated as Fe=(Ae\[0-t\]/dose)×100.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK urine concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MLN3126 300 mg | Fe: Fraction of MLN3126 Excreted in the Urine | 0.02 Percentage | Standard Deviation 0.005 |
| MLN3126 600 mg | Fe: Fraction of MLN3126 Excreted in the Urine | 0.02 Percentage | Standard Deviation 0.007 |
| MLN3126 1000 mg | Fe: Fraction of MLN3126 Excreted in the Urine | 0.01 Percentage | Standard Deviation 0.002 |
| MLN3126 1500 mg | Fe: Fraction of MLN3126 Excreted in the Urine | 0.01 Percentage | Standard Deviation 0.003 |
| MLN3126 2000 mg | Fe: Fraction of MLN3126 Excreted in the Urine | 0.01 Percentage | Standard Deviation 0.005 |
| Placebo | Fe: Fraction of MLN3126 Excreted in the Urine | 0.01 Percentage | Standard Deviation 0.007 |
Secondary
Renal Clearance (CLr) of MLN3126 and Metabolite M-I
Renal clearance was calculated as CLr=Ae(0-96)/AUC (0-96).
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK urine concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 | 0.03 mL/min | Standard Deviation 0.01 |
| MLN3126 300 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 16.00 mL/min | Standard Deviation 9.945 |
| MLN3126 600 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 | 0.04 mL/min | Standard Deviation 0.01 |
| MLN3126 600 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 16.15 mL/min | Standard Deviation 3.426 |
| MLN3126 1000 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 | 0.02 mL/min | Standard Deviation 0.01 |
| MLN3126 1000 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 10.34 mL/min | Standard Deviation 7.285 |
| MLN3126 1500 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 | 0.02 mL/min | Standard Deviation 0.01 |
| MLN3126 1500 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 7.89 mL/min | Standard Deviation 2.544 |
| MLN3126 2000 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 | 0.02 mL/min | Standard Deviation 0.012 |
| MLN3126 2000 mg | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 13.69 mL/min | Standard Deviation 7.728 |
| Placebo | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 | 0.01 mL/min | Standard Deviation 0.004 |
| Placebo | Renal Clearance (CLr) of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 9.05 mL/min | Standard Deviation 5.598 |
Secondary
T ½: Half-life of MLN3126 and Metabolite M-I
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK plasma concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 | 13.94 Hours | Standard Deviation 0.992 |
| MLN3126 300 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 13.44 Hours | Standard Deviation 1.815 |
| MLN3126 600 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 | 12.80 Hours | Standard Deviation 0.624 |
| MLN3126 600 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 13.47 Hours | Standard Deviation 1.524 |
| MLN3126 1000 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 | 16.07 Hours | Standard Deviation 5.899 |
| MLN3126 1000 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 19.88 Hours | Standard Deviation 16.767 |
| MLN3126 1500 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 | 16.31 Hours | Standard Deviation 3.706 |
| MLN3126 1500 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 20.89 Hours | Standard Deviation 9.006 |
| MLN3126 2000 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 | 13.63 Hours | Standard Deviation 1.888 |
| MLN3126 2000 mg | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 14.09 Hours | Standard Deviation 3.053 |
| Placebo | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 | 13.92 Hours | Standard Deviation 0.894 |
| Placebo | T ½: Half-life of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 13.56 Hours | Standard Deviation 1.96 |
Secondary
Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I
Tmax is the time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Time frame: Pre-dose and multiple timepoints post-dose (Up to 96 Hours)
Population: PK analysis set included all participants who received study drug and who had at least 1 measurable PK plasma concentration.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| MLN3126 300 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 2.00 Hours | Full Range 1.884 |
| MLN3126 300 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 4.00 Hours | — |
| MLN3126 600 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 3.00 Hours | Full Range 0.894 |
| MLN3126 600 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 4.00 Hours | — |
| MLN3126 1000 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 3.14 Hours | Full Range 0.902 |
| MLN3126 1000 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 4.00 Hours | — |
| MLN3126 1500 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 2.50 Hours | Full Range 2.345 |
| MLN3126 1500 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 4.00 Hours | — |
| MLN3126 2000 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 3.01 Hours | Full Range 0.752 |
| MLN3126 2000 mg | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 4.00 Hours | — |
| Placebo | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 | 6.00 Hours | — |
| Placebo | Tmax: Time to Maximum Plasma Concentration of MLN3126 and Metabolite M-I | MLN3126 M-I Metabolite | 8.00 Hours | — |