Healthy
Conditions
Keywords
Bioavailability, Healthy
Brief summary
The study will assess the relative bioavailability of 2 different formulations of ALXN1840 in healthy participants.
Detailed description
This is a two-way crossover study consisting of 2 dosing periods assessing a test and reference formulation of ALXN1840. A dose-proportionality parallel group design extension period will be conducted following completion of the two-way crossover period of the study and will assess 5 different ascending doses of ALXN1840. There will be at least a 14-day washout following doses between Periods 1 and 2 and also at least a 14-day washout following the dose in Period 2 and the following dose in the Dose-Proportionality Extension Period. Safety will be assessed throughout the study.
Interventions
DRUGALXN1840
ALXN1840 will be administered orally.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a 2-period, 2-sequence, crossover study with a parallel group extension.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* No clinically significant history or presence of electrocardiogram findings * Body weight ≥50 to ≤100 kilograms (kg) and body mass index 18 to \<32 kg/meter squared for all participants * Willing and able to follow protocol-specified contraception requirements
Exclusion criteria
* History or presence of clinical and/or laboratory disorders * Abnormal blood pressure, defined as supine blood pressure ≤90/60 millimeters of mercury (mmHg) or \>140/90 mmHg * Lymphoma, leukemia, or any malignancy within the past 5 years * Alanine aminotransferase, aspartate aminotransferase, or total bilirubin \> upper limit of normal * Serum copper or serum ceruloplasmin below lower limit of normal * Hemoglobin \<130 grams (g)/liter (L) for males and hemoglobin \<115 g/L for females * Significant allergies * Smoker
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) For Plasma Total Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS. |
| Two-way Crossover Period: Maximum Observed Concentration (Cmax) For Plasma Total Molybdenum (Mo) | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of total Mo via inductively coupled plasma-mass spectroscopy (ICP-MS). |
| Two-way Crossover Period: Cmax for PUF Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS. |
| Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) For Plasma Total Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS. |
| Two-way Crossover Period: AUCt for Plasma PUF Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Proportionality Extension Period: Cmax For Plasma Total Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS. |
| Dose-Proportionality Extension Period: Cmax For Plasma PUF Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS. |
| Dose-Proportionality Extension Period: AUCt For Plasma Total Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS. |
| Dose-Proportionality Extension Period: AUCt For Plasma PUF Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS. |
| Dose-Proportionality Extension Period: AUCinf For Plasma Total Mo | predose (0.5 hour) and up to 336 hours postdose | Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS. |
Countries
Australia
Participant flow
Pre-assignment details
The study included a 2-way crossover period and a dose-proportionality extension period. Participants were randomized to 1 of the 2 treatment sequences (A-B) or (B-A) in crossover period with washout between. Participants were scheduled to receive either treatment A or B on Day 1 of each dosing period. After a 14-day washout period, participants were rerandomized in dose-proportionality extension period to receive treatment C, D, E, or F.
Participants by arm
| Arm | Count |
|---|---|
| Overall Population Crossover: Participants first received a single dose of ALXN1840 test formulation (15 mg; 12 × 1.25 mg EC mini-tablets) orally on Day 1 of Period 1 and then after a washout period of 14 days, received a single dose of ALXN1840 reference formulation (15 mg EC tablet) orally on Day 1 of Period 2. Dose-proportionality extension: Participants received a single dose of ALXN1840 2.5, 5, 10, or 30 mg orally on Day 1. | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Dose-Proportionality Extension Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Two-way Crossover Period | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Two-way Crossover Period | Other than specified | 0 | 1 | 0 | 0 | 0 | 0 |
| Two-way Crossover Period | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Two-way Crossover Period | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Before Extension Period | Other than specified | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Before Extension Period | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Population |
|---|---|
| Age, Continuous | 30.9 years STANDARD_DEVIATION 7.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 19 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants |
| Race/Ethnicity, Customized Race White | 24 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 46 | 0 / 10 | 0 / 11 | 0 / 9 | 0 / 11 |
| other Total, other adverse events | 18 / 46 | 20 / 46 | 2 / 10 | 5 / 11 | 3 / 9 | 4 / 11 |
| serious Total, serious adverse events | 0 / 46 | 0 / 46 | 0 / 10 | 0 / 11 | 0 / 9 | 0 / 11 |
Outcome results
Primary
Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) For Plasma Total Mo
Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-CO included all participants who received at least 1 dose of ALXN1840 in the Two-way Crossover Periods and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) For Plasma Total Mo | 10149.7531 hours*ng/mL | Geometric Coefficient of Variation 29.2 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) For Plasma Total Mo | 10068.8862 hours*ng/mL | Geometric Coefficient of Variation 23 |
Comparison: The formulation impact (12 × 1.25 mg EC mini-tablet versus 1 × 15 mg EC tablet) on plasma total Mo PK parameters was assessed using ANOVA statistical model with dosing period, treatment, and treatment sequence as the fixed effects and the participant (sequence) as a random effect, using the natural logarithms of the data.90% CI: [89.3, 109.9]
Primary
Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) For Plasma Total Mo
Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-CO included all participants who received at least 1 dose of ALXN1840 in the Two-way Crossover Periods and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) For Plasma Total Mo | 8654.3114 hours*ng/mL | Geometric Coefficient of Variation 46.6 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Two-way Crossover Period: Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) For Plasma Total Mo | 9253.7266 hours*ng/mL | Geometric Coefficient of Variation 44.6 |
Comparison: The formulation impact (12 × 1.25 mg EC mini-tablet versus 1 × 15 mg EC tablet) on plasma total Mo PK parameters was assessed using ANOVA statistical model with dosing period, treatment, and treatment sequence as the fixed effects and the participant (sequence) as a random effect, using the natural logarithms of the data.90% CI: [81.6, 110.5]
Primary
Two-way Crossover Period: AUCt for Plasma PUF Mo
Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-CO included all participants who received at least 1 dose of ALXN1840 in the Two-way Crossover Periods and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Two-way Crossover Period: AUCt for Plasma PUF Mo | 766.7655 hours*ng/mL | Geometric Coefficient of Variation 25.6 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Two-way Crossover Period: AUCt for Plasma PUF Mo | 811.7275 hours*ng/mL | Geometric Coefficient of Variation 27.2 |
Comparison: The formulation impact (12 × 1.25 mg EC mini-tablet versus 1 × 15 mg EC tablet) on plasma total Mo PK parameters was assessed using ANOVA statistical model with dosing period, treatment, and treatment sequence as the fixed effects and the participant (sequence) as a random effect, using the natural logarithms of the data.90% CI: [70.6, 145.1]
Primary
Two-way Crossover Period: Cmax for PUF Mo
Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-CO included all participants who received at least 1 dose of ALXN1840 in the Two-way Crossover Periods and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Two-way Crossover Period: Cmax for PUF Mo | 11.758 ng/mL | Geometric Coefficient of Variation 43.7 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Two-way Crossover Period: Cmax for PUF Mo | 12.120 ng/mL | Geometric Coefficient of Variation 40.7 |
Comparison: The formulation impact (12 × 1.25 mg EC mini-tablet versus 1 × 15 mg EC tablet) on plasma total Mo PK parameters was assessed using ANOVA statistical model with dosing period, treatment, and treatment sequence as the fixed effects and the participant (sequence) as a random effect, using the natural logarithms of the data.90% CI: [86.384, 107.227]
Primary
Two-way Crossover Period: Maximum Observed Concentration (Cmax) For Plasma Total Molybdenum (Mo)
Whole blood samples were collected for the measurement of plasma concentrations of total Mo via inductively coupled plasma-mass spectroscopy (ICP-MS).
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The Pharmacokinetic/Pharmacodynamic Set for the Two-way Crossover Periods (PKDS-CO) included all participants who received at least 1 dose of ALXN1840 in the Two-way Crossover Periods and had evaluable pharmacokinetic (PK) data for total and/or plasma ultrafiltrate (PUF) Mo (as surrogate measures of ALXN1840 PK) in plasma. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Two-way Crossover Period: Maximum Observed Concentration (Cmax) For Plasma Total Molybdenum (Mo) | 227.0186 nanograms (ng)/milliliter (mL) | Geometric Coefficient of Variation 47.5 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Two-way Crossover Period: Maximum Observed Concentration (Cmax) For Plasma Total Molybdenum (Mo) | 238.2725 nanograms (ng)/milliliter (mL) | Geometric Coefficient of Variation 30.8 |
Comparison: The formulation impact (12 × 1.25 mg EC mini-tablet versus 1 × 15 mg EC tablet) on plasma total Mo PK parameters was assessed using analysis of variance (ANOVA) statistical model with dosing period, treatment, and treatment sequence as the fixed effects and the participant (sequence) as a random effect, using the natural logarithms of the data.90% CI: [82.1, 110]
Secondary
Dose-Proportionality Extension Period: AUCinf For Plasma Total Mo
Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-E included all participants who receive at least 1 dose of ALXN1840 in the Dose-Proportionality Extension Period and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. Only data for Treatments D, E, and F were collected for this Outcome Measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Dose-Proportionality Extension Period: AUCinf For Plasma Total Mo | 4920.5103 hours*ng/mL | Standard Deviation 1035.21136 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Dose-Proportionality Extension Period: AUCinf For Plasma Total Mo | 9057.1367 hours*ng/mL | Standard Deviation 1345.89511 |
| Dose-proportionality Extension: ALXN1840 10 mg (Treatment E) | Dose-Proportionality Extension Period: AUCinf For Plasma Total Mo | 17842.1736 hours*ng/mL | Standard Deviation 5496.9419 |
Secondary
Dose-Proportionality Extension Period: AUCt For Plasma PUF Mo
Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-E included all participants who receive at least 1 dose of ALXN1840 in the Dose-Proportionality Extension Period and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Dose-Proportionality Extension Period: AUCt For Plasma PUF Mo | 584.5782 hours*ng/mL | Standard Deviation 177.03965 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Dose-Proportionality Extension Period: AUCt For Plasma PUF Mo | 826.2629 hours*ng/mL | Standard Deviation 623.23702 |
| Dose-proportionality Extension: ALXN1840 10 mg (Treatment E) | Dose-Proportionality Extension Period: AUCt For Plasma PUF Mo | 805.6937 hours*ng/mL | Standard Deviation 449.64768 |
| Dose-proportionality Extension: ALXN1840 30 mg (Treatment F) | Dose-Proportionality Extension Period: AUCt For Plasma PUF Mo | 976.4214 hours*ng/mL | Standard Deviation 220.56479 |
Secondary
Dose-Proportionality Extension Period: AUCt For Plasma Total Mo
Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-E included all participants who receive at least 1 dose of ALXN1840 in the Dose-Proportionality Extension Period and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Dose-Proportionality Extension Period: AUCt For Plasma Total Mo | 1677.8616 hours*ng/mL | Standard Deviation 736.42903 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Dose-Proportionality Extension Period: AUCt For Plasma Total Mo | 4053.6004 hours*ng/mL | Standard Deviation 1601.44215 |
| Dose-proportionality Extension: ALXN1840 10 mg (Treatment E) | Dose-Proportionality Extension Period: AUCt For Plasma Total Mo | 7439.1004 hours*ng/mL | Standard Deviation 2213.01844 |
| Dose-proportionality Extension: ALXN1840 30 mg (Treatment F) | Dose-Proportionality Extension Period: AUCt For Plasma Total Mo | 16778.1770 hours*ng/mL | Standard Deviation 4707.76069 |
Secondary
Dose-Proportionality Extension Period: Cmax For Plasma PUF Mo
Whole blood samples were collected for the measurement of plasma concentrations of PUF Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The PKDS-E included all participants who receive at least 1 dose of ALXN1840 in the Dose-Proportionality Extension Period and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Dose-Proportionality Extension Period: Cmax For Plasma PUF Mo | 8.505 ng/mL | Standard Deviation 9.3638 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Dose-Proportionality Extension Period: Cmax For Plasma PUF Mo | 9.341 ng/mL | Standard Deviation 11.6589 |
| Dose-proportionality Extension: ALXN1840 10 mg (Treatment E) | Dose-Proportionality Extension Period: Cmax For Plasma PUF Mo | 16.557 ng/mL | Standard Deviation 20.7835 |
| Dose-proportionality Extension: ALXN1840 30 mg (Treatment F) | Dose-Proportionality Extension Period: Cmax For Plasma PUF Mo | 25.945 ng/mL | Standard Deviation 11.0632 |
Secondary
Dose-Proportionality Extension Period: Cmax For Plasma Total Mo
Whole blood samples were collected for the measurement of plasma concentrations of total Mo via ICP-MS.
Time frame: predose (0.5 hour) and up to 336 hours postdose
Population: The Pharmacokinetic/Pharmacodynamic Set for the Dose-Proportionality Extension Period (PKDS-E) included all participants who receive at least 1 dose of ALXN1840 in the Dose-Proportionality Extension Period and had evaluable PK data for total and/or PUF molybdenum (as surrogate measures of ALXN1840 PK) in plasma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crossover: ALXN1840 Test Formulation (Treatment A) | Dose-Proportionality Extension Period: Cmax For Plasma Total Mo | 41.0441 ng/mL | Standard Deviation 19.48739 |
| Crossover: ALXN1840 Reference Formulation (Treatment B) | Dose-Proportionality Extension Period: Cmax For Plasma Total Mo | 104.4313 ng/mL | Standard Deviation 52.55264 |
| Dose-proportionality Extension: ALXN1840 10 mg (Treatment E) | Dose-Proportionality Extension Period: Cmax For Plasma Total Mo | 199.4759 ng/mL | Standard Deviation 55.17849 |
| Dose-proportionality Extension: ALXN1840 30 mg (Treatment F) | Dose-Proportionality Extension Period: Cmax For Plasma Total Mo | 396.0000 ng/mL | Standard Deviation 190.18412 |