Healthy Subjects, Pharmacokinetics, Pharmacodynamics
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics
Brief summary
This study is designed to assess pharmacokinetics and pharmacodynamics of interferon beta-1a and peginterferon beta-1a across an appropriate dose range to inform clinical trial operating characteristics for future clinical pharmacology pharmacodynamics similarity studies. This is a randomized, placebo-controlled, single-dose, parallel arm study in 84 healthy subjects assigned to one of three dose groups (low, intermediate, and high) of each drug (interferon beta-1a and peginterferon beta-1a) or placebo.
Detailed description
This study is designed to assess pharmacokinetics and pharmacodynamics of interferon beta-1a and peginterferon beta-1a across an appropriate dose range to inform clinical trial operating characteristics for future clinical pharmacology pharmacodynamics similarity studies. This is a randomized, placebo-controlled, single-dose, parallel arm study in 84 healthy subjects assigned to one of three dose groups (low, intermediate, and high) of each drug (interferon beta-1a and peginterferon beta-1a) or placebo. Interferon beta-1a doses are 7.5, 15, and 30 µg. Peginterferon beta-1a doses are 31.25, 62.5, and 125 µg. Each arm will include 12 subjects (6 male and 6 female). Subjects will be admitted for treatment on day -1 and receive a single dose of study drug or placebo on day 1. Depending on the treatment arm, subjects will remain in confinement for 7 days (interferon beta-1a) or 14 days (peginterferon beta-1a and placebo). Blood samples (approximately 5 mL per sample) will be collected for determination of plasma concentrations for study drug and neopterin levels. Additional blood samples will be collected for determination of lipids (5 mL per sample; pharmacodynamic measure) and exploratory proteomics analyses (5 mL per sample). Safety evaluations will include adverse event (AE) monitoring, vital sign measurements, and physical examinations. All AEs reported by the subject or observed by the investigator or clinical research unit (CRU) staff will be recorded. Any AE reported after the informed consent is signed and before study drug application will be recorded as medical history.
Interventions
BIOLOGICALInterferon beta-1a
Interferon beta-1a 7.5 µg administered IM
BIOLOGICALPeginterferon beta-1a
Peginterferon beta-1a 31.25 µg administered SC
BIOLOGICALPlacebo
Placebo (administered either IM or SC)
Sponsors
Spaulding Clinical Research LLC
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing. Subjects and staff will be blinded to treatment assignment during confinement, but route of administration will not be blinded. The blind will be maintained through a randomization schedule held by the dispensing pharmacist. Subjects and staff will be informed of a subject's end of study day when discharged from confinement. Subjects and staff will not be informed of the specific treatment arm assignment. The clinical research nurse will administer the subcutaneous study drug in unit dose containers that are not transparent.
Intervention model description
Subjects will be randomized to one of three dose groups (low, intermediate, and high) of each drug (interferon beta-1a and peginterferon beta-1a) or placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject signs an institutional review board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed. 2. Subject is a healthy man or woman, 18 to 55 years of age, inclusive, who has a body mass index of 18.5 to 29.9 kg/m2, inclusive, at Screening. 3. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead electrocardiogram (ECG) results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee). 4. Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day -1). 5. Female subjects must be of non-childbearing potential or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before Check in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1 month after the last application of study drug; OR 2) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before Check in (Day -1) until at least 1 month after the last application of study drug. 6. Female subjects must not be pregnant or lactating before enrollment in the study. 7. Male subjects must agree to practice 1 highly effective method of birth control (as determined by the investigator or designee) from at least 1 month before Check-in (Day -1) until at least 1 month after the end of study 8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.
Exclusion criteria
1. Subject has had previous exposure to the biologic Avonex or Plegridy. 2. Subject is anemic (i.e., with Hct or Hgb considered clinically significant by Investigator or chronic history of anemia) or has any chronic condition(s) that may impact blood sample collection. 3. Subject has a history of asthma. 4. Subject has a history of anaphylaxis from environmental exposures such as peanuts or bee stings. 5. Subject has an allergic history that includes urticaria, angioedema or respiratory coughing or bronchospasm. 6. Subject has a history of severe local reactions or generalized erythema from skin allergen testing. 7. Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug. 8. Subjects are currently participating in another clinical study of an investigational drug or are have been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound. 9. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening. 10. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 hours of dosing. Subjects must refrain from ingesting these throughout the study. 11. Subject has any underlying disease or surgical or medical condition (e.g., cancer, human immunodeficiency virus \[HIV\], severe hepatic or renal impairment) that could put the subject at risk or would normally prevent participation in a clinical study. This includes subjects with any underlying medical conditions that put subjects at higher risk for coronavirus disease of 2019 (COVID-19) complications. Per current Center for Disease Control and Prevention (CDC) recommendations, this includes: * People with chronic lung disease or moderate to severe asthma * People who have serious heart conditions * People who are immunocompromised * Many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV, and prolonged use of corticosteroids and other immune weakening medications * People with severe obesity (BMI of 40 or higher) * People with diabetes * People with chronic kidney disease undergoing dialysis * People with liver disease 12. Subject has any signs or symptoms that are consistent with COVID-19. Per current CDC recommendations, this includes subjects with the symptoms of cough or shortness of breath or difficulty breathing, or at least two of the following symptoms: fever, chills, repeated shaking with chills, muscle pain, headache, sore throat or new loss of taste/smell. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator. 13. Subject tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission. 14. Subject has been diagnosed with any autoimmune disease or other chronic inflammatory disease. 15. Subject has been diagnosed with depression, suicidal ideation or psychosis. 16. Subject has been diagnosed with congestive heart failure. 17. Subject has been diagnosed with seizures of any type. 18. Subject has known or suspected allergies or sensitivities to any study drug. 19. Subject has clinical laboratory test results (hematology, serum chemistry lipid panel and comprehensive metabolic panel) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. 20. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen. 21. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | The values and variability of standard pharmacodynamic (PD) metric (AUEC \[baseline subtracted\]) for neopterin at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a |
| Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | The values and variability of standard pharmacodynamic (PD) metric (maximal difference at a single time-point) for neopterin at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | The values and variability of standard PD metric (AUEC \[baseline subtracted\]) for MxA at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a |
| Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | The values and variability of standard PD metric (maximal difference at a single time-point) for MxA at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a |
| Pharmacodynamic Model Parameter, Emax (Maximum Effect), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | Model parameter (Emax) for neopterin area under the effect curve models calculated after combining data from low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses. |
| Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | The values and variability of pharmacokinetic characteristic (AUC of free drug concentration) at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a |
| Pharmacodynamic Model Parameter, Emax, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | Model parameter (Emax) for neopterin maximum change from baseline models calculated after combining data from low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses. |
| Pharmacodynamic Model Parameter, ED50, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | Model parameter (ED50) for neopterin maximum change from baseline models calculated after combining data from low, intermediate, and high doses of interferon beta-1a or peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses. |
| Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | Model parameter (ED50) for neopterin area under the effect curve models calculated after combining data from low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses. |
| Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F) | The values and variability of pharmacokinetic characteristic (Cmax) at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Interferon Beta-1a Low Dose Single dose of interferon beta-1a 7.5 µg intramuscular (IM)
Interferon beta-1a: Interferon beta-1a 7.5 µg administered IM | 12 |
| Arm B: Interferon Beta-1a Intermediate Dose Single dose of interferon beta-1a 15 µg IM
Interferon beta-1a: Interferon beta-1a 15 µg administered IM | 12 |
| Arm C: Interferon Beta-1a High Dose Single dose of interferon beta-1a 30 µg IM
Interferon beta-1a: Interferon beta-1a 30 µg administered IM | 12 |
| Arm D: Peginterferon Beta-1a Low Dose Single dose of peginterferon beta-1a 31.25 µg subcutaneous (SC)
Peginterferon beta-1a: Peginterferon beta-1a 31.25 µg administered SC | 12 |
| Arm E: Peginterferon Beta-1a Intermediate Dose Single dose of peginterferon beta-1a 62.5 µg SC
Peginterferon beta-1a: Peginterferon beta-1a 62.5 µg administered SC | 12 |
| Arm F: Peginterferon Beta-1a High Dose Single dose of peginterferon beta-1a 125 µg SC
Peginterferon beta-1a: Peginterferon beta-1a 125 µg administered SC | 12 |
| Arm G: Placebo Single dose of placebo
Placebo: Placebo (administered either IM or SC) | 12 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm B: Interferon Beta-1a Intermediate Dose | Arm C: Interferon Beta-1a High Dose | Arm D: Peginterferon Beta-1a Low Dose | Arm E: Peginterferon Beta-1a Intermediate Dose | Arm A: Interferon Beta-1a Low Dose | Arm F: Peginterferon Beta-1a High Dose | Arm G: Placebo | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 35.1 years STANDARD_DEVIATION 9.7 | 38.3 years STANDARD_DEVIATION 10.9 | 37.7 years STANDARD_DEVIATION 12.7 | 31.9 years STANDARD_DEVIATION 11.1 | 36.0 years STANDARD_DEVIATION 8.6 | 35.5 years STANDARD_DEVIATION 8 | 36.9 years STANDARD_DEVIATION 10.6 | 35.9 years STANDARD_DEVIATION 10.2 |
| Body mass index | 25.9 kg/m^2 STANDARD_DEVIATION 2.7 | 27.0 kg/m^2 STANDARD_DEVIATION 3 | 26.2 kg/m^2 STANDARD_DEVIATION 3.2 | 27.0 kg/m^2 STANDARD_DEVIATION 2.6 | 24.5 kg/m^2 STANDARD_DEVIATION 2.3 | 25.6 kg/m^2 STANDARD_DEVIATION 2.5 | 27.1 kg/m^2 STANDARD_DEVIATION 2.4 | 26.2 kg/m^2 STANDARD_DEVIATION 2.7 |
| Body weight | 72.7 kg STANDARD_DEVIATION 12.2 | 80.0 kg STANDARD_DEVIATION 14.5 | 78.5 kg STANDARD_DEVIATION 10.7 | 76.3 kg STANDARD_DEVIATION 13.2 | 73.5 kg STANDARD_DEVIATION 11.4 | 76.3 kg STANDARD_DEVIATION 10.9 | 79.3 kg STANDARD_DEVIATION 9.1 | 76.7 kg STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 12 Participants | 9 Participants | 11 Participants | 9 Participants | 11 Participants | 11 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 7 Participants | 6 Participants | 8 Participants | 2 Participants | 4 Participants | 6 Participants | 41 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 6 Participants | 4 Participants | 8 Participants | 8 Participants | 5 Participants | 38 Participants |
| Region of Enrollment United States | 12 participants | 12 participants | 12 participants | 12 participants | 12 participants | 12 participants | 12 participants | 84 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 4 Participants | 32 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 7 Participants | 7 Participants | 7 Participants | 8 Participants | 8 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 7 / 12 | 7 / 12 | 10 / 12 | 7 / 12 | 9 / 12 | 11 / 12 | 4 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a
The values and variability of standard pharmacodynamic (PD) metric (AUEC \[baseline subtracted\]) for neopterin at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 7.82 ng*day/mL | Standard Deviation 2.87 |
| Arm B: Interferon Beta-1a Intermediate Dose | Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 9.61 ng*day/mL | Standard Deviation 3.2 |
| Arm C: Interferon Beta-1a High Dose | Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 11.08 ng*day/mL | Standard Deviation 5.42 |
| Arm D: Peginterferon Beta-1a Low Dose | Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 11.52 ng*day/mL | Standard Deviation 7.92 |
| Arm E: Peginterferon Beta-1a Intermediate Dose | Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 18.20 ng*day/mL | Standard Deviation 8.8 |
| Arm F: Peginterferon Beta-1a High Dose | Area Under Effect Curve (AUEC) for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 21.59 ng*day/mL | Standard Deviation 15.15 |
Primary
Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a
The values and variability of standard pharmacodynamic (PD) metric (maximal difference at a single time-point) for neopterin at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 3.50 ng/mL | Standard Deviation 1.06 |
| Arm B: Interferon Beta-1a Intermediate Dose | Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 4.22 ng/mL | Standard Deviation 1.67 |
| Arm C: Interferon Beta-1a High Dose | Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 4.93 ng/mL | Standard Deviation 1.85 |
| Arm D: Peginterferon Beta-1a Low Dose | Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 3.17 ng/mL | Standard Deviation 2.23 |
| Arm E: Peginterferon Beta-1a Intermediate Dose | Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 5.01 ng/mL | Standard Deviation 2.1 |
| Arm F: Peginterferon Beta-1a High Dose | Maximum Change From Baseline for Neopterin for Interferon Beta-1a and Peginterferon Beta-1a | 5.87 ng/mL | Standard Deviation 1.7 |
Secondary
Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a
The values and variability of standard PD metric (AUEC \[baseline subtracted\]) for MxA at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 140 ng*day/mL | Standard Deviation 63 |
| Arm B: Interferon Beta-1a Intermediate Dose | Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 172 ng*day/mL | Standard Deviation 92 |
| Arm C: Interferon Beta-1a High Dose | Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 211 ng*day/mL | Standard Deviation 102 |
| Arm D: Peginterferon Beta-1a Low Dose | Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 458 ng*day/mL | Standard Deviation 303 |
| Arm E: Peginterferon Beta-1a Intermediate Dose | Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 732 ng*day/mL | Standard Deviation 591 |
| Arm F: Peginterferon Beta-1a High Dose | Area Under Effect Curve (AUEC) for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 1137 ng*day/mL | Standard Deviation 592 |
Secondary
Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a
The values and variability of pharmacokinetic characteristic (AUC of free drug concentration) at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 99.4 pg/mL*day | Geometric Coefficient of Variation 45 |
| Arm B: Interferon Beta-1a Intermediate Dose | Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 223 pg/mL*day | Geometric Coefficient of Variation 46 |
| Arm C: Interferon Beta-1a High Dose | Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 386 pg/mL*day | Geometric Coefficient of Variation 28 |
| Arm D: Peginterferon Beta-1a Low Dose | Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 970 pg/mL*day | Geometric Coefficient of Variation 44 |
| Arm E: Peginterferon Beta-1a Intermediate Dose | Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 2226 pg/mL*day | Geometric Coefficient of Variation 37 |
| Arm F: Peginterferon Beta-1a High Dose | Area Under the Curve (AUC) for Interferon Beta-1a and Peginterferon Beta-1a | 2740 pg/mL*day | Geometric Coefficient of Variation 65 |
Secondary
Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a
The values and variability of standard PD metric (maximal difference at a single time-point) for MxA at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 52.9 ng/mL | Standard Deviation 28.7 |
| Arm B: Interferon Beta-1a Intermediate Dose | Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 62.9 ng/mL | Standard Deviation 31.7 |
| Arm C: Interferon Beta-1a High Dose | Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 73.4 ng/mL | Standard Deviation 35.5 |
| Arm D: Peginterferon Beta-1a Low Dose | Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 86.7 ng/mL | Standard Deviation 49 |
| Arm E: Peginterferon Beta-1a Intermediate Dose | Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 117.6 ng/mL | Standard Deviation 73 |
| Arm F: Peginterferon Beta-1a High Dose | Maximum Change From Baseline for Myxovirus-resistance Protein A (MxA) for Interferon Beta-1a and Peginterferon Beta-1a | 175.5 ng/mL | Standard Deviation 93.5 |
Secondary
Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a
The values and variability of pharmacokinetic characteristic (Cmax) at low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 39.5 pg/mL | Geometric Coefficient of Variation 54 |
| Arm B: Interferon Beta-1a Intermediate Dose | Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 90.8 pg/mL | Geometric Coefficient of Variation 66 |
| Arm C: Interferon Beta-1a High Dose | Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 143 pg/mL | Geometric Coefficient of Variation 33 |
| Arm D: Peginterferon Beta-1a Low Dose | Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 191 pg/mL | Geometric Coefficient of Variation 49 |
| Arm E: Peginterferon Beta-1a Intermediate Dose | Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 434 pg/mL | Geometric Coefficient of Variation 49 |
| Arm F: Peginterferon Beta-1a High Dose | Maximum Concentration (Cmax) for Interferon Beta-1a and Peginterferon Beta-1a | 509 pg/mL | Geometric Coefficient of Variation 65 |
Secondary
Pharmacodynamic Model Parameter, ED50, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a
Model parameter (ED50) for neopterin maximum change from baseline models calculated after combining data from low, intermediate, and high doses of interferon beta-1a or peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses.
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population for each group was limited to those subjects administered interferon beta-1a or placebo (the interferon beta-1a group) or administered peginterferon beta-1a or placebo (peginterferon beta-1a) who completed the study. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Pharmacodynamic Model Parameter, ED50, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a | 4.8 ug |
| Arm B: Interferon Beta-1a Intermediate Dose | Pharmacodynamic Model Parameter, ED50, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a | 44.3 ug |
Secondary
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a
Model parameter (ED50) for neopterin area under the effect curve models calculated after combining data from low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses.
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population for each group was limited to those subjects administered interferon beta-1a or placebo (interferon beta-1a group) or peginterferon beta-1a or placebo (peginterferon beta-1a group) who completed the study. One outlying result from peginterferon beta-1a high dose was excluded. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a | 4.5 ug |
| Arm B: Interferon Beta-1a Intermediate Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a | 84.1 ug |
Secondary
Pharmacodynamic Model Parameter, Emax, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a
Model parameter (Emax) for neopterin maximum change from baseline models calculated after combining data from low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses.
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population for each group was limited to those subjects administered interferon beta-1a or placebo (the interferon beta-1a group) or administered peginterferon beta-1a or placebo (peginterferon beta-1a) who completed the study. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Pharmacodynamic Model Parameter, Emax, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a | 5.7 ng/mL |
| Arm B: Interferon Beta-1a Intermediate Dose | Pharmacodynamic Model Parameter, Emax, for Neopterin Maximum Change From Baseline Models With Interferon Beta-1a or Peginterferon Beta-1a | 8.2 ng/mL |
Secondary
Pharmacodynamic Model Parameter, Emax (Maximum Effect), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a
Model parameter (Emax) for neopterin area under the effect curve models calculated after combining data from low, intermediate, and high doses of interferon beta-1a and peginterferon beta-1a with placebo data. As such, the placebo arm was included in both analyses.
Time frame: 0, 1, 3, 6, 8, 16, 24, 32, 40, 48, 72, hours post-dose; once daily from Day 4 onwards until 7 days post-dose for Interferon Beta-1a treatment arms (Arms A, B and C) and 14 days post-dose for Peginterferon Beta-1a treatment arms (Arms D, E, and F)
Population: Analysis population for each group was limited to those subjects administered interferon beta-1a or placebo (interferon beta-1a group) or peginterferon beta-1a or placebo (peginterferon beta-1a group) who completed the study. One outlying result from peginterferon beta-1a high dose was excluded. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Interferon Beta-1a Low Dose | Pharmacodynamic Model Parameter, Emax (Maximum Effect), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a | 13.3 ng/mL*day |
| Arm B: Interferon Beta-1a Intermediate Dose | Pharmacodynamic Model Parameter, Emax (Maximum Effect), for Neopterin Area Under the Effect Curve Models With Interferon Beta-1a or Peginterferon Beta-1a | 44.0 ng/mL*day |