Relapsing-Remitting Multiple Sclerosis
Conditions
Keywords
Pre-filled syringe, Pharmacokinetic, Daclizumab High Yield Process, immunogenicity
Brief summary
The primary objective of the study is to assess the immunogenicity of Daclizumab High Yield Process (DAC HYP) 150 mg administered every 4 weeks by subcutaneous (SC) injection using the pre-filled syringe (PFS) in participants with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives of this study are to characterize the pharmacokinetics (PK) of DAC HYP following single and multiple doses of DAC HYP administered by the PFS in a subset of participants with RRMS and to evaluate the effect of DAC HYP on the PK of probe drugs for cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A).
Detailed description
Following a screening period, participants will receive DAC HYP over a 24-week treatment period (6 monthly injections) and then enter a 20-week washout period for assessment of immunogenicity, PK, pharmacodynamics, safety, and tolerability. The 20-week washout is necessary to ensure measurement of anti-DAC HYP binding antibodies (ADAbs) and neutralizing antibodies (NAbs) in the absence of drug interference. After washout, the participants may resume monthly treatment with DAC HYP 150 mg for an additional 3 years. All participants will be followed for 6 months after their last dose for safety monitoring. Additionally, two sub-studies will be performed: (1) an intensive serial PK sampling performed over the first and last dosing interval following DAC HYP doses administered at week 0 and at week 20, and (2) a therapeutic protein-drug interaction (TP-DI) sub-study, during which a probe drug cocktail will be administered at weeks 43 and 53 followed by serial probe-drug PK sampling up to 96 hours after probe-drug administration. A maximum of 20 participants will be enrolled in the TP-DI sub-study.
Interventions
DRUGMidazolam
5 mg
OTHERCaffeine
200 mg
DRUGS-warfarin
10 mg
OTHERVitamin K
10 mg
DRUGOmeprazole
40 mg
DRUGDextromethorphan
30 mg
BIOLOGICALBIIB019 (Daclizumab)
150 mg in 1 ml PFS
Sponsors
Biogen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have a confirmed diagnosis of RRMS according to McDonald criteria and previous cranial magnetic resonance imaging demonstrating lesion(s) consistent with MS * Must have a baseline Expanded Disability Status Scale (EDSS) between 0.0 and 5.0, inclusive * Must have had 1 or more clinical relapses within the previous 2 years * Women of child bearing potential must be willing to practice effective contraception during the study and 4 months after the last dose Key
Exclusion criteria
* Other chronic disease of the immune system, malignancies, acute urologic, pulmonary, gastrointestinal disease * Female subjects who are currently pregnant or breastfeeding Key Inclusion criteria for 3-Year Treatment Extension: To be eligible for participation in the 3-year treatment extension, participants must meet the following eligibility criteria at the time of reinitiation of DAC HYP: * Must have been compliant with the 205MS302 (NCT01462318) protocol during the initial 24-week treatment period and the 20-week washout period in the opinion of the Investigator * Must resume DAC HYP treatment ≤12 weeks after completion of the washout period (i.e., ≤12 weeks after their Week 44 visit). * Participants who are currently receiving an approved IFN ß preparation must discontinue interferon (IFN) ß treatment at the time of reinitiation of DAC HYP dosing (no washout is required). Key Inclusion criteria for the TP-DI Sub-study: To be eligible for participation in the TP-DI Sub-Study, subjects must meet the following eligibility criteria at the Screening Visit at Week 40: * Must have been compliant with the 205MS302 (NCT01462318) protocol during the initial 24-week treatment period and through Week 40 of the 20-week washout period in the opinion of the Investigator. * Must agree to resume DAC HYP treatment ≤12 weeks after completion of the washout period (i.e., ≤12 weeks after their Week 44 visit). * Must have normal liver function test results (total bilirubin ≤1.5 × upper limit of normal (ULN), alanine aminotransferase/aspartate aminotransferase ≤2 × ULN, and prothrombin time/partial thromboplastin time ≤1.2 × ULN). * Must have normal renal function as estimated creatinine clearance \>60 mL/min (Cockcroft-Gault formula). NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | Up to 44 weeks | Participants with post-baseline (PB) ADAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose). |
| Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | Up to 44 weeks | Participants with PB NAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose). |
| TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration | AUCinf of each of the following cytochrome P450 (CYP) isoenzyme substrates: midazolam (CYP3A), S-warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19). The AUC from zero to 12 hours (AUC0-12) was calculated for caffeine (CYP1A2). |
| TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio | Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and for 12 hours after probe-drug cocktail administration | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP | Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose | — |
| Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP | Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose | — |
| Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP | Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose | — |
| Intensive PK Sub-study: Cmax of DAC HYP | Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14 and 21 days post-dose | — |
| TP-DI Sub-study: CL/F of Each Probe Drug | Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration | CL/F of each of the following CYP isoenzyme substrates: midazolam (CYP3A), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19). |
| TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing | Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration) at 2 hours after probe drug cocktail administration | — |
| TP-DI Sub-study: Cmax of Each Probe Drug | Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration | Cmax of each of the following CYP isoenzyme substrates: midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19). |
| Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP | Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14 and 21 days post-dose | — |
| Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP | Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14, and 21 days post-dose | — |
| Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP | Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose | — |
Countries
Czechia, Hungary, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Main Study All participants received DAC HYP 150 mg SC injections every 4 weeks over an initial 24-week treatment period (for a total of 6 injections), followed by a 20-week washout period.
Those participants from the Main Study who enrolled in the Intensive PK sub-study underwent serial DAC HYP PK sampling over the first and the last dosing intervals (on Day 1 \[Week 0\] and again on Day 141 \[Week 20\], the last dosing visit). | 113 |
| TP-DI Sub-study In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, where the oral vitamin K was used prophylactically to counteract warfarin's anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase.
In Period 2, pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP. | 20 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Phase | Adverse Event | 0 | 0 | 22 |
| Extension Phase | Disease Progression | 0 | 0 | 1 |
| Extension Phase | Investigator Decision | 0 | 0 | 5 |
| Extension Phase | Lost to Follow-up | 0 | 0 | 1 |
| Extension Phase | Other | 0 | 0 | 1 |
| Extension Phase | Withdrawal by Subject | 0 | 0 | 15 |
| Main Study / TP-DI Study | Adverse Event | 4 | 0 | 0 |
| Main Study / TP-DI Study | Other | 2 | 0 | 0 |
| Main Study / TP-DI Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Main Study | TP-DI Sub-study | Total |
|---|---|---|---|
| Age, Customized 18 - 19 years | 0 participants | 1 participants | 1 participants |
| Age, Customized < 18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 20 - 29 years | 28 participants | 4 participants | 32 participants |
| Age, Customized 30 - 39 years | 40 participants | 7 participants | 47 participants |
| Age, Customized 40 - 49 years | 31 participants | 5 participants | 36 participants |
| Age, Customized 50 - 55 years | 14 participants | 3 participants | 17 participants |
| Age, Customized > 55 years | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 72 Participants | 13 Participants | 85 Participants |
| Sex: Female, Male Male | 41 Participants | 7 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 106 / 133 |
| serious Total, serious adverse events | 33 / 133 |
Outcome results
Primary
Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay
Participants with post-baseline (PB) ADAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose).
Time frame: Up to 44 weeks
Population: Immunogenicity evaluable population: all participants in the main study population who received at least 1 dose of DAC HYP and had at least 1 post-study baseline immunogenicity assessment; n=participants with an assessment during the given period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Main Study | Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | PB ADAbs through Week 44=negative; n=113 | 78 participants |
| Main Study | Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | PB ADAbs through Week 44=positive; n=113 | 35 participants |
| Main Study | Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | PB ADAbs in treatment period=negative; n=113 | 92 participants |
| Main Study | Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | PB ADAbs in treatment period=positive; n=113 | 21 participants |
| Main Study | Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | PB ADAbs in post-treatment period=negative; n=110 | 89 participants |
| Main Study | Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay | PB ADAbs in post-treatment period=positive; n=110 | 21 participants |
Primary
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
Participants with PB NAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose).
Time frame: Up to 44 weeks
Population: Immunogenicity evaluable population: all participants in the main study population who received at least 1 dose of DAC HYP and had at least 1 post-study baseline immunogenicity assessment; n=participants with an assessment during the given period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Main Study | Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | PB NAbs in treatment period=positive; n=113 | 4 participants |
| Main Study | Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | PB NAbs through Week 44=negative; n=113 | 105 participants |
| Main Study | Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | PB NAbs through Week 44=positive; n=113 | 8 participants |
| Main Study | Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | PB NAbs in treatment period=negative; n=113 | 109 participants |
| Main Study | Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | PB NAbs in post-treatment period=negative; n=110 | 104 participants |
| Main Study | Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay | PB NAbs in post-treatment period=positive; n=110 | 6 participants |
Primary
TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug
AUCinf of each of the following cytochrome P450 (CYP) isoenzyme substrates: midazolam (CYP3A), S-warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19). The AUC from zero to 12 hours (AUC0-12) was calculated for caffeine (CYP1A2).
Time frame: Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration
Population: TP-DI Sub-study population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter; n=participants with an evaluable assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Midazolam (Period 1) AUCinf; n=20 | 786.75 hr*ng/mL | Standard Deviation 328.794 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Midazolam+DAC HYP (Period 2) AUCinf; n=19 | 816.87 hr*ng/mL | Standard Deviation 403.958 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | S-warfarin (Period 1) AUCinf; n=17 | 19292.9 hr*ng/mL | Standard Deviation 5524.6 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | S-warfarin+DAC HYP (Period 2) AUCinf; n=18 | 19609.3 hr*ng/mL | Standard Deviation 4620.64 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Omeprazole (Period 1) AUCinf; n=18 | 2214.5 hr*ng/mL | Standard Deviation 2622.15 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Omeprazole+DAC HYP (Period 2) AUCinf; n=19 | 1770.0 hr*ng/mL | Standard Deviation 1673.8 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Caffeine (Period 1) AUC0-12; n=20 | 35742.4 hr*ng/mL | Standard Deviation 13942.71 |
| Main Study | TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug | Caffeine+DAC HYP (Period 2) AUC0-12; n=20 | 37449.2 hr*ng/mL | Standard Deviation 14367.04 |
Comparison: Pairwise comparison: midazolam. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.894, 1.153]
Comparison: Pairwise comparison: S-warfarin. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.951, 1.063]
Comparison: Pairwise comparison: omeprazole. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.88, 1.127]
Comparison: Pairwise comparison: caffeine. Based on linear mixed model with fixed effect for treatment and random effect for participants. Excludes participants with high predose concentration (\>5% of maximum observed concentration \[Cmax\]).90% CI: [0.93, 1.145]
Primary
TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio
Time frame: Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and for 12 hours after probe-drug cocktail administration
Population: TP-DI Sub-study population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter; n=participants with an evaluable assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio | Dextromethorphan (Period 1) | 0.42468 ratio | Standard Deviation 1.258565 |
| Main Study | TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio | Dextromethorphan+DAC HYP (Period 2) | 0.48939 ratio | Standard Deviation 1.813077 |
Comparison: Pairwise comparison: dextromethorphan. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.764, 1.342]
Secondary
Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP
Time frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study | Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP | 0.27 L/day | Standard Deviation 0.108 |
Secondary
Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP
Time frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study | Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP | 8.21 Liters | Standard Deviation 2.81 |
Secondary
Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP
Time frame: Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14, and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter; n=participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP | Week 20; n=24 | 638.10 day*mcg/mL | Standard Deviation 256.076 |
| Main Study | Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP | Week 0 (Day 1); n=25 | 255.25 day*mcg/mL | Standard Deviation 88.569 |
Secondary
Intensive PK Sub-study: Cmax of DAC HYP
Time frame: Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter; n=participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | Intensive PK Sub-study: Cmax of DAC HYP | Day 1 (Week 0); n=25 | 12.63 mcg/mL | Standard Deviation 4.639 |
| Main Study | Intensive PK Sub-study: Cmax of DAC HYP | Day 141 (Week 20); n=24 | 29.07 mcg/mL | Standard Deviation 10.812 |
Secondary
Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP
Time frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study | Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP | 21.92 day | Standard Deviation 5.473 |
Secondary
Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP
Time frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study | Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP | 14.93 mcg/mL | Standard Deviation 6.327 |
Secondary
Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP
Time frame: Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Population: PK population: all participants who participated in the Intensive PK sub-study and had enough post-study baseline measurable drug concentrations to calculate the parameter; n=participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP | Day 1 (Week 0); n=25 | 9.31 day | Standard Deviation 6.368 |
| Main Study | Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP | Day 141 (Week 20); n=24 | 6.41 day | Standard Deviation 3.273 |
Secondary
TP-DI Sub-study: CL/F of Each Probe Drug
CL/F of each of the following CYP isoenzyme substrates: midazolam (CYP3A), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19).
Time frame: Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration
Population: TP-DI Sub-study population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter; n=participants with an evaluable assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | TP-DI Sub-study: CL/F of Each Probe Drug | Midazolam (Period 1); n=20 | 7625.7 mL/hr | Standard Deviation 3849.92 |
| Main Study | TP-DI Sub-study: CL/F of Each Probe Drug | Midazolam+DAC HYP (Period 2); n=19 | 7298.6 mL/hr | Standard Deviation 2844.22 |
| Main Study | TP-DI Sub-study: CL/F of Each Probe Drug | S-Warfarin (Period 1); n=17 | 565.86 mL/hr | Standard Deviation 184.129 |
| Main Study | TP-DI Sub-study: CL/F of Each Probe Drug | S-Warfarin+DAC HYP (Period 2); n=18 | 541.46 mL/hr | Standard Deviation 150.298 |
| Main Study | TP-DI Sub-study: CL/F of Each Probe Drug | Omeprazole (Period 1); n=18 | 41612.4 mL/hr | Standard Deviation 30003.48 |
| Main Study | TP-DI Sub-study: CL/F of Each Probe Drug | Omeprazole+DAC HYP (Period 2); n=19 | 41772.4 mL/hr | Standard Deviation 29810.3 |
Secondary
TP-DI Sub-study: Cmax of Each Probe Drug
Cmax of each of the following CYP isoenzyme substrates: midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19).
Time frame: Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration
Population: TP-DI Substudy population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter; n=participants with an evaluable assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | Midazolam (Period 1); n=20 | 271.05 ng/mL | Standard Deviation 106.925 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | Midazolam+DAC HYP (Period 2); n=19 | 311.21 ng/mL | Standard Deviation 147.912 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | Caffeine (Period 1); n=20 | 4965.0 ng/mL | Standard Deviation 1312.69 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | Caffeine+DAC HYP (Period 2); n=19 | 5399.5 ng/mL | Standard Deviation 1364.05 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | S-Warfarin (Period 1); n=20 | 635.65 ng/mL | Standard Deviation 140.291 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | S-Warfarin+DAC HYP (Period 2); n=19 | 649.74 ng/mL | Standard Deviation 155.977 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | Omeprazole (Period 1); n=19 | 776.95 ng/mL | Standard Deviation 513.344 |
| Main Study | TP-DI Sub-study: Cmax of Each Probe Drug | Omeprazole+DAC HYP (Period 2); n=19 | 771.16 ng/mL | Standard Deviation 540.331 |
Comparison: Pairwise comparison: midazolam. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.912, 1.276]
Comparison: Pairwise comparison: S-warfarin. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.952, 1.075]
Comparison: Pairwise comparison: omeprazole. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.804, 1.392]
Comparison: Pairwise comparison: caffeine. Based on linear mixed model with fixed effect for treatment and random effect for participants. Excludes participants with high predose concentration (\>5% of Cmax).90% CI: [1.005, 1.238]
Secondary
TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing
Time frame: Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration) at 2 hours after probe drug cocktail administration
Population: TP-DI Sub-study population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study | TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing | Omeprazole (Period 1) | 2.673 ratio | Standard Deviation 4.7878 |
| Main Study | TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing | Omeprazole+ DAC HYP (Period 2) | 1.028 ratio | Standard Deviation 0.9297 |
Comparison: Pairwise comparison: omeprazole. Based on linear mixed model with fixed effect for treatment and random effect for participants.90% CI: [0.697, 1.105]