Trial Outcomes & Findings for An Open-Label Immunogenicity and Pharmacokinetics Study of Daclizumab High Yield Process Prefilled Syringe in Relapsing Remitting Multiple Sclerosis (NCT NCT01462318)
NCT ID: NCT01462318
Last Updated: 2017-03-14
Results Overview
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).
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
133 participants
Primary outcome timeframe
Up to 44 weeks
Results posted on
2017-03-14
Participant Flow
Participant milestones
| Measure |
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).
|
Therapeutic Protein-Drug Interaction (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.
|
Extension Phase
After completion of the washout period from the Main Study or the TP-DI sub-study, eligible participants had the option to resume monthly open-label treatment with DAC HYP 150 mg in the extension phase of the study for up to 3 additional years.
|
|---|---|---|---|
|
Main Study / TP-DI Study
STARTED
|
113
|
20
|
0
|
|
Main Study / TP-DI Study
Enrolled in Intensive PK Substudy
|
26
|
0
|
0
|
|
Main Study / TP-DI Study
COMPLETED
|
105
|
20
|
0
|
|
Main Study / TP-DI Study
NOT COMPLETED
|
8
|
0
|
0
|
|
Extension Phase
STARTED
|
0
|
0
|
115
|
|
Extension Phase
COMPLETED
|
0
|
0
|
70
|
|
Extension Phase
NOT COMPLETED
|
0
|
0
|
45
|
Reasons for withdrawal
| Measure |
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).
|
Therapeutic Protein-Drug Interaction (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.
|
Extension Phase
After completion of the washout period from the Main Study or the TP-DI sub-study, eligible participants had the option to resume monthly open-label treatment with DAC HYP 150 mg in the extension phase of the study for up to 3 additional years.
|
|---|---|---|---|
|
Main Study / TP-DI Study
Other
|
2
|
0
|
0
|
|
Main Study / TP-DI Study
Withdrawal by Subject
|
2
|
0
|
0
|
|
Main Study / TP-DI Study
Adverse Event
|
4
|
0
|
0
|
|
Extension Phase
Lost to Follow-up
|
0
|
0
|
1
|
|
Extension Phase
Other
|
0
|
0
|
1
|
|
Extension Phase
Disease Progression
|
0
|
0
|
1
|
|
Extension Phase
Withdrawal by Subject
|
0
|
0
|
15
|
|
Extension Phase
Investigator Decision
|
0
|
0
|
5
|
|
Extension Phase
Adverse Event
|
0
|
0
|
22
|
Baseline Characteristics
An Open-Label Immunogenicity and Pharmacokinetics Study of Daclizumab High Yield Process Prefilled Syringe in Relapsing Remitting Multiple Sclerosis
Baseline characteristics by cohort
| Measure |
Main Study
n=113 Participants
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).
|
TP-DI Sub-study
n=20 Participants
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.
|
Total
n=133 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Customized
< 18 years
|
0 participants
n=5 Participants
|
0 participants
n=7 Participants
|
0 participants
n=5 Participants
|
|
Age, Customized
18 - 19 years
|
0 participants
n=5 Participants
|
1 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Age, Customized
20 - 29 years
|
28 participants
n=5 Participants
|
4 participants
n=7 Participants
|
32 participants
n=5 Participants
|
|
Age, Customized
30 - 39 years
|
40 participants
n=5 Participants
|
7 participants
n=7 Participants
|
47 participants
n=5 Participants
|
|
Age, Customized
40 - 49 years
|
31 participants
n=5 Participants
|
5 participants
n=7 Participants
|
36 participants
n=5 Participants
|
|
Age, Customized
50 - 55 years
|
14 participants
n=5 Participants
|
3 participants
n=7 Participants
|
17 participants
n=5 Participants
|
|
Age, Customized
> 55 years
|
0 participants
n=5 Participants
|
0 participants
n=7 Participants
|
0 participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
72 Participants
n=5 Participants
|
13 Participants
n=7 Participants
|
85 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
41 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
48 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Up to 44 weeksPopulation: 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.
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).
Outcome measures
| Measure |
Main Study
n=113 Participants
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).
|
|---|---|
|
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
|
|
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
|
|
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
|
|
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
|
|
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
|
|
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
|
PRIMARY outcome
Timeframe: Up to 44 weeksPopulation: 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.
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).
Outcome measures
| Measure |
Main Study
n=113 Participants
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).
|
|---|---|
|
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
PB NAbs through Week 44=negative; n=113
|
105 participants
|
|
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
PB NAbs in post-treatment period=negative; n=110
|
104 participants
|
|
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
PB NAbs in post-treatment period=positive; n=110
|
6 participants
|
|
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
PB NAbs through Week 44=positive; n=113
|
8 participants
|
|
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
PB NAbs in treatment period=negative; n=113
|
109 participants
|
|
Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
PB NAbs in treatment period=positive; n=113
|
4 participants
|
PRIMARY outcome
Timeframe: 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 administrationPopulation: 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.
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).
Outcome measures
| Measure |
Main Study
n=20 Participants
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).
|
|---|---|
|
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
|
|
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
|
|
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 5524.60
|
|
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
|
|
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
|
|
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 1673.80
|
|
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
|
|
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
|
PRIMARY outcome
Timeframe: 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 administrationPopulation: 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.
Outcome measures
| Measure |
Main Study
n=20 Participants
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).
|
|---|---|
|
TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio
Dextromethorphan (Period 1)
|
0.42468 ratio
Standard Deviation 1.258565
|
|
TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio
Dextromethorphan+DAC HYP (Period 2)
|
0.48939 ratio
Standard Deviation 1.813077
|
SECONDARY outcome
Timeframe: 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-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=25 Participants
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).
|
|---|---|
|
Intensive PK Sub-study: Cmax of DAC HYP
Day 1 (Week 0); n=25
|
12.63 mcg/mL
Standard Deviation 4.639
|
|
Intensive PK Sub-study: Cmax of DAC HYP
Day 141 (Week 20); n=24
|
29.07 mcg/mL
Standard Deviation 10.812
|
SECONDARY outcome
Timeframe: 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-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=25 Participants
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).
|
|---|---|
|
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
|
|
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 outcome
Timeframe: 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-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=25 Participants
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).
|
|---|---|
|
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
|
|
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
|
SECONDARY outcome
Timeframe: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=24 Participants
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).
|
|---|---|
|
Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP
|
14.93 mcg/mL
Standard Deviation 6.327
|
SECONDARY outcome
Timeframe: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=24 Participants
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).
|
|---|---|
|
Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP
|
8.21 Liters
Standard Deviation 2.810
|
SECONDARY outcome
Timeframe: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=24 Participants
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).
|
|---|---|
|
Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP
|
21.92 day
Standard Deviation 5.473
|
SECONDARY outcome
Timeframe: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dosePopulation: 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.
Outcome measures
| Measure |
Main Study
n=24 Participants
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).
|
|---|---|
|
Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP
|
0.27 L/day
Standard Deviation 0.108
|
SECONDARY outcome
Timeframe: 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 administrationPopulation: 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.
Cmax of each of the following CYP isoenzyme substrates: midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19).
Outcome measures
| Measure |
Main Study
n=20 Participants
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).
|
|---|---|
|
TP-DI Sub-study: Cmax of Each Probe Drug
Midazolam (Period 1); n=20
|
271.05 ng/mL
Standard Deviation 106.925
|
|
TP-DI Sub-study: Cmax of Each Probe Drug
Midazolam+DAC HYP (Period 2); n=19
|
311.21 ng/mL
Standard Deviation 147.912
|
|
TP-DI Sub-study: Cmax of Each Probe Drug
Caffeine (Period 1); n=20
|
4965.0 ng/mL
Standard Deviation 1312.69
|
|
TP-DI Sub-study: Cmax of Each Probe Drug
Caffeine+DAC HYP (Period 2); n=19
|
5399.5 ng/mL
Standard Deviation 1364.05
|
|
TP-DI Sub-study: Cmax of Each Probe Drug
S-Warfarin (Period 1); n=20
|
635.65 ng/mL
Standard Deviation 140.291
|
|
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
|
|
TP-DI Sub-study: Cmax of Each Probe Drug
Omeprazole (Period 1); n=19
|
776.95 ng/mL
Standard Deviation 513.344
|
|
TP-DI Sub-study: Cmax of Each Probe Drug
Omeprazole+DAC HYP (Period 2); n=19
|
771.16 ng/mL
Standard Deviation 540.331
|
SECONDARY outcome
Timeframe: 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 administrationPopulation: 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.
CL/F of each of the following CYP isoenzyme substrates: midazolam (CYP3A), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19).
Outcome measures
| Measure |
Main Study
n=20 Participants
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).
|
|---|---|
|
TP-DI Sub-study: CL/F of Each Probe Drug
Midazolam (Period 1); n=20
|
7625.7 mL/hr
Standard Deviation 3849.92
|
|
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
|
|
TP-DI Sub-study: CL/F of Each Probe Drug
S-Warfarin (Period 1); n=17
|
565.86 mL/hr
Standard Deviation 184.129
|
|
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
|
|
TP-DI Sub-study: CL/F of Each Probe Drug
Omeprazole (Period 1); n=18
|
41612.4 mL/hr
Standard Deviation 30003.48
|
|
TP-DI Sub-study: CL/F of Each Probe Drug
Omeprazole+DAC HYP (Period 2); n=19
|
41772.4 mL/hr
Standard Deviation 29810.30
|
SECONDARY outcome
Timeframe: 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 administrationPopulation: TP-DI Sub-study population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter.
Outcome measures
| Measure |
Main Study
n=17 Participants
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).
|
|---|---|
|
TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing
Omeprazole (Period 1)
|
2.673 ratio
Standard Deviation 4.7878
|
|
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
|
Adverse Events
DAC HYP 150 mg
Serious events: 33 serious events
Other events: 106 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
DAC HYP 150 mg
n=133 participants at risk
DAC HYP 150 mg by SC injection using the PFS every 4 weeks for24 weeks followed by a 20-week washout period. After completion of the washout period, participants could resume monthly DAC HYP 150 mg using the PFS for up to 3 additional years. Participants in the TP-DI sub-study received s probe-drug cocktail administration at Weeks 43 and 53. The probe-drug cocktail consisted of midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg. The oral vitamin K was used to counteract warfarin's anticoagulant effect prophylactically.
|
|---|---|
|
Blood and lymphatic system disorders
Haemolytic anaemia
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Blood and lymphatic system disorders
Lymphadenopathy
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Blood and lymphatic system disorders
Neutropenia
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Hepatobiliary disorders
Autoimmune hepatitis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Immune system disorders
Sarcoidosis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Furuncle
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Hepatitis E
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Infection
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Pharyngitis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Pneumonia
|
1.5%
2/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Streptococcal urinary tract infection
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Injury, poisoning and procedural complications
Toxicity to various agents
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Investigations
Hepatic enzyme increased
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Metabolism and nutrition disorders
Obesity
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Muscular weakness
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Nervous system disorders
Multiple sclerosis relapse
|
7.5%
10/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Pregnancy, puerperium and perinatal conditions
Abortion missed
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Psychiatric disorders
Depression
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Psychiatric disorders
Suicide attempt
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Renal and urinary disorders
Hydronephrosis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Reproductive system and breast disorders
Endometrial hypertrophy
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Reproductive system and breast disorders
Endometriosis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Reproductive system and breast disorders
Ovarian cyst
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Reproductive system and breast disorders
Postmenopausal haemorrhage
|
1.5%
2/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Skin and subcutaneous tissue disorders
Cutaneous sarcoidosis
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Skin and subcutaneous tissue disorders
Erythema nodosum
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.75%
1/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
Other adverse events
| Measure |
DAC HYP 150 mg
n=133 participants at risk
DAC HYP 150 mg by SC injection using the PFS every 4 weeks for24 weeks followed by a 20-week washout period. After completion of the washout period, participants could resume monthly DAC HYP 150 mg using the PFS for up to 3 additional years. Participants in the TP-DI sub-study received s probe-drug cocktail administration at Weeks 43 and 53. The probe-drug cocktail consisted of midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg. The oral vitamin K was used to counteract warfarin's anticoagulant effect prophylactically.
|
|---|---|
|
Blood and lymphatic system disorders
Lymphadenopathy
|
6.0%
8/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Endocrine disorders
Hypothyroidism
|
5.3%
7/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Gastrointestinal disorders
Diarrhoea
|
6.8%
9/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
General disorders
Fatigue
|
9.0%
12/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
General disorders
Influenza like illness
|
9.8%
13/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
General disorders
Pyrexia
|
9.0%
12/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Influenza
|
6.0%
8/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Nasopharyngitis
|
14.3%
19/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Oral herpes
|
5.3%
7/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Pharyngitis
|
11.3%
15/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Sinusitis
|
8.3%
11/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Upper respiratory tract infection
|
24.8%
33/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Infections and infestations
Urinary tract infection
|
22.6%
30/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Investigations
Alanine aminotransferase increased
|
6.8%
9/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
7.5%
10/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
10.5%
14/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Muscle spasms
|
5.3%
7/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Muscular weakness
|
7.5%
10/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
6.8%
9/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Musculoskeletal and connective tissue disorders
Spinal pain
|
5.3%
7/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Nervous system disorders
Headache
|
15.8%
21/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Nervous system disorders
Hypoaesthesia
|
6.8%
9/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Nervous system disorders
Migraine
|
5.3%
7/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Nervous system disorders
Multiple sclerosis relapse
|
43.6%
58/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Nervous system disorders
Muscle spasticity
|
5.3%
7/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Psychiatric disorders
Anxiety
|
8.3%
11/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Psychiatric disorders
Depression
|
6.8%
9/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
|
Psychiatric disorders
Insomnia
|
6.8%
9/133 • From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
- Publication restrictions are in place
Restriction type: OTHER