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An Open-Label Immunogenicity and Pharmacokinetics Study of Daclizumab High Yield Process Prefilled Syringe in Relapsing Remitting Multiple Sclerosis (OBSERVE)

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ClinicalTrials.gov Identifier: NCT01462318
Recruitment Status : Completed
First Posted : October 31, 2011
Results First Posted : March 14, 2017
Last Update Posted : March 14, 2017
Sponsor:
Information provided by (Responsible Party):
Biogen

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Other
Condition Relapsing-Remitting Multiple Sclerosis
Interventions Drug: Midazolam
Other: Caffeine
Drug: S-warfarin
Other: Vitamin K
Drug: Omeprazole
Drug: Dextromethorphan
Biological: BIIB019 (Daclizumab)
Enrollment 133
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Main Study Therapeutic Protein-Drug Interaction (TP-DI)Sub-study Extension Phase
Hide Arm/Group Description

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).

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.

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.
Period Title: Main Study / TP-DI Study
Started 113 20 0
Enrolled in Intensive PK Substudy 26 0 0
Completed 105 20 0
Not Completed 8 0 0
Reason Not Completed
Not Specified             2             0             0
Withdrawal by Subject             2             0             0
Adverse Event             4             0             0
Period Title: Extension Phase
Started 0 [1] 0 [2] 115 [3]
Completed 0 0 70
Not Completed 0 0 45
Reason Not Completed
Lost to Follow-up             0             0             1
Not Specified             0             0             1
Disease Progression             0             0             1
Withdrawal by Subject             0             0             15
Investigator Decision             0             0             5
Adverse Event             0             0             22
[1]
95 participants from the Main Study entered the Extension Phase
[2]
20 participants from the TP-DI Study entered the Extension Phase
[3]
10 participants from the Main Study did not enter the Extension Phase.
Arm/Group Title Main Study TP-DI Sub-study Total
Hide Arm/Group Description

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).

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 of all reporting groups
Overall Number of Baseline Participants 113 20 133
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 113 participants 20 participants 133 participants
< 18 years 0 0 0
18 - 19 years 0 1 1
20 - 29 years 28 4 32
30 - 39 years 40 7 47
40 - 49 years 31 5 36
50 - 55 years 14 3 17
> 55 years 0 0 0
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 113 participants 20 participants 133 participants
Female
72
  63.7%
13
  65.0%
85
  63.9%
Male
41
  36.3%
7
  35.0%
48
  36.1%
1.Primary Outcome
Title Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay
Hide Description 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
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Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 113
Measure Type: Number
Unit of Measure: participants
PB ADAbs through Week 44=negative; n=113 78
PB ADAbs through Week 44=positive; n=113 35
PB ADAbs in treatment period=negative; n=113 92
PB ADAbs in treatment period=positive; n=113 21
PB ADAbs in post-treatment period=negative; n=110 89
PB ADAbs in post-treatment period=positive; n=110 21
2.Primary Outcome
Title Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 113
Measure Type: Number
Unit of Measure: participants
PB NAbs through Week 44=negative; n=113 105
PB NAbs through Week 44=positive; n=113 8
PB NAbs in treatment period=negative; n=113 109
PB NAbs in treatment period=positive; n=113 4
PB NAbs in post-treatment period=negative; n=110 104
PB NAbs in post-treatment period=positive; n=110 6
3.Primary Outcome
Title TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title TP-DI Sub-study
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: hr*ng/mL
Midazolam (Period 1) AUCinf; n=20 786.75  (328.794)
Midazolam+DAC HYP (Period 2) AUCinf; n=19 816.87  (403.958)
S-warfarin (Period 1) AUCinf; n=17 19292.9  (5524.60)
S-warfarin+DAC HYP (Period 2) AUCinf; n=18 19609.3  (4620.64)
Omeprazole (Period 1) AUCinf; n=18 2214.5  (2622.15)
Omeprazole+DAC HYP (Period 2) AUCinf; n=19 1770.0  (1673.80)
Caffeine (Period 1) AUC0-12; n=20 35742.4  (13942.71)
Caffeine+DAC HYP (Period 2) AUC0-12; n=20 37449.2  (14367.04)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: midazolam. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.015
Confidence Interval (2-Sided) 90%
0.894 to 1.153
Estimation Comments test/reference = midazolam+DAC HYP/midazolam
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: S-warfarin. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.005
Confidence Interval (2-Sided) 90%
0.951 to 1.063
Estimation Comments test/reference = S-warfarin+DAC HYP/S-warfarin
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: omeprazole. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 0.996
Confidence Interval (2-Sided) 90%
0.880 to 1.127
Estimation Comments test/reference = omeprazole+DAC HYP/omeprazole
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments 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]).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.032
Confidence Interval (2-Sided) 90%
0.930 to 1.145
Estimation Comments test/reference = caffeine+DAC HYP/caffeine
4.Primary Outcome
Title TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title TP-DI Sub-study
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: ratio
Dextromethorphan (Period 1) 0.42468  (1.258565)
Dextromethorphan+DAC HYP (Period 2) 0.48939  (1.813077)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: dextromethorphan. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.012
Confidence Interval (2-Sided) 90%
0.764 to 1.342
Estimation Comments test/reference = dextromethorphan+DAC HYP/dextromethorphan
5.Secondary Outcome
Title Intensive PK Sub-study: Cmax of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 25
Mean (Standard Deviation)
Unit of Measure: mcg/mL
Day 1 (Week 0); n=25 12.63  (4.639)
Day 141 (Week 20); n=24 29.07  (10.812)
6.Secondary Outcome
Title Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 25
Mean (Standard Deviation)
Unit of Measure: day
Day 1 (Week 0); n=25 9.31  (6.368)
Day 141 (Week 20); n=24 6.41  (3.273)
7.Secondary Outcome
Title Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 25
Mean (Standard Deviation)
Unit of Measure: day*mcg/mL
Week 0 (Day 1); n=25 255.25  (88.569)
Week 20; n=24 638.10  (256.076)
8.Secondary Outcome
Title Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 24
Mean (Standard Deviation)
Unit of Measure: mcg/mL
14.93  (6.327)
9.Secondary Outcome
Title Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 24
Mean (Standard Deviation)
Unit of Measure: Liters
8.21  (2.810)
10.Secondary Outcome
Title Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 24
Mean (Standard Deviation)
Unit of Measure: day
21.92  (5.473)
11.Secondary Outcome
Title Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Main Study
Hide Arm/Group Description:

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).

Overall Number of Participants Analyzed 24
Mean (Standard Deviation)
Unit of Measure: L/day
0.27  (0.108)
12.Secondary Outcome
Title TP-DI Sub-study: Cmax of Each Probe Drug
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title TP-DI Sub-study
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: ng/mL
Midazolam (Period 1); n=20 271.05  (106.925)
Midazolam+DAC HYP (Period 2); n=19 311.21  (147.912)
Caffeine (Period 1); n=20 4965.0  (1312.69)
Caffeine+DAC HYP (Period 2); n=19 5399.5  (1364.05)
S-Warfarin (Period 1); n=20 635.65  (140.291)
S-Warfarin+DAC HYP (Period 2); n=19 649.74  (155.977)
Omeprazole (Period 1); n=19 776.95  (513.344)
Omeprazole+DAC HYP (Period 2); n=19 771.16  (540.331)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: midazolam. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.079
Confidence Interval (2-Sided) 90%
0.912 to 1.276
Estimation Comments test/reference = midazolam+DAC HYP/midazolam
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: S-warfarin. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.012
Confidence Interval (2-Sided) 90%
0.952 to 1.075
Estimation Comments test/reference = S-warfarin+DAC HYP/S-warfarin
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: omeprazole. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.058
Confidence Interval (2-Sided) 90%
0.804 to 1.392
Estimation Comments test/reference = omeprazole+DAC HYP/omeprazole
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments 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).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 1.116
Confidence Interval (2-Sided) 90%
1.005 to 1.238
Estimation Comments test/reference = caffeine+DAC HYP/caffeine
13.Secondary Outcome
Title TP-DI Sub-study: CL/F of Each Probe Drug
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title TP-DI Sub-study
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: mL/hr
Midazolam (Period 1); n=20 7625.7  (3849.92)
Midazolam+DAC HYP (Period 2); n=19 7298.6  (2844.22)
S-Warfarin (Period 1); n=17 565.86  (184.129)
S-Warfarin+DAC HYP (Period 2); n=18 541.46  (150.298)
Omeprazole (Period 1); n=18 41612.4  (30003.48)
Omeprazole+DAC HYP (Period 2); n=19 41772.4  (29810.30)
14.Secondary Outcome
Title TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title TP-DI Sub-study
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 17
Mean (Standard Deviation)
Unit of Measure: ratio
Omeprazole (Period 1) 2.673  (4.7878)
Omeprazole+ DAC HYP (Period 2) 1.028  (0.9297)
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Statistical Analysis Overview Comparison Group Selection TP-DI Sub-study
Comments Pairwise comparison: omeprazole. Based on linear mixed model with fixed effect for treatment and random effect for participants.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio
Estimated Value 0.878
Confidence Interval (2-Sided) 90%
0.697 to 1.105
Estimation Comments test/reference = omeprazole+DAC HYP/omeprazole
Time Frame From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title DAC HYP 150 mg
Hide Arm/Group Description 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.
All-Cause Mortality
DAC HYP 150 mg
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
DAC HYP 150 mg
Affected / at Risk (%)
Total   33/133 (24.81%) 
Blood and lymphatic system disorders   
Haemolytic anaemia  1  1/133 (0.75%) 
Lymphadenopathy  1  1/133 (0.75%) 
Neutropenia  1  1/133 (0.75%) 
Hepatobiliary disorders   
Autoimmune hepatitis  1  1/133 (0.75%) 
Immune system disorders   
Sarcoidosis  1  1/133 (0.75%) 
Infections and infestations   
Furuncle  1  1/133 (0.75%) 
Hepatitis E  1  1/133 (0.75%) 
Infection  1  1/133 (0.75%) 
Pharyngitis  1  1/133 (0.75%) 
Pneumonia  1  2/133 (1.50%) 
Streptococcal urinary tract infection  1  1/133 (0.75%) 
Injury, poisoning and procedural complications   
Toxicity to various agents  1  1/133 (0.75%) 
Investigations   
Hepatic enzyme increased  1  1/133 (0.75%) 
Metabolism and nutrition disorders   
Obesity  1  1/133 (0.75%) 
Musculoskeletal and connective tissue disorders   
Back pain  1  1/133 (0.75%) 
Lumbar spinal stenosis  1  1/133 (0.75%) 
Muscular weakness  1  1/133 (0.75%) 
Nervous system disorders   
Multiple sclerosis relapse  1  10/133 (7.52%) 
Pregnancy, puerperium and perinatal conditions   
Abortion missed  1  1/133 (0.75%) 
Psychiatric disorders   
Depression  1  1/133 (0.75%) 
Suicide attempt  1  1/133 (0.75%) 
Renal and urinary disorders   
Hydronephrosis  1  1/133 (0.75%) 
Reproductive system and breast disorders   
Endometrial hypertrophy  1  1/133 (0.75%) 
Endometriosis  1  1/133 (0.75%) 
Ovarian cyst  1  1/133 (0.75%) 
Postmenopausal haemorrhage  1  2/133 (1.50%) 
Skin and subcutaneous tissue disorders   
Cutaneous sarcoidosis  1  1/133 (0.75%) 
Erythema nodosum  1  1/133 (0.75%) 
Rash  1  1/133 (0.75%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
DAC HYP 150 mg
Affected / at Risk (%)
Total   106/133 (79.70%) 
Blood and lymphatic system disorders   
Lymphadenopathy  1  8/133 (6.02%) 
Endocrine disorders   
Hypothyroidism  1  7/133 (5.26%) 
Gastrointestinal disorders   
Diarrhoea  1  9/133 (6.77%) 
General disorders   
Fatigue  1  12/133 (9.02%) 
Influenza like illness  1  13/133 (9.77%) 
Pyrexia  1  12/133 (9.02%) 
Infections and infestations   
Influenza  1  8/133 (6.02%) 
Nasopharyngitis  1  19/133 (14.29%) 
Oral herpes  1  7/133 (5.26%) 
Pharyngitis  1  15/133 (11.28%) 
Sinusitis  1  11/133 (8.27%) 
Upper respiratory tract infection  1  33/133 (24.81%) 
Urinary tract infection  1  30/133 (22.56%) 
Investigations   
Alanine aminotransferase increased  1  9/133 (6.77%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  10/133 (7.52%) 
Back pain  1  14/133 (10.53%) 
Muscle spasms  1  7/133 (5.26%) 
Muscular weakness  1  10/133 (7.52%) 
Pain in extremity  1  9/133 (6.77%) 
Spinal pain  1  7/133 (5.26%) 
Nervous system disorders   
Headache  1  21/133 (15.79%) 
Hypoaesthesia  1  9/133 (6.77%) 
Migraine  1  7/133 (5.26%) 
Multiple sclerosis relapse  1  58/133 (43.61%) 
Muscle spasticity  1  7/133 (5.26%) 
Psychiatric disorders   
Anxiety  1  11/133 (8.27%) 
Depression  1  9/133 (6.77%) 
Insomnia  1  9/133 (6.77%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
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Name/Title: Biogen Study Medical Director
Organization: Biogen
EMail: clinicaltrials@biogen.com
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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT01462318     History of Changes
Other Study ID Numbers: 205MS302
2010-023856-97 ( EudraCT Number )
First Submitted: July 14, 2011
First Posted: October 31, 2011
Results First Submitted: January 23, 2017
Results First Posted: March 14, 2017
Last Update Posted: March 14, 2017