An Open-Label Immunogenicity and Pharmacokinetics Study o... | NCT01462318

ID	Type	Description	Link
2010-023856-97	EudraCT Number

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
DAC HYP	Experimental	DAC HYP 150 mg by a subcutaneous (SC) injection using the pre-filled syringe (PFS) every 4 weeks for 24 weeks followed by a 20-week washout period. After completion of the washout period, participants may resume monthly DAC HYP 150 mg using the PFS for up to 3 additional years. Participants in the TP-DI sub-study will receive probe-drug cocktail administration at Weeks 43 and 53. The probe-drug cocktail consists of oral 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 is used to counteract warfarin's anticoagula nt effect prophylactically.	Drug: Midazolam Other: Caffeine Drug: S-warfarin Other: Vitamin K Drug: Omeprazole Drug: Dextromethorphan Biological: BIIB019 (Daclizumab)

Name	Type	Description	Arm Group Labels	Other Names
Midazolam	Drug	5 mg	DAC HYP
Caffeine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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).	Up to 44 weeks
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).	Up to 44 weeks
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).	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
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 Outcomes

Measure	Description	Time Frame
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
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

Eligibility Module

Eligibility 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/Exclusion criteria may apply.

Name	Affiliation	Role
Medical Director	Biogen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Centennial	Colorado	80112	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
27411694	Derived	Gold R, Stefoski D, Selmaj K, Havrdova E, Hurst C, Holman J, Tornesi B, Akella S, McCroskery P. Pregnancy Experience: Nonclinical Studies and Pregnancy Outcomes in the Daclizumab Clinical Study Program. Neurol Ther. 2016 Dec;5(2):169-182. doi: 10.1007/s40120-016-0048-2. Epub 2016 Jul 13.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	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).
BG001	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.
BG002	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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).

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.

Posted

Number

participants

Up to 44 weeks

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000113

Title

Denominators

Categories

PB ADAbs through Week 44=negative; n=113

Title	Measurements
	OG00078

PB ADAbs through Week 44=positive; n=113

Title	Measurements
	OG00035

PB ADAbs in treatment period=negative; n=113

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).

Posted

Number

participants

Up to 44 weeks

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

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).

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.

Posted

Mean

Standard Deviation

hr*ng/mL

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

ID	Title	Description
OG000	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.

Units	Counts

Primary

TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio

Posted

Mean

Standard Deviation

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

ID	Title	Description
OG000	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.

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Cmax of DAC HYP

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.

Posted

Mean

Standard Deviation

mcg/mL

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP

Posted

Mean

Standard Deviation

day

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP

Posted

Mean

Standard Deviation

day*mcg/mL

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP

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.

Posted

Mean

Standard Deviation

mcg/mL

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP

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.

Posted

Mean

Standard Deviation

Liters

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP

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.

Posted

Mean

Standard Deviation

day

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

Secondary

Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP

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.

Posted

Mean

Standard Deviation

L/day

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

ID	Title	Description
OG000	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).

Units	Counts
Participants	OG000

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).

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.

Posted

Mean

Standard Deviation

ng/mL

ID	Title	Description
OG000	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.

Units	Counts
Participants

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).

Posted

Mean

Standard Deviation

mL/hr

ID	Title	Description
OG000	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.

Units	Counts
Participants

Secondary

TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing

TP-DI Sub-study population: all participants in the TP-DI substudy who had enough post-baseline measurable drug concentrations to calculate the parameter.

Posted

Mean

Standard Deviation

ratio

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

ID	Title	Description
OG000	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.

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	DAC HYP 150 mg	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.			33	133	106	133

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Haemolytic anaemia	Blood and lymphatic system disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Autoimmune hepatitis	Hepatobiliary disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Sarcoidosis	Immune system disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Furuncle	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Hepatitis E	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Pharyngitis	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Pneumonia	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0002 affected133 at risk
Streptococcal urinary tract infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Toxicity to various agents	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Hepatic enzyme increased	Investigations	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Obesity	Metabolism and nutrition disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Lumbar spinal stenosis	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Multiple sclerosis relapse	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG00010 affected133 at risk
Abortion missed	Pregnancy, puerperium and perinatal conditions	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Depression	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Suicide attempt	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Hydronephrosis	Renal and urinary disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Endometrial hypertrophy	Reproductive system and breast disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Endometriosis	Reproductive system and breast disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Ovarian cyst	Reproductive system and breast disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Postmenopausal haemorrhage	Reproductive system and breast disorders	MedDRA 16.1	Systematic Assessment	EG0002 affected133 at risk
Cutaneous sarcoidosis	Skin and subcutaneous tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Erythema nodosum	Skin and subcutaneous tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected133 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA 16.1	Systematic Assessment	EG0008 affected133 at risk
Hypothyroidism	Endocrine disorders	MedDRA 16.1	Systematic Assessment	EG0007 affected133 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0009 affected133 at risk
Fatigue	General disorders	MedDRA 16.1	Systematic Assessment	EG00012 affected133 at risk
Influenza like illness	General disorders	MedDRA 16.1	Systematic Assessment	EG00013 affected133 at risk
Pyrexia	General disorders	MedDRA 16.1	Systematic Assessment	EG00012 affected133 at risk
Influenza	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0008 affected133 at risk
Nasopharyngitis	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG00019 affected133 at risk
Oral herpes	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0007 affected133 at risk
Pharyngitis	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG00015 affected133 at risk
Sinusitis	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG00011 affected133 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG00033 affected133 at risk
Urinary tract infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG00030 affected133 at risk
Alanine aminotransferase increased	Investigations	MedDRA 16.1	Systematic Assessment	EG0009 affected133 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG00010 affected133 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG00014 affected133 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0007 affected133 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG00010 affected133 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0009 affected133 at risk
Spinal pain	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0007 affected133 at risk
Headache	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG00021 affected133 at risk
Hypoaesthesia	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0009 affected133 at risk
Migraine	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0007 affected133 at risk
Multiple sclerosis relapse	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG00058 affected133 at risk
Muscle spasticity	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0007 affected133 at risk
Anxiety	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG00011 affected133 at risk
Depression	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG0009 affected133 at risk
Insomnia	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG0009 affected133 at risk

Ancestor Terms

ID	Term
D001569	Benzodiazepines
D001552	Benzazepines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D014970	Xanthines
D000470	Alkaloids
D011688	Purinones
D011687	Purines
D015110	4-Hydroxycoumarins
D003374	Coumarins
D001578	Benzopyrans
D011714	Pyrans
D006573	Heterocyclic Compounds, 1-Ring
D009285	Naphthoquinones
D009281	Naphthalenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D010836	Phytol
D004224	Diterpenes
D013729	Terpenes
D011083	Polycyclic Compounds
D053799	2-Pyridinylmethylsulfinylbenzimidazoles
D013454	Sulfoxides
D013457	Sulfur Compounds
D011725	Pyridines
D001562	Benzimidazoles
D009019	Morphinans
D053610	Opiate Alkaloids
D006572	Heterocyclic Compounds, Bridged-Ring
D006576	Heterocyclic Compounds, 4 or More Rings
D010616	Phenanthrenes
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Term
D009103	Multiple Sclerosis
D020278	Demyelinating Autoimmune Diseases, CNS
D020274	Autoimmune Diseases of the Nervous System
D009422	Nervous System Diseases
D003711	Demyelinating Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
D008874	Midazolam
D002110	Caffeine
D014859	Warfarin
D014812	Vitamin K
D009853	Omeprazole
D003915	Dextromethorphan
D000077561	Daclizumab
C000598527	daclizumab HYP