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

A Multicenter, Single-Arm, Open-Label Study to Evaluate the Immunogenicity and Pharmacokinetics of BIIB019, Daclizumab High Yield Process (DAC HYP), Prefilled Syringe Administered by Subcutaneous Injection in Subjects With Relapsing-Remitting Multiple Sclerosis

The primary objective of the study is to assess the immunogenicity of Daclizumab High Yield Process (DAC HYP) 150 mg administered every 4 weeks by subcutaneous (SC) injection using the pre-filled syringe (PFS) in participants with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives of this study are to characterize the pharmacokinetics (PK) of DAC HYP following single and multiple doses of DAC HYP administered by the PFS in a subset of participants with RRMS and to evaluate the effect of DAC HYP on the PK of probe drugs for cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A).

Study Overview

• Status: Completed
• Conditions: Relapsing-Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Midazolam; Other: Caffeine; Drug: S-warfarin; Other: Vitamin K; Drug: Omeprazole; Drug: Dextromethorphan; Biological: BIIB019 (Daclizumab)

Detailed Description

Following a screening period, participants will receive DAC HYP over a 24-week treatment period (6 monthly injections) and then enter a 20-week washout period for assessment of immunogenicity, PK, pharmacodynamics, safety, and tolerability. The 20-week washout is necessary to ensure measurement of anti-DAC HYP binding antibodies (ADAbs) and neutralizing antibodies (NAbs) in the absence of drug interference. After washout, the participants may resume monthly treatment with DAC HYP 150 mg for an additional 3 years. All participants will be followed for 6 months after their last dose for safety monitoring. Additionally, two sub-studies will be performed: (1) an intensive serial PK sampling performed over the first and last dosing interval following DAC HYP doses administered at week 0 and at week 20, and (2) a therapeutic protein-drug interaction (TP-DI) sub-study, during which a probe drug cocktail will be administered at weeks 43 and 53 followed by serial probe-drug PK sampling up to 96 hours after probe-drug administration. A maximum of 20 participants will be enrolled in the TP-DI sub-study.

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czech Republic
  • Brno, Czech Republic, 65691
    • Research Site
  • Jihlava, Czech Republic, 58633
    • Research Site
  • Ostrava, Czech Republic, 70852
    • Research Site
  • Pardubice, Czech Republic, 53203
    • Research Site
  • Teplice, Czech Republic, 41501
    • Research Site
• Hungary
  • Budapest, Hungary, 1134
    • Research Site
  • Debrecen, Hungary, 4031
    • Research Site
  • Esztergom, Hungary, 2500
    • Research Site
  • Szekesfehervar, Hungary
    • Research Site
  • Korhazu 1
    • Veszprem, Korhazu 1, Hungary, 8200
      • Research Site
• Poland
  • Katowice, Poland
    • Research Site
  • Krakow, Poland, 31-501
    • Research Site
• United States
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Research Site
  • Illinois
    • Lake Barrington, Illinois, United States, 60010
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40513
      • Research Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Research Site
  • Ohio
    • Dayton, Ohio, United States, 45417
      • Research Site
  • Tennessee
    • Franklin, Tennessee, United States, 37064
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: DAC HYP; 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; 5 mg; Other: Caffeine; 200 mg; Drug: S-warfarin; 10 mg; Other: Vitamin K; 10 mg; Drug: Omeprazole; 40 mg; Drug: Dextromethorphan; 30 mg; Biological: BIIB019 (Daclizumab); 150 mg in 1 ml PFS; Other Names: Daclizumab High Yield Process; DAC HYP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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
Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP		Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14, and 21 days post-dose
Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP		Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP		Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP		Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP		Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
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).	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: 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).	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: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 Hours Post-omeprazole Dosing		Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration) at 2 hours after probe drug cocktail administration

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: July 14, 2011
• First Submitted That Met QC Criteria: October 28, 2011
• First Posted (ESTIMATE): October 31, 2011

Study Record Updates

• Last Update Posted (ACTUAL): March 14, 2017
• Last Update Submitted That Met QC Criteria: January 23, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: immunogenicity; Pharmacokinetic; Pre-filled syringe; Daclizumab High Yield Process
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Fibrin Modulating Agents; Purinergic Antagonists; Purinergic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Respiratory System Agents; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Antitussive Agents; Midazolam; Vitamin K; Dextromethorphan; Warfarin; Caffeine; Omeprazole; Daclizumab
• Other Study ID Numbers: 205MS302; 2010-023856-97 (EUDRACT_NUMBER)