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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Biogen
ClinicalTrials.gov Identifier:
NCT01462318
First received: July 14, 2011
Last updated: January 23, 2017
Last verified: January 2017
  Purpose
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).

Condition Intervention Phase
Relapsing-Remitting Multiple Sclerosis
Drug: Midazolam
Other: Caffeine
Drug: S-warfarin
Other: Vitamin K
Drug: Omeprazole
Drug: Dextromethorphan
Biological: BIIB019 (Daclizumab)
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Other
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Biogen:

Primary Outcome Measures:
  • Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay [ Time Frame: Up to 44 weeks ]
    Participants with post-baseline (PB) ADAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose).

  • Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay [ Time Frame: Up to 44 weeks ]
    Participants with PB NAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose).

  • TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug [ 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 ]
    AUCinf of each of the following cytochrome P450 (CYP) isoenzyme substrates: midazolam (CYP3A), S-warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19). The AUC from zero to 12 hours (AUC0-12) was calculated for caffeine (CYP1A2).

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

Secondary Outcome Measures:
  • Intensive PK Sub-study: Cmax of DAC HYP [ Time Frame: Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14 and 21 days post-dose ]
  • Intensive PK Sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP [ Time Frame: Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14 and 21 days post-dose ]
  • Intensive PK Sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP [ Time Frame: Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72, and 120 hours post-dose and 7, 10, 14, and 21 days post-dose ]
  • Intensive PK Sub-study: Minimum Concentrations (Cmin) of DAC HYP [ Time Frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose ]
  • Intensive PK Sub-study: Apparent Volume of Distribution (V/F) of DAC HYP [ Time Frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose ]
  • Intensive PK Sub-study: Elimination Half-life (t½) of DAC HYP [ Time Frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose ]
  • Intensive PK Sub-study: Apparent Clearance (CL/F) of DAC HYP [ Time Frame: Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose ]
  • TP-DI Sub-study: Cmax of Each Probe Drug [ 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 ]
    Cmax of each of the following CYP isoenzyme substrates: midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19).

  • TP-DI Sub-study: CL/F of Each Probe Drug [ 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 ]
    CL/F of each of the following CYP isoenzyme substrates: midazolam (CYP3A), warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19).

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

Enrollment: 133
Study Start Date: November 2011
Study Completion Date: January 2016
Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Daclizumab High Yield Process; DAC HYP

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.
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01462318

Locations
United States, Colorado
Research Site
Centennial, Colorado, United States, 80112
United States, District of Columbia
Research Site
Washington, District of Columbia, United States, 20057
United States, Illinois
Research Site
Lake Barrington, Illinois, United States, 60010
United States, Kentucky
Research Site
Lexington, Kentucky, United States, 40513
United States, Michigan
Research Site
Farmington Hills, Michigan, United States, 48334
United States, Ohio
Research Site
Dayton, Ohio, United States, 45417
United States, Tennessee
Research Site
Franklin, Tennessee, United States, 37064
Czech Republic
Research Site
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
Hungary
Research Site
Veszprem, Korhazu 1, Hungary, 8200
Research Site
Budapest, Hungary, 1134
Research Site
Debrecen, Hungary, 4031
Research Site
Esztergom, Hungary, 2500
Research Site
Szekesfehervar, Hungary
Poland
Research Site
Katowice, Poland
Research Site
Krakow, Poland, 31-501
Sponsors and Collaborators
Biogen
Investigators
Study Director: Medical Director Biogen
  More Information

Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT01462318     History of Changes
Other Study ID Numbers: 205MS302
2010-023856-97 ( EudraCT Number )
Study First Received: July 14, 2011
Results First Received: January 23, 2017
Last Updated: January 23, 2017

Keywords provided by Biogen:
Pre-filled syringe
Pharmacokinetic
Daclizumab High Yield Process
immunogenicity

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Vitamins
Vitamin K
Warfarin
Caffeine
Omeprazole
Midazolam
Dextromethorphan
Daclizumab
Immunoglobulin G
Micronutrients
Growth Substances
Physiological Effects of Drugs
Anticoagulants
Central Nervous System Stimulants
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents

ClinicalTrials.gov processed this record on April 21, 2017