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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

Tracking Information
First Submitted Date  ICMJE July 14, 2011
First Posted Date  ICMJE October 31, 2011
Results First Submitted Date  ICMJE January 23, 2017
Results First Posted Date  ICMJE March 14, 2017
Last Update Posted Date March 14, 2017
Study Start Date  ICMJE November 2011
Actual Primary Completion Date January 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2017)
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 28, 2011)
  • Safety as a measure of the incidence of anti-DAC HYP binding antibodies (ADAbs) [ Time Frame: Patients will be followed for a maximum duration of 44 weeks ]
  • Safety as a measure of the incidence of anti-DAC HYP neutralizing antibodies (NAbs) [ Time Frame: Patients will be followed for a maximum duration of 44 weeks ]
Change History Complete list of historical versions of study NCT01462318 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2017)
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2011)
Blood Daclizumab trough concentrations (Ctrough) [ Time Frame: Patients will be followed for a maximum duration of 44 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Open-Label Immunogenicity and Pharmacokinetics Study of Daclizumab High Yield Process Prefilled Syringe in Relapsing Remitting Multiple Sclerosis
Official Title  ICMJE 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
Brief Summary 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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Relapsing-Remitting Multiple Sclerosis
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.

Interventions:
  • Drug: Midazolam
  • Other: Caffeine
  • Drug: S-warfarin
  • Other: Vitamin K
  • Drug: Omeprazole
  • Drug: Dextromethorphan
  • Biological: BIIB019 (Daclizumab)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 25, 2014)
133
Original Estimated Enrollment  ICMJE
 (submitted: October 28, 2011)
150
Actual Study Completion Date  ICMJE January 2016
Actual Primary Completion Date January 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Czech Republic,   Hungary,   Poland,   United States
Removed Location Countries Russian Federation
 
Administrative Information
NCT Number  ICMJE NCT01462318
Other Study ID Numbers  ICMJE 205MS302
2010-023856-97 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP