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A 12 Week Randomized Open Label Parallel Group Multicenter Study to Evaluate Bioequivalence of 20 mg Subcutaneous Ofatumumab Injected by Pre-filled Syringe or Autoinjector in Adult RMS Patients

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ClinicalTrials.gov Identifier: NCT03560739
Recruitment Status : Completed
First Posted : June 18, 2018
Results First Posted : October 9, 2020
Last Update Posted : October 8, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE May 15, 2018
First Posted Date  ICMJE June 18, 2018
Results First Submitted Date  ICMJE September 16, 2020
Results First Posted Date  ICMJE October 9, 2020
Last Update Posted Date October 8, 2021
Actual Study Start Date  ICMJE September 11, 2018
Actual Primary Completion Date August 26, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 16, 2020)
  • Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by AUCtau [ Time Frame: Week 8 to Week 12 dosing interval ]
    Bioequivalence of AUCtau ) will be measured over the time period of Week 8 to Week 12 dosing interval comparing the pre-filled syringe (PFS) and autoinjector (AI) devices both administered to the abdomen. Bioequivalence established if both measures meet the corresponding criterion specified by the reference-scaled average bioequivalence (RSABE) approach
  • Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by Cmax [ Time Frame: Week 8 to Week 12 dosing interval ]
    Bioequivalence of Cmax will be measured over the time period of Week 8 to Week 12 dosing interval comparing the pre-filled syringe (PFS) and autoinjector (AI) devices both administered to the abdomen. Bioequivalence established if both measures meet the corresponding criterion specified by the reference-scaled average bioequivalence (RSABE) approach
Original Primary Outcome Measures  ICMJE
 (submitted: June 6, 2018)
  • Cmax between the two drug-device combinations [ Time Frame: 12 weeks ]
    Bioequivalence (Cmax) will be measured over the time period from 8-12 weeks comparing the PFS and autoinjector devices both administered to the abdomen.
  • Area Under the Curve (AUC)tau between the two drug-device combinations [ Time Frame: 12 weeks ]
    Bioequivalence (AUCtau) will be measured over the time period from 8-12 weeks comparing the PFS and autoinjector devices both administered to the abdomen.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2020)
  • Pharmacokinetics of the Study Drug as Measured by AUCtau for PFS and AI Devices When Administered to Abdomen or Thigh [ Time Frame: Week 8 to Week 12 dosing interval ]
    Pharmacokinetics following subcutaneous administration of ofatumumab to either the abdominal region or the thigh as measured by the area under the concentration-time curve over the Week 8 - Week 12 dosing interval (AUCtau)
  • Pharmacokinetics of the Study Drug as Measured by Cmax for PFS and AI Devices When Administered to Abdomen or Thigh [ Time Frame: Week 8 to Week 12 dosing interval ]
    Pharmacokinetics following subcutaneous administration of ofatumumab to either the abdominal region or the thigh as measured by the maximum concentration (Cmax)
  • Plasma Concentrations of the Study Drug for PFS and AI Devices When Administered to Abdomen or Thigh [ Time Frame: Days 4, 7, 14, 28, 42, 56, 57, 59, 63, 70, 77, 84 ]
    Plasma concentrations following subcutaneous administration of ofatumumab via PFS or AI to either the abdominal region or the thigh
  • Percentage of Patients With Anti-ofatumumab Antibodies [ Time Frame: Baseline, Week 4, 8, 12 and Overall ]
    Anti-drug antibodies (ADA) were assessed to evaluate the immunogenicity potential of ofatumumab. Samples for ADA assessment were taken prior to dosing at the visit. Samples were analyzed as per laboratory's SOPs by a Meso Scale Discovery (MSD) electrochemiluminescense assay. All samples confirmed to be positive for the presence of anti-ofatumumab antibodies were assessed to evaluate their ability to neutralize the ofatumumab biologic effect.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2018)
  • Cmax between the two drug-device combinations to the abdominal region and the thigh [ Time Frame: 12 weeks ]
    Characterize the pharmacokinetics following subcutaneous administration of ofatumumab to either the abdominal region or the thigh
  • AUCtau between the two drug-device combinations to the abdominal region and the thigh [ Time Frame: 12 weeks ]
    Characterize the pharmacokinetics following subcutaneous administration of ofatumumab to either the abdominal region or the thigh
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A 12 Week Randomized Open Label Parallel Group Multicenter Study to Evaluate Bioequivalence of 20 mg Subcutaneous Ofatumumab Injected by Pre-filled Syringe or Autoinjector in Adult RMS Patients
Official Title  ICMJE A 12 Week Randomized Open Label Parallel Group Multicenter Study to Evaluate Bioequivalence of 20 mg Subcutaneous Ofatumumab Injected by Pre-filled Syringe or Autoinjector in Adult RMS Patients
Brief Summary The primary purpose of this study is to demonstrate pharmacokinetic bioequivalence of ofatumumab injected by Pre-filled Syringe (PFS) versus Auto-Injector (AI) devices and thereby establish a bridge between the ongoing Phase 3 program and the to-be-marketed drug-device combinations
Detailed Description

Characterization of the pharmacokinetics of ofatumumab administered via the PFS used inclinical trials and the to-be-marketed autoinjector at the clinical dose of 20 mg will be conducted after an initial depletion of CD20 positive B-cells. Comparing the ofatumumab pharmacokinetics between the two drug-device combinations only after the induction period is expected to reduce initial high variability due to target-mediated clearance. This ensures a more stable baseline for PK comparison in a parallel group study design and reflects the clinical situation where systemic concentrations are at steady-state. In order to justify the resulting longterm B-cell depletion, a PK comparability study between the PFS and the AI can only be conducted in MS patients rather than in healthy subjects to balance the risk/benefit and to obtain PK data from the relevant patient population. In order for patients to obtain a clinical benefit from participation in the study, continued treatment with ofatumumab will be offered to all eligible patients through enrollment into the open-label Phase 3 extension study (separate protocol, COMB157G2399).

A secondary objective of the study is to characterize the pharmacokinetics following subcutaneous administration of ofatumumab to either the abdominal region or the thigh which are two injections sites allowed in the Phase 3 study and planned for inclusion in the label. Another secondary objective is assessment of immunogenicity during the 12 weeks duration of the study addressing potential differences in ofatumumab anti-drug antibody formation between the PFS and AI devices as well as between abdomen and thigh injection sites.

This was a randomized, open-label, multi-center, parallel group 12-week study to evaluate the pharmacokinetic bioequivalence of ofatumumab injected by pre-filled syringe (PFS) or autoinjector (AI) devices. The study design included four parallel groups of relapsing multiple sclerosis (RMS) patients. Assessment of the primary and secondary endpoints was based on data collected through the dosing interval between Week 8 and Week 12 where approximate steady-state pharmacokinetics was anticipated.

All patients received open-label ofatumumab 20 mg sc every 4 weeks (after an initial loading regimen of three weekly 20 mg doses in the first 14 days) and were randomized (5:5:1:1) into 4 groups dependent on device and location of injection. Randomization was not blinded. Groups: 1: PFS, abdomen, 2: AI, abdomen 3: PFS, thigh 4: AI, thigh.

The study had 3 Parts. Part 1 was a 30 day screening period. Part 2 was a treatment period which had an induction period of 4 weeks, followed by 4 weeks to ensure steady state was reached and a 4 week pharmacokinetics phase for a total of 12 weeks.

Part 3 was a safety follow-up period for patients who completed the study but did not enter the extension study and patients who prematurely discontinued the study. This period was 9 months for patients who had repleted their B-cells (back to baseline value). For patients who had not repleted their B-cells, 3 month assessments were done until their B-cells were repleted or patients had initiated other disease modifying/immunosuppressive thereapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
To address the primary objective of testing bioequivalence at dosing interval after Week 8 between Pre-filled Syringe (PFS) and Auto-Injector (AI), the primary analysis involves the two groups (PFS (abdomen) and AI (abdomen)). Further the pharmacokinetcs of ofatumumab will be compared between using the thigh or abdomen for injections.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE
  • Combination Product: ofatumumab with PRF
    ofatumumab 20 mg subcutanious injection administered with pre-filled syringe (PRF)
  • Combination Product: ofatumumab with AI
    ofatumumab 20 mg subcutaneous injection administered with autoinjector (AI)
Study Arms  ICMJE
  • OMB 20mg PFS abdomen
    ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on abdomen
    Intervention: Combination Product: ofatumumab with PRF
  • OMB 20mg AI abdomen
    ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on abdomen
    Intervention: Combination Product: ofatumumab with AI
  • OMB 20mg PFS thigh
    ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on thigh
    Intervention: Combination Product: ofatumumab with PRF
  • OMB 20mg AI thigh
    ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on thigh
    Intervention: Combination Product: ofatumumab with AI
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: June 6, 2018)
284
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 5, 2020
Actual Primary Completion Date August 26, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of multiple sclerosis (MS)
  • Relapsing MS: relapsing-remitting course (RRMS), or Secondary progressive (SPMS) course
  • EDSS score of 0 to 5.5
  • Documentation of at least: 1 relapse during the previous year OR 2 relapses during the previous 2 years prior to Screening OR a positive Gd-enhancing MRI scan during the year prior to randomization.
  • Neurologically stable within 1 month prior to randomization

Exclusion Criteria:

  • Patients with primary progressive MS or SPMS without disease activity
  • Disease duration of more than 10 years in patients with EDSS score of 2 or less
  • Patients with an active chronic disease of the immune system other than MS
  • Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS or to test positive for HIV antibody at Screening
  • Patients with neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML), or confirmed PML
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Bulgaria,   Czechia,   Estonia,   Latvia,   Lithuania,   Russian Federation,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03560739
Other Study ID Numbers  ICMJE COMB157G2102
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

URL: https://www.clinicalstudydatarequest.com
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date October 2021

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