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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03560739
Recruitment Status : Completed
First Posted : June 18, 2018
Results First Posted : October 9, 2020
Last Update Posted : October 9, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Combination Product: ofatumumab with PRF Combination Product: ofatumumab with AI Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 284 participants
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
Official Title: 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
Actual Study Start Date : September 11, 2018
Actual Primary Completion Date : August 26, 2019
Actual Study Completion Date : May 5, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Ofatumumab

Arm Intervention/treatment
OMB 20mg PFS abdomen
ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on abdomen
Combination Product: ofatumumab with PRF
ofatumumab 20 mg subcutanious injection administered with pre-filled syringe (PRF)

OMB 20mg AI abdomen
ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on abdomen
Combination Product: ofatumumab with AI
ofatumumab 20 mg subcutaneous injection administered with autoinjector (AI)

OMB 20mg PFS thigh
ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on thigh
Combination Product: ofatumumab with PRF
ofatumumab 20 mg subcutanious injection administered with pre-filled syringe (PRF)

OMB 20mg AI thigh
ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on thigh
Combination Product: ofatumumab with AI
ofatumumab 20 mg subcutaneous injection administered with autoinjector (AI)




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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)

  2. 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)

  3. 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

  4. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03560739


Locations
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United States, California
Novartis Investigative Site
Fullerton, California, United States, 92835
United States, Colorado
Novartis Investigative Site
Aurora, Colorado, United States, 80045
Novartis Investigative Site
Basalt, Colorado, United States, 81621
Novartis Investigative Site
Boulder, Colorado, United States, 80301
United States, Florida
Novartis Investigative Site
Miami, Florida, United States, 33136
Novartis Investigative Site
Tampa, Florida, United States, 33609
Novartis Investigative Site
Tampa, Florida, United States, 33612
Novartis Investigative Site
West Palm Beach, Florida, United States, 33407
United States, Indiana
Novartis Investigative Site
Indianapolis, Indiana, United States, 46256
United States, Missouri
Novartis Investigative Site
Ozark, Missouri, United States, 65721
United States, Tennessee
Novartis Investigative Site
Knoxville, Tennessee, United States, 37922
United States, Texas
Novartis Investigative Site
Round Rock, Texas, United States, 78681
Novartis Investigative Site
Sherman, Texas, United States, 75092
Austria
Novartis Investigative Site
Vienna, Austria, 1010
Novartis Investigative Site
Vienna, Austria, 1090
Bulgaria
Novartis Investigative Site
Sofia, Bulgaria, 1113
Novartis Investigative Site
Sofia, Bulgaria, 1309
Novartis Investigative Site
Sofia, Bulgaria, 1413
Novartis Investigative Site
Sofia, Bulgaria, 1431
Czechia
Novartis Investigative Site
Brno, Czech Republic, Czechia, 656 91
Novartis Investigative Site
Havirov, Czech Republic, Czechia, 736 01
Novartis Investigative Site
Teplice, Czech Republic, Czechia, 415 01
Novartis Investigative Site
Hradec Kralove, CZE, Czechia, 500 05
Novartis Investigative Site
Pardubice, Czechia, 532 03
Estonia
Novartis Investigative Site
Tallinn, Estonia, 10617
Novartis Investigative Site
Tartu, Estonia, 51014
Latvia
Novartis Investigative Site
Riga, LV, Latvia, LV-1005
Novartis Investigative Site
Riga, Latvia, LV 1002
Novartis Investigative Site
Riga, Latvia, LV-1038
Lithuania
Novartis Investigative Site
Kaunas, LTU, Lithuania, LT 50161
Novartis Investigative Site
Vilnius, Lithuania, LT-08661
Russian Federation
Novartis Investigative Site
Kazan, Russian Federation, 420021
Novartis Investigative Site
Krasnoyarsk, Russian Federation, 660049
Novartis Investigative Site
Moscow, Russian Federation, 127015
Novartis Investigative Site
Novosibirsk, Russian Federation, 630007
Novartis Investigative Site
Saint Petersburg, Russian Federation, 197022
Novartis Investigative Site
St Petersburg, Russian Federation, 190000
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Pozuelo de Alarcon, Madrid, Spain, 28223
Novartis Investigative Site
El Palmar, Murcia, Spain, 30120
Novartis Investigative Site
Castilleja de la cuesta, Sevilla, Spain, 41950
Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Statistical Analysis Plan  [PDF] May 8, 2020
Study Protocol  [PDF] March 30, 2018

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03560739    
Other Study ID Numbers: COMB157G2102
First Posted: June 18, 2018    Key Record Dates
Results First Posted: October 9, 2020
Last Update Posted: October 9, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Relapsing Multiple Sclerosis
Relapsing-remitting Multiple Sclerosis
Secondary progressive Multiple Sclerosis
Bioequivalence
Pharmacokinetics
Neurofilament light chain
Pre-filled Syringe
Auto-injector
adult
AI
PFS
OMB157
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Ofatumumab
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs