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 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

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Combination product: ofatumumab with PRF; Combination product: ofatumumab with AI

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: Interventional
• Enrollment (Actual): 284
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Novartis Investigative Site
  • Vienna, Austria, 1010
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1113
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1309
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1413
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1431
    • Novartis Investigative Site
• Czechia
  • Pardubice, Czechia, 532 03
    • Novartis Investigative Site
  • CZE
    • Hradec Kralove, CZE, Czechia, 500 05
      • Novartis Investigative Site
  • Czech Republic
    • 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
• Estonia
  • Tallinn, Estonia, 10617
    • Novartis Investigative Site
  • Tartu, Estonia, 51014
    • Novartis Investigative Site
• Latvia
  • Riga, Latvia, LV 1002
    • Novartis Investigative Site
  • Riga, Latvia, LV-1038
    • Novartis Investigative Site
  • LV
    • Riga, LV, Latvia, LV-1005
      • Novartis Investigative Site
• Lithuania
  • Vilnius, Lithuania, LT-08661
    • Novartis Investigative Site
  • LTU
    • Kaunas, LTU, Lithuania, LT 50161
      • Novartis Investigative Site
• Russian Federation
  • 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
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Madrid
    • Pozuelo de Alarcon, Madrid, Spain, 28223
      • Novartis Investigative Site
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Novartis Investigative Site
  • Sevilla
    • Castilleja de la cuesta, Sevilla, Spain, 41950
      • Novartis Investigative Site
• United States
  • California
    • Fullerton, California, United States, 92835
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
    • Basalt, Colorado, United States, 81621
      • Novartis Investigative Site
    • Boulder, Colorado, United States, 80301
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33612
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33609
      • Novartis Investigative Site
    • West Palm Beach, Florida, United States, 33407
      • Novartis Investigative Site
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Novartis Investigative Site
  • Missouri
    • Ozark, Missouri, United States, 65721
      • Novartis Investigative Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37922
      • Novartis Investigative Site
  • Texas
    • Round Rock, Texas, United States, 78681
      • Novartis Investigative Site
    • Sherman, Texas, United States, 75092
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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)
Other: 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)
Other: 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)
Other: 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by AUCtau	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	Week 8 to Week 12 dosing interval
Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by Cmax	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	Week 8 to Week 12 dosing interval

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of the Study Drug as Measured by AUCtau for PFS and AI Devices When Administered to Abdomen or Thigh	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)	Week 8 to Week 12 dosing interval
Pharmacokinetics of the Study Drug as Measured by Cmax for PFS and AI Devices When Administered to Abdomen or Thigh	Pharmacokinetics following subcutaneous administration of ofatumumab to either the abdominal region or the thigh as measured by the maximum concentration (Cmax)	Week 8 to Week 12 dosing interval
Plasma Concentrations of the Study Drug for PFS and AI Devices When Administered to Abdomen or Thigh	Plasma concentrations following subcutaneous administration of ofatumumab via PFS or AI to either the abdominal region or the thigh	Days 4, 7, 14, 28, 42, 56, 57, 59, 63, 70, 77, 84
Percentage of Patients With Anti-ofatumumab Antibodies	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.	Baseline, Week 4, 8, 12 and Overall

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Jones B, Li B, Bagger M, Goodyear A, Ludwig I. Statistical methodology for highly variable compounds: A novel design approach for the Ofatumumab Phase 2 bioequivalence study. Pharm Stat. 2022 May 23. doi: 10.1002/pst.2233. [Epub ahead of print]
• Bar-Or A, Wiendl H, Montalban X, Alvarez E, Davydovskaya M, Delgado SR, Evdoshenko EP, Giedraitiene N, Gross-Paju K, Haldre S, Herrman CE, Izquierdo G, Karelis G, Leutmezer F, Mares M, Meca-Lallana JE, Mickeviciene D, Nicholas J, Robertson DS, Sazonov DV, Sharlin K, Sundaram B, Totolyan N, Vachova M, Valis M, Bagger M, Häring DA, Ludwig I, Willi R, Zalesak M, Su W, Merschhemke M, Fox EJ. Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study. Mult Scler. 2022 May;28(6):910-924. doi: 10.1177/13524585211044479. Epub 2021 Oct 4.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2018
• Primary Completion (Actual): August 26, 2019
• Study Completion (Actual): May 5, 2020

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: June 6, 2018
• First Posted (Actual): June 18, 2018

Study Record Updates

• Last Update Posted (Actual): October 8, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Relapsing Multiple Sclerosis; adult; OMB157; Pharmacokinetics; Bioequivalence; Relapsing-remitting Multiple Sclerosis; Secondary progressive Multiple Sclerosis; Neurofilament light chain; Pre-filled Syringe; Auto-injector; AI; PFS
• 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; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Ofatumumab; Antibodies, Monoclonal
• Other Study ID Numbers: COMB157G2102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No