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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Combination Product: ofatumumab with PRF
* Combination Product: ofatumumab with AI


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: OMB 20mg PFS abdomen<br>ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on abdomen | Combination Product: ofatumumab with PRF<br>* ofatumumab 20 mg subcutanious injection administered with pre-filled syringe (PRF)<br>|
| Other: OMB 20mg AI abdomen<br>ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on abdomen | Combination Product: ofatumumab with AI<br>* ofatumumab 20 mg subcutaneous injection administered with autoinjector (AI)<br>|
| Other: OMB 20mg PFS thigh<br>ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on thigh | Combination Product: ofatumumab with PRF<br>* ofatumumab 20 mg subcutanious injection administered with pre-filled syringe (PRF)<br>|
| Other: OMB 20mg AI thigh<br>ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on thigh | Combination Product: ofatumumab with AI<br>* ofatumumab 20 mg subcutaneous injection administered with autoinjector (AI)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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