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

Phase 2

Completed

• Conditions: Multiple Sclerosis
• Interventions: Combination Product: ofatumumab with AI; Combination Product: ofatumumab with PRF

• Registration Number: NCT03560739
• Lead Sponsor: 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

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 Timeline

• Study First Submitted: 2018-05-15
• Study First Submitted QC: 2018-06-06
• Study First Posted: 2018-06-18
• Study Start: 2018-09-11
• Primary Completion: 2019-08-26
• Disposition First Submitted: 2019-11-06
• Disposition First Submitted QC: 2019-12-30
• Disposition First Posted: 2020-01-02
• Study Completion: 2020-05-05
• Results First Submitted: 2020-09-16
• Results First Submitted QC: 2020-09-16
• Results First Posted: 2020-10-09
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-07
• Last Update Posted: 2021-10-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 284

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
OMB 20mg AI abdomen	ofatumumab with AI	ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on abdomen
OMB 20mg AI thigh	ofatumumab with AI	ofatumumab 20 mg subcutaneous (sc.) injection with autoinjector (AI) administrated on thigh
OMB 20mg PFS abdomen	ofatumumab with PRF	ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on abdomen
OMB 20mg PFS thigh	ofatumumab with PRF	ofatumumab 20 mg subcutaneous (sc.) injection with pre-filled syringes (PFS) administrated on thigh

Primary Outcome Measures

Name	Time	Method
Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by AUCtau	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	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

Name	Time	Method
Pharmacokinetics of the Study Drug as Measured by AUCtau for PFS and AI Devices When Administered to Abdomen or Thigh	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)
Plasma Concentrations of the Study Drug for PFS and AI Devices When Administered to Abdomen or Thigh	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	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.
Pharmacokinetics of the Study Drug as Measured by Cmax for PFS and AI Devices When Administered to Abdomen or Thigh	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)

Trial Locations

Locations (1)

Novartis Investigative Site; 🇪🇸 Castilleja de la cuesta, Sevilla, Spain