Clinical trial NCT03560739: 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: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-06-18
Enrollment: 284
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by AUCtau
timeFrame: Week 8 to Week 12 dosing interval
measure: Bioequivalence of 20 mg Ofatumumab Injected by Pre-filled Syringe (PFS) vs Autoinjector (AI) to Abdomen as Measured by Cmax
timeFrame: Week 8 to Week 12 dosing interval
Secondary outcomes:
measure: Pharmacokinetics of the Study Drug as Measured by AUCtau for PFS and AI Devices When Administered to Abdomen or Thigh
timeFrame: Week 8 to Week 12 dosing interval
measure: Pharmacokinetics of the Study Drug as Measured by Cmax for PFS and AI Devices When Administered to Abdomen or Thigh
timeFrame: Week 8 to Week 12 dosing interval
measure: Plasma Concentrations of the Study Drug for PFS and AI Devices When Administered to Abdomen or Thigh
timeFrame: Days 4, 7, 14, 28, 42, 56, 57, 59, 63, 70, 77, 84
measure: Percentage of Patients With Anti-ofatumumab Antibodies
timeFrame: Baseline, Week 4, 8, 12 and Overall
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Basalt
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Boulder
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: West Palm Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Ozark
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Knoxville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Round Rock
country: United States
facility: Novartis Investigative Site
state: Texas
city: Sherman
country: United States
facility: Novartis Investigative Site
state: Texas
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Havirov
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Teplice
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Hradec Kralove
country: Czechia
facility: Novartis Investigative Site
state: CZE
city: Pardubice
country: Czechia
facility: Novartis Investigative Site
city: Tallinn
country: Estonia
facility: Novartis Investigative Site
city: Tartu
country: Estonia
facility: Novartis Investigative Site
city: Riga
country: Latvia
facility: Novartis Investigative Site
state: LV
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Kaunas
country: Lithuania
facility: Novartis Investigative Site
state: LTU
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Krasnoyarsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Pozuelo de Alarcon
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Castilleja de la cuesta
country: Spain
facility: Novartis Investigative Site
state: Sevilla
Study officials:
References:
citation: 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 Nov;21(6):1357-1365. doi: 10.1002/pst.2233. Epub 2022 May 23.
citation: 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, Haring 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.