Clinical trial NCT02980042: Safety of Switching From Rituximab to Ocrelizumab in MS Patients
Official title: Evaluating the Tolerability and Safety Profile of Switching From Rituximab to Ocrelizumab: A Real World Evaluation of Patients With Relapsing Forms of Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2016-12-02
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a prospective between and within group observational study to determine differences in tolerability, immunogenicity and safety related outcomes for 100 multiple sclerosis (MS) patients who have been administered at least two infusions of rituximab, six months apart and are willing to be switched to ocrelizumab compared to a 100 patients who are continuing on rituximab as a comparison cohort from the clinic population treated as part of clinical care.

Detailed description: Studies of rituximab, a chimeric monoclonal antibody against CD20 have shown that B-cell depletion is of clinical beneﬁt as a potential treatment in relapsing forms of multiple sclerosis (MS).1 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and selectively depletes CD20 expressing cells, while preserving the capacity for B cell reconstitution. When compared with rituximab, ocrelizumab is associated with increased antibody-dependent cell-mediated cytotoxic eﬀects, and reduced complement-dependent cytotoxic eﬀects in vitro.2 By increasing antibody-dependent cell mediated cytotoxic eﬀects, ocrelizumab might modulate tissue-dependent mechanisms of pathogenic response more eﬀectively compared to rituximab. As a humanized molecule, ocrelizumab is expected to be less immunogenic with repeated infusions and might thus present a more favorable safety profile when compared to rituximab.2

Despite rituximab's current off label use in the treatment of MS, currently there is only data available from phase 2 trials. The HERMES group conducted a phase 2, double-blind, 48-week trial involving 104 patients with relapsing forms of MS; 69 patients received 1000 mg of intravenous rituximab and 35 patients received placebo on days 1 and 15.3 A significantly higher number of patients in the rituximab group (78.3%) versus the placebo group (40.0%) had an infusion related reaction (IRR) events within 24 hours after the first infusion. Within 24 hours after the second infusion, fewer patients in the rituximab group (20.3%) than in the placebo group (40%) had similar events. A majority of the rituximab group with IRR events (92.6%) were classified as mild to moderate (grade 1 or 2) in severity.

Safety data from the Investigators Brochure on the OPERA I and II phase 3 trials comparing ocrelizumab to interferon β-1a on relapsing MS patients showed that IRRs were the most common adverse events experienced by patients treated with 600 mg of ocrelizumab.4 The percentage of patients experiencing IRRs was higher in the ocrelizumab group (relapsing forms of MS: 34.3%; primary progressive forms of MS 39.9%) compared with the interferon β-1a (active control) group who received placebo infusions (relapsing forms of MS: 9.7%; primary progressive forms of MS: 25.5%). The rate of IRRs was highest during the first infusion or Dose 1 (27.5% on Day 1; 4.71% on Day 15 of Dose 1) and decreased over time (13.7%; 9.6% and 7.8% following Dose 2, 3, and 4 respectively) for the ocrelizumab treated group. Comparatively, interferon β-1a users experienced 6.5% of IRRs on Day 1, 2.58% on Day 15, \< 2.00% after doses 2, 3 and 4 respectively. The reported IRRs were primarily mild-to-moderate in severity (Grades 1 and 2). Serious IRRs occurred in 0.1% and 1.0% respectively of relapsing and progressive patients and treated with ocrelizumab.

Clinical data describing the efficacy and tolerability profile of rituximab and ocrelizumab has utilized populations with different prior treatment characteristics. In the phase 2 HERMES trials, a majority (78.5%) of rituximab patients had been previously been treated with a disease modifying therapy in the last 2 years.3 In contrast, the OPERA I and II phase 3 clinical trials, a majority of ocrelizumab patients (72.9% in OPERA I and 73.8% in OPERA II) represented a treatment naïve population.4 Examining IRRs in patients who have switched from rituximab to ocrelizumab versus those continuing on rituximab will examine the magnitude of the IRRs and subsequent tolerability of ocrelizumab in a real world population.

Earlier concepts of MS disease pathology have suggested that pathogenic T cells are sufficient for the full expression of MS. However, it is now evident that full autoimmune B cells and humoral immune mechanisms also play key roles. 5 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells. CD20 is a B cell surface molecule that is expressed on pre B cells and mature B cells, but not expressed earlier in the development of B cells or on mature plasma cells. In all three ocrelizumab studies (with relapsing and progressive populations), treatment with 600 mg of ocrelizumab led to rapid and complete depletion of circulating CD19+ B cells within 14 days post treatment. 4 B cell depletion was sustained throughout treatment period. The median time to repletion of B cells was 72 weeks (range 27-175 weeks). We hypothesize that in switching rituximab treated patients to ocrelizumab, the proportion of patients with B cell depletion (\< 1%) 6 months after the first and third infusion of ocrelizumab will be the same as the baseline assessment which will be 6 months after the last dose of rituximab and similar to findings in OPERA I and II.

Immunogenicity results from the OPERA I and II trials examined the number of patients who had treatment induced anti-drug antibodies (ADA) to ocrelizumab. 4 Of the 807 patients who received ocrelizumab and had an ADA assay from a post baseline sample during the controlled treatment period, 3 patients (0.4%) showed treatment induced ADA to ocrelizumab. Of these, 1 patient tested positive for neutralizing antibodies (NAB) to ocrelizumab. During the open label extension phase, the prevalence of ADA continued to remain low with post baseline incidence of 1.9% (2/103 with treatment induced ADA). Currently there is little evidence examining the prevalence of treatment induced ADAs to both rituximab and ocrelizumab in patients that switch from the former to the latter in comparison to continuing rituximab patients. Therefore, we will perform assays to detect ADAs to both rituximab and ocrelizumab in all patients switching from rituximab to ocrelizumab at Day 1, 6 months and 12 months on ocrelizumab.

Finally, IRRs have been hypothesized to be a reaction by autoantibodies to the treatment drug or possibly from the release of cytokines from CD20 expressing cells as they are destroyed by ocrelizumab causing a "cytokine storm". Understanding this process may lead to mechanisms that may aid in ameliorating these infusion reactions. If they are associated with ADA, then it might be possible to predictively premedicate these patients only. Alternatively, if they are associated with cytokine release, it may be possible to eliminate premedication in patients who are already CD20+cell depleted in subsequent infusions. Therefore, we will assay the profile of certain cytokines in the serum 4 hours after start of ocrelizumab infusion.

With ocrelizumab expected to enter the MS therapeutic market within the next year, we expect third party payers within and outside the US will require that the FDA or EMA approved versions of anti-CD20 monoclonal antibodies be used in the treatment of MS, namely ocrelizumab. Currently, we estimate several thousand MS patients in the US and Sweden are taking rituximab currently. Thus, it will be important to demonstrate that switching from a chimeric anti-CD20 to a fully humanized anti-CD20 does not lead to unexpected infusion reactions and does not increase the probability of development of anti-drug antibodies.

The Rocky Mountain MS Center (RMMSC) at the University of Colorado Anschutz Medical Campus prescribed rituximab infusions for 533 MS patients in the last 12 months, of which 323 patients received their infusion at the University of Colorado Hospital's Outpatient Infusion Center between September, 2015-March, 2016. The RMMSC is one of the few sites nationwide with large numbers of MS patients treated with rituximab. With the anticipated approval of ocrelizumab, current rituximab users are being counselled by their MS providers at RMMSC to consider switching to ocrelizumab post approval, particularly if US Payers adopt the FDA approved version as the preferred anti-CD20 agent for MS.

Eligibility criteria: Inclusion Criteria:

Switching group:

* Current active patient of RMMSC
* 18-65 years
* Diagnosis of relapsing forms of MS
* Completed ≥ two doses of rituximab with the last dose having been administered:

  1. Within 12 months of screening and
  2. At least 6 months prior to the first planned infusion of study drug
* Are receiving their current infusions of rituximab at the University of Colorado Outpatient Infusion Center
* Have discussed the possibility of switching to ocrelizumab with their MS provider
* Screened for Hepatitis B and C and TB within 2 years of first dose of ocrelizumab
* A negative serum pregnancy test must be available for premenopausal women and for women \<12 months after the onset of menopause, unless they have undergone surgical sterilization.
* Women of childbearing potential must agree to use a "highly effective", hormonal form of contraception or two "effective" forms of non-hormonal contraception. Contraception must continue for the duration of study treatment and for at least three months after the last dose of study treatment
* Are able to complete patient reported outcomes developed as English written scales.
* Must be able and willing to give meaningful, written informed consent prior to participation in the trial, in accordance with local regulatory requirements

Comparator group:

* Current active patient of RMMSC
* 18-65 years
* Diagnosis of relapsing forms of MS
* Completed ≥ two doses of rituximab with the last dose having been administered within 12 months of screening as standard of care
* Are receiving their current infusions of rituximab as standard of care at the University of Colorado Outpatient Infusion Center and will continue to do so
* Are willing to be followed for up to two additional rituximab infusions during the study period as standard of care
* Must be able and willing to give meaningful, written informed consent prior to participation in the trial, in accordance with local regulatory requirements

Exclusion Criteria:

Both groups:

* Pregnant or lactating women
* Hypersensitivity to trial medications
* Hepatic Dysfunction (liver enzymes are 5 times greater than normal)
* History of Congestive Heart Failure
* Any history of a positive blood assay for Hepatitis B or C
* Any history of TB or a positive Quantiferon Gold Assay
* Concurrent use of immunosuppressant medications
* Any history of immunodeficiency or other medical condition increasing risk of anti-CD 20 therapy.
* No serious infection at the time of a scheduled study infusion.
* Any medical, psychiatric or other condition that could result in the patient not being able to give fully informed consent, or to comply with the protocol requirements as determined by the investigator

Primary outcomes:
measure: Proportion of Infusions With >= 1 IRR Between the Switching and Comparator Groups
timeFrame: Day 1, Day 15, Week 24
measure: Difference in the Total Number of IRRs After Each Infusion of Ocrelizumab Compared to Rituximab Infusions in the Comparator Group.
timeFrame: Pre-study (Enrollment), Day 1, Day 15, Week 24
measure: Severity of IRRs Following the Day 1 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions
timeFrame: Day 1, pre-study infusions
measure: Severity of IRRs Following the Day 15 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions
timeFrame: Day 15, pre-study infusions
measure: Severity of IRRs Following the Week 24 Infusion of Ocrelizumab in the Switching and the Comparator Groups Infusions
timeFrame: Week 24, pre-study infusions
measure: Proportion of Patients With an IRR at Day 1 Versus Day 15 and Week 24 Infusions
timeFrame: Day 1, Day 15, Week 24
Secondary outcomes:
measure: Presence of Ocrelizumab Anti-drug Anti-bodies
timeFrame: Day 1 and Week 24
measure: Presence of Rituximab Anti-drug Anti-bodies
timeFrame: Day 1 and Week 24
measure: B Cell Depletion (CD19)
timeFrame: Day 1, Week 24, 1 Year
measure: B Cell Depletion (CD20)
timeFrame: Day 1, Week 24, 1 Year
measure: Cytokine: Eotaxin - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IFN-gamma - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-10 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-12/IL-23p40 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-16 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-1RA - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-27 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-6 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-7 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: IL-8(HA) - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: MCP-1 - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: MDC - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: MIP-1alpha - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: MIP-1beta - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: MIP-3alpha - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: TARC - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: TNF-alpha - Pre-Post Infusion - Day 1
timeFrame: Day 1
measure: Cytokine: Exotaxin - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IFN-gamma - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IL-10 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IL-12/IL-23p40 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IL-16 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IL-1beta - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IL-7 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: IL-8 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: MCP-1 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: MCP-4 - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: MDC - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: MIP-1beta - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: MIP-3alpha - Pre-Post Infusion - Day 15
timeFrame: Day 15
measure: Cytokine: TNF-alpha - Pre-Post Infusion - Day 15
timeFrame: Day 15
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Timothy Vollmer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: Kavita Nair, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: Enrique Alvarez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: