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Clinical Review Report: Ocrelizumab (Ocrevus): (Hoffmann-La Roche Limited): Indication: Management of adult patients with early primary progressive multiple sclerosis as defined by disease duration and level of disability, in conjunction with imaging features characteristic of inflammatory activity [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 May.

Cover of Clinical Review Report: Ocrelizumab (Ocrevus)

Clinical Review Report: Ocrelizumab (Ocrevus): (Hoffmann-La Roche Limited): Indication: Management of adult patients with early primary progressive multiple sclerosis as defined by disease duration and level of disability, in conjunction with imaging features characteristic of inflammatory activity [Internet].

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Results

Findings from the Literature

A total of 214 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 5. There were no excluded studies.

Figure 1. Flow Diagram for Inclusion and Exclusion of Studies.

Figure 1

Flow Diagram for Inclusion and Exclusion of Studies.

Table 5. Details of Included Study.

Table 5

Details of Included Study.

Included Studies

Description of Studies

The ORATORIO study was a phase III, multinational, multi-centre, parallel-group, double-blind, placebo-controlled randomized controlled trial (RCT). Enrolled patients were randomized (2:1) to receive infusions of ocrelizumab or placebo every six months (as two infusions 14 days apart). Randomization was stratified by geographic region (US or non-US) and age (≤ 45 years or > 45 years). During the 120-week treatment period, study participants were required to attend 17 scheduled assessment and/or infusion visits. Additionally, structured telephone interviews were conducted every four weeks starting at week 8 to identify any new or worsening neurological symptoms that would require an unscheduled clinic visit.

Each study site had the following two blinded investigators:

  • A treating investigator responsible for patient care, who had access to patients’ safety and blinded efficacy data
  • An examining investigator, who performed the neurological examination, documented the Functional Systems scores, assessed patients using the Expanded Disability Status Scale (EDSS) and the Karnofsky Performance Status Scale.

Patients were instructed not to discuss any symptoms related to the study treatment with the examining investigator.

The trial was conducted at 182 sites in 29 countries, including (sites): Australia (2), Austria (5), Belgium (2), Bulgaria (2), Brazil (4), Canada (7), Switzerland (2), Czech Republic (3), Germany (18), Spain (14), Finland (3), France (17), UK (5), Greece (3), Hungary (5), Israel (6), Italy (4), Lithuania (3), Mexico (4), Netherlands (2), Norway (1), New Zealand (2), Peru (3), Poland (7), Portugal (5), Romania (4), Russian Federation (1), Ukraine (11), and US (37). There were seven Canadian sites involving 22 patients (12 [4.9%] in the placebo group and 20 [4.1%] in the ocrelizumab group).

Figure 2. Schematic Showing the Design of the ORATORIO Trial.

Figure 2

Schematic Showing the Design of the ORATORIO Trial. Source: Clinical Study Report for ORATORIO.

Populations

Inclusion and Exclusion Criteria

Patients aged 18 years to 55 years with PPMS were eligible for enrolment in the ORATORIO trial if they had an EDSS score between 3.0 and 6.5 and a score of at least 2.0 on the functional systems scale for the pyramidal system that was due to lower extremity findings. The diagnosis of PPMS was made in accordance with the revised 2005 McDonald criteria. Patients also had to have a disease duration of less than 15 years for those with an EDSS greater than 5.0 or less than 10 years for those with an EDSS of 5.0 or less at screening.1

Patients were excluded from the study if they had a history of RRMS, SPMS, or PRMS. Patients were also excluded if they had any of the following: neurologic disorders other than PPMS (including a history of progressive multifocal leukoencephalopathy [PML]); known active bacterial, viral, fungal, or mycobacterial infections; history of recurrent aspiration pneumonia requiring antibiotic therapy; or a history of cancer. As shown in Table 5, there were a number of exclusion criteria associated with laboratory values (e.g., CD4 count, serum creatinine, aspartate transaminase, alanine aminotransferase, platelet count, hemoglobin, absolute neutrophil count, serum immunoglobulin G [IgG] and immunoglobulin M [IgM]).1

Patients with prior exposure to a number of medications that could potentially be used for the treatment of MS were excluded from the study. These included any B-cell targeted therapies (e.g., rituximab), alemtuzumab, anti-CD4, cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, natalizumab, total body irradiation, or bone marrow transplantation. Treatment with beta-interferons, glatiramer acetate, immunoglobulin, plasmapheresis, or other immunomodulatory therapies were not permitted with 12 weeks of randomization. Systemic corticosteroid therapy was not permitted within four weeks prior of screening.1

Baseline Characteristics

A summary of key baseline and demographic characteristics is provided in Table 6. The mean age was similar in the placebo and ocrelizumab groups (44.4 and 44.7 years, respectively). Almost half of the participants in each group were older than 45 years of age at baseline (51.6% and 52.9% in the placebo and ocrelizumab groups, respectively). The percentage of females was 50.8% in the placebo group and 48.6% in the ocrelizumab group. More than 90% of patients in each group were white and a majority were recruited from centres located in Europe (64.3% and 64.5% in the placebo and ocrelizumab groups, respectively). The mean duration since the onset of MS symptoms was 6.1 years in the placebo group and 6.7 years in the ocrelizumab group. The mean time since PPMS diagnosis was 2.8 and 2.9 years in the placebo and ocrelizumab groups, respectively. The mean EDSS at baseline was 4.7 in both groups.

Table 6. Summary of Baseline and Demographic Characteristics.

Table 6

Summary of Baseline and Demographic Characteristics.

Prior Therapy with Multiple Sclerosis Treatments

The majority of patients had not received treatment with a disease-modifying therapy (DMT) for MS within two years of randomization (87.7% and 88.7% in the placebo and ocrelizumab groups, respectively). Of those who had prior exposure to a DMT, the majority received interferon beta-1a or interferon beta-1b (Table 7). Similarly, fewer than 20% of patients in each group had received treatment with steroids for their MS (18.4% and 18.2% with placebo and ocrelizumab, respectively). A detailed list of medications that had been received by the study participants is provided in Table 28. The proportion of patients with prior exposure to therapies that could potentially be used for the treatment of MS are summarized in Table 7. Overall, 11.3% of patients in the ocrelizumab group and 12.3% in placebo group reported exposure to at least one MS treatment prior to randomization. Interferon beta-1a and interferon beta-1b were the most common treatments, followed by glatiramer acetate. Although listed in the exclusion criteria of the study, one ocrelizumab-treated patient reported prior experience with natalizumab.1

Table 7. Prior Exposure to Multiple Sclerosis Therapies.

Table 7

Prior Exposure to Multiple Sclerosis Therapies.

Interventions

Study Treatments

Patients randomized to ocrelizumab received IV infusions every six months (as two 300 mg infusions 14 days apart). Those randomized to the placebo group received infusions with the matching IV placebo. In the event of an infusion-related reaction, the infusion rate could be reduced or interrupted according to the following pre-specified protocols:1

  • Grade 1 or 2: the infusion rate was to be reduced to half the rate that was being given at the time of onset of the event, and, if tolerated, increased again 30 minutes after the event had resolved.
  • Grade 3, or flushing, fever, and throat pain cluster: infusion interrupted immediately and the patient to receive aggressive symptomatic treatment. The infusion was to be restarted only after all of the symptoms had disappeared, with a rate at restart of half of the rate being given at the time of onset of the event.
  • Grade 4: infusion stopped immediately and patient to receive appropriate treatment; these patients were to be withdrawn from study treatment and initiate the safety follow-up period.

Pre-Medication for Infusion-Related Reactions

All patients were to receive prophylactic treatment with 100 mg of methylprednisolone IV approximately 30 minutes before the start of each ocrelizumab infusion. In the event that the use of methylprednisolone was contraindicated, the patient was to receive an equivalent dose of an alternative steroid. The trial protocol also recommended that the infusions be accompanied by prophylactic treatment with an analgesic/antipyretic (e.g., acetaminophen 1,000 mg) and an IV or oral antihistamine (e.g., diphenhydramine 50 mg) 30 minutes to 60 minutes prior to the start of the infusion.1

Outcomes

The complete list of primary, secondary, and exploratory efficacy end points that were evaluated in the ORATORIO trial are provided in Table 8. Details regarding the end points of interest for this review are summarized after the table.

Table 8. Efficacy End Points in ORATORIO.

Table 8

Efficacy End Points in ORATORIO.

Confirmed Disability Progression

Time to confirmed disability progression (CDP) for 12 weeks was the primary end point of the study. Time to CDP for at least 24 weeks was a secondary end point. Disability progression was defined as an increase in a patient’s EDSS score of at least 1.0 from baseline when the baseline score was ≤ 5.5; or an increase of 0.5 from baseline when the baseline score was > 5.5. Disability progression was considered to be confirmed when the increase from baseline in EDSS was documented at a regularly scheduled clinic visit at least 12 weeks or 24 weeks after the patient’s neurological worsening was initially documented. The EDSS is an ordinal scale used to measure disability in MS. It relies on the following eight functional systems: pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral total, and cerebral mentation. Each functional system is graded separately on a scale ranging from 0 (normal) to either 5 or 6. The EDSS score is a composite ranging from 0 to 10 (in increments of 0.5) that incorporates functional system grades as well as the degree of functional disability and ambulation. Scores from 0 to 4.5 represent normal ambulation, while scores of 5 and above represent progressive loss of ambulatory ability. All EDSS assessments were performed by blinded examiners who were not otherwise involved in the care of the study patients.

Timed 25-Foot Walk

The Timed 25-Foot Walk (T25FW) is one of three components of the Multiple Sclerosis Functional Composite (MSFC). The T25FW assessment involves the patient walking a 25-foot course as quickly as possible (but safely).20 The time required to complete the 25-foot course is recorded and the task is immediately administered again by having the patient walk back the same distance. The score for the T25FW is the average of the two completed trials. Patients may use assistive devices when completing the T25FW (e.g., canes, crutches, walkers).20 A change of at least 20% in the T25FW is commonly cited as the minimal clinically important difference (MCID) for patients with MS.2124

Magnetic Resonance Imaging End Points

Efficacy end points that were evaluated using magnetic resonance imaging (MRI) included the following: change in brain volume from week 24 to week 120 (secondary end point); change in volume of T2 lesions from week 24 to week 120 (secondary end point); total number of new or newly enlarged T2 hyperintense lesions by week 120 (exploratory end point); total number of new T1 gadolinium (Gd)-enhancing lesions by week 120 (exploratory end point). MRIs were scheduled for day 1, week 24, week 48, and week 120. For those who withdrew early, an MRI was also to be performed at the visit when the patient withdrew.1 Change in brain volume was assessed after 24 weeks of treatment due the potential for reduced inflammation following the initiation of treatment. Such a reduction in inflammation could appear as reduced volume due to reduced inflammation as opposed to capturing atrophy.

Multiple Sclerosis Functional Composite

Change from baseline to 96 weeks in the MSFC score was a secondary end point. The MSFC includes three objective and quantitative continuous scales that assess leg function and ambulation (with T25FW), arm and hand function (with the 9-Hole Peg Test [9-HPT]), and cognitive function (with the 3-second Paced Auditory Serial Addition Test [PASAT-3]). Scores on component measures are converted to standard scores (z-scores), which are averaged to form a single MSFC score. A positive change in the composite z score indicates improvement, and a negative change indicates worsening. A 20% change in scores on T25FW trials and 9-HPT, and a 0.5 standard deviation (SD) change on PASAT-3, are considered clinically meaningful.25,26 An MCID for the overall MSFC score has not been reported.

Short Form (36) Health Survey Physical Component Summary

The Short Form (36) Health Survey (SF-36) is a 36-item generic health status measure. It measures eight general health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Higher scores indicate better health-related quality of life (HRQoL). The eight sub-domains are each measured on a scale of 0 to 100, with an increase in score indicating improvement in health status. The SF-36 items can be analyzed in the following two categories: the physical component summary (PCS), which measures physical functioning, role physical, bodily pain, and general health; and the mental component summary (MCS), which measures vitality, social functioning, role emotional, and mental health. Change from baseline in the SF-36 PCS and SF-36 MCS were secondary and exploratory end points in the ORATORIO trial, respectively.

Statistical Analysis

All statistical hypotheses for the primary and secondary end points were tested at a 5% significance level using a two-sided test. The methods used for statistical analysis of the efficacy end points are summarized in Table 9. The proportion of patients with CDP for at least 12 weeks or 24 weeks was estimated using Kaplan–Meier methodology; the hazard ratios were estimated using a Cox regression model stratified by region (US versus non-US) and age (≤ 45 years versus > 45 years).The ocrelizumab and placebo groups were compared using a two-sided log-rank test for the CDP end points.1 In the primary analyses of CDP for at least 12 weeks (primary end point) and 24 weeks (secondary end point), any patients with an initial progression event who withdrew prior to confirmation at a follow-up visit (and thus, had a missing follow-up value) were counted as events (i.e., the data were included in the analyses as imputed CDP events and were not censored). Those who had an initial progression event and remained on treatment, but did not have a confirmation visit prior to the clinical cut-off, were censored.1

Table 9. Statistical Analysis of Efficacy End Points.

Table 9

Statistical Analysis of Efficacy End Points.

Sensitivity analyses used different approaches for handling missing data — including an intention-to-treat (ITT) analysis conducted without imputation, a multiple imputation approach where 50% of patients who discontinued after an initial progression event (but prior to a confirmation visit) were imputed as having CDP events, and a post hoc analysis where patients with initial disability progression who discontinued treatment prior to a confirmation visit were imputed as having CDP events if the reasons for withdrawal were reported as either “lack of efficacy” or “withdrawal by subject.” Additional sensitivity analyses were conducted for the CDP end points, including the use of a per-protocol data set; an analysis using baseline Gd-enhancing lesions (presence or absence) and baseline EDSS score (≤ 5.5 versus > 5.5) as additional covariates; an analysis that excluded events that occurred during the first 12 weeks of the trial; an analysis using the original planned sample size of 630 patients; and an analysis that excluded patients who had events that met the criteria for an MS relapse.1

Analysis Populations

Three analysis populations were used in the evaluation of efficacy and safety end points in the ORATORIO study: ITT, per-protocol, and safety populations. Details of each analysis population are provided in Table 10.

Table 10. Efficacy and Safety Analysis Populations.

Table 10

Efficacy and Safety Analysis Populations.

Multiple Comparisons

A summary of the statistical testing hierarchy used in the ORATORIO trial to adjust for inflated type I error associated with multiple statistical comparisons is provided in Table 11. All secondary efficacy end points were only tested in a confirmatory manner if the secondary end point located immediately above it in the hierarchy was statistically significant at P < 0.05.1

Table 11. Statistical Testing Hierarchy.

Table 11

Statistical Testing Hierarchy.

Sample Size

The planned sample size for the ORATORIO trial was 630 patients.1 This was estimated based on the following assumptions: progression rates of 30% and 43% in patients receiving ocrelizumab and placebo (respectively); a one-year accrual period with a 3.5-year maximum treatment period; and a dropout rate of 20% over two years. It was calculated that 630 patients would provide approximately 80% and 92% power with type I error rates of 0.01 and 0.05, respectively. The statistical analysis plan indicated that 253 CDP events were required to maintain statistical power to detect the planned treatment difference. The manufacturer reported that there was an unexpected increase in screening for the study after the closing of enrolment was announced, resulting in 732 patients being randomized as opposed to the planned 630 patients. A sensitivity analysis was performed using the results of the first 630 randomized patients.

Subgroup Analyses

The manufacturer conducted the following univariate subgroup analyses: age (≤ 45 years or > 45 years); sex (male or female); EDSS (≤ 5.5 or > 5.5); region (non-US or US); Gd-enhancing lesion(s) at baseline (presence or absence); prior exposure to MS DMT (yes or no); duration since MS symptom onset (≤ 3 years, > 3 to ≤ 5 years, > 5 to ≤ 10 years, or > 10 years); weight (< 75 kg or ≥ 75 kg); and body mass index (BMI) (< 25 or ≥ 25 kg/m2).1 In addition, the manufacturer conducted a multivariate sensitivity analysis using all of the subgroup variables noted previously as main and treatment interaction effects, with the exception of weight (due to close association with BMI). In the multivariate analysis, the continuous subgroup variables (i.e., age, EDSS, duration since MS symptom onset, and BMI) were included as linear covariates. Subgroup interaction P values below 0.1 were considered statistically significant; those below 0.2 were considered “a trend;” and those between 0.2 and 0.3 were considered “a weak trend.”

Patient Disposition

Patient disposition for the double-blind phase of the ORATORIO study is summarized in Table 12. Patients were screened and enrolled in 29 countries at 182 investigational sites. A total of 943 patients were screened for the ORATORIO study; 732 were randomized. The manufacturer reported that the 211 screening failures were the result of patients failing to meet the eligibility criteria of the study or withdrawing consent (reasons for screening failure were not reported in aggregate, but individual reasons were included in the Clinical Study Report). Of the 732 patients who were randomized, 725 (99%) received at least one dose of the study treatment. Withdrawals were more common in the placebo group (34%) compared with the ocrelizumab group (21%). The manufacturer reported that the difference in withdrawals was primarily due to increases in withdrawals due to “lack of efficacy” and “withdrawal by subject” in the placebo group compared with ocrelizumab group (11% versus 4% and 9% versus 5%, respectively). The FDA conducted a detailed review of the reasons for discontinuation (including those in the “other” or “withdrawal by subject” categories) to assess if lack of efficacy could have been a contributing factor. They reported that the proportions of patients who most likely withdrew due to a lack of efficacy was 7.2% and 17.2% in the ocrelizumab and placebo groups, respectively.16 The proportions of patients who withdrew as a result of adverse events (AEs) was similar in the placebo (5%) and ocrelizumab (4%) groups.1

Table 12. Patient Disposition.

Table 12

Patient Disposition.

Exposure to Study Treatments

Study Treatments

Table 13 provides a summary of exposure to the study treatments. The mean and median number of doses was greater in the ocrelizumab group compared with the placebo group (6.6 versus 6.1 and 7.0 versus 6.0, respectively).1 The majority of patients in both groups received at least 120 weeks of exposure, though the proportion was greater in the ocrelizumab group (81%) compared with the placebo group (70%).

Table 13. Summary of Exposure to Study Treatments.

Table 13

Summary of Exposure to Study Treatments.

Concomitant Medications

Concomitant medications used in the ORATORIO trial are summarized in Table 14. At least one concomitant medication was used by 93.0% of patients in the ocrelizumab group and 89.5% in the placebo group. The proportion of patients who were receiving treatment with fampridine or dalfampridine was 21.8% in the placebo group and 18.9% in the ocrelizumab group. A greater proportion of placebo-treated patients received corticosteroids during the trial compared with ocrelizumab-treated patients (38.9% versus 32.7%). The use of antispasmodics/anticholinergics (20.1% with placebo and 21.0% with ocrelizumab) and anticonvulsants (19.2% with placebo and 20.4% with ocrelizumab) was balanced between the groups. Patients treated with ocrelizumab were more likely to use antihistamines (22.2% versus 9.6%).

Table 14. Summary of Exposure to Concomitant Medications.

Table 14

Summary of Exposure to Concomitant Medications.

Critical Appraisal

Internal Validity

Randomization in the ORATORIO trial was conducted using appropriate methods with adequate measures to conceal treatment allocation (i.e., independent Interactive Voice/Web Response System). The randomization list was not available to the study personnel. Randomization was stratified by geographic region (US or non-US) and age (≤ 45 years or > 45 years). Key demographic characteristics were generally balanced between the ocrelizumab and placebo groups.16 However, the mean number of Gd-enhancing lesions at baseline was greater in the ocrelizumab group compared with the placebo group (1.21 [5.14] versus 0.60 [1.55]). This imbalance could introduce bias if the efficacy of ocrelizumab is different in the presence of acute inflammation; the clinical expert consulted for this review agreed with this potential limitation, and the FDA medical review also noted this as a potential concern.16 However, post hoc sensitivity analyses were conducted for the CDP end points that included the presence or absence of a Gd-enhancing lesion as an additional covariate, and the results were similar to the primary analyses. The study protocol for the ORATORIO trial stated that investigators should attempt to maintain treatments for MS symptoms throughout the study; however, changes in therapy were permitted if they were considered appropriate for the well-being of the patient.1 The number of patients using fampridine or dalfampridine increased throughout the study in both the placebo group (5.0% to 21.8%) and ocrelizumab group (7.2% to 18.9%). Since fampridine is indicated for improving walking ability in MS patients, the use of this medication could influence the results of the T25FW (a secondary end point of the study). Analyses were not performed to examine any potential impact of fampridine use; therefore, the magnitude and direction of any potential bias due to fampridine use is unclear. Of note, this was not cited as a concern by the FDA or the European Medicines Agency (EMA).9,1618

The study treatments in ORATORIO were administered in a double-blind manner. Differences in the AE profiles related to the administration of the study drugs could have allowed some patients and investigators to infer which patients had been administered the active treatment. For example, infusion-related reactions were more commonly reported in the ocrelizumab group compared with the placebo group (39.9% versus 25.5%) and the use of antihistamines was more common in patients treated with ocrelizumab (22.2% versus 9.6%).1 EDSS was evaluated by a blinded examining investigator who was not involved in the medical management of patients and did not have access to the patients’ data. MRI scans for efficacy end points were evaluated by a centralized reading centre that was blinded to allocated treatment.

The disposition of patients who were screened and enrolled in ORATORIO was appropriately reported in the Clinical Study Report.1 The planned sample size for the ORATORIO trial was 630 patients; however, 732 patients were randomized due to an unexpected increase in screening after the closing of enrolment was announced by the manufacturer. This 16.2% increase in the sample size of the trial was not specified in a protocol amendment and had a measurable impact on the results of the study. A sensitivity analysis demonstrated that the primary end point of the trial would have not have met statistical significance without the enrolment of these additional patients.

The rate of withdrawal was disproportionate, with more patients discontinuing in the placebo group (33.6%) compared with the ocrelizumab group (20.7%). The proportion of patients who withdrew from the study exceeded the 20% cited in the sample-size calculation.1,9 The FDA noted that the proportion of withdrawals in each group exceeded the absolute difference of 7.1% between the two groups with respect to the primary end point, leading to uncertainty regarding the accuracy of treatment effect.18

Significant protocol violations were rare in the ORATORIO trial and were balanced between the two treatment groups (i.e., the per-protocol population included 96% and 95% of patients in the ocrelizumab and placebo groups, respectively); therefore, protocol violations were unlikely to affect the interpretation of the study results. Reviewers for the FDA also noted this.16 Although not counted as significant protocol violations by the manufacturer, 67% of patients in the study had their baseline EDSS measurements recorded after randomization (29% after receiving an infusion of the study treatment). A breakdown by treatment group was not reported; therefore, it is unclear whether the percentage of patients in the study who had their baseline EDSS measurement recorded after randomization was differential between groups and may have affected internal validity. The FDA reviewers noted that this is an unusually extensive failure of study investigators to follow a clinical trial protocol.16

Pre-specified sensitivity analyses that did not use imputed data for the primary end point failed to demonstrate statistical significance for 12-week and 24-week CDP. The use of imputed data in the primary efficacy analysis (which demonstrated statistical significance in favour of ocrelizumab) is not the method that is typically used to evaluate CDP in relapsing MS trials.16 The primary method of analysis that is typically used for CDP end points in relapsing trials does not include imputed data, as was the case with pivotal ocrelizumab trials for the RRMS indication (OPERA-I and OPERA-II). The manufacturer reported that this approach was used because disability progression is different in PPMS than in RRMS. Specifically, they cited evidence of a higher rate of EDSS confirmation in progressive MS versus relapsing MS from a 2008 study27 that reported 12-week CDP confirmation rates in progressive MS patients of approximately 80%. An FDA reviewer had concerns regarding the analysis of the CDP end point in the ORATORIO trial, noting that the use of imputed data in the primary analysis may have biased the results in favour of ocrelizumab with respect to demonstrating statistical significance for the primary end point. Further analysis demonstrated that 23% of patients who had an initial disability progression event did not have it confirmed at least 12 weeks afterwards in ORATORIO (which is similar to the 80% confirmation rate cited by the manufacturer). The FDA conducted additional analyses of the CDP end point, investigating the assumption that 23% of the 21 patients (i.e., five patients) who had imputed CDP events would not have satisfied the criteria for CDP. In particular, they randomly selected five of these 21 patients, modified their event status from the CDP to censoring at withdrawal, applied the same log-rank test as the manufacturer’s primary analysis to obtain a P value for the treatment comparison, then repeated this procedure 500 times, each with a different set of five randomly selected patients. According to the FDA, the results “indicated that the statistical significance of the primary outcome was a valid representation” of the observed treatment in ORATORIO (Table 31 on page 12).18

Similar to the results for CDP, the results for the T25FW test were sensitive to the method of imputation that was used to handle missing values. Missing T25FW values were imputed using last observation carried forward; there were more patients in the placebo group with imputed values compared with the ocrelizumab group at week 120 (29% and 19%, respectively). However, the FDA noted that there were slightly more patients in the ocrelizumab group than in the placebo group who had only baseline measurements available (15 [3.1%] versus five [2.1%]). The FDA conducted an exploratory analysis excluding patients who lacked post-baseline T25FW values and reported that the analysis was no longer statistically significant (i.e., the P value increased from 0.0404 to 0.0528). Similarly, the FDA conducted an analysis using MMRM to handle missing T25FW values and reported a non-statistically significant P value of 0.0783. Baseline T25FW was greater in the ocrelizumab group (14.6 seconds) compared with the placebo group (12.8 seconds); however, the T25FW analyses were adjusted for the baseline values.

All efficacy end points were reported as being analyzed using the ITT population, which was to consist of all randomized patients. However, the evaluation of the MRI end points, SF-36, and T25FW were conducted with a subset of randomized patients. The rationale for reporting that these analyses were conducted in the ITT population is unclear. There was a considerable amount of missing data for these outcome measures (e.g., data for change in brain volume were missing for approximately 35% of randomized patients by week 120), and the impact of this missing data is uncertain. A hierarchical testing procedure was used to control the overall type I error rate at 0.05 for the primary and secondary end points in the ORATORIO study. The EMA noted that the hierarchy used in the ORATORIO trial was appropriate.9 A rationale regarding the order of outcomes in the hierarchy (e.g., clinical importance) was not specified.

External Validity

The clinical expert consulted by CADTH suggested that the patients enrolled in the pivotal trials were reasonably reflective of patients encountered in routine Canadian practice, though they may have been slightly younger on average than the overall Canadian PPMS patient population. This likely reflects the inclusion criteria, which limited enrolment to patients between the ages of 18 and 55 years of age. Patients were required to have an EDSS score of 3.0 to 6.5 to be eligible for the ORATORIO trial. This excludes a number of patients with more severe disability (i.e., EDSS between 7 and 8) or less severe disability (EDSS < 3.0) who could be eligible to receive ocrelizumab in clinical practice. The efficacy and safety of ocrelizumab in such patients is uncertain and will be evaluated in future phase IIIb studies.9 Clinical experts who provided input into the EMA review of ocrelizumab also suggested that the ORATORIO study population had a greater proportion of younger patients who were more likely to have active disease and suggested that the generalizability of the results to the full spectrum of PPMS patients was questionable.9

The proportions of patients with at least one T1 Gd-enhancing lesion at baseline were 27.5% and 24.7% in the ocrelizumab and placebo groups, respectively. The proportions are similar to those reported in a prior phase II/III study of rituximab in PPMS (24.5%; OLYMPUS),28 but higher than the proportion enrolled in PPMS studies for glatiramer acetate (14%; PROMISE) or fingolimod (13%; INFORMS).9,29 The EMA also noted that data regarding the presence of T1 Gd-enhancing lesions in PPMS are sparse and largely limited to characteristics reported in clinical trials.9 The clinical expert consulted by CADTH noted that patients with PPMS are not routinely scanned for T1 Gd-enhancing lesions; therefore, it is challenging to evaluate whether or not this reflects the Canadian PPMS patient population. Furthermore, the clinical expert also indicated that inflammatory activity is not typically observed in PPMS patients and that the appearance of Gd-enhancing lesions could lead them to question the diagnosis (e.g., the patient may have a form of progressive relapsing MS where relapses are not occurring or being detected).

The diagnosis of PPMS for inclusion in the ORATORIO trial was based on the 2005 revised MacDonald criteria, as opposed to the more recent 2010 McDonald criteria (Table 3). The clinical expert consulted by CADTH noted that the 2010 criteria are currently used in Canadian clinical practice, but that the use of the 2005 criteria in the ORATORIO trial is acceptable and does not limit the generalizability of the findings. It should also be noted that the initial version of the protocol for the ORATORIO trial (August 25, 2010) pre-dated the publication of the MacDonald 2010 criteria.1

Placebo is considered an appropriate comparator and is aligned with guidance from the EMA, which states that a placebo-controlled trial is required due to the absence of any other of any treatments approved for PPMS.1,9 The outcomes in the ORATORIO trial included clinical end points (e.g., disability progression), MRI end points (e.g., changes in T2 lesions and brain volume), and patient-reported end points (e.g., SF-36 PCS and SF-36 MCS). The primary and secondary end points are in accordance with guidance from the EMA on the design of trials for PPMS treatments.9,30 However, the manufacturer used 12-week CDP as the primary end point as opposed to 24-week CDP, which the clinical expert indicated was a more clinically relevant end point. The clinical expert noted that the CDP end points studied in the pivotal trials are typically only used in clinical trials, as disability progression is evaluated over a much longer period in Canadian clinical practice.

The dose of ocrelizumab was administered in accordance with recommendations in the product monograph for the first dosage

(i.e., 300 mg on day 1 and 300 mg on day 15).13 However, the subsequent dosages during the double-blind phase were also administered as two 300 mg infusions separated by 14 days, which is not reflective of the product monograph, which recommends a single 600 mg IV infusion once every six months. The clinical expert consulted by CADTH suggested that the dosage regimen used in the ORATORIO trial is unlikely to have affected the efficacy of the treatment relative to the dosage regimen that would be used in clinical practice; however, it could make the treatment more tolerable for some patients. Use of the split dosage regimen required patients to undergo twice as many infusion visits than would be required in routine clinical practice. It is unclear if this additional treatment burden could have influenced patient adherence with the study protocol. All-cause withdrawal for ocrelizumab-treated patients was greater in the ORATORIO trial (20.7%) compared with the pivotal ocrelizumab RRMS trials, which used single 600 mg IV infusions (10.7% to 13.7%); however, this could be attributable to the greater duration of the PPMS trial or to differences in the patient populations. The clinical expert consulted by CADTH noted that increasing the number of clinic visits can be particularly challenging for patients with ambulatory difficulties.

The recommendations in the product monograph for pre-medication and dosage adjustment (i.e., slowing, interrupting, or stopping the infusion) for the management of infusion-related reactions are also consistent with the protocols that were used in the study for PPMS (ORATORIO)1 and RRMS (OPERA-I and OPERA-II).31 The clinical expert consulted by CADTH suggested similar protocols would be applied in Canadian clinical practice.

As is common in clinical trials, the study participants received extensive contact with health professionals, including 17 scheduled assessment and/or treatment visits and telephone interviews every four weeks.1 This is not reflective of routine clinical practice in Canada, where follow-up with patients is considerably less frequent. The clinical expert consulted by CADTH indicated that patients with PPMS are typically seen once every six months after they first present with symptoms; after the diagnosis has been established, they are seen approximately once every 12 months, or as needed.

Efficacy

Only those efficacy outcomes identified in the review protocol are reported here (Methods, Table 4).

Confirmed Disability Progression

Confirmed Disability Progression for at Least 12 Weeks

Figure 3 provides a summary of the results for CDP for at least 12 weeks. In the primary efficacy analysis, ocrelizumab treatment was associated with a statistically significant reduction in the hazard for CDP for at least 12 weeks (hazard ratio: 0.76; 95% confidence interval [CI], 0.59 to 0.98). As shown in Figure 5, the rate of CDP events in the ocrelizumab and placebo groups shows initial separation at the 12-week to 18-week range, then remains relatively stable between the two groups for approximately two years. The rate of CDP events shows additional separation between the two groups beginning at approximately week 120. However, the FDA noted that the number of patients remaining in the trial began to diminish rapidly diminish after the two-year time point.16

Figure 3. Time to Confirmed Disability Progression for at Least 12 Weeks.

Figure 3

Time to Confirmed Disability Progression for at Least 12 Weeks. Adj. = adjusted; CDP = confirmed disability progression; CI = confidence interval; EDSS = Expanded Disability Status Scale; HR = hazard ratio; ITT = intention-to-treat population; GdE = gadolinium-enhancing; (more...)

Figure 5. Kaplan–Meier Curves for Time to Onset of CDP for at Least 12 Weeks (A) and 24 Weeks (B).

Figure 5

Kaplan–Meier Curves for Time to Onset of CDP for at Least 12 Weeks (A) and 24 Weeks (B). N = number of patients in the analysis; OCR = ocrelizumab. Source: Clinical Study Report for ORATORIO.

The results in the ITT population were sensitive to the method of imputation that was used to account for missing data. There were 21 patients (12 placebo and nine ocrelizumab) who experienced an initial progression event but withdrew prior to having the event confirmed at least 12 weeks later. When these patients were considered as having CDP events, the imputed results of the primary end point were statistically significant (hazard ratio: 0.76; 95% CI, 0.59 to 0.98); however, when these events were not imputed, the results were no longer statistically significant (hazard ratio: 0.82; 95% CI, 0.63 to 1.07). Similarly, an analysis using multiple imputation (i.e., 50% of these events were imputed as CDP) failed to demonstrate statistical significance (hazard ratio: 0.78; 95% CI, 0.60 to 1.02). An additional sensitivity analysis was conducted to adjust for the presence or absence of Gd-enhancing lesions at baseline and baseline EDSS score (≤ 5.5 versus > 5.5); the results were identical to the primary analysis (hazard ratio: 0.76; 95% CI, 0.59 to 0.98).

As the planned sample size for the study was 630 patients, the manufacturer conducted a sensitivity analysis using the results for the first 630 patients who were randomized; the results were not statistically significant (hazard ratio: 0.79; 95% CI, 0.60 to 1.04). This analysis also imputed events where initial disability progression was recorded, but not confirmed due to withdrawal by patient, as CDP events. A sensitivity analysis that excluded early progression events (i.e., those that occurred within 12 weeks of randomization) demonstrated results that were nearly identical to the primary analysis (hazard ratio: 0.78; 95% CI, 0.60 to 1.00). This analysis only excluded two events from the placebo group, which further highlights the sensitivity of the observed treatment effect, as the P value shifted from 0.0321 with the primary analysis to a non-statistically significant 0.05 with the exclusion of these two events. Results for the following sensitivity analyses were statistically significant and favoured treatment with ocrelizumab: per-protocol data set (hazard ratio: 0.74, 95% CI, 0.57 to 0.96); exclusion of patients with relapses (hazard ratio: 0.74; 95% CI, 0.56 to 0.98); and an analysis where patients with an initial progression event but no confirmation were counted as having CDP if the reason for withdrawal was cited as “withdrawal by subject” or “lack of efficacy” (hazard ratio: 0.77; 95% CI, 0.60 to 1.00).

The manufacturer conducted univariate subgroup analyses and a multivariate Cox regression analysis to investigate potential treatment-modifying effects. The results for the subgroup analyses of interest for this review are summarized in Table 29. Ocrelizumab was statistically significantly superior to placebo in reducing 12-week CDP only in the subgroup of patients who were less than 45 years of age at baseline (hazard ratio: 0.64; 95% CI, 0.45 to 0.92). The interaction tests for the univariate subgroups were not statistically significant (i.e., P > 0.1).1,32 The multivariate analysis demonstrated no statistically significant interaction effects, but the manufacturer reported a potential for interaction for T1 Gd-enhancing lesions.

Confirmed Disability Progression for at Least 24 Weeks

Figure 4 provides a summary of the results for CDP for at least 24 weeks, a secondary end point of the ORATORIO trial. Ocrelizumab treatment was associated with a statistically significant reduction in the hazard for CDP for at least 24 weeks compared with placebo (hazard ratio: 0.75; 95% CI, 0.59 to 0.98). Similar to the results for CDP for at least 12 weeks, the rate of CDP for at least 24 weeks in the ocrelizumab and placebo groups shows initial separation at the 12-week to 18-week range, then remains relatively unchanging between the two groups for approximately two years (Figure 5). The rate of CDP events shows additional separation between the two groups beginning at approximately week 120.

Figure 4. Time to Confirmed Disability Progression for at Least 24 Weeks.

Figure 4

Time to Confirmed Disability Progression for at Least 24 Weeks. CDP = confirmed disability progression; CI = confidence interval; HR = hazard ratio; Imp. = imputation; ITT = intention-to-treat population; OCR = ocrelizumab; n = number of patients with (more...)

Similar to CDP for at least 12 weeks, the results for the 24-week end point were sensitive to the method of imputation that was used to account for patients who experienced an initial progression event, but who discontinued prior to an EDSS evaluation to meet the criteria for CDP. When analyzed without imputation or with multiple imputation (i.e., 50% of these events were imputed as CDP), the results were no longer statistically significant (hazard ratio: 0.82 [95% CI, 0.62 to 1.10] and 0.78 [95% CI, 0.59 to 1.04], respectively). Likewise, an analysis that excluded progression events that occurred within 12 weeks of randomization failed to demonstrate statistical significance (hazard ratio: 0.77; 95% CI, 0.59 to 1.01; P = 0.0589). Results for the following sensitivity analyses were statistically significant and favoured treatment with ocrelizumab: per-protocol data set (hazard ratio: 0.74; 95% CI, 0.56 to 0.97); exclusion of patients with relapses (hazard ratio: 0.71; 95% CI, 0.53 to 0.95); and an analysis where patients with a disease progression event but no confirmation were counted as having CDP if the reason for withdrawal was cited as “withdrawal by subject” or “lack of efficacy” (hazard ratio: 0.76; 95% CI, 0.58 to 1.00). Subgroup analyses were similar to those reported for 12-week CDP (Table 29).

Walking Ability

Change from baseline in T25FW was a secondary outcome. The results are summarized in Table 15. T25FW times increased in both groups throughout the trial (Table 30). There was a statistically significant difference between the ocrelizumab and placebo groups (relative difference: 29.337%; 95% CI, −1.618% to 51.456%). At week 120, the absolute difference between the placebo and ocrelizumab groups in mean change in T25FW time was 3.03 seconds (increase of 11.76 seconds in the placebo group and 8.79 seconds in the ocrelizumab group). Figure 6 shows the percentage change in T25FW from baseline to week 120 for both the placebo and ocrelizumab groups.

Table 15. Change From Baseline to Week 120 in Timed 25-Foot Walk.

Table 15

Change From Baseline to Week 120 in Timed 25-Foot Walk.

Figure 6. Percentage Change From Baseline in T25FW (A) and Time to 20% Increase in T25FW (B).

Figure 6

Percentage Change From Baseline in T25FW (A) and Time to 20% Increase in T25FW (B). CI = confidence interval; N = number of patients in the analysis; OCR = ocrelizumab. Source: Clinical Study Report for ORATORIO.

The manufacturer conducted an exploratory analysis to investigate the time to a 20% increase from baseline in T25FW and reported that ocrelizumab was associated with a reduced risk for experiencing an increase of 20% compared with placebo during the study period (hazard ratio: 0.75; 95% CI, 0.61 to 0.92; P = 0.0053). The Kaplan–Meier curves are shown in Figure 6.

T1 and T2 Lesions

Volume of T2 Lesions

Table 16 summarizes the change from baseline in the volume of T2 lesions. The percentage change from baseline in the volume of T2 lesions was a pre-specified secondary end point. Baseline data were reported for 95.9% (234/244) of patients in the placebo group and 95.1% (464/488) of those in the ocrelizumab group. The mean volume of T2 lesions at baseline was greater in the ocrelizumab group compared with the placebo group (12.761 cm3 versus 11.039 cm3). At week 120, results were available for 78.2% (183/244) of placebo-treated patients and 82.0% (400/464) of ocrelizumab-treated patients. Treatment with ocrelizumab treatment was associated with a statistically significant reduction in T2 lesion volume compared with placebo (decrease of 3.4% versus increase of 7.4%, respectively; P < 0.0001).

Table 16. Change From Baseline to Week 120 in Volume of T2 Lesions.

Table 16

Change From Baseline to Week 120 in Volume of T2 Lesions.

New and Enlarging T2 Hyperintense Lesions

The number of new and enlarging T2 hyperintense lesions was an exploratory end point. As shown in Table 17, the rate of new and enlarging T2 hyperintense lesions was lower in the ocrelizumab group compared with the placebo group (adjusted rate ratio: 0.081; 95% CI, 0.058 to 0.111). At 120 weeks, placebo-treated patients had experienced 2027 new and enlarging T2 hyperintense lesions compared with 388 in the ocrelizumab group.

Table 17. Change From Baseline to Week 120 in T2 Lesions.

Table 17

Change From Baseline to Week 120 in T2 Lesions.

T1 Gadolinium-Enhancing Lesions

The number of Gd-enhancing T1 lesions was an exploratory end point. Treatment with ocrelizumab was associated with a reduction in the number of T1 Gd-enhancing lesions compared with the placebo group. The adjusted rate ratio was 0.024 (95% CI, 0.011 to 0.051) favouring ocrelizumab compared with placebo (Table 18).

Table 18. Change From Baseline to Week 120 in T1 Lesions.

Table 18

Change From Baseline to Week 120 in T1 Lesions.

Change in Brain Volume

Table 19 summarizes the results for change in brain volume from week 24 to week 120, a pre-specified secondary end point of the ORATORIO trial. There was a statistically significant difference favouring ocrelizumab compared with placebo with a relative reduction in brain volume loss of 17.475% (95% CI, 3.206 to 29.251). The absolute difference between the two groups was 0.192% (95% CI, 0.030 to 0.354).

Table 19. Change in Brain Volume From Week 24 to Week 120.

Table 19

Change in Brain Volume From Week 24 to Week 120.

Multiple Sclerosis Functional Composite

Results for change from baseline in the MSFC are summarized in Table 20. There was no difference between the ocrelizumab and placebo groups for change from baseline in the MSFC (least squares mean difference [LSMD]: 0.086; 95% CI, ‒0.051 to 0.222).

Table 20. Change from Baseline to Week 120 in Multiple Sclerosis Functional Composite.

Table 20

Change from Baseline to Week 120 in Multiple Sclerosis Functional Composite.

Modified Fatigue Impact Scale

Ocrelizumab was associated with a decrease in fatigue compared with placebo as assessed by the Modified Fatigue Impact Scale (MFIS) from baseline to week 120 (LSMD: ‒3.456; 95% CI, ‒6.048 to ‒0.863). As shown in Figure 7, treatment with ocrelizumab was also superior to placebo in the MFIS subscales (i.e., physical impact, cognitive impact, and psychosocial impact).1

Figure 7. Change From Baseline in Modified Fatigue Impact Scale.

Figure 7

Change From Baseline in Modified Fatigue Impact Scale. CI = confidence interval; LSMD = least squares mean difference; OCR = ocrelizumab; PLC = placebo; SE = standard error. Source: Clinical Study Report for ORATORIO.

Short Form (36) Health Survey

Results for change from baseline in the SF-36 PCS and SF-36 MCS are summarized in Table 21. Change from baseline to week 120 in the SF-36 PCS was a pre-specified secondary end point and there was no statistically significant difference between the ocrelizumab and placebo groups (LSMD: 0.377; 95% CI, ‒1.048 to 1.802). Change from baseline to week 120 in the SF-36 MCS was an exploratory end point. Ocrelizumab-treated patients demonstrated an improvement in mean SF-36 MCS; those treated with placebo experienced a reduction in mean SF-36 MCS (LSMD: 3.318; 95% CI, 1.414 to 5.221).

Table 21. Change From Baseline to Week 120 in Short Form (36) Health Survey PCS and MCS.

Table 21

Change From Baseline to Week 120 in Short Form (36) Health Survey PCS and MCS.

Harms

Only those harms identified in the review protocol are reported. A summary of key harms data is reported in Table 22. The overall proportion of patients who experienced at least one AE was 95.1% in the ocrelizumab group and 90.0% in the placebo group. Serious adverse events (SAEs) were reported for 22.2% of patients in the placebo group and 20.4% of those in the ocrelizumab group. Events leading to withdrawal from the study treatments occurred for 4.1% in ocrelizumab group and 3.3% in the placebo group.

Table 22. Summary of Adverse Events.

Table 22

Summary of Adverse Events.

Adverse Events

AEs that occurred in at least 5% of patients in either of the treatment groups are summarized in Table 23. Infusion-related reactions were the most commonly reported AEs in the ocrelizumab group. Infections and infestations were the most frequently reported category of AEs, with a similar frequency in the ocrelizumab and placebo groups (69.8% and 67.8%, respectively). Relative to the placebo group, the ocrelizumab group reported a lower frequency of nasopharyngitis (22.6% versus 27.2%, respectively) and a greater frequency of upper respiratory tract infections (10.9% versus 5.9%, respectively). Depression and contusions were more commonly reported in the placebo group compared with the ocrelizumab group (12.6% versus 7.6% and 17.9% versus 2.9%).

Table 23. Adverse Events Occurring in at Least 5% of Patients.

Table 23

Adverse Events Occurring in at Least 5% of Patients.

Serious Adverse Events

SAEs that occurred during the double-blind portion of the ORATORIO trial are summarized in Table 24. The overall proportion of patients who experienced at least one event was similar in the ocrelizumab and placebo groups (22.2% versus 20.4%). The overall rate of SAEs was 11.67 per 100 person-years in the placebo group and 10.24 per 100 person-years in the ocrelizumab group during the controlled treatment period. The proportion of patients who experienced a serious event that was categorized as an infection or infestation was similar in both the ocrelizumab and placebo groups (6.2% versus 5.9%). The proportion of patients with a serious event that was categorized as a neoplasm was greater in the placebo group compared with the ocrelizumab group (2.9% versus 1.6%).

Table 24. Serious Adverse Events Occurring in at Least 1% of Patients.

Table 24

Serious Adverse Events Occurring in at Least 1% of Patients.

Withdrawals Due to Adverse Events

AEs that led to withdrawal from the study treatment are summarized in Table 25. Overall, 20 patients (4.1%) withdrew from ocrelizumab treatment as a result of AEs, and eight patients (3.3%) withdrew from the placebo group. Cancers were the most frequently reported category of AE leading to discontinuation from the ocrelizumab group (seven patients [1.4%]) and it occurred at a greater frequency than in the placebo group (one patient [0.4%]). The proportion of patients who withdrew as a result of an infection was 0.8% in the ocrelizumab group compared with 1.3% in the placebo group. The proportion of patients who withdrew as a result of an infusion-related reaction was the same in the placebo and ocrelizumab groups (0.4% in each). A greater proportion of ocrelizumab-treated patients experienced at least one AE that led to a modification or interruption of the study treatment compared with those who received placebo (9.7% [65 events] versus 5.0% [14 events]) (Table 32).

Table 25. Withdrawals Due to Adverse Events.

Table 25

Withdrawals Due to Adverse Events.

Mortality

There were five deaths during the double-blind phase of the ORATORIO study: four in the ocrelizumab group (pulmonary embolism, pancreatic metastatic carcinoma, desquamative pneumonia, and aspiration pneumonia) and one in the placebo group (traffic accident). The investigators reported that all of the deaths were considered to be unrelated to the study drug, but the sponsor reported deaths due to desquamative pneumonia and aspiration pneumonia as related to the study drug.1

Infusion-Related Reactions

Table 26 provides a summary of the frequency, severity, and timing of the infusion-related AEs reported in the ORATORIO trial. Infusion-related reactions were the most commonly reported AE in the ocrelizumab group (39.9%); these events occurred with a greater frequency than in the placebo group (25.5%). The most commonly reported symptoms associated with infusion-related AEs in the ocrelizumab group were pruritus, flushing, rash, pyrexia, headache, and throat irritation. Nearly all of the infusion-related AEs were mild or moderate in severity (98.8% in the ocrelizumab group and 98.3% in the placebo group were grade 1 or 2 events). Grade 3 infusion-related AEs were reported for six ocrelizumab-treated patients (1.2%) compared with four (1.7%) patients in the placebo group. There were no infusion-related AEs of grade 4 or grade 5 severity. The proportion of patients who withdrew as a result of an infusion-related reaction was 0.4% in both the placebo and ocrelizumab groups.

Table 26. Infusion-Related Adverse Events.

Table 26

Infusion-Related Adverse Events.

The proportion of patients who experienced infusion-related AEs tended to decrease throughout the trial. The first 300 mg dosage of ocrelizumab was associated with the highest proportions of patients with an infusion-related event (27.4%). This was reduced to 11.5% with the next dose (i.e., six months later), and subsequently reduced to ≤ 7.0% for the remaining infusions.

Serious Infections

Table 27 provides a summary of the categories of serious infections that were documented during the double-blind phase of the ORATORIO study. The proportion of patients who experienced at least one serious infection was 8.8% in the placebo group and 7.6% in the ocrelizumab group. Urinary tract infections and pneumonia were the most frequently reported serious infections in both the ocrelizumab and placebo groups (1.4% versus 1.7% and 1.2% versus 1.2%, respectively). When adjusted for exposure, the event rates for serious infections were 4.24 per 100 patient-years with placebo and 3.74 per 100 patient-years with ocrelizumab (rate ratio: 0.8818; 95% CI, 0.558 to 1.394).

Table 27. Serious Infections.

Table 27

Serious Infections.

Opportunistic Infections

Potential opportunistic infections were analyzed using a basket of terms, including upper respiratory tract infection, lower respiratory tract infection, herpes virus-associated infections, skin infections, urinary tract infections, sepsis, and sepsis/systemic inflammatory response. The manufacturer conducted a detailed medical review of all potential opportunistic infections (i.e., identification of the pathogen, location, and endemicity of the infection) and reported that none of the infections were considered opportunistic.

The overall proportion of patients with at least one potential opportunistic infection was slightly greater in the ocrelizumab group than in the placebo group (5.3% versus 3.8%). However, when adjusted for exposure, the overall rate of potential opportunistic infections was lower in the ocrelizumab group (2.33 per 100 patient-years) compared with the placebo group (3.03 per 100 patient-years). All of the events were mild to moderate in severity, with the exception of one serious event in the ocrelizumab group (neutropenic sepsis, which required hospitalization). The manufacturer reported that the majority of potential opportunistic infections were associated with the herpes virus and that oral herpes was more commonly reported in the ocrelizumab group compared with the placebo group (2.3% versus 0.4%).

Malignancies

Malignancies were reported in a greater proportion of ocrelizumab-treated patients (11 patients [2.3%]; 13 events) compared with the placebo group (two patients [0.8%]; two events). The rate of malignancy was 0.92 per 100 patient-years (95% CI, 0.49 to 1.57) in the ocrelizumab group and 0.30 per 100 patient-years (95% CI, 0.04 to 1.10) in the placebo group. The most commonly reported malignancies included breast cancer in women (four ocrelizumab-treated patients and no placebo-treated patients) and basal cell carcinoma (three ocrelizumab-treated patients and one placebo-treated patient). Events of basal cell carcinoma were not classified as SAEs; hence, the proportion of ocrelizumab-treated patients with malignancies (2.3%) is greater than the proportion of patients who experienced an SAE that was classified as a neoplasm (1.6%).

Copyright © 2018 Canadian Agency for Drugs and Technologies in Health.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

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