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• Content META

  Title	Evaluating efficacy and safety of ocrelizumab biosimilar (Xacrel) compared to the originator (Ocrevus) in relapsing multiple sclerosis: a phase III, randomized, equivalency, clinical trial
  ID	3471130
  External ID	7236370259
  Author	Unknown
  Published Date	Oct. 22, 2024, 11:54 a.m.
  Summary	Study design and intervention This was a randomized, two-armed, double-blind, phase III clinical trial performed from August 2019 to October 2021 in 15 centers in Iran. Patients were randomly assigne
  Tags	None
  URL	https://www.nature.com/articles/s41598-024-75745-y
  Sentiment	Negative: 0.08750    Neutral: 0.88480    Positive: 0.02770
  Relevance	0.00000

• Content Details

  Content ID	1814118
  Key	db349a9b-feea-451a-b14f-ae544dcebae0
  Content	Study design and intervention This was a randomized, two-armed, double-blind, phase III clinical trial performed from August 2019 to October 2021 in 15 centers in Iran. Patients were randomly assigned (1:1) to receive 300 mg of either Xacrel or Ocrevus at an interval of 2 weeks for the first two doses, followed by 600 mg every 24 weeks for 96 weeks. To reduce the infusion reactions, all patients received 100 mg intravenous methylprednisolone (or the equivalent dose of the other corticosteroids) 30 min prior to infusion. An oral or intravenous antihistamine (i.e., chlorpheniramine) and an antipyretic medication (i.e., acetaminophen) were also administered 30–60 min before infusion. Participants Adult patients diagnosed with MS (according to the McDonald 2010 criteria) were enrolled in the study if they were 18–55 years of age and had a history of at least two documented relapses in the last two years or one documented relapse in the last year before the screening visit. The Expanded Disability Status Scale (EDSS) score had to be between 0 and 5.5 for inclusion. The exclusion criteria were as follows: the diagnosis of PPMS; disease duration of more than 10 years in patients with EDSS ≤ 2 at the screening visit; previous anti B-cell targeted therapy (including rituximab, ocrelizumab, atacicept, belimumab, and ofatumumab); the presence of known neurological disorders that mimic the MS symptoms (including neuromyelitis optica, untreated vitamin B 12 deficiency, neurosarcoidosis, and cerebrovascular disorders); the presence of any limitation for MRI conduction (including claustrophobia, body weight > 140 kg, etc.); pregnancy and lactation; suffering from any chronic disease requiring corticosteroids (oral or parenteral) or immunosuppressive therapy during the study; history or a case of primary or secondary immunodeficiency; inaccessibility of peripheral vessels; history of hypersensitivity reactions or anaphylaxis to monoclonal antibodies; the presence of any serious or uncontrolled medical disorders that prevent the patient from being enrolled in the study (including heart failure class III or IV according to New York Heart Association (NYHA) criteria); the presence of any clinical symptoms of active bacterial, viral, fungal, mycobacterial or other infections; suffering from any infection requiring hospitalization or treatment with parenteral antibiotics within four weeks before the baseline visit or oral antibiotics within two weeks before the baseline visit; history of chronic or recurrent infections (including HIV, hepatitis B, and hepatitis C); history of progressive multifocal leukoencephalopathy (PML); history of malignancies (including solid tumor and hematologic malignancies except for basal cell carcinoma); drug or alcohol abuse within 24 weeks before the screening visit; history of coagulation disorders; receiving any live vaccines within 6 weeks before the screening visit; being under treatment with any other investigational medications within 24 weeks before the screening visit; contraindications or intolerance to oral and parenteral corticosteroids; being under treatment with dalfampridine (unless the patient was receiving a constant dose within 30 days before the screening visit and throughout the study); receiving systemic corticosteroids within 4 weeks before the screening visit (for patients who received parenteral corticosteroids for MS attacks, the duration could be extended to 8 weeks); previous treatment with alemtuzumab, anti-CD4 therapies, cladribine, mitoxantrone, daclizumab, teriflunomide and laquinimod; history of whole-body radiotherapy or hematopoietic stem cell transplantation; treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, or natalizumab within 24 months before the screening visit (patients receiving natalizumab for less than 1 year could be enrolled); treatment with fingolimod or dimethyl fumarate within 4 weeks before the screening visit (patients receiving these medications more than 4 weeks prior to screening could be enrolled provided that their lymphocyte count was more than the lower limit of normal (LLN)); receiving intravenous immunoglobulin (IVIg) within 12 weeks before the baseline visit; a positive beta-hCG result at the screening visit; and laboratory abnormalities (including CD4 + levels < 300/mcL, AST/SGOT or ALT/SGPT ≥ 2 times of the upper limit of normal (ULN), platelet count < 100,000/mcL, serum IgG levels of 18% below the LLN, serum IgM levels of 8% below the LLN, and absolute neutrophil count (ANC) < 1500/mcL). Written informed consent was provided by all the participants. The study was carried out in accordance with the Declaration of Helsinki and was approved by the ethics committees of Tehran University of Medical Sciences (IR.TUMS.VCR.REC.1398.164) and Shahid Beheshti University of Medical Sciences (IR.SBMU.REC.1398.024). The trial was registered in Iranian registry of clinical trials (IRCT) on 10/06/2019 with the registration number of IRCT20150303021315N13 and in Clinicaltrials.gov on 19/07/2021 with the registration code of NCT04966338. Randomization and blinding Eligible patients were assigned to each treatment arm using a dynamic randomization algorithm (minimization) designed to achieve an overall balance between groups. Randomization was stratified according to the baseline EDSS score (≤ 4 vs. > 4). The participants, the medication administrators, and the outcome assessors were all blinded to the allocation. Outcomes The study duration was 96 weeks. The primary outcome of the study was to evaluate the equivalency of Xacrel to Ocrevus in reducing the annualized relapse rate (ARR) at week 48 in patients with RMS. Relapse was defined as new or worsening MS-related neurological symptoms (at least 0.5 scores increase in EDSS, 2 points increase in one of the appropriate FSS, or 1 point increase in at least two of the appropriate FSS) that persisted for more than 24 h, proceeded after at least 30 days of stable or improving neurological conditions, and were not attributed to other clinical conditions (e.g., infection, fever, injury, drug-related adverse reactions). Episodic spasms, sexual dysfunction, fatigue, mood changes, urinary incontinence, and urinary retention were not considered a relapse. The secondary efficacy outcomes included the time to the onset of disability progression confirmed at 12 and 24 weeks over 96 weeks. Disability progression was defined as an increase in the EDSS score by at least 1.5 steps if the baseline EDSS was 0, at least 1 step if the baseline EDSS was 0 > and ≤ 5.5, or at least 0.5 steps if the baseline EDSS was > 5.5. Other secondary outcomes were the proportion of relapse-free patients at 96 weeks, the total number of gadolinium-enhancing lesions, and new or enlarged T 2 hyperintense lesions identified on brain MRI at weeks 24, 48, and 96. The change in the volume of T 2 lesions identified on brain MRI from baseline to week 96 was also assessed. Safety outcomes included the incidence of adverse events (AE) every 12 weeks and infusion reactions every 24 weeks for 96 weeks. All the reported events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 15. In addition, the causality relation was assessed based on World Health Organization (WHO) criteria. All AEs were classified based on the Medical Dictionary for Regulatory Activities (MedDRA) terms as the preferred term (PT) and system organ class (SOC). Serious adverse events (SAEs) were documented according to ICH guidelines (E2B(R2)); SAE was defined as any AE that “results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results in congenital anomaly or birth defect.” Infusion-related reactions were defined as symptoms including pruritus, rash, urticaria, erythema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, throat irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, nausea and tachycardia during or within 24 h after the infusion. Adverse events of special interest (AESIs), included infusion-related reactions, infections and infestations (including herpes infections, urinary tract infections, and respiratory tract infections), and neoplasm benign, malignant, and unspecified (including cysts and polyps). The immunogenicity assessments were also conducted at baseline as well as weeks 24, 48, and 96. The enzyme-linked immunosorbent assay (ELISA) was used for anti-drug antibodies (ADAs) measurements. All the assessments and interventions complied with the valid international guidelines and Good Clinical Practice (GCP) standards. The laboratory methods were validated and implemented by trained staff using reliable kits and in compliance with international and national standards. Statistical analysis A sample size of 76 patients in each group was assumed to provide at least 80% power to detect equivalency when assessed by the risk difference between groups for ARR with a predefined margin of ± 0.20 and a significance level of 0.05. ARR in the reference group (Ocrevus) was reported as 0.16 8. The total sample size of 170 patients was calculated considering the drop-out rate of 10% 16. The primary outcome of ARR at 48 weeks was compared between the two groups using a Poisson regression model, adjusted for baseline EDSS score, and the LS-Means was used to estimate the rate difference between the two groups. Xacrel efficacy was judged equivalent to Ocrevus if the lower and the upper limits of the two-sided 95% confidence intervals (95% CIs) of difference in the ARR between the two study groups (Xacrel and Ocrevus) were within the accepted equivalence margin (− 0.2, 0.2). The primary outcome analysis was performed using the per protocol set (PPS) and the intention to treat (ITT) population. PPS was defined as the patients who completed the study without any major protocol deviation. The ITT population was defined as all randomized patients receiving at least one dose of the study treatment. Data for patients were analyzed based on the assigned study arm. All secondary efficacy analyses were based on the ITT principle. To evaluate the time to the onset of confirmed disability progression (CDP) for 12 and 24 weeks, the overall hazard ratio and its corresponding 95% CI were estimated using a stratified Cox regression model with the same stratification factors used in the stratified log-rank test. In addition, the cumulative probability of disease progression was estimated using the Kaplan–Meier methodology. Finally, the percentages of relapse-free patients between the treatment groups at week 96 were compared using the chi-squared test. The total number of new and/or enlarging T 2 hyperintense lesions identified on the brain MRI at weeks 24, 48, and 96 were compared between study arms using a negative binomial model adjusted for baseline EDSS score and baseline T 2 lesions number. The percent change in the volume of T 2 lesions on brain MRI from baseline to week 96 was compared between the two groups using t-test. The exploratory endpoint of ARR at 96 weeks was compared between two treatment groups using a Poisson regression model, adjusted for baseline EDSS score. The proportion of patients experiencing CD19 levels of less than 1% at least once (%) between treatment groups was compared using the chi-squared test. A missing value for the number of T 2 hyperintense lesions at a particular week was imputed by the average number of new and/or enlarging lesions on available scans obtained during the 96 weeks of study, and the missing values in the volume of T 2 lesions were imputed using last-observation-carried forward (LOCF) methodology. In addition, the missing values were imputed for patients in any study arm if they had a baseline and at least one post-baseline MRI assessment. Safety assessments were performed on all randomly assigned patients who received at least one dose of the medication. Safety outcomes were reported based on the incidence rate of AEs and SAEs. All the statistical analyses were performed using STATA (version 14, StataCorp LP, USA) and R 4.0.3 17.
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• Publisher

  Publisher Name	Nature (#2153)
  Publisher URL	https://www.nature.com/
  Description	None
  Trust Flow Score	61
  Citation Flow Score	58

• Data Source

  Data Source Name	Quantexa News (#5)
  Data Source Type	news
  Data Source URL	https://app.aylien.com/dashboard
  Description	Welcome to Quantexa News API — the most powerful way to aggregate, filter, and integrate global news data into your apps and models.
  Weight	10