A Comparative Study of Pharmacokinetics, Pharmacodynamics, Safety, and Immunogenicity of RPH-035 and Ocrevus® in Patients With Relapsing-remitting or Secondary Progressive Multiple Sclerosis With Exacerbations

A Multicentre, Double-blind, Randomised, Comparative Pharmacokinetics, Pharmacodynamics, Safety, and Immunogenicity Study of RPH-035 Versus Ocrevus® in Patients With Relapsing-remitting or Secondary Progressive Multiple Sclerosis With Exacerbations

The study goal is to establish the equivalence of pharmacokinetic (PK) properties, as well as the comparability of safety, immunogenicity (IG) and pharmacodynamics (PD) of the drug product RPH-035 (R-Pharm JSC, Russia) in comparison with the drug product Ocrevus® (F. Hoffmann-La Roche Ltd., Switzerland) when used in patients with multiple sclerosis (MS)

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: RPH-035; Drug: Ocrevus®

Detailed Description

This study is a multicentre, double-blind, randomised, comparative Phase I study

The clinical study includes the following periods:

1. Screening period: days [-27…-0] (up to 1st administration of study therapy)

2. Main period: weeks [1-49]

   Patients who meet the eligibility criteria shall be randomised in a 1: 1 ratio to one of two study arms: RPH-035 and Ocrevus®

   During the Main Period, the patients will receive their first infusion of ocrelizumab (RPH-035 or Ocrevus®) at a dose of 300 mg, followed by another 300 mg of the drug product after 2 weeks. The duration of ocrelizumab administration will be 2.5 hours ± 15 minutes. The third infusion at a dose of 600 mg should be administered 6 months after the first infusion of the initial dose. The administration is scheduled for the "Week 25" visit.

   The Main Period includes regular collection of data on complaints and symptoms, physical examination, assessment of vital signs (measurement of body temperature, blood pressure (BP), pulse), body weight measurement, monitoring of laboratory parameters (clinical and biochemical blood tests, measurement of the concentration of immunoglobulin type G (IgG), general urine analysis), IG analysis, electrocardiogram (ECG), magnetic resonance imaging (MRI) at weeks 9, 17, 25, 49, neurological examination, assessment according to the Expanded Disability Status Scale (EDSS), registration of adverse events/serious adverse events (AEs/SAEs). MRI and assessment of response to therapy within the Main Period will be performed approximately once every 8 weeks during the first six months of the study (week 1 - week 25), then at week 49

   The week 49 visit consists of two stages: prior to drug administration, procedures are performed to assess the safety and effectiveness of the blinded therapy. After receiving and analysing the results, the research physician decides whether to terminate or extend therapy. If therapy needs to be continued, the patient is transferred to the follow-up period

3. After-Therapy period: weeks [49-97]

   During the After-Therapy Period, beginning at week 49, all patients will receive RPH-035 therapy, including those who received Ocrevus® therapy during the Main Period. Visits are also included in this period, which are conducted in the form of telephone contacts to assess the patient's well-being, collect data on concomitant therapy and possible AEs

   During the After-Therapy Period, patients will receive an IV infusion of ocrelizumab (RPH-035) at a dose of 600 mg at "Week 49", "Week 73", and "Week 97" visits

4. Follow-up period (FU)

The first follow-up visit (FU) is performed 28 ± 3 days after the last visit (scheduled or unscheduled)

• For patients who have completed their participation in the Main Period as planned and are not included in the After-Therapy Period, the FU visit will be conducted once 28 ± 3 days after day 337
• For patients who completed therapy early before day 337 in the study due to treatment failure, the first FU visit will be conducted 28 ± 3 days after the last visit conducted within the therapy (scheduled or unscheduled), but within 337 days. Further FU visits will be conducted in the form of telephone contacts with the patient/patient's relatives with a frequency of 1 time per 8 weeks (±7 days) until day 337 during the study or informed consent (IC) recall (whichever occurs first)
• If a patient completes therapy in the study early before day 337 of the study for a reason not related to treatment failure and is not prescribed another treatment regimen, FU visits will be conducted in the form of an assessment of the response to therapy with MRI once every 8 weeks ± 3 days (from the date of the first FU visit) until day 337 of the study or until another therapy is prescribed/IC is recalled (whichever occurs first). If another treatment regimen is prescribed, FU visits for these patients will continue at a frequency of once every 8 weeks (±7 days) until day 337 within the study or IC recall (whichever occurs first) in the form of telephone contacts with the patient/patient's relatives
• For patients who completed therapy during the after-therapy period either planned or early for any reason, 1 FU visit is scheduled 28 ± 3 days after the last visit during the after-therapy period. After this visit, the patient is considered to have completed the study

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 1

Contacts and Locations

Study Locations

• Russia
  • Chelyabinsk, Russia, 454021
    • State Autonomous Healthcare Institution Regional Clinical Hospital No. 3
  • Kazan', Russia, 420061
    • Kazan State Medical Academy, branch of the Federal State Budgetary Educational Institution of Additional Professional Education Russian Medical Academy of Continuing Professional Education
  • Kazan', Russia, 420101
    • State Autonomous Healthcare Institution "Interregional Clinical and Diagnostic Center"
  • Kirov, Russia, 610007
    • Kirov Regional State Clinical Budgetary Healthcare Institution "Center for Cardiology and Neurology"
  • Krasnodar, Russia, 350049
    • Limited Liability Company DOCKBRAIN
  • Krasnoyarsk, Russia, 660037
    • Federal State Budgetary Institution Federal Siberian Scientific and Clinical Center of the Federal Medical and Biological Agency
  • Moscow, Russia, 127521
    • Research Lab LLC
  • Moscow, Russia, 125367
    • Federal State Budgetary Scientific Institution "Russian Center for Neurology and Neurosciences"
  • Moscow, Russia, 127015
    • State Budgetary Healthcare Institution of the City of Moscow "City Clinical Hospital No. 24 of the Moscow Health Department"
  • Nizhny Novgorod, Russia, 603126
    • State Budgetary Healthcare Institution of the Nizhny Novgorod Region "Nizhny Novgorod Regional Clinical Hospital named after N. A. Semashko"
  • Nizhny Novgorod, Russia, 603137
    • MEDIS Limited Liability Company
  • Novosibirsk, Russia, 630007
    • Federal State Budgetary Healthcare Institution "Siberian District Medical Center of the Federal Medical and Biological Agency"
  • Novosibirsk, Russia, 630087
    • State Budgetary Healthcare Institution of the Novosibirsk Region "State Novosibirsk Regional Clinical Hospital"
  • Perm, Russia, 614045
    • State Budgetary Healthcare Institution of the Perm Region "Perm Regional Clinical Hospital of the Order of the Badge of Honor"
  • Rostov-on-Don, Russia, 344015
    • Rostov Regional Clinical Hospital, State Budgetary Institution of the Rostov Region
  • Saint Petersburg, Russia, 194223
    • LLC "Center for Diagnostics and Rehabilitation "PRAKSIMED"
  • Saint Petersburg, Russia, 194291
    • State Budgetary Healthcare Institution Leningrad Regional Clinical Hospital
  • Saint Petersburg, Russia, 197110
    • St. Petersburg State Budgetary Healthcare Institution "City Clinical Hospital No. 31"
  • Saransk, Russia, 430032
    • State Budgetary Healthcare Institution of the Republic of Mordovia "Republican Clinical Hospital No. 4"
  • Smolensk, Russia, 214018
    • Smolensk Regional Clinical Hospital, Regional State Budgetary Healthcare Institution
  • Tomsk, Russia, 634050
    • Federal State Budgetary Educational Institution of Higher Education "Siberian State Medical University" of the Ministry of Health of the Russian Federation
  • Tyumen, Russia, 625048
    • Joint Stock Company "Medical and Sanitary Unit "Neftyanik"
  • Ulyanovsk, Russia, 432017
    • Ulyanovsk Regional Clinical Hospital, a public health institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Patients shall meet all of the following inclusion criteria:

1. Availability of the voluntarily signed and dated patient Informed Consent (IC) form for participation in this study
2. Multiple sclerosis with exacerbations (relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS) with exacerbations) according to the McDonald diagnostic criteria as revised in 2017, with symptoms lasting at least 1 year before signing the IC form
3. The patient's medical history includes the use of ≤ 3 prior multiple sclerosis disease modifying drugs (DMT)

4. The patient has one of the following signs of disease activity:

   1. ≥ 2 documented disease exacerbations in the previous 24 months before the IC signing date
   2. ≥ 1 documented disease exacerbation in the previous 12 months before the IC signing date
   3. 1 documented exacerbation in the previous 24 months before the IC signing date and ≥ 1 documented brain lesion on the contrast-enhanced Magnetic Resonance Imaging (MRI) scan in the previous 6 months before the IC signing date
5. Expanded Disability Status Scale (EDSS) index is 0-5.5 points inclusively on screening
6. No Multiple sclerosis (MS) exacerbations within 30 days before the IC signing date and throughout the entire screening examination
7. Ability, in the Investigator's opinion, to comply with the Protocol procedures and requirements
8. Negative pregnancy test for female participants with preserved reproductive potential
9. Consent of the patient with preserved reproductive potential to abstain from heterosexual contacts or to use reliable contraceptive methods, starting from the moment of the IC form signing, throughout the entire treatment period within the study, as well as for 12 months after the last ocrelizumab administration. Female participants are considered infertile if definitive amenorrhea was determined (from patient's words) retrospectively after 12 months of natural amenorrhea, i.e amenorrhea with an appropriate clinical status, such as a suitable age (between 45 and 55 years )

Patients cannot be included in the study if they meet at least one of the following exclusion criteria:

1. Medical history of hypersensitivity to monoclonal antibody drugs or to any component of the investigational medicinal products
2. Prior therapy with ocrelizumab
3. Primary progressive multiple sclerosis or SPMS without exacerbations
4. Contraindications for MRI, including intolerance to Gd-containing contrast agents and claustrophobia

5. Medical history of other neurological diseases (excluding migraines) or first diagnosed on screening, including but not limited to the following:

   1. ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or spinal cord ischemia
   2. malignant and benign central nervous system (CNS) tumours (meningiomas, gliomas, etc.) requiring surgical intervention
   3. potential metabolic causes of myelopathy, identified from the medical history or in patient words (untreated vitamin B12 deficiency, etc.)
   4. infectious myelopathy (syphilis, Lyme disease, human T-lymphotropic virus 1 [HTLV-1], herpes zoster)
   5. hereditary progressive CNS degenerative disorder, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke)
   6. neuromyelitis optical spectrum disorders
   7. progressive multifocal leukoencephalopathy
6. Systemic autoimmune disease (lupus, rheumatoid arthritis, antiphospholipid antibody syndrome, Sjorgen's syndrome, Behcet's syndrome)
7. Sarcoidosis
8. Medical history of severe, clinically significant brain or spinal cord injury (brain contusion, spinal cord compression)

9. Medical history of the patient includes the following therapy:

   1. targeted biological B-cell therapy (ocrelizumab, rituximab or ofatumumab, etc.)
   2. bone marrow transplantation, lymphocyte irradiation
   3. any unregistered biological drug product for MS treatment

10. The patient received any of the following therapies (subject to the time/dose restrictions specified):

    1. natalizumab (inclusion of such patients in the study is allowed, provided that the therapy was completed > 12 months before the IC signing date)
    2. fampridine (administration is allowed, provided only that the patient has been receiving continuous therapy with the drug product for at least 3 months before the IC signing date)
    3. alemtuzumab (< 4 years before the IC signing date)
    4. fingolimod (< 6 weeks before the IC signing date)
    5. dimethyl fumarate, siponimod (< 4 before the IC signing date)
    6. teriflunomide (< 3.5 months before the IC signing date), in case of accelerated elimination procedure < 2 weeks before the IC signing date)
    7. immunosuppressive drug products: azathioprine, mycophenolate mofetil, methotrexate, TNF-α inhibitors (< 6 months before the IC signing date) cyclophosphamide, mitoxantrone, cladribine (< 24 months before the IC signing date)
    8. interferon beta/glatiramer acetate (< 2 weeks before the IC signing date)
    9. immunoglobulin intravenous administration within < 12 weeks before the IC signing date
    10. plasmapheresis or plasma adsorption (< 21 days before the randomisation date)
    11. therapy with systemic glucocorticosteroids (GCS), adrenocorticotropic hormones (ACTH) < 1 month before MRI screening
    12. live or live attenuated vaccine within < 3 months before the IC signing date or vaccination plans for the study period

11. Concomitant diseases that increase the patient's risk of AE development during the use of the investigational therapy or may affect the assessment of MS symptoms severity; mask, intensify, modify MS symptoms or cause clinical and laboratory-instrumental symptoms similar to those in MS as confirmed by primary documentation data:

    1. uncontrolled arterial hypertension characterised by systolic blood pressure (BP) above 150 mmHg or diastolic BP above 90 mmHg during the antihypertensive therapy
    2. medical history of moderate or severe heart failure (functional class III/IV according to the New York Heart Association (NYHA) classification), stable effort angina of functional class III-IV, unstable effort angina, or medical history of myocardial infarction less than 6 months before randomisation
    3. diagnosis of any clinically significant (in the opinion of the investigator) respiratory disease including, but not limited to, chronic obstructive pulmonary disease of grade 3 or 4 severity
    4. diagnosis of active liver disease or liver failure based on medical history

12. Haematological disorders:

    1. haemoglobin < 80 g/L
    2. white blood cells (WBC) < 3.0 × 10^9/L
    3. absolute neutrophil count < 1.5 × 10^9/L
    4. absolute lymphocyte count < 0.5 × 10^9/L
    5. platelets < 100 × 10^9/L

13. Renal impairment:

    a. creatinine > 1.5 × upper limit of normal (ULN) or glomerular filtration rate < 45 mL/min, calculated using CKD-EPI formula

14. Hepatic impairment:

    a. bilirubin, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 2 × ULN

15. Presence of oncological pathology that is progressing or requires anti-tumour therapy (including hormonal therapy) within 5 years before the IC signing date, except for radically resected cervical carcinoma in situ or radically resected basal cell/squamous-cell carcinoma of skin
16. Medical history of diverticulitis or other gastrointestinal tract (GI) disorders (e.g., inflammatory bowel disease, mechanical ileus, hernia) that can cause gastrointestinal (GI) perforations in patients

17. Diseases (e.g., asthma, psoriasis) that require treatment with immunosuppressive biological drugs or systemic corticosteroids during the study

    1. medical history of primary and/or secondary immunodeficiencies (most commonly manifested by recurrent severe infections that are refractory to the standard treatment, in typical cases, these include upper and lower respiratory tract infections (e.g., sinusitis, bronchitis, pneumonia) and gastroenteritis, as well as severe bacterial infections (e.g., meningitis, sepsis))
    2. any other acute or chronic diseases in the medical history that may affect the interpretation of the study results or pose an unacceptable risk to the patient when using the investigational therapy (in the Investigator's opinion)

18. One or more signs of depressed immune system function in the patient:

    1. serum IgG concentration < 4.0 g/L
    2. absolute CD4 + lymphocyte count < 0.25 × 10^9/L
19. Absence of IgG antibodies to Varicella zoster or a positive PCR reaction to herpes viruses of types 4, 5, 6
20. Positive result for any of the following tests: hepatitis B surface antigen (HBs Ag), hepatitis C virus antibodies (anti-HCV), human immunodeficiency virus antibodies 1 and 2 (anti-HIV1 and anti-HIV2 Ab), or a blood test for syphilis on screening

21. Presence of the following infections in a patient:

    1. infections that caused an increased body temperature above normal range or required the use of oral antibacterial and/or antiviral drugs within 4 weeks before randomisation, hospitalisation, or the use of parenteral anti-infective drugs within 2 months before randomisation (the exception is detection of asymptomatic herpes virus types 4, 5 and/or 6 on screening and their treatment within screening according to the study site's standards)
    2. confirmed SARS-CoV-2 coronavirus infection within 1 month before randomisation
    3. medical history of severe, recurrent, or chronic infections (including severe herpes infection, herpes zoster, sepsis, abscess, invasive fungal infections) in which, in the Investigator's opinion, the investigational medicinal product may cause harm to the patient
    4. medical history of active or latent tuberculosis, signs of tuberculosis infection based on the TB-feron test or Quantiferon test results and the chest X-ray performed during screening (it is possible to use the chest X-ray results performed no more than 2 months before the IC signing date)
22. Inability to administer the investigational medicinal product intravenously and to collect venous blood
23. Intolerance to oral or intravenous corticosteroids
24. Pregnancy, breastfeeding, and planning pregnancy during the period of participation in the study
25. Major surgeries (i.e., those involving opening of the abdominal cavity, chest cavity, skull) less than 60 days before the IC signing date (it is acceptable to include patients who have been fully recovered according to the Investigator's assessment), or the patient is scheduled to undergo major surgery during the period of participation in the study
26. Conditions that limit the patient's ability to comply with the protocol requirements, in the Investigator's opinion (e.g., medical history of dementia or mental disorders (including depression, schizophrenia), as well as information about drug or alcohol addiction within 12 months before the IC signing date, etc.)
27. Concurrent participation in other interventional clinical trials, participation in other clinical trials less than 30 days or less than 5 T1/2 of the investigational drugs before the IC signing date (provided the patient has received at least one administration of the investigational therapy), and previous participation in this clinical trial (provided the patient has received at least one administration of the investigational therapy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RPH-035; During the Main Period, the patients receive their first infusion of ocrelizumab (RPH-035) at a dose of 300 mg, followed by another 300 mg of the drug product after 2 weeks. The duration of ocrelizumab administration is 2.5 hours ± 15 minutes. The third infusion at a dose of 600 mg is administered 6 months after the first infusion of the initial dose During the After-Therapy Period, patients will receive an IV infusion of 600 mg of ocrelizumab (RPH-035) at weeks 49, 73, and 97 Premedication is mandatory and is carried out according to the following scheme: methylprednisolone at a dose of 100 mg (or dexamethasone at a dose of 18.8 mg, or an equivalent drug product) intravenously 30 ± 10 minutes before the start of each infusion; antihistamine drug (e.g., diphenhydramine, suprastin, or an equivalent drug product) 30-60 minutes before the start of each infusion; antipyretic drug (e.g., paracetamol) 30-60 minutes before the start of each infusion	Drug: RPH-035; 300 mg/10 mL (30 mg/mL) concentrate for solution for infusions in a single-dose vial For the 1st and 2nd infusions, 300 mg (10 mL) of ocrelizumab is diluted in 0.9% sodium chloride to a final concentration of approximately 1.2 mg/mL. For the 3rd infusion, 600 mg (20 mL) of ocrelizumab is diluted in 0.9% sodium chloride to a final concentration of approximately 1.2 mg/mL; Other Names: ocrelizumab; L04785
Active Comparator: Ocrevus®; During the Main Period, the patients receive their first infusion of ocrelizumab (Ocrevus®) at a dose of 300 mg, followed by another 300 mg of the drug product after 2 weeks. The duration of ocrelizumab administration is 2.5 hours ± 15 minutes. The third infusion at a dose of 600 mg is administered 6 months after the first infusion of the initial dose Premedication is mandatory and is carried out according to the following scheme: methylprednisolone at a dose of 100 mg (or dexamethasone at a dose of 18.8 mg, or an equivalent drug product) intravenously 30 ± 10 minutes before the start of each infusion; antihistamine drug (e.g., diphenhydramine, suprastin, or an equivalent drug product) 30-60 minutes before the start of each infusion; antipyretic drug (e.g., paracetamol) 30-60 minutes before the start of each infusion	Drug: Ocrevus®; 300 mg/10 mL (30 mg/mL) concentrate for solution for infusions in a single-dose vial For the 1st and 2nd infusions, 300 mg (10 mL) of ocrelizumab is diluted in 0.9% sodium chloride to a final concentration of approximately 1.2 mg/mL. For the 3rd infusion, 600 mg (20 mL) of ocrelizumab is diluted in 0.9% sodium chloride to a final concentration of approximately 1.2 mg/mL; Other Names: ocrelizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The area under the concentration-time pharmacokinetic curve (AUC (14-169 days)) of ocrelizumab	The area under the concentration-time pharmacokinetic curve of ocrelizumab after the second (single) administration, truncated at Day 169 (AUC (14-169 days))	Day 14 to Day 169

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The area under the concentration-time pharmacokinetic curve (AUC (0-14 days)) of ocrelizumab	The area under the concentration-time pharmacokinetic curve of ocrelizumab after the first (single) IV administration, truncated at Day 14 (AUC (0-14 days))	Up to Day 14
Maximum serum concentration of ocrelizumab after the first administration (Cmax (0-14 days))	Maximum serum concentration of ocrelizumab after the first administration (Cmax (0-14 days))	Up to Day 14
Maximum serum concentration of ocrelizumab after the second administration (Cmax (14-169 days))	Maximum serum concentration of ocrelizumab after the second administration (Cmax (14-169 days))	Day 14 to Day 169
Percentage of patients with adverse reactions (ARs) of any severity	Adverse reactions (ARs) are all unfavourable and unintended reactions to the drug products associated with their administration in any dose, the causal relationship between their administration and adverse events (AEs) is at least possible, meaning that such a relationship cannot be excluded	Up to Day 337
Percentage of patients with adverse events (AEs) of any severity	An adverse event (AE) is any event observed in a clinical trial subject after the drug product administration, which is unfavourable from a medical point of view and may not have a causal relationship with its administration	Up to Day 337
Percentage of patients with AEs of severity grade ≥ 3	Percentage of patients with AEs of severity grade ≥ 3 per CTCAE 5.0	Up to Day 337
Percentage of patients with ARs of severity grade ≥ 3	Percentage of patients with ARs of severity grade ≥ 3 per CTCAE 5.0	Up to Day 337
Percentage of patients with serious adverse events (SAEs)	A serious adverse event (SAE) is any unfavourable medical event that, regardless of the drug product dose: leads to death; poses a threat to life; requires hospitalisation or its prolongation; leads to persistent or severe disability/incapacitation; is a congenital abnormality or developmental defect; requires medical intervention to prevent the development of the conditions listed above	Up to Day 337
Percentage of patients with serious adverse reactions (SARs)	A serious adverse reaction (SAR) is an adverse reaction that is characterised by the criteria of seriousness: leads to death; poses a threat to life; requires hospitalisation or its prolongation; leads to persistent or severe disability/incapacitation; is a congenital abnormality or developmental defect; requires medical intervention to prevent the development of the conditions listed above	Up to day 337
Percentage of patients who required discontinuation of therapy due to adverse events/adverse reactions (AEs/ARs)	Percentage of patients who required discontinuation of therapy due to AEs/ARs	Up to Day 337
Binding anti-drug antibodies (ADA) to ocrelizumab over a period of up to 24 weeks from the start of the therapy	Binding anti-drug antibodies (ADA) to ocrelizumab are assessed on Day 1 (pre-dose), 57, 113, 169 (pre-dose)	Up to Day 169
Binding anti-drug antibodies (ADA) to ocrelizumab over a period of up to 48 weeks from the start of the therapy	Binding anti-drug antibodies (ADA) to ocrelizumab are assessed on Day 1 (pre-dose), 57, 113, 169 (pre-dose), 225, 281, 337 (pre-dose)	Up to Day 337
Neutralizing antibodies (nAB) to ocrelizumab over a period of up to 24 weeks from the start of therapy	Neutralizing antibodies (nAB) to ocrelizumab are assessed on Day 1 (pre-dose), 57, 113, 169 (pre-dose)	Up to Day 169
Neutralizing antibodies (nAB) to ocrelizumab over a period of up to 48 weeks from the start of therapy	Neutralizing antibodies (nAB) to ocrelizumab are assessed on Day 1 (pre-dose), 57, 113, 169 (pre-dose), 225, 281, 337 (pre-dose)	Up to Day 337

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to reach the maximum ocrelizumab concentration in serum after the first administration (Tmax (0-14 days))	Time to reach the maximum ocrelizumab concentration in serum after the first administration (Tmax (0-14 days))	Up to Day 14
Elimination half-life of ocrelizumab after the first administration (T1/2 (0-14 days))	Elimination half-life of ocrelizumab after the first administration (T1/2 (0-14 days))	Up to Day 14
Volume of distribution of ocrelizumab after the first administration (Vd (0-14 days))	Volume of distribution of ocrelizumab after the first administration (Vd (0-14 days))	Up to Day 14
Elimination rate constant of ocrelizumab after the first administration (Kel (0-14 days))	Elimination rate constant of ocrelizumab after the first administration (Kel (0-14 days))	Up to Day 14
Time to reach the maximum serum concentration of ocrelizumab after the second administration (Tmax (14-169d))	Time to reach the maximum serum concentration of ocrelizumab after the second administration (Tmax (14-169d))	Day 14 to Day 169
Elimination half-life of ocrelizumab after the second administration (T1/2 (14-169d))	Elimination half-life of ocrelizumab after the second administration (T1/2 (14-169d))	Day 14 to Day 169
Volume of distribution of ocrelizumab after the second administration (Vd (14-169d))	Volume of distribution of ocrelizumab after the second administration (Vd (14-169d))	Day 14 to Day 169
Elimination rate constant of ocrelizumab after the second administration (Kel (14-169d))	Elimination rate constant of ocrelizumab after the second administration (Kel (14-169d))	Day 14 to Day 169
Area under the pharmacokinetic curve "concentration-time" (AUC(0-∞)) of ocrelizumab	Area under the pharmacokinetic "concentration-time" curve of ocrelizumab after the second administration, truncated at the point from zero to infinity (AUC(0-∞))	Up to Day 169
The average value of the absolute and relative number of CD19+ B-lymphocytes for a period of up to 2 weeks from the start of the therapy inclusively	The average value of the absolute and relative number of CD19+ B-lymphocytes for a period of up to 2 weeks from the start of the therapy inclusively	Up to Day 14
The average value of the absolute and relative number of CD19+ B-lymphocytes for a period of up to 24 weeks from the start of the therapy inclusively	The average value of the absolute and relative number of CD19+ B-lymphocytes for a period of up to 24 weeks from the start of the therapy inclusively	Up to Day 169
The average value of the absolute and relative number of CD19+ B-lymphocytes for a period of up to 48 weeks from the start of the therapy inclusively	The average value of the absolute and relative number of CD19+ B-lymphocytes for a period of up to 48 weeks from the start of the therapy inclusively	Up to Day 337
Average incidence of MS exacerbations for a period of up to 24 weeks from the start of the therapy inclusively	Disease exacerbation is considered to be subjective symptoms (reported by the patient) and/or (detected during a neurological examination) objective symptoms characteristic of an acute inflammatory demyelinating (focal or multifocal) process in the central nervous system, either in the form of an aggravation of existing neurological symptoms or in the form of the appearance of new not observed previously neurological symptoms, with an acute or, more often, subacute onset, with complete or incomplete regression of symptoms. The deviation must be present for ≥ 24 hours and must be not associated with concomitant clinical factors (e.g., fever, infection, trauma, drug-related adverse reactions)	Up to Day 169
The number of combined lesions for a period of up to 24 weeks from the start of the therapy inclusively	The number of combined lesions assessed at baseline and on Days 57, 113, 169 of the Main Period The number of combined lesions defined as the total number of new contrast-enhancing lesions in T1-WI and new lesions in T2-WI or enlarging lesions in T2-WI, without double addition	Up to Day 169
The number of new Gd+ lesions on T1-WI for a period of up to 24 weeks from the start of the therapy inclusively	The number of new Gd+ lesions on T1-WI assessed at baseline and on Days 57, 113, 169 of the Main Period	Up to Day 169
The number of new or enlarging hyperintense lesions on T2-weighted images for a period of up to 24 weeks from the start of the therapy	The number of new or enlarging hyperintense lesions on T2-weighted images assessed at baseline and on Days 57, 113, 169 of the Main Period	Up to Day 169
Percentage of patients with new or enlarging hyperintense lesions on T2-WI for a period of up to 24 weeks from the start of the therapy	New or enlarging hyperintense lesions on T2-WI are assessed at baseline and on Days 57, 113, 169 of the Main Period	Up to Day 169
The number of new hypointense lesions on T1-WI for a period of up to 24 weeks from the start of the therapy inclusively	The number of new hypointense lesions on T1-WI assessed at baseline and on days 57, 113, 169 of the Main Period	Up to Day 169
Change in EDSS score after 24 weeks of the therapy inclusively compared to values obtained at screening	The EDSS scale is a rating system with a range from 0 (normal neurological status) to 10 (death due to MS) in 0.5-point increments	Baseline, Day 169
Annualized rate of MS exacerbations for a period of up to 48 weeks from the start of the therapy inclusively	Disease exacerbation is considered to be subjective symptoms (reported by the patient) and/or (detected during a neurological examination) objective symptoms characteristic of an acute inflammatory demyelinating (focal or multifocal) process in the central nervous system, either in the form of an aggravation of existing neurological symptoms or in the form of the appearance of new not observed previously neurological symptoms, with an acute or, more often, subacute onset, with complete or incomplete regression of symptoms. The deviation must be present for ≥ 24 hours and must be not associated with concomitant clinical factors (e.g., fever, infection, trauma, drug-related adverse reactions).	Up to Day 337
The number of combined lesions for a period of up to 48 weeks from the start of the therapy inclusively	The number of combined lesions assessed at baseline and on Days 57, 113, 169, 337 of the Main Period The number of combined lesions defined as the total number of new contrast-enhancing lesions in T1-WI and new lesions in T2-WI or enlarging lesions in T2-WI, without double addition	Up to Day 337
The number of new Gd+ lesions on T1-WI for a period of up to 48 weeks from the start of the therapy inclusively	The number of new Gd+ lesions on T1-WI assessed at baseline and on Days 57, 113, 169, 337 of the Main Period	Up to Day 337
The number of new or enlarging hyperintense lesions on T2-weighted images for a period of up to 48 weeks from the start of the therapy	The number of new or enlarging hyperintense lesions on T2-weighted images assessed at baseline and on Days 57, 113, 169, 337 of the Main Period	Up to Day 337
Percentage of patients with new or enlarging hyperintense lesions on T2-WI for a period of up to 48 weeks from the start of the therapy	New or enlarging hyperintense lesions on T2-WI are assessed at baseline and on Days 57, 113, 169, 337 of the Main Period	Up to Day 337
The number of new hypointense lesions on T1-WI for a period of up to 48 weeks from the start of the therapy inclusively	The number of new hypointense lesions on T1-WI assessed at baseline and on Days 57, 113, 169, 337 of the Main Period	Up to Day 337
Change in EDSS score after 48 weeks of the therapy inclusively compared to values obtained at screening	The EDSS scale is a rating system with a range from 0 (normal neurological status) to 10 (death due to MS) in 0.5-point increments	Up to Day 337
Percentage of patients with confirmed disability progression according to the EDSS scale after 48 weeks of the therapy inclusively compared with the values obtained at screening	Confirmed disability progression is considered to be a persistent increase in neurological abnormality according to the EDSS scale compared to the baseline, beyond the period of exacerbations and not associated with a previous exacerbation. Confirmed disability progression is defined as a patient's EDSS score maintaining or increasing compared to the date of the first recorded increase in neurological impairment for at least 6 months, provided there have been no exacerbations during the measurement period. A significant neurological disorders increase is EDSS ≥ 1.5 points with an initial EDSS score of 0, EDSS ≥ 1.0 points for patients with an initial EDSS of 1.0-5.5 points, or EDSS ≥ 0.5 points for patients with EDSS ≥ 6.0 at baseline	Baseline, Day 337
Percentage of patients with confirmed disability reduction according to the EDSS scale after 48 weeks of the therapy inclusively compared with the values obtained at screening	A confirmed disability reduction is defined as a sustained reduction in neurological abnormality as measured by the EDSS compared to the baseline EDSS score. A confirmed reduction is scored when a patient's EDSS score reduction, compared to the first recorded reduction in neurological abnormality, is maintained for 6 months. A reduction in neurological abnormality is defined as a decrease in EDSS by 1.0 point compared to the baseline score.	Baseline, Day 337
Change in the quality of life assessment score for the "Physical component of health" after 24 weeks of the therapy inclusively	Change in the quality of life assessment score for the "Physical component of health" parameter according to the SF-36 questionnaire after 24 weeks of the therapy inclusively compared with the values obtained at screening. The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role functioning, physical pain, general health (assesses the patient's physical well-being), and viability, social functioning, emotional state, and mental health (assesses psychological state). The scores on each scale range from 0 to 100 points, where 100 corresponds to complete health. The processing of the research results is presented in the form of point assessments with a maximum score of 100. The higher the score, the higher the quality of life	Day 1, Day 169
Change in the quality of life assessment score for the and "Mental component of health" parameter after 24 weeks of the therapy inclusively	Change in the quality of life assessment score for the and "Mental component of health" parameter according to the SF-36 questionnaire after 24 weeks of the therapy inclusively compared with the values obtained at screening. The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role functioning, physical pain, general health (assesses the patient's physical well-being), and viability, social functioning, emotional state, and mental health (assesses psychological state). The scores on each scale range from 0 to 100 points, where 100 corresponds to complete health. The processing of the research results is presented in the form of point assessments with a maximum score of 100. The higher the score, the higher the quality of life	Day 1, Day 169
Change in the quality of life assessment score for the "Physical component of health" parameter after 48 weeks of the therapy inclusively	Change in the quality of life assessment score for the "Physical component of health" parameter according to the SF-36 questionnaire after 48 weeks of the therapy inclusively compared with the values obtained at screening. The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role functioning, physical pain, general health (assesses the patient's physical well-being), and viability, social functioning, emotional state, and mental health (assesses psychological state). The scores on each scale range from 0 to 100 points, where 100 corresponds to complete health. The processing of the research results is presented in the form of point assessments with a maximum score of 100. The higher the score, the higher the quality of life	Day 1, Day 337
Change in the quality of life assessment score for the "Mental component of health" parameter after 48 weeks of the therapy inclusively	Change in the quality of life assessment score for the "Mental component of health" parameter according to the SF-36 questionnaire after 48 weeks of the therapy inclusively compared with the values obtained at screening. The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role functioning, physical pain, general health (assesses the patient's physical well-being), and viability, social functioning, emotional state, and mental health (assesses psychological state). The scores on each scale range from 0 to 100 points, where 100 corresponds to complete health. The processing of the research results is presented in the form of point assessments with a maximum score of 100. The higher the score, the higher the quality of life	Day 1, Day 337

Collaborators and Investigators

• Sponsor: R-Pharm
• Investigators: Study Director: Mikhail Samsonov, R-Pharm

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2025
• Primary Completion (Actual): January 12, 2026
• Study Completion (Estimated): December 20, 2027

Study Registration Dates

• First Submitted: April 13, 2026
• First Submitted That Met QC Criteria: May 13, 2026
• First Posted (Actual): May 19, 2026

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Ocrelizumab; RPH-035
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; ocrelizumab
• Other Study ID Numbers: CL04785171

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No