| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Progressive multiple sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Sclerosis (MS) is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063401 |
| E.1.2 | Term | Primary progressive multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| ● To evaluate the efficacy of fenebrutinib compared with ocrelizumab in patients with PPMS regardless of adherence to randomized treatment |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the efficacy of fenebrutinib treatment compared with ocrelizumab
● To evaluate the safety of fenebrutinib compared with ocrelizumab
● To characterize the fenebrutinib PK profile
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: CSF BIOMARKER SUBSTUDY ASSOCIATED WITH A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP STUDY (GN41791) TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED WITH OCRELIZUMAB IN ADULT PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS.
Protocol Date: 10-DEC-2020
Protocol Version: 3
Primary Objective:
The primary CSF biomarker objective for this substudy is to evaluate the impact of fenebrutinib compared with ocrelizumab treatment on a potential progression biomarker related to neuronal injury, as well as specific biomarkers related to B cells and myeloid lineage cells on the basis of the following endpoints:
-Changes in NfL
-Changes in B-cell activity, including IgG oligoclonal bands (OCBs) and IgG index
-Changes in myeloid lineage cells including CCL4
Exploratory Objectives:
-B cells and B cell subsets
-T cells and T cell subsets
-Myeloid lineage cells and myeloid lineage cell subsets
-Other immune cell types and potential progression biomarkers
Pharmacokinetic Objective:
The pharmacokinetic (PK) objective for this study is to characterize the fenebrutinib PK profile on the basis of the following endpoint:
-CSF concentration of fenebrutinib at specified timepoints |
|
| E.3 | Principal inclusion criteria |
● Age 18-65 years inclusive at time of signing Informed Consent Form. For sites in Germany and Italy only, enrollment is restricted to patients aged 46-65 years
● Ability to comply with the study protocol
● A diagnosis of PPMS in accordance to the revised 2017 McDonald Criteria
● Disability progression in the 12 months prior to screening, as assessed by the Pre-Baseline Disability Progression Questionnaire
● EDSS score from 3.0 to 6.5 inclusive at screening
● Pyramidal functional system sub score >=2 at screening
● For patients currently receiving proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs): treatment at a stable dose during the screening period prior to the initiation of study treatment and plans to remain at a stable dose for the duration of study treatment
● For patients requiring symptomatic treatment for MS (e.g., fampridine, cannabis) and/or physiotherapy: treatment at a stable dose/regimen during the screening period prior to the initiation of study drug and plans to remain at a stable dose/regimen for the duration of study treatment
● Neurologically stable for at least 30 days prior to randomization and baseline assessments
● Ability to complete the 9 hole peg test for each hand in < 240 seconds
● Ability to perform timed 25-foot walk test in <150 seconds
● For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 6 or 12 months (as applicable by the local label for ocrelizumab) after the final dose of study medication. Women must refrain from donating eggs during this same period.
● For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm as defined below:
o With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of study medication to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
|
|
| E.4 | Principal exclusion criteria |
● For patients enrolled in Germany and in Italy only: Presence of T1Gd + lesion on the screening MRI
● Any known or suspected active infection at screening or baseline, (excluding onychomycosis) or any major episode of infection requiring hospitalization or treatment with IV anti-microbials within 8 weeks prior to and during screening or treatment with oral anti-microbials within 2 weeks prior to and during screening. Onychomycosis is not exclusionary unless it is being treated with systemic therapy
● History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)
● Patients with a previous history of a serious IRR and/or any hypersensitivity reaction to ocrelizumab
● History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
● Immunocompromised state
● Known presence of other neurological disorders, that could interfere with the diagnosis of MS or assessments of efficacy or safety during the study
● Presence of cirrhosis (Child-Pugh Class A, B, or C)
● Evidence of clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, or gastrointestinal (GI) disease that, in the investigator’s opinion, would preclude patient participation
● Patients meeting the New York Heart Association Class III and Class IV criteria for congestive heart failure
● Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
● History of alcohol or other drug abuse within 12 months prior to screening
● Positive screening tests for active, latent, or inadequately treated hepatitis B and hepatitis C
● Evidence of active or latent or inadequately treated infection with tuberculosis (TB)
● History of hospitalizations or transfusion for a GI bleed
● Known bleeding diathesis
● Any condition possibly affecting oral drug absorption
● History of or currently active primary or secondary (non-drug related) immunodeficiency, including known history of HIV infection or IgG < 500 mg/dL
● Contraindications to mandatory premedications for infusion-related reactions (IRRs)
● Inability to complete an MRI scan or contraindication to gadolinium administration
● Lack of peripheral venous access
● Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
● Any previous history of transplantation or anti-rejection therapy
● Systemic corticosteroid therapy within 4 weeks prior to screening or during the screening period (inhaled and topical corticosteroids are allowed)
● Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
● Sensitivity or intolerance to any ingredient (including excipients) of fenebrutinib or ocrelizumab
● Receipt of a live or live attenuated vaccine within 6 weeks prior to randomization
● Need for systemic anticoagulation (oral or injectable) or anti platelet agent other than nonsteroidal anti-inflammatory drugs, aspirin, and other salicylates (aspirin up to 162 mg once daily is allowed)
● Previous treatment with fenebrutinib or another BTK inhibitor for any indication
● Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
● Requirement for any prohibited concomitant medications
● Treatment with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, within 7 days or 5 drug elimination half-lives (whichever is longer) prior to randomization
● Treatment with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug elimination half-lives (whichever is longer) prior to randomization
● Previous use of an anti-CD20 therapy (including rituximab, ocrelizumab, ofatumumab, and ublituximab) within 6 months of randomization, and treatment discontinuation was must not have been motivated by safety reasons or lack of efficacy
● Previous use of fingolimod, siponimod, or ozanimod within 8 weeks of randomization or ponesimod within 4 weeks of randomization
● Previous use of natalizumab within 6 months of randomization
● Previous treatment with dimethyl fumarate, interferons, and glatiramer acetate within 4 weeks of randomization
● Previous treatment with mycophenolate mofetil, or methotrexate or azathioprine within 12 weeks of randomization
● Previous use of teriflunomide, unless 24 months from screening or teriflunomide plasma concentrations are 0.02 mg/L at screening
● Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide
● Previous treatment with any other immunomodulatory or immunosuppressive medication without an adequate washout period
● Adequate laboratory values.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Time to onset of composite 12-week confirmed disability progression (cCDP12) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to 4.7 years [estimated duration of Double-Blind Treatment (DBT)] |
|
| E.5.2 | Secondary end point(s) |
1. Time to onset of composite 24 week CDP (cCDP24)
2. Time to onset of 12-week CDP (CDP12)
3. Time to onset of 24 week CDP (CDP24)
4. Percent change in total brain volume from Week 24 as assessed by MRI scan
5. Percent change from screening to Week 120 in serum neurofilament light chain (NfL) levels
6. Change from baseline in patient-reported physical impacts of MS (as measured by Multiple Sclerosis Impact Scale, 29-Item [MSIS-29] physical scale
7. Time to onset of 12 week confirmed 4 point worsening in Symbol Digit Modality Test (SDMT) score
8. The nature, frequency, timing, and severity of adverse events; serious adverse events; and adverse events leading to study treatment withdrawal
9. Change from baseline in targeted vital signs
10. Change from baseline in targeted ECG parameters
11. Change from baseline in clinical laboratory results following study treatment administration
12. Change from baseline in the Proportion of patients with suicidal ideation or behavior, as assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
13. Plasma concentration of fenebrutinib at specified timepoints
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to 4.7 years (estimated duration of DBT)
4-6. At Week 120
7-12. Up to 4.7 years (estimated duration of DBT)
13. Week 2, 12, 24, 48, 72, 96, 120, at treatment discontinuation or unscheduled visit
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| New Zealand |
| Peru |
| Switzerland |
| Ukraine |
| Australia |
| Brazil |
| Canada |
| Israel |
| Mexico |
| Russian Federation |
| South Africa |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Latvia |
| Lithuania |
| Poland |
| Portugal |
| Romania |
| Spain |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of this study is defined as the date when the last patient, last visit occurs in the OLE or the last patient last visit in the SFU, whichever occurs later. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 369 weeks or approximately 7 years.
In addition, the Sponsor may decide to terminate the study at any time. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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