A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

23 Oct 2020 → ongoing

Decision date (initial)

2024-02-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche AG

External identifiers

EU CT number

2023-506515-18-00

EudraCT number

2020-000894-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Pharmacodynamic, Others, Efficacy

To demonstrate the superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab as assessed by risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks.

Secondary objectives 7

1. 1. To demonstrate superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab on the basis of: time to onset of 24-week cCDP (cCDP24); time to onset of cCDP12 independent of protocol-defined relapses (PDR), also termed progression independent of relapse activity (PIRA) as per Kappos et al. 2020; time to onset of CDP12; time to ≥ 20% increase in 12-week confirmed timed 25-foot walk test (T25FWT); annual rate of percent change from baseline in total brain volume and thalamic volume; time to 12-week confirmed 4-point worsening in Symbol Digit Modalities test (SDMT); change in NfL (i.e. ratio to baseline) at Week 96; and time to 12-week confirmed 8-point increase in 12-Item Multiple Sclerosis Walking Scale (MSWS12)
2. 2. To demonstrate that both the higher dose and standard dose of ocrelizumab can significantly reduce NfL from baseline by evaluating the change in NfL (i.e. ratio to baseline) at Week 96 for patients in the higher dose ocrelizumab group and for patients in the approved dose ocrelizumab group
3. 3. To evaluate the safety profile of a higher dose of ocrelizumab compared with the approved dose of ocrelizumab
4. 4. To assess the exposure to ocrelizumab in serum in all patients in both study arms
5. 5. To characterize the ocrelizumab pharmacodynamic (PD) profile
6. 6. To evaluate the immune response to ocrelizumab
7. 7. To identify biomarkers that are predictive of response to a higher dose of ocrelizumab

Conditions and MedDRA coding

Primary Progressive Multiple Sclerosis (PPMS)

Study design 5 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Ages 18-55 years at time of screening
2. 2. Diagnosis of PPMS, in accordance with the revised McDonald criteria 2017
3. 3. Expanded disability status scale (EDSS) score at screening and baseline 3- 6.5, inclusive
4. 4. Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings at screening and baseline
5. 5. Documented MRI of brain with abnormalities consistent with MS
6. 6. Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments

Exclusion criteria 6

1. 1. History of relapsing remitting or secondary progressive MS at screening
2. 2. Any known or suspected active infection at screening or baseline, 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
3. 3. History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
4. 4. Immunocompromised state
5. 5. Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
6. 6. History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. Time to onset of cCDP sustained for at least 12 weeks. Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT

Secondary endpoints 24

1. 1. Time to onset of 24 week cCDP (cCDP24)
2. 2. Time to onset of cCDP12 independent of protocol-defined relapses (PDR), also termed progression independent of relapse activity (PIRA) as per Kappos et al.2020
3. 3. Time to onset of 12-week CDP (CDP12)
4. 4. Time to ≥ 20% increase in 12 week confirmed T25FWT
5. 5. Annual rate of percent change from baseline in total brain volume
6. 6. Annual rate of percent change from baseline in thalamic volume
7. 7. Time to 12-week confirmed 4-point worsening in Symbol Digit Modalities Test (SDMT)
8. 8. Change in NfL (i.e. ratio to baseline) at Week 96
9. 9.Time to 12-week confirmed 8-point increase in 12-Item Multiple Sclerosis Walking Scale (MSWS12)
10. 10. Change in NfL (i.e. ratio to baseline) at Week 96 for patients in the higher dose ocrelizumab group
11. 11. Change in NfL (i.e. ratio to baseline) at Week 96 for patients in the approved dose ocrelizumab group
12. 12. Incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
13. 13. Change from baseline in clinical laboratory test results (including hematology, chemistry, and Ig levels)
14. 14. Change from baseline in vital signs (including systolic and diastolic blood pressure, and pulse rate) following study treatment administration
15. 15. Serum concentration of ocrelizumab at specified timepoints
16. 16. B-cell levels in blood (including comparing the degree of B-cell depletion between the doses)
17. 17. Proportion of participants achieving 5 or less B-cells per microliter of blood
18. 18. Proportion of participants achieving 5 or less B-cells per microliter of blood in participants with the high versus low affinity Fcgamma Receptor 3A (FcγR3A) genotype per arm
19. 19. Change from Baseline in the anti-drug antibodies (ADAs) levels
20. 20. Levels of Neurofilament Light Chain (NfL) in blood
21. 21. Levels of Interleukin-6 (IL-6) in blood
22. 22. Levels of blood B-cells
23. 23. Levels of Lymphocytes in blood
24. 24. Proportion of participants with different DNA genotypes

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 13

Locations

11 EU/EEA countries · 56 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 80 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications