Clinical trial NCT05704361: A Study to Investigate the Safety, Tolerability, and Processing by the Body of Intravenous and Subcutaneous RO7121932 in Participants With Multiple Sclerosis.
Official title: Official Title: A Multiple-Center, Non-randomized, Open-label, Adaptive, Single-Ascending Dose (Part 1 and Part 2) and Multiple-Ascending Dose (Part 3) Parallel, Phase IB Study to Investigate the Safety, Tolerability, Immunogenicity, Pharmacokinetics, and Pharmacodynamics of RO7121932 Following Intravenous (Part 1) and Subcutaneous Administration (Parts 2 and 3) in Participants With Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Multiple Sclerosis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2023-01-30
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary purpose of the study is to evaluate the safety and tolerability of single ascending intravenous (IV) (Part 1) and subcutaneous (SC) (Part 2) doses of RO7121932 and multiple ascending SC (Part 3) doses of RO7121932 in participants with multiple sclerosis (MS).


Eligibility criteria: Inclusion Criteria:

* Expanded Disability Status Scale (EDSS) score ≤7.0 at Screening
* Participants with relapsing multiple sclerosis (RMS) or progressive multiple sclerosis (PMS) who fulfil international panel criteria for diagnosis (McDonald 2017 criteria)
* Participants not treated with any approved MS treatment at Screening and not planning to start on any MS therapy during the study (including follow-up)
* Female participants must practice abstinence or otherwise use contraception

Exclusion Criteria:

* Evidence of clinical disease activity as defined by any clinical relapse within 3 months prior to screening, or by \>1 clinical relapse within 12 months prior to screening
* Evidence of magnetic resonance imaging (MRI) activity as defined by the presence of ≥ 1 Gadolinium-enhancing T1 lesion in the screening MRI scan or by ≥ 4 new or enlarging T2 lesions in the screening scan as compared to a reference scan
* Participants who have active progressive multifocal leukoencephalopathy (PML), have had confirmed PML, or have a high degree of suspicion for PML
* Known presence of other neurological disorders that may mimic MS including but not limited to: neuromyelitis optica spectrum disease, Lyme disease, untreated Vitamin B12 deficiency, neurosarcoidosis, cerebrovascular disorders, and untreated hypothyroidism
* Known active or uncontrolled bacterial, viral, fungal, mycobacterial infection or other infection, excluding fungal infection of nail beds, including participants exhibiting symptoms consistent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 6 weeks prior to Day 1
* Participants with a current diagnosis of epilepsy
* Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal, or other major diseases
* History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening. Basal or squamous cell carcinoma of the skin that has been excised and is considered cured and in situ carcinoma of the cervix treated with apparent success by curative therapy \>1 year prior to screening is not exclusionary
* Any concomitant disease that may require treatment with systemic corticosteroids or immunosuppressants during course of the study
* History of currently active primary or secondary (non-drug-related) immunodeficiency
* History of hypersensitivity to biologic agents or any of the excipients in the formulation
* Only for cohorts where CSF samples are planned to be collected: Participants with a history of spinal cord compression, raised intra-cerebral pressure, clinically significant vertebral joint pathology or any other current abnormalities in the lumbar region which could prevent the lumbar puncture procedure.

Prior/Concomitant Therapy:

* Treatment with any approved MS treatment at Screening. Participants may become eligible after completion of a washout period prior to acquiring any screening laboratory tests but should not be withdrawn from therapies for the sole purpose of meeting eligibility for the trial
* Previous treatment with RO7121932, alemtuzumab, cladribine, mitoxantrone, cyclophosphamide, total body irradiation, bone marrow transplantation, and hematopoietic stem cell transplantation. For the USA only, previous treatment with daclizumab
* Previous treatment with anti-CD20 B-cell-depleting therapies (e.g., rituximab, ocrelizumab, or ofatumumab)

  * \<12 months prior to acquiring any screening laboratory tests,
  * ≥12 months prior to acquiring any screening laboratory tests, if B-cells are outside the normal range, or not back to individual baseline ± 20% (if data are available),
  * If discontinuation of a prior B-cell depletion therapy was motivated by safety reasons
* Current or prior treatment with natalizumab (if \<24 months prior to acquiring any screening laboratory tests)

Prior/Concurrent Clinical Study Experience:

- Participation in an investigational drug medicinal product or medical device study within 30 days before Screening or within five times the pharmacodynamic (PD) or pharmacokinetic (PK) half-life (if known), whichever is longer

Diagnostic Assessments:

* Positive result on human immunodeficiency virus (HIV1) and HIV2, hepatitis C, or hepatitis B
* Participants with suicidal ideation or behavior within 6 months prior to Screening or participants who, in the Investigator's judgment, pose a suicidal or homicidal risk
* Vaccination with a live or live-attenuated vaccine within 6 weeks prior to Day 1

Primary outcomes:
measure: Part 1, Part 2 and 3: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) with Severity of AEs Measured According to National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI CTCAE v5)
timeFrame: Day 1 to Day 169 for part 1 and part 2; Day 1 to Day 197 for part 3
measure: Part 1, Part 2 and Part 3: Percentage of Participants With Abnormal Laboratory Findings
timeFrame: Day 1 to Day 169 for part 1 and part 2; Day 1 to Day 197 for part 3
measure: Part 1, Part 2 and Part 3: Percentage of Participants With Abnormal Vital Signs and Electrocardiogram (ECG) Parameters
timeFrame: Day 1 to Day 169 for part 1 and part 2; Day 1 to Day 197 for part 3
measure: Part 1, Part 2 and Part 3: Change From Baseline in Suicide Risk as Assessed Using the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Day 1 to Day 169 for part 1 and part 2; Day 1 to Day 197 for part 3
measure: Part 2 and Part 3: Percentage of Participants with Local Pain at the Site of Injection Assessed Using the Visual Analog Scale (VAS)
timeFrame: Day 1, 2, 5, 8 for part 2; Day 1, 2, 5, 8, 15, 22, 29, 36 for part 3
measure: Part 2 and Part 3: Percentage of Participants with Local Injection Site Reaction Using Local Injection-site Symptom Assessment (LISSA)
timeFrame: Day 1,2, 5, 8 for part 2; Day 1, 2, 5, 8, 15, 22, 29, 36 for part 3
Secondary outcomes:
measure: Part 1, Part 2 and Part 3 (Week 1 and Week 4): Time to Maximum Observed Concentration (Tmax) of RO7121932
timeFrame: Day 1 to Day 169 for part 1 and part 2; Days 1, 2, 5 and, 22 for part 3
measure: Part 1, Part 2 and Part 3 (Week 1 and Week 4): Maximum Observed Serum Concentration (Cmax) of RO7121932
timeFrame: Day 1 to Day 169 for part 1 and part 2; Days 1, 2, 5 and, 22 for part 3
measure: Part 1, Part 2 and Part 3 (Week 1 and Week 4): Area Under the Serum Concentration-Time Curve From Time 0 to 168 Hours (h) (AUC0-168h) Postdose
timeFrame: Day 1 (predose) to Day 8 (168 hours post-dose) for parts 1, 2, and 3 (Week 1) and Day 22 (predose) to Day 29 (168 hours post-dose) for part 3 (Week 4)
measure: Part 1 and Part 2: Area Under the Serum Concentration-Time Curve up to the Last Measurable Concentration (AUClast)
timeFrame: Day 1 to Day 169 for part 1 and part 2
measure: Part 1 and Part 2: AUC From Time 0 to Infinity (AUCinf)
timeFrame: Day 1 to Day 169 for part 1 and part 2
measure: Part 1: Total Body Clearance (CL) Of RO7121932
timeFrame: Day 1 to Day 169
measure: Part 2 and Part 3 (Week 4): Apparent Clearance (CL/F) of RO7121932
timeFrame: Day 1 to Day 169 for part 2; Day 22 to Day 29 for part 3
measure: Part 1, Part 2 and Part 3: Terminal Rate Constant of RO7121932
timeFrame: Day 1 to Day 169 for part 1 and part 2; Day 22 to Day 197 for part 3
measure: Part 1, Part 2 and Part 3: Apparent Terminal Half-Life (T1/2) of RO7121932
timeFrame: Day 1 to Day 169 for part 1 and part 2; Day 22 to Day 197 for part 3
measure: Part 3: Trough Concentrations (Ctrough) of RO7121932
timeFrame: Day 1 to Day 197
measure: Part 1 and Part 3: Cerebrospinal Fluid (CSF) Concentration of RO7121932
timeFrame: Screening, Day 2 to Day 169 for part 1; Screening, Day 2 to Day 197 for part 3
measure: Part 1, Part 2 and Part 3: Percentage of Participants With Anti-RO7121932 Antibodies
timeFrame: Predose on Day 1, and on Days 8, 22, 29, 57, 85, 169 for part 1; Predose on Day 1, and on Days 8, 22, 57, 85, 169 for part 2 Predose on Days 1, 8, 15, 22, and on Days 29, 57, 85, 120, 197 for part 3
measure: Part 1, Part 2 and Part 3: Time Course of B-cell Frequencies in Blood
timeFrame: Screening, Days 1, 2, 8, 22, 57, 85, 169 for part 1; Screening, Days 1, 2, 8, 22, 57, 85, 169 for part 2; Screening, Days 1, 2, 8, 15, 22, 57, 85, 120, 197 for part 3
measure: Part 1 and Part 3: Time Course of B-cell Frequencies in CSF
timeFrame: Screening, Day 2 to 169 for part 1; Screening, Day 2 to 197 for part 3
measure: Part 1, Part 2 and Part 3: Change From Baseline in B-cell Frequencies in Blood
timeFrame: Screening, Days 1, 2, 8, 22, 57, 85, 169 for part 1; Screening, Days 1, 2, 8, 22, 57, 85, 169 for part 2; Screening, Days 1, 2, 8, 15, 22, 57, 85, 120, 197 for part 3
measure: Part 1 and Part 3: Change From Baseline in B-cell Frequencies in CSF
timeFrame: Screening, Day 2 to 169 for part 1; Screening, Day 2 to 197 for part 3
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: New Haven
country: United States
facility: Yale University Multiple Sclerosis Center
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Cincinnati
country: United States
facility: UC Health, LLC.
state: Ohio
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus"
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen Georg-August-Universität
city: München
country: Germany
facility: Klinikum rechts der Isar der TU Muenchen
city: Münster
country: Germany
facility: Universitätsklinikum Münster Klinik u. Poliklinik f. Neurologie
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Zentrum für Neurologie
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Jerusalem
country: Israel
facility: Hadassah University Hospital - Ein Kerem
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Lombardia
city: Milano
country: Italy
facility: Fond. Istituto Neurologico C.Besta
state: Lombardia
city: Chisinau
country: Moldova, Republic of
facility: ARENSIA Exploratory Medicine Phase I, PMSI Republican Clinical Hospital
city: Gda?sk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Grudzi?dz
country: Poland
facility: Regionalny Szpital Specjalistyczny im. W. Bieganskiego
city: Poznan
country: Poland
facility: MedPolonia
city: Szczecin
country: Poland
facility: Osrodek Badan Klinicznych Euromedis
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii II Klinika Neurologiczna
city: Zabrze
country: Poland
facility: SPSK nr 1
city: Braga
country: Portugal
facility: Hospital de Braga
city: Lisboa
country: Portugal
facility: Hospital Santo Antonio dos Capuchos
city: Santa Maria Da Feira
country: Portugal
facility: Centro Hospitalar Entre o Douro e Vouga E.P.E. - Hospital de São Sebastião
city: Bucharest
country: Romania
facility: ARENSIA Exploratory Medicine SRL - Bucharest (Monza Medical Center)
city: Cluj Napoca
country: Romania
facility: ARENSIA Exploratory Medicine, County Emergency Hospital
city: Belgrade
country: Serbia
facility: University Clinical Center of Serbia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall dHebron (CEMCAT)
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: