Safety and Efficacy of Cladribine Therapy After Anti CD20 Therapy

Sponsor

Claudio Gobbi (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04640818

Collaborator

Merck AG Switzerland (Other)

Enrollment

Location

22.4

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Prolonged anti CD20 therapy for the treatment of active multiple sclerosis leading to continuous B cell depletion is associated with hypogammaglobulinemia predisposing to a potentially increased risk of serious infections, particularly in the more disabled and aged patients. No data have been published on the sequential use of anti CD20 therapies and cladribine, that is thought to act as an immune reconstitution agent. his study aims at investigating IgG and IgM serum concentration changes at 6 and 12 months after switching to cladribine in patients previously treated with anti CD20 therapies (ie, ocrelizumab ≥1.8 gr or rituximab 3.0 gr) for ≥18 months, as compared to continued anti CD20 therapies.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Cladribine Oral Tablet Drug: Rituximab Drug: Ocrelizumab

Detailed Description

The study population will include patients with remitting relapsing multiple sclerosis consulting the Multiple Sclerosis Center of Neurocenter of Southern Switzerland.

Enrolled patients will have 5 Study Visits, one every 3 months according to clinical practice. At visits at 3 and 6 months only adverse events will be collected for study purposes. Clinical assessments will be performed at baseline, Month 6 and Month 12. Clinical assessments correspond to medical exams performed routinely in MS patients treated with anti CD20 or cladribine therapy: clinical assessments, monitoring haemoglobin parameters, serum immunoglobulins, liver and renal function.(6, 12 months), radiological disability progression and biomarker of ongoing neurodegeneration (12 months).

Study Design

Study Type:

Observational

Anticipated Enrollment :

45 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Safety and Efficacy of a Therapy With Cladribine Following a Treatment With Anti CD20 Compounds in Relapsing Multiple Sclerosis Patients: a Pilot Study

Actual Study Start Date :

Dec 17, 2020

Anticipated Primary Completion Date :

Oct 31, 2022

Anticipated Study Completion Date :

Oct 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
CLAD-GROUP Patients with cladribine therapy	Drug: Cladribine Oral Tablet Treatment according to the label and medical prescription Other Names: Mavenclade
CD20-GROUP Patients with anti CD20 therapy (ocrelizumab or rituximab)	Drug: Rituximab Treatment according to the label and medical prescription Other Names: Mabthera, Rixathon Drug: Ocrelizumab Treatment according to the label and medical prescription Other Names: Ocrevus

Arm

Intervention/Treatment

CLAD-GROUP

Patients with cladribine therapy

Drug: Cladribine Oral Tablet

Treatment according to the label and medical prescription

Other Names:

Mavenclade

CD20-GROUP

Patients with anti CD20 therapy (ocrelizumab or rituximab)

Drug: Rituximab

Treatment according to the label and medical prescription

Other Names:

Mabthera, Rixathon

Drug: Ocrelizumab

Treatment according to the label and medical prescription

Other Names:

Ocrevus

Outcome Measures

Primary Outcome Measures

Changes in IgG serum concentrations in Cald-Group [6 months]
Standard laboratory test
Changes in IgM serum concentrations in Cald-Group [6 months]
Standard laboratory test
Changes in IgG serum concentrations in Clad-Group [12 months]
Standard laboratory test
Changes in IgM serum concentrations in Clad-Group [12 months]
Standard laboratory test

Secondary Outcome Measures

Changes in IgG serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies [6 months]
Standard laboratory test
Changes in IgM serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies [6 months]
Standard laboratory test
Changes in IgG serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies [12 months]
Standard laboratory test
Changes in IgM serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies [12 months]
Standard laboratory test
Proportion of patients reaching NEDA -3 [12 months]
NEDA -3: no relapses, no disability progression, no new/enlarging or Gd enhancing brain or spinal MR lesions
Annualized relapse rate (ARR) over 12 months after switching to cladribine as compared to patients continuing anti CD20 therapies [12 months]
ARR will be calculated based on recorded number of relapses
Proportion of patients with disability progression [6 months]
Expanded disability scale 0-6 (6 worst outcome)
Proportion of patients with disability progression [12 months]
Expanded disability scale 0-6 (6 worst outcome)
Number/volume of cumulative new T2/ enlarging lesions at brain and spinal MRI over 12 months after switching to cladribine, as compared to patients continuing anti CD20 therapies [12 months]
Evaluation of MRI
Number/volume of cumulative Gd enhancing lesions at brain and spinal MRI over 12 months after switching to cladribine, as compared to patients continuing anti CD20 therapies [12 months]
Evaluation of MRI
Changes in serum neurofilament light chain concentration [12 months]
single-molecule array (Simoa) assay

Other Outcome Measures

Frequency of infections [6 months]
Safety endpoint
Frequency of infections [12 months]
Safety endpoint
Intensity of infections [6 months]
Safety endpoint, intensity will be rated according to the following definitions: Mild: Awareness of a sign or symptom that does not interfere with the study participant's usual activity or is transient, resolved without treatment and with no sequelae; Moderate: Interferes with the study participant's usual activity and/or requires symptomatic treatment; Severe: Symptom(s) causing severe discomfort and significant impact of the study participant's usual activity and requires treatment. Serious: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, or is otherwise considered as medically important.
Intensity of infections [12 months]
Safety endpoint, intensity will be rated according to the following definitions: Mild: Awareness of a sign or symptom that does not interfere with the study participant's usual activity or is transient, resolved without treatment and with no sequelae; Moderate: Interferes with the study participant's usual activity and/or requires symptomatic treatment; Severe: Symptom(s) causing severe discomfort and significant impact of the study participant's usual activity and requires treatment. Serious: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, or is otherwise considered as medically important.
Proportion of patients with abnormal creatinine values of clinical relevance [6 months]
Safety endpoint
Proportion of patients with abnormal creatinine values of clinical relevance [12 months]
Safety endpoint
Proportion of patients with abnormal ASAT values of clinical relevance [6 months]
Safety endpoint
Proportion of patients with abnormal ASAT values of clinical relevance [12 months]
Safety endpoint
Proportion of patients with abnormal ALAT values of clinical relevance [6 months]
Safety endpoint
Proportion of patients with abnormal ALAT values of clinical relevance [12 months]
Safety endpoint
Proportion of patients with any abnormal hematology values of clinical relevance [6 months]
Safety endpoint
Proportion of patients with any abnormal hematology values of clinical relevance [12 months]
Safety endpoint

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Relapsing MS according to Lublin;
Treatment with ocrelizumab or rituximab for ≥18 months and having received 1.8 / 3.0 gr, respectively;
CLAD_GROUP: Planning to switch to cladribine because of concerns about increased risks of infections related to hypogammaglobulinemia developing during long term anti CD20 therapies or a documented decrease of ≥10% IgG and/or IgM compared to pre- anti CD20 therapy;
or CD20_GROUP: no need to stop CD20 therapy due decrease of ≥10% IgG and/or IgM, or increased risk of infections related to hypogammaglobulinemia or other reasons, continued anti CD20 therapies clinically indicated;
EDSS ≤7.0;
Age >18 years.