search
Back to results

Ocrelizumab or Alemtuzumab Compared With Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis - a Phase-2 Randomised Controlled Trial (COAST)

Primary Purpose

Relapsing-Remitting Multiple Sclerosis

Status
Terminated
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Autologous Hematopoietic Stem Cell Transplantation
Ocrelizumab
Alemtuzumab
Sponsored by
Universitätsklinikum Hamburg-Eppendorf
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing-Remitting Multiple Sclerosis focused on measuring autologous hematopoetic stem cell transplantation, alemtzumab, ocrelizumab, randomised controlled trial, aggressive highly active multiple sclerosis, no evidence of diseae activity (NEDA)

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria (Based on CARE-MS-II3, guidelines and Rio-criteria for treatment failure):

  • Written informed consent and agreement to comply to study protocol
  • Age: 18-55 years
  • EDSS: 0.0 - 6.0
  • RRMS according to McDonald 2010
  • < 10 years of disease course after symptom onset
  • Active disease with one of the following treatment failures occur-ring not earlier than 6 months after initiation of an approved DMT
  • 2 or more relapses within the last 12 months

or

  • 1 relapse within the last 12 months and a Gd-enhancing lesion on MRI > 3 mm > 3 months before or after relapse onset or 2 new T2-lesions

or

  • On-going signs of MRI activity in the last 6 months (either Gd-en-hancing of ≥ 3 mm lesion at any exam in the last year; or more than 5 new T2 lesions (≥ 3 mm)

or

  • Patients stable under natalizumab but who have to stop treatment due to an increasing PML risk are defined as active, if a MRI within 6 months after termination of natalizumab shows new T2 or Gd-enhancing lesions and at least one other treatment fail-ure prior to natalizumab is documented.

Exclusion Criteria:

  • Secondary or primary progressive MS
  • Pregnancy, or other medical condition incompatible with aHSCT
  • Any treatment or medical condition that, according to the haematologist / transplant specialist precludes the use of aHSCT
  • John Cunningham virus (JCV) antibody index of > 1.5 in previ-ously natalizumab-treated patients, if a negative CSF JCV-PCR prior to screening is not available
  • Relapse during 30 days before initiation of treatment. If a relapse occurs during this period and eligibility criteria are otherwise ful-filled, start of treatment will be delayed until at least 30 days after receiving steroids.
  • Concurrent clinically significant (as determined by the investiga-tors and haematologist / transplant specialist) cardiac, immuno-logical, pulmonary, neurological, renal or other major disease such as:

    • Prominent cardial disease (Left ventricular ejection frac-tion (LVEF) < 40%, myocardial infarction or ischemia, un-controlled arrhythmias, pericardial effusion > 1 cm)
    • Cerebrovascular disease
    • Renal disease (creatinine clearance < 30 ml/min/m2)
    • Respiratory disease (DLCO < 40% predicted)
    • Active bleeding or clotting disease
    • History of human immunodeficiency virus (HIV) or posi-tive HIV antibody testing
    • Any uncontrolled acute or chronic infection, including HIV, hepatitis B surface antigen positivity and hepatitis C PCR positivity
    • Cancer except in situ cervix or cutaneous
  • Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, men-tal, or social) that is likely to affect the patient returning for follow-up visits on schedule. Unwillingness to use contraception.
  • Previous participation in this study, previous treatment with aHSCT or already both comparators
  • Ongoing immunotherapy. Treatment with interferon or glati-rameracetate will need no wash-out. Treatment pause before oc-relizumab/alemtuzumab or aHSCT will be:

    • for dimethylfumarate and fingolimod: 8 weeks
    • for natalizumab: 8 weeks
    • for ocrelizumab: 12 weeks
    • for alemtuzumab: 12 months
    • for teriflunomide: 4 weeks after elimination with cholesty-ramine
    • for cladribine: 24 weeks
  • Patients with cognitive impairments who are unable to provide written, informed consent prior to any testing under this protocol, including screening and baseline investigations that are not con-sidered part of routine patient care.

Sites / Locations

  • Universitätsklinikum Hamburg-Eppendorf
  • Universitätsklinikum Mannheim

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention (aHSCT)

Control

Arm Description

Autologous Hematopoietic Stem Cell Transplantation. Mobilisation will be performed with 2 g/m2 cyclophosphamide and 10 μg/kg G-CSF from day 5 until apheresis is completed. Conditioning will be 200 mg/kg cyclo-phosphamide and Anti-T-lymphocyteglobuline (Grafalon®, Neovii) with cu-mulative doses of 20 mg/kg given on day +1 (10 mg/kg) and day +2 (10 mg/kg).

In the control arm patient and physician will decide which treatment to choose. Patients will be either treated with ocrelizumab according to the SmPC (600 mg every 6 months continuously) or with alemtuzumab according to the SmPC (12 mg/day for 5 consecutive days and again after 365 days for 3 days).

Outcomes

Primary Outcome Measures

Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity)
Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) during follow-up as defined by: 3 months confirmed EDSS (Expanded disability status scale) progression confirmed relapse new/enlarging T2-hyperintense lesion on MRI (Magnetic resonance imaging) any Gd-enhancing lesion on MRI

Secondary Outcome Measures

Efficacy of treatment defined by EDSS
EDSS change and EDSS improvement will be considered. EDSS improvement defined as confirmed improvement after 3 months
Efficacy of treatment defined by the annualized relapse rate
calculated as number of relapses per year
Efficacy of treatment defined by the number of new T2 lesions
calculated as cumulative number of new T2 lesions
Efficacy of treatment defined by the number of Gd-enhancing lesions
calculated as cumulative number of GD-enhancing lesions
Efficacy of treatment defined by multiple sclerosis functional composite (MSFC) change
based on summed up Z-scores for individual measures (SDMT, 9 HPT, 25 FWT)
Efficacy of treatment defined by Hamburg quality of life scale in MS (HAQUAMS)
based on HAQUAMS sum score ratings (values between 1 and 5)
Efficacy of treatment defined by the Percentage Brain Volume Change (PBVC)
Brain tissue volume (grey matter, white matter) will be evaluated on T1 weighted images to compute absolute percentage brain volume change
Efficacy of treatment defined by grey and white matter atrophy
based on grey and white matter volume change evaluated on T1 weighted images
Rate of AE / SAE including NCI grade 3 and 4 non-haematological toxicities
Safety of treatment defined by the rate of AE / SAE including NCI grade 3 and 4 non-haematological toxicities

Full Information

First Posted
August 12, 2020
Last Updated
March 1, 2022
Sponsor
Universitätsklinikum Hamburg-Eppendorf
Collaborators
Neovii Biotech, Clinical Trial Center North (CTC North GmbH & Co. KG)
search

1. Study Identification

Unique Protocol Identification Number
NCT04971005
Brief Title
Ocrelizumab or Alemtuzumab Compared With Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis - a Phase-2 Randomised Controlled Trial
Acronym
COAST
Official Title
A Randomised Controlled Trial to Compare Ocrelizumab or Alemtuzumab With Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in High Inflammatory Multiple Sclerosis (COAST)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
Lack of recruitment due to low acceptance of the control arm.
Study Start Date
August 27, 2021 (Actual)
Primary Completion Date
February 4, 2022 (Actual)
Study Completion Date
February 4, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universitätsklinikum Hamburg-Eppendorf
Collaborators
Neovii Biotech, Clinical Trial Center North (CTC North GmbH & Co. KG)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A multicentre controlled phase II trial to compare the efficacy and safety of ocrelizumab or alemtuzumab and autologous Hematopoietic Stem Cell Transplantation (aHSCT). Active relapsing-remitting MS-Patients will be included and randomised to ocrelizumab or alemtuzumab versus aHSCT. Primary endpoint will be the time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) as represented by: no expanded disability status scale (EDSS) progression, no relapse, no new T2 lesion and no Gd-enhancing lesion. This trial offers the opportunity to gain further information about efficacy and safety of all treatments and will give new insights into the immunology of highly active RRMS.
Detailed Description
A rater-blinded multicentre randomised controlled phase II trial to compare the efficacy and safety of ocrelizumab or alemtuzumab and aHSCT. Active RRMS-Patients will be included and randomised to ocrelizumab or alemtuzumab versus aHSCT. Primary endpoint will be the time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) as represented by: no expanded disability status scale (EDSS) progression, no relapse, no new T2 lesion and no Gd-enhancing lesion. aHSCT appears highly efficacious in reducing inflammatory disease activity and relapses in active relapsing-remitting MS. Cohort data show a long-term stagnation of inflammatory disease activity for up to 10 years and more after aHSCT. However, efficacy data from randomised controlled trials comparing aHSCT with approved treatments are still lacking. The best available data concerning disease activity in MS patients with a documented treatment failure are from the CARE-MS II trial. The rate of patients without clinical or radiological disease activity after 2 years was 32% with alemtuzumab. aHSCT trial data on absence of disease activity show NEDA rates between 70 and 90% after 2 years. Here we assume 40% and 80% after 2 years for the ocrelizumab/alemtuzumab and aHSCT groups, respectively. For all three treatments, a potential long-term benefit has to be balanced with potentially harmful treatment related risks. A randomised controlled trial offers the opportunity to gain further information about efficacy and safety of all treatments and will give new insights into the immunology of high active RRMS.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing-Remitting Multiple Sclerosis
Keywords
autologous hematopoetic stem cell transplantation, alemtzumab, ocrelizumab, randomised controlled trial, aggressive highly active multiple sclerosis, no evidence of diseae activity (NEDA)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Patients will be randomised to control (ocrelizumab or alemtuzumab) or intervention (aHSCT).
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intervention (aHSCT)
Arm Type
Experimental
Arm Description
Autologous Hematopoietic Stem Cell Transplantation. Mobilisation will be performed with 2 g/m2 cyclophosphamide and 10 μg/kg G-CSF from day 5 until apheresis is completed. Conditioning will be 200 mg/kg cyclo-phosphamide and Anti-T-lymphocyteglobuline (Grafalon®, Neovii) with cu-mulative doses of 20 mg/kg given on day +1 (10 mg/kg) and day +2 (10 mg/kg).
Arm Title
Control
Arm Type
Active Comparator
Arm Description
In the control arm patient and physician will decide which treatment to choose. Patients will be either treated with ocrelizumab according to the SmPC (600 mg every 6 months continuously) or with alemtuzumab according to the SmPC (12 mg/day for 5 consecutive days and again after 365 days for 3 days).
Intervention Type
Drug
Intervention Name(s)
Autologous Hematopoietic Stem Cell Transplantation
Intervention Description
Autologous Hematopoietic Stem Cell Transplantation
Intervention Type
Drug
Intervention Name(s)
Ocrelizumab
Intervention Description
600 mg every 6 months continuously
Intervention Type
Drug
Intervention Name(s)
Alemtuzumab
Intervention Description
12 mg/day for 5 consecutive days and again after 365 days for 3 days
Primary Outcome Measure Information:
Title
Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity)
Description
Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) during follow-up as defined by: 3 months confirmed EDSS (Expanded disability status scale) progression confirmed relapse new/enlarging T2-hyperintense lesion on MRI (Magnetic resonance imaging) any Gd-enhancing lesion on MRI
Time Frame
through study completion, on average at least 2 years
Secondary Outcome Measure Information:
Title
Efficacy of treatment defined by EDSS
Description
EDSS change and EDSS improvement will be considered. EDSS improvement defined as confirmed improvement after 3 months
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by the annualized relapse rate
Description
calculated as number of relapses per year
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by the number of new T2 lesions
Description
calculated as cumulative number of new T2 lesions
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by the number of Gd-enhancing lesions
Description
calculated as cumulative number of GD-enhancing lesions
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by multiple sclerosis functional composite (MSFC) change
Description
based on summed up Z-scores for individual measures (SDMT, 9 HPT, 25 FWT)
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by Hamburg quality of life scale in MS (HAQUAMS)
Description
based on HAQUAMS sum score ratings (values between 1 and 5)
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by the Percentage Brain Volume Change (PBVC)
Description
Brain tissue volume (grey matter, white matter) will be evaluated on T1 weighted images to compute absolute percentage brain volume change
Time Frame
through study completion, on average at least 2 years
Title
Efficacy of treatment defined by grey and white matter atrophy
Description
based on grey and white matter volume change evaluated on T1 weighted images
Time Frame
through study completion, on average at least 2 years
Title
Rate of AE / SAE including NCI grade 3 and 4 non-haematological toxicities
Description
Safety of treatment defined by the rate of AE / SAE including NCI grade 3 and 4 non-haematological toxicities
Time Frame
through study completion, on average at least 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria (Based on CARE-MS-II3, guidelines and Rio-criteria for treatment failure): Written informed consent and agreement to comply to study protocol Age: 18-55 years EDSS: 0.0 - 6.0 RRMS according to McDonald 2010 < 10 years of disease course after symptom onset Active disease with one of the following treatment failures occur-ring not earlier than 6 months after initiation of an approved DMT 2 or more relapses within the last 12 months or 1 relapse within the last 12 months and a Gd-enhancing lesion on MRI > 3 mm > 3 months before or after relapse onset or 2 new T2-lesions or On-going signs of MRI activity in the last 6 months (either Gd-en-hancing of ≥ 3 mm lesion at any exam in the last year; or more than 5 new T2 lesions (≥ 3 mm) or Patients stable under natalizumab but who have to stop treatment due to an increasing PML risk are defined as active, if a MRI within 6 months after termination of natalizumab shows new T2 or Gd-enhancing lesions and at least one other treatment fail-ure prior to natalizumab is documented. Exclusion Criteria: Secondary or primary progressive MS Pregnancy, or other medical condition incompatible with aHSCT Any treatment or medical condition that, according to the haematologist / transplant specialist precludes the use of aHSCT John Cunningham virus (JCV) antibody index of > 1.5 in previ-ously natalizumab-treated patients, if a negative CSF JCV-PCR prior to screening is not available Relapse during 30 days before initiation of treatment. If a relapse occurs during this period and eligibility criteria are otherwise ful-filled, start of treatment will be delayed until at least 30 days after receiving steroids. Concurrent clinically significant (as determined by the investiga-tors and haematologist / transplant specialist) cardiac, immuno-logical, pulmonary, neurological, renal or other major disease such as: Prominent cardial disease (Left ventricular ejection frac-tion (LVEF) < 40%, myocardial infarction or ischemia, un-controlled arrhythmias, pericardial effusion > 1 cm) Cerebrovascular disease Renal disease (creatinine clearance < 30 ml/min/m2) Respiratory disease (DLCO < 40% predicted) Active bleeding or clotting disease History of human immunodeficiency virus (HIV) or posi-tive HIV antibody testing Any uncontrolled acute or chronic infection, including HIV, hepatitis B surface antigen positivity and hepatitis C PCR positivity Cancer except in situ cervix or cutaneous Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, men-tal, or social) that is likely to affect the patient returning for follow-up visits on schedule. Unwillingness to use contraception. Previous participation in this study, previous treatment with aHSCT or already both comparators Ongoing immunotherapy. Treatment with interferon or glati-rameracetate will need no wash-out. Treatment pause before oc-relizumab/alemtuzumab or aHSCT will be: for dimethylfumarate and fingolimod: 8 weeks for natalizumab: 8 weeks for ocrelizumab: 12 weeks for alemtuzumab: 12 months for teriflunomide: 4 weeks after elimination with cholesty-ramine for cladribine: 24 weeks Patients with cognitive impairments who are unable to provide written, informed consent prior to any testing under this protocol, including screening and baseline investigations that are not con-sidered part of routine patient care.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolaus Kröger, Prof. Dr.
Organizational Affiliation
University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitätsklinikum Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Universitätsklinikum Mannheim
City
Mannheim
ZIP/Postal Code
68167
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

Ocrelizumab or Alemtuzumab Compared With Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis - a Phase-2 Randomised Controlled Trial

We'll reach out to this number within 24 hrs