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

Sponsor

Universitätsklinikum Hamburg-Eppendorf (Other)

Overall Status

Terminated

CT.gov ID

NCT04971005

Collaborator

Neovii Biotech (Industry), Clinical Trial Center North (CTC North GmbH & Co. KG) (Other)

Enrollment

Locations

Arms

5.3

Actual Duration (Months)

0.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsing-Remitting Multiple Sclerosis	Drug: Autologous Hematopoietic Stem Cell Transplantation Drug: Ocrelizumab Drug: Alemtuzumab	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

1 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will be randomised to control (ocrelizumab or alemtuzumab) or intervention (aHSCT).Patients will be randomised to control (ocrelizumab or alemtuzumab) or intervention (aHSCT).

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomised Controlled Trial to Compare Ocrelizumab or Alemtuzumab With Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in High Inflammatory Multiple Sclerosis (COAST)

Actual Study Start Date :

Aug 27, 2021

Actual Primary Completion Date :

Feb 4, 2022

Actual Study Completion Date :

Feb 4, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention (aHSCT) 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).	Drug: Autologous Hematopoietic Stem Cell Transplantation Autologous Hematopoietic Stem Cell Transplantation
Active Comparator: Control 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).	Drug: Ocrelizumab 600 mg every 6 months continuously Drug: Alemtuzumab 12 mg/day for 5 consecutive days and again after 365 days for 3 days

Arm

Intervention/Treatment

Experimental: Intervention (aHSCT)

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).

Drug: Autologous Hematopoietic Stem Cell Transplantation

Autologous Hematopoietic Stem Cell Transplantation

Active Comparator: Control

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).

Drug: Ocrelizumab

600 mg every 6 months continuously

Drug: Alemtuzumab

12 mg/day for 5 consecutive days and again after 365 days for 3 days

Outcome Measures

Primary Outcome Measures

Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) [through study completion, on average at least 2 years]
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 [through study completion, on average at least 2 years]
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 [through study completion, on average at least 2 years]
calculated as number of relapses per year
Efficacy of treatment defined by the number of new T2 lesions [through study completion, on average at least 2 years]
calculated as cumulative number of new T2 lesions
Efficacy of treatment defined by the number of Gd-enhancing lesions [through study completion, on average at least 2 years]
calculated as cumulative number of GD-enhancing lesions
Efficacy of treatment defined by multiple sclerosis functional composite (MSFC) change [through study completion, on average at least 2 years]
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) [through study completion, on average at least 2 years]
based on HAQUAMS sum score ratings (values between 1 and 5)
Efficacy of treatment defined by the Percentage Brain Volume Change (PBVC) [through study completion, on average at least 2 years]
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 [through study completion, on average at least 2 years]
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 [through study completion, on average at least 2 years]
Safety of treatment defined by the rate of AE / SAE including NCI grade 3 and 4 non-haematological toxicities

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts 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

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

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)

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.