Back to resultsAHSCT With Fludarabine and Cyclophosphamide Based Conditioning Regimes in Patients With Multiple Sclerosis
Primary Purpose
Multiple Sclerosis
Status
Recruiting
Phase
Phase 1
Locations
Russian Federation
Study Type
Interventional
Intervention
Fludarabine Phosphate for Injection
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Sclerosis focused on measuring Autoimmune Diseases, AHSCT, Fludarabine
Eligibility Criteria
Inclusion Criteria: Age 18-65; 1.0-6.5 points on the EDSS scale (for MS); Length of illness - any; Disease progression during the last 6 months while taking drugs of 1st and 2nd lines; An established and confirmed diagnosis of an autoimmune disease in the previous stages of treatment; Ineffectiveness, inaccessibility or intolerance of Disease-Modifying Therapies; Relapse after AHSCT. Absence of severe concomitant somatic pathology; Left ventricular injection fraction > 50%; Karnofsky Performance Score (KPS) > 30%; The ability to take oral medications; Life expectancy is more than 1 month; Signed informed consent of the patient or legal representatives. Exclusion Criteria: Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50% Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted Respiratory distress >grade I Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits Creatinine clearance < 60 mL/min Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Karnofsky performans status <30% Pregnancy Somatic or psychiatric disorder making the patient unable to sign informed consent
Sites / Locations
- First Pavlov State Medical University of St. PetersburgRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
AHSCT: FluCy200
Arm Description
AHSCT with reduced intensity condition regimen (RIC): cyclophosphamide intravenously at a dose of 50 mg/kg/day from -5 to day -2 inclusive; fludarabine intravenously at a dose of 30 mg/m2 from -5 to day -2 inclusive. Immunotherapy: ATG - ATGAM intravenously 20 mg/kg from -3 to -1 or Thymoglobulin 2.5 mg/kg from -3 to -1 day. Also, within the framework of immunotherapy, instead of ATG, it is allowed to use anti-B-cell therapy - Rituximab 500 mg / m2 per day +12 AHSCT.
Outcomes
Primary Outcome Measures
Multiple sclerosis progression free survival
To evaluate safety and effectiveness of immunoablative conditioning regimen FluCy200 in patients with refractory multiple sclerosis after AHSCT.
Secondary Outcome Measures
Cumulative incidence of mortality
Death from any cause after AHSCT
To evaluate adverse effects after FluCy200 conditioning regimen
Toxicity based NCI CTCAE ver.5.0, including analysis of severe bacterial, fungal and viral infections incidence
Quality of life status 1
Multiple sclerosis-specific questionnaire - HADS (Hospital Anxiety and Depression Scale) before and after AHSCT:
0-7 points - normal; 8-10 - subclinically expressed anxiety/depression; 11-21 - clinically expressed anxiety/depression.
Quality of life status 2
Multiple sclerosis-specific questionnaire - The Short Form-36 (SF-36) before and after AHSCT: The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role-physical functioning, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The indicators of each scale are compiled in such a way that the higher the value of the indicator (from 0 to 100), the better the score on the chosen scale. Of these, two parameters are formed: the psychological and physical components of health.
Quality of life status 3
Multiple sclerosis-specific questionnaire - Multiple Sclerosis Impact Scale (MSIS-29) before and after AHSCT:
The MSIS-29 scale consists of 29 items and includes indicators observed over the previous two weeks, including 20 of which characterize physical condition, coordination and mobility, and 9 questions reflect the patient's mental state. Answers are ranked on a 5-point Likert scale from 1 to 5 (1 = none; 2 = little; 3 = moderate; 4 = significant; 5 = very strong) in one direction.
The total score is the sum of all 29 responses and can range from 29 to 145. A higher score means a higher degree of disability. The result is assessed on a scale from 0 to 100, where a higher result means worse health.
Quality of life status 4
Multiple sclerosis-specific questionnaire - Functional Assessment of Multiple Sclerosis (FAMS) before and after AHSCT:
FAMS Total score (range=0-176) is derived by adding: 1) Mobility (r=0-28). 2) Symptoms (r=0-28). 3) Emotional well- being (r=0-28). 4) General contentment (r=0-28). 5) Thinking and fatigue (r=0-36). 6) Family/social wellbeing (r=0-28).
Higher scores indicate better quality of life.
Neurological status 1
Multiple sclerosis-specific questionnaire - EDSS (Expanded Disability Status Scale) before and after AHSCT:
0 points - Normal neurologic exam; 1.0-1.5 - No disability, minimal signs in one or two Functional Systems (FS); 2.0-2.5 - Minimal disability in one or two FS; 3.0-3,5 - Moderate disability in one FS, fully ambulatory; 4.0-4.5 - Fully ambulatory without aid. Able to walk without aid or rest some 500 or 300 meters; 5.0-5.5 - Ambulatory without aid or rest for about 200 or 100 meters; 6.0 - Intermittent assistance required to walk about 100 meters; 6.5 - Constant bilateral assistance required to walk about 20 meters; 7.0-7.5 - Unable to walk beyond about 5 meters or more than a few steps; 8.0 - Essentially restricted to bed, but may be out of bed itself; 8.5 - Essentially restricted to bed; 9.0 - Helpless bed patient; can communicate and eat; 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow; 10 - Death due to MS
Immune reconstitution
Absolute number of CD3+, CD4+, CD8+, CD45+, CD19+ T-lymphocytes in cells/ml
Magnetic resonance imaging response
Measured by Magnetic Resonance Disease Severity Scale (MRDSS)
Full Information
NCT ID
NCT05832515
First Posted
April 4, 2022
Last Updated
April 14, 2023
Sponsor
St. Petersburg State Pavlov Medical University
1. Study Identification
Unique Protocol Identification Number
NCT05832515
Brief Title
AHSCT With Fludarabine and Cyclophosphamide Based Conditioning Regimes in Patients With Multiple Sclerosis
Official Title
Trial of the Efficacy and Safety of High-dose Immunosuppressive Therapy Based on Fludarabine and Cyclophosphamide-containing Conditioning Regimen Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Sclerosis.
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2020 (Actual)
Primary Completion Date
October 1, 2025 (Anticipated)
Study Completion Date
December 1, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
St. Petersburg State Pavlov Medical University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
One of the possible options for the treatment of MS at present is a high-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HIST-AHSCT), which is a highly effective treatment for patients with relapsing-remitting MS.
This method of MS treatment was introduced in 1997. Significant complications and mortality associated with HIST-ATHSC is an obstacle to broad use of this method. The risk is even greater in patients with advanced disease, long duration of previous treatment and aggressive forms of MS.
Despite toxicity certain progressive cases of MS are still an indication for HIST-autoHSCT.
Most commonly used conditioning regimens for multiple sclerosis include high-dose cyclophosphamide. One of the options to reduce cyclophosphamide-related toxicity and dose is addition of fludarabine. Fludarabine is a cytostatic drug, an antimetabolite from the group of purine antagonists. It has a pronounced immunosuppressive activity and no overlapping toxicity with cyclophosphamide. The study will evaluate the safety and efficacy of this combination.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis
Keywords
Autoimmune Diseases, AHSCT, Fludarabine
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
200 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
AHSCT: FluCy200
Arm Type
Experimental
Arm Description
AHSCT with reduced intensity condition regimen (RIC):
cyclophosphamide intravenously at a dose of 50 mg/kg/day from -5 to day -2 inclusive; fludarabine intravenously at a dose of 30 mg/m2 from -5 to day -2 inclusive. Immunotherapy: ATG - ATGAM intravenously 20 mg/kg from -3 to -1 or Thymoglobulin 2.5 mg/kg from -3 to -1 day.
Also, within the framework of immunotherapy, instead of ATG, it is allowed to use anti-B-cell therapy - Rituximab 500 mg / m2 per day +12 AHSCT.
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate for Injection
Other Intervention Name(s)
Fludarabine
Intervention Description
Intravenous injection of fludarabine phosphate at a dose of 30 mg/m2 from day -5 to day -2 of immunoablative conditioning regimen.
Primary Outcome Measure Information:
Title
Multiple sclerosis progression free survival
Description
To evaluate safety and effectiveness of immunoablative conditioning regimen FluCy200 in patients with refractory multiple sclerosis after AHSCT.
Time Frame
365 days
Secondary Outcome Measure Information:
Title
Cumulative incidence of mortality
Description
Death from any cause after AHSCT
Time Frame
365 days
Title
To evaluate adverse effects after FluCy200 conditioning regimen
Description
Toxicity based NCI CTCAE ver.5.0, including analysis of severe bacterial, fungal and viral infections incidence
Time Frame
365 days
Title
Quality of life status 1
Description
Multiple sclerosis-specific questionnaire - HADS (Hospital Anxiety and Depression Scale) before and after AHSCT:
0-7 points - normal; 8-10 - subclinically expressed anxiety/depression; 11-21 - clinically expressed anxiety/depression.
Time Frame
365 days
Title
Quality of life status 2
Description
Multiple sclerosis-specific questionnaire - The Short Form-36 (SF-36) before and after AHSCT: The SF-36 consists of 36 questions grouped into eight scales: physical functioning, role-physical functioning, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The indicators of each scale are compiled in such a way that the higher the value of the indicator (from 0 to 100), the better the score on the chosen scale. Of these, two parameters are formed: the psychological and physical components of health.
Time Frame
365 days
Title
Quality of life status 3
Description
Multiple sclerosis-specific questionnaire - Multiple Sclerosis Impact Scale (MSIS-29) before and after AHSCT:
The MSIS-29 scale consists of 29 items and includes indicators observed over the previous two weeks, including 20 of which characterize physical condition, coordination and mobility, and 9 questions reflect the patient's mental state. Answers are ranked on a 5-point Likert scale from 1 to 5 (1 = none; 2 = little; 3 = moderate; 4 = significant; 5 = very strong) in one direction.
The total score is the sum of all 29 responses and can range from 29 to 145. A higher score means a higher degree of disability. The result is assessed on a scale from 0 to 100, where a higher result means worse health.
Time Frame
365 days
Title
Quality of life status 4
Description
Multiple sclerosis-specific questionnaire - Functional Assessment of Multiple Sclerosis (FAMS) before and after AHSCT:
FAMS Total score (range=0-176) is derived by adding: 1) Mobility (r=0-28). 2) Symptoms (r=0-28). 3) Emotional well- being (r=0-28). 4) General contentment (r=0-28). 5) Thinking and fatigue (r=0-36). 6) Family/social wellbeing (r=0-28).
Higher scores indicate better quality of life.
Time Frame
365 days
Title
Neurological status 1
Description
Multiple sclerosis-specific questionnaire - EDSS (Expanded Disability Status Scale) before and after AHSCT:
0 points - Normal neurologic exam; 1.0-1.5 - No disability, minimal signs in one or two Functional Systems (FS); 2.0-2.5 - Minimal disability in one or two FS; 3.0-3,5 - Moderate disability in one FS, fully ambulatory; 4.0-4.5 - Fully ambulatory without aid. Able to walk without aid or rest some 500 or 300 meters; 5.0-5.5 - Ambulatory without aid or rest for about 200 or 100 meters; 6.0 - Intermittent assistance required to walk about 100 meters; 6.5 - Constant bilateral assistance required to walk about 20 meters; 7.0-7.5 - Unable to walk beyond about 5 meters or more than a few steps; 8.0 - Essentially restricted to bed, but may be out of bed itself; 8.5 - Essentially restricted to bed; 9.0 - Helpless bed patient; can communicate and eat; 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow; 10 - Death due to MS
Time Frame
365 days
Title
Immune reconstitution
Description
Absolute number of CD3+, CD4+, CD8+, CD45+, CD19+ T-lymphocytes in cells/ml
Time Frame
365 days
Title
Magnetic resonance imaging response
Description
Measured by Magnetic Resonance Disease Severity Scale (MRDSS)
Time Frame
365 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18-65;
1.0-6.5 points on the EDSS scale (for MS);
Length of illness - any;
Disease progression during the last 6 months while taking drugs of 1st and 2nd lines;
An established and confirmed diagnosis of an autoimmune disease in the previous stages of treatment;
Ineffectiveness, inaccessibility or intolerance of Disease-Modifying Therapies;
Relapse after AHSCT.
Absence of severe concomitant somatic pathology;
Left ventricular injection fraction > 50%;
Karnofsky Performance Score (KPS) > 30%;
The ability to take oral medications;
Life expectancy is more than 1 month;
Signed informed consent of the patient or legal representatives.
Exclusion Criteria:
Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%
Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted
Respiratory distress >grade I
Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits
Creatinine clearance < 60 mL/min
Uncontrolled bacterial or fungal infection at the time of enrollment
Requirement for vasopressor support at the time of enrollment
Karnofsky performans status <30%
Pregnancy
Somatic or psychiatric disorder making the patient unable to sign informed consent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alexey Yu Polushin
Phone
+79118167559
Email
alexpolushin@yandex.ru
First Name & Middle Initial & Last Name or Official Title & Degree
Yury R Zalyalov
Phone
+79112193127
Email
yz21@mail.ru
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ivan S Moiseev
Organizational Affiliation
Pavlov First Saint-Petersburg State Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
First Pavlov State Medical University of St. Petersburg
City
Saint Petersburg
ZIP/Postal Code
197022
Country
Russian Federation
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexey Yu Polushin, MD
Phone
+79118167559
Email
alexpolushin@yandex.ru
First Name & Middle Initial & Last Name & Degree
Yury R Zalyalov, MD
Phone
+79112193127
Email
yz21@mail.ru
First Name & Middle Initial & Last Name & Degree
Alexey Yu Polushin, MD
First Name & Middle Initial & Last Name & Degree
Yury R Zalyalov, MD
First Name & Middle Initial & Last Name & Degree
Alexandr A Tsynchenko
First Name & Middle Initial & Last Name & Degree
Evgenia I Kakoulina
First Name & Middle Initial & Last Name & Degree
Elena S Saganova, MD
12. IPD Sharing Statement
Learn more about this trial
AHSCT With Fludarabine and Cyclophosphamide Based Conditioning Regimes in Patients With Multiple Sclerosis
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