Sequential Natalizumab - Alemtuzumab Therapy in Patients With Relapsing Forms of Multiple Sclerosis

Multiple Sclerosis (MS) Clinical Trial

— SUPPRESS  

Official title:

Sequential Natalizumab - Alemtuzumab Therapy in Patients With Relapsing Forms of Multiple Sclerosis (SUPPRESS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03135249
• Other study ID #: STU 112016-060
• Status: Completed
• Phase: Phase 4
• Start date: May 1, 2018
• Est. completion date: November 4, 2020

Study information

• Verified date: January 2022
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if a sequential combination therapy of natalizumab and alemtuzumab induces peripheral tolerance and reduces the annualized relapse rate (ARR) in patients with relapsing-remitting multiple sclerosis (RRMS).

Description:

To determine if treatment with alemtuzumab after natalizumab reduces the ARR in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy. The target population for this study are RRMS patients nearing the end of their natalizumab treatment regimen.Participants will be recruited from four different sites. Patients who meet all inclusion/exclusion criteria will be eligible for enrollment in the study.

Alemtuzumab (Lemtrada®) will be administered at a dose of 12 mg/d by intravenous (i.v.) infusion every day for five consecutive days within 14 days of the last dose of natalizumab. After 12 months, patients will be treated with a second course of alemtuzumab 12 mg/d by intravenous (i.v.) infusion every day for three consecutive days, and participants will be followed open-label for another 12 months per standard of care. Outside the scope of this study, the intention is to follow all study participants in participating centers long-term, and to record disease activity and treatment response.

Natalizumab treatment sequesters leukocytes out of the central nervous system (CNS) into the peripheral blood. Immediate sequential alemtuzumab therapy will deplete these cells more completely than alemtuzumab monotherapy, and prevent reactivation of disease activity previously treated with natalizumab. Thus, investigators hypothesize that sequential natalizumab - alemtuzumab therapy will prevent disease activation after cessation of natalizumab, and will provide sustained disease remission in many patients.

Clinical follow up by the treating physician will occur at months 0, 3, 6, 9, 12, 18 and 24 or immediately following clinical exacerbations months. During clinical visits, comprehensive medical history data will be obtained by the treating physician. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to reevaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made.

Standardized MRI studies of the brain will be performed at 0, 6, 12 and 24 months. Clinical imaging studies of the brain will be performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the brain with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: November 4, 2020
• Est. primary completion date: November 4, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Age between 18 and 60 years, inclusive.

2. Diagnosis of relapsing forms of MS using revised McDonald Criteria1.

3. Expanded Disability Status Scale (EDSS) 0 - 5.5 (note: functional system changes in cerebral (or mental) functions and in bowel and bladder functions not used in determining EDSS for protocol eligibility).

4. Has had a minimum of 12 monthly doses of continuous natalizumab therapy (300 mg/d).

5. Understands English, and gives informed consent.

Exclusion Criteria:

1. Natalizumab failure based on clinician's discretion.

2. Any prior exposure to alemtuzumab.

3. Progressive MS.

4. A diagnosis of Progressive multifocal leukoencephalopathy (PML).

5. Known hypersensitivity to alemtuzumab.

6. Initiation of new immunosuppressant treatment after the subject becomes protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial with immuno-active pharmacotherapies.

7. Uncontrolled diabetes mellitus defined as HbA1c > 8% and/or requiring intensive management.

8. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome.

9. Clinically significant autoimmune disease other than MS that may affect the CNS, including neuromyelitis optica (NMO), systemic lupus erythematosus (SLE), or Behcet disease.

10. Active hepatitis B or C infection or evidence of cirrhosis.

11. HIV positivity.

12. Uncontrolled viral, fungal, or bacterial infection.

13. Positive pregnancy test or inability or unwillingness to use effective means of birth control. Effective birth control is defined as:

1. Refraining from all acts of vaginal intercourse (abstinence),

2. Consistent use of birth control pills,

3. Tubal sterilization or male partner who has undergone vasectomy

4. Placement of intrauterine device

5. Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam.

14. Presence of metallic objects implanted in the body that would preclude the ability of the subject to safely have MRI exams.

15. Psychiatric illness, mental deficiency, or cognitive dysfunction making compliance with treatment or informed consent impossible.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis (MS)
• Sclerosis

Intervention

Drug:
• Alemtuzumab
Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.

Locations

Country	Name	City	State
United States	UT Southwestern Medical center	Dallas	Texas
United States	VA North Texas Health Care System	Dallas	Texas

Sponsors (2)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

References & Publications (27)

Berger JR, Fox RJ. Erratum to: Reassessing the risk of natalizumab-associated PML. J Neurovirol. 2016 Aug;22(4):536-537. — View Citation

Berger JR, Fox RJ. Reassessing the risk of natalizumab-associated PML. J Neurovirol. 2016 Aug;22(4):533-5. doi: 10.1007/s13365-016-0427-6. Epub 2016 Feb 3. Erratum in: J Neurovirol. 2016 Aug;22(4):536-7. — View Citation

Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870-80. doi: 10.1056/NEJMoa1107829. — View Citation

Bologna L, Gotti E, Manganini M, Rambaldi A, Intermesoli T, Introna M, Golay J. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J Immunol. 2011 Mar 15;186(6):3762-9. doi: 10.4049/jimmunol.1000303. Epub 2011 Feb 4. — View Citation

CAMMS223 Trial Investigators, Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008 Oct 23;359(17):1786-801. doi: 10.1056/NEJMoa0802670. — View Citation

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28. doi: 10.1016/S0140-6736(12)61769-3. Epub 2012 Nov 1. — View Citation

Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108. Epub 2005 Jul 27. — View Citation

Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab more effective than interferon ß-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012 Apr 3;78(14):1069-78. doi: 10.1212/WNL.0b013e31824e8ee7. Epub 2012 Mar 21. — View Citation

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1829-39. doi: 10.1016/S0140-6736(12)61768-1. Epub 2012 Nov 1. — View Citation

Cossburn MD, Harding K, Ingram G, El-Shanawany T, Heaps A, Pickersgill TP, Jolles S, Robertson NP. Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis. Neurology. 2013 Jan 1;80(1):55-61. doi: 10.1212/WNL.0b013e31827b5927. Epub 2012 Dec 12. — View Citation

del Pilar Martin M, Cravens PD, Winger R, Frohman EM, Racke MK, Eagar TN, Zamvil SS, Weber MS, Hemmer B, Karandikar NJ, Kleinschmidt-DeMasters BK, Stüve O. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol. 2008 Dec;65(12):1596-603. doi: 10.1001/archneur.65.12.noc80051. Epub 2008 Oct 13. — View Citation

Hale G, Rye PD, Warford A, Lauder I, Brito-Babapulle A. The glycosylphosphatidylinositol-anchored lymphocyte antigen CDw52 is associated with the epididymal maturation of human spermatozoa. J Reprod Immunol. 1993 Mar;23(2):189-205. — View Citation

Hederer RA, Guntermann C, Miller N, Nagy P, Szollosi J, Damjanovich S, Hale G, Alexander DR. The CD45 tyrosine phosphatase regulates Campath-1H (CD52)-induced TCR-dependent signal transduction in human T cells. Int Immunol. 2000 Apr;12(4):505-16. — View Citation

Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, Green A, Giovannoni G, Compston DA, Fahey MT, Coles AJ. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304. doi: 10.1136/jnnp-2011-300826. Epub 2011 Nov 5. — View Citation

Hu Y, Turner MJ, Shields J, Gale MS, Hutto E, Roberts BL, Siders WM, Kaplan JM. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology. 2009 Oct;128(2):260-70. doi: 10.1111/j.1365-2567.2009.03115.x. — View Citation

Kivisäkk P, Healy BC, Viglietta V, Quintana FJ, Hootstein MA, Weiner HL, Khoury SJ. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology. 2009 Jun 2;72(22):1922-30. doi: 10.1212/WNL.0b013e3181a8266f. — View Citation

Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kümpfel T, Buck D, Hohlfeld R, Berthele A, Hemmer B. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS. Neurology. 2011 Apr 5;76(14):1214-21. doi: 10.1212/WNL.0b013e3182143564. — View Citation

Krumbholz M, Meinl I, Kümpfel T, Hohlfeld R, Meinl E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology. 2008 Oct 21;71(17):1350-4. doi: 10.1212/01.wnl.0000327671.91357.96. — View Citation

O'Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, Rudick RA, Aschenbach W, Lucas N. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011 May 31;76(22):1858-65. doi: 10.1212/WNL.0b013e31821e7c8a. Epub 2011 May 4. — View Citation

Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910. — View Citation

Rowan WC, Hale G, Tite JP, Brett SJ. Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes. Int Immunol. 1995 Jan;7(1):69-77. — View Citation

Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):911-23. — View Citation

Stauch D, Dernier A, Sarmiento Marchese E, Kunert K, Volk HD, Pratschke J, Kotsch K. Targeting of natural killer cells by rabbit antithymocyte globulin and campath-1H: similar effects independent of specificity. PLoS One. 2009;4(3):e4709. doi: 10.1371/journal.pone.0004709. Epub 2009 Mar 5. — View Citation

Stüve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von Geldern G, Cepok S, Singh MP, Tervaert JW, De Baets M, MacManus D, Miller DH, Radü EW, Cameron EM, Monson NL, Zhang S, Kim R, Hemmer B, Racke MK. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009 Feb 3;72(5):396-401. doi: 10.1212/01.wnl.0000327341.89587.76. Epub 2008 Nov 5. — View Citation

Stüve O, Marra CM, Bar-Or A, Niino M, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Jerome KR, Cook L, Grand'Maison F, Hemmer B, Monson NL, Racke MK. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol. 2006 Oct;63(10):1383-7. — View Citation

Stüve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Hemmer B, Monson NL, Racke MK. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2006 May;59(5):743-7. — View Citation

Xia MQ, Tone M, Packman L, Hale G, Waldmann H. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur J Immunol. 1991 Jul;21(7):1677-84. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Neurological Disability Outcome	Neurological disability The Expanded Disability Status Scale (EDSS) will be utilized to measure the accumulation of neurological disability.; The EDSS is a scale providing a disability score (0 to 10) based on neurological examination and information about how the patient is able to perform tasks such as long walking. Higher the score, worse the outcomes.	12 months
Other	Quality of Life Outcome	Quality of life (QoL) will be measured by a pre-defined, self-administered testing battery. It measures the pleasure one derives from being able to do their work well, feelings of hopelessness and difficulties in dealing with work or in doing their job effectively, and work-related, secondary exposure to extremely stressful events. Possible scores range from 0-100, with higher scores indicating a better quality of life.	12 months
Primary	Annualized Relapse Rate (ARR) From the Time of Cessation of Natalizumab Treatment.	The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy.; ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study.	12 months
Primary	Relapse-free Period	Relapse free period, number of months until relapse, was measured only among participants who may relapse.	Baseline until progression up to 12 months
Secondary	Number of New T2 Lesions	Number of new T2 lesions as measured by MRI.	12 months
Secondary	Number of Enlarging T2 Lesions	Number of enlarging T2 lesions as measured by MRI.	12 months
Secondary	Number of Gadolinium (Gd)-Enhancing Lesions	Number of gadolinium (Gd)-enhancing lesions as measured by MRI.	12 months