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

NCT03135249 | Completed Phase 4 Results FDA Drug

• 1 other identifier: STU 112016-060
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief 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).

Conditions

Multiple Sclerosis (MS)

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (3)

• Number of New T2 Lesions

  12 months

• Number of Enlarging T2 Lesions

  12 months

• Number of Gadolinium (Gd)-Enhancing Lesions

  12 months

Other Outcomes (2)

• Neurological Disability Outcome

  12 months

• Quality of Life Outcome

  12 months

Study Arms (1)

Alemtuzumab treatment.

OTHER

Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution.

Drug: Alemtuzumab

Interventions

Alemtuzumab DRUG

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

Also known as: Lemtrada

Alemtuzumab treatment.

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age between 18 and 60 years, inclusive.
• Diagnosis of relapsing forms of MS using revised McDonald Criteria1.
• 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).
• Has had a minimum of 12 monthly doses of continuous natalizumab therapy (300 mg/d).
• Understands English, and gives informed consent.

You may not qualify if:

• Natalizumab failure based on clinician's discretion.
• Any prior exposure to alemtuzumab.
• Progressive MS.
• A diagnosis of Progressive multifocal leukoencephalopathy (PML).
• Known hypersensitivity to alemtuzumab.
• Initiation of new immunosuppressant treatment after the subject becomes protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial with immuno-active pharmacotherapies.
• Uncontrolled diabetes mellitus defined as HbA1c \> 8% and/or requiring intensive management.
• History of cytopenia consistent with the diagnosis of myelodysplastic syndrome.
• Clinically significant autoimmune disease other than MS that may affect the CNS, including neuromyelitis optica (NMO), systemic lupus erythematosus (SLE), or Behcet disease.
• Active hepatitis B or C infection or evidence of cirrhosis.
• HIV positivity.
• Uncontrolled viral, fungal, or bacterial infection.
• Positive pregnancy test or inability or unwillingness to use effective means of birth control. Effective birth control is defined as:
• Refraining from all acts of vaginal intercourse (abstinence),
• Consistent use of birth control pills,

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (2)

VA North Texas Health Care System

Dallas, Texas, 75216, United States

Location

UT Southwestern Medical center

Dallas, Texas, 75390, United States

Location

Related Publications (28)

• 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. doi: 10.1056/NEJMoa044396.

  PMID: 16510745 BACKGROUND

• 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. doi: 10.1056/NEJMoa044397.

  PMID: 16510744 BACKGROUND

• Stuve 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. doi: 10.1001/archneur.63.10.1383.

  PMID: 17030653 BACKGROUND

• Stuve 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. doi: 10.1002/ana.20858.

  PMID: 16634029 BACKGROUND

• Stuve 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, Radu 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.

  PMID: 18987352 BACKGROUND

• Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kumpfel 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.

  PMID: 21464424 BACKGROUND

• 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, Stuve 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.

  PMID: 18852339 BACKGROUND

• 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.

  PMID: 22591293 BACKGROUND

• 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.

  PMID: 26843383 BACKGROUND

• Berger JR, Fox RJ. Erratum to: Reassessing the risk of natalizumab-associated PML. J Neurovirol. 2016 Aug;22(4):536-537. doi: 10.1007/s13365-016-0431-x. No abstract available.

  PMID: 27026534 BACKGROUND

• 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.

  PMID: 21543733 BACKGROUND

• Krumbholz M, Meinl I, Kumpfel 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.

  PMID: 18936427 BACKGROUND

• Kivisakk 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.

  PMID: 19487650 BACKGROUND

• 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.

  PMID: 23122652 BACKGROUND

• 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.

  PMID: 23122650 BACKGROUND

• 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. doi: 10.1016/0165-0378(93)90007-5.

  PMID: 7685389 BACKGROUND

• 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. doi: 10.1002/eji.1830210714.

  PMID: 1711975 BACKGROUND

• 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. doi: 10.1093/intimm/7.1.69.

  PMID: 7718516 BACKGROUND

• 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. doi: 10.1093/intimm/12.4.505.

  PMID: 10744652 BACKGROUND

• 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.

  PMID: 19266059 BACKGROUND

• 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. doi: 10.1007/s00415-005-0934-5. Epub 2005 Jul 27.

  PMID: 16044212 BACKGROUND

• 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.

  PMID: 18946064 BACKGROUND

• 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.

  PMID: 19740383 BACKGROUND

• 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.

  PMID: 21296976 BACKGROUND

• 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.

  PMID: 22056965 BACKGROUND

• 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.

  PMID: 23243077 BACKGROUND

• 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 beta-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.

  PMID: 22442431 BACKGROUND

• Hussain RZ, Sguigna PV, Okai A, Wright C, Madinawala M, Bass AD, Cutter GR, Manouchehri N, Stuve O. The sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS) trial - Part I: Rationale and objectives. J Cent Nerv Syst Dis. 2022 Aug 29;14:11795735221123911. doi: 10.1177/11795735221123911. eCollection 2022.

  PMID: 36062026 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Alemtuzumab

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Olaf Stuve, Principal Investigator
• Organization: UT Southwestern Medical Center

olaf.stuve@utsouthwestern.edu

12146484559

Study Officials

• Olaf Stuve, M.D., Ph.D.

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PROFESSOR

Model Details: To determine if treatment with alemtuzumab after natalizumab maintains or 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.

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: May 1, 2017
• Study Start: May 1, 2018
• Primary Completion: November 4, 2020
• Study Completion: November 4, 2020
• Last Updated: February 15, 2022
• Results First Posted: February 15, 2022

Record last verified: 2022-01

Locations

US (2)