Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis - Full Text View

Purpose

The purpose of this study is to test a novel strategy to prevent the clinical problem of secondary autoimmunity following alemtuzumab treatment of multiple sclerosis.

The hypothesis is that autoimmunity after alemtuzumab can be prevented by giving a drug that promotes thymic T cell regeneration (Palifermin, Kepivance®).

Condition	Intervention	Phase
Multiple Sclerosis	Drug: Palifermin Drug: Alemtuzumab	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	Keratinocyte Growth Factor - Promoting Thymic Reconstitution and Preventing Autoimmunity After Alemtuzumab (Campath-1H) Treatment of Multiple Sclerosis

Resource links provided by NLM:

Genetics Home Reference related topics: multiple sclerosis

MedlinePlus related topics: Autoimmune Diseases Multiple Sclerosis

Drug Information available for: Palifermin Alemtuzumab

U.S. FDA Resources

Further study details as provided by Cambridge University Hospitals NHS Foundation Trust:

Primary Outcome Measures:

incidence of clinical autoimmunity [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: Yes ]
The primary endpoint is incidence of clinical autoimmunity within 30 months of starting treatment with alemtuzumab

Secondary Outcome Measures:

Absolute numbers of naive T cells [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: No ]
Absolute numbers of naive T cells
Safety events [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: Yes ]
Safety outcomes - incidence and nature of adverse events

Other Outcome Measures:

Time at which autoimmunity develops [ Time Frame: Within 30 months after alemtuzumab ] [ Designated as safety issue: No ]
Reconstitution of lymphocyte subsets [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: No ]
Percentage of naive, central memory, effector memory and effector memory RA cells within the CD4 and CD8 T cell populations
T cell receptor (TCR) clonality [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: No ]
T cell receptor (TCR) clonality
Thymic function [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: No ]
Thymic function - determined by measuring TRECs
Thymic volume [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: No ]
Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.
Thymic density [ Time Frame: within 30 months of starting treatment with alemtuzumab ] [ Designated as safety issue: No ]
Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.


Estimated Enrollment:	86
Study Start Date:	June 2012
Estimated Study Completion Date:	October 2017
Estimated Primary Completion Date:	August 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Palifermin (and Alemtuzumab) Palifermin (Kepivance®), at the maximum identified tolerated dose will be administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose. Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).	Drug: Palifermin Palifermin (Kepivance®) administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose. Other Names: Kepivance keratinocyte growth factor Drug: Alemtuzumab Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day). Other Name: Campath-1H
Placebo Comparator: Placebo (and Alemtuzumab) Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).	Drug: Alemtuzumab Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day). Other Name: Campath-1H

Arms

Assigned Interventions

Experimental: Palifermin (and Alemtuzumab)

Palifermin (Kepivance®), at the maximum identified tolerated dose will be administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose. Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).

Drug: Palifermin

Palifermin (Kepivance®) administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose.

Other Names:

Kepivance
keratinocyte growth factor

Drug: Alemtuzumab

Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).

Other Name: Campath-1H

Placebo Comparator: Placebo (and Alemtuzumab)

Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).

Drug: Alemtuzumab

Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).

Other Name: Campath-1H

Detailed Description:

This is a single-centre, double-blinded, randomised controlled trial of palifermin (Kepivance) vs. placebo in the prevention of autoimmunity following alemtuzumab treatment of multiple sclerosis.

The dose of palifermin (kepivance)used in this trial will be informed by a dose-escalation study.

Eligibility


Ages Eligible for Study:	18 Months to 50 Years (Child, Adult)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Male or non-pregnant, non-lactating female patients
> 18 years of age, and <50 years of age inclusive
Diagnosis of MS using McDonald's 2010 criteria, including MRI abnormalities consistent with McDonald's 2010 criteria.
Onset of first MS symptoms within 10 years on the date the ICF is signed
EDSS score 0.0 to 5.0 (inclusive) at screening
At least 2 clinical episodes of MS in the 2 years prior to study entry, with at least 1 attack within 12 months, which may have occurred whilst on disease-modifying therapy, namely any beta interferon or glatiramer acetate.
Serum IL-7≤7pg/mL

Exclusion Criteria:

Any progressive form of multiple sclerosis
Previous thymectomy
Previous treatment with alemtuzumab, natalizumab, mitoxantrone, cyclophosphomide, cladribine, rituximab or any other immunosuppressant or cytotoxic therapy (other than steroids and disease-modifying therapies listed above)
History of malignancy
Personal history of clinically significant autoimmune disease, other than multiple sclerosis (including but not limited to: thyroid disease, immune cytopenias, inflammatory bowel disease, diabetes, lupus, severe asthma)
Intolerance of pulsed corticosteroids, especially a history of steroid psychosis
Major systemic disease or other illness that would, in the opinion of the investigator, compromise patient safety or interfere with the interpretation of study results.
Seropositivity for human immunodeficiency virus (HIV)
Past or present hepatitis B infection (positive hepatitis B serology)
Pregnant women or male and female patients who do not agree to use effective contraception during the study.
Medical, psychiatric, cognitive or other conditions that, in the investigator's opinion, compromise the patient's ability to understand the patient information, to give informed consent, to comply with the trial protocol, or to complete the study.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01712945

Contacts


Contact: Alasdair Coles, PhD FRCP	441223216751	ajc1020@medschl.cam.ac.uk
Contact: Joanne Jones, PhD MRCP	441223216751	jls53@medschl.cam.ac.uk

Locations


United Kingdom
Addenbrooke's Hospital	Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB2 2QQ
Contact: Karen May 441223216751 km480@medschl.cam.ac.uk
Principal Investigator: Alasdair Coles, PhD FRCP

Sponsors and Collaborators

Cambridge University Hospitals NHS Foundation Trust

Investigators


Principal Investigator:	Alasdair Coles, Phd FRCP	University of Cambridge

More Information

Additional Information:

Information for patients on protocol This link exits the ClinicalTrials.gov site

Publications:

Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-48. doi: 10.1016/S1474-4422(11)70020-5.

Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009 Jul;119(7):2052-61. doi: 10.1172/JCI37878. Epub 2009 Jun 22.

Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, Compston DA, Coles AJ. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005 Nov;35(11):3332-42.

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.

Bruinsma M, van Soest PL, Leenen PJ, Lambrecht BN, Cupedo T, Löwenberg B, Cornelissen JJ, Braakman E. Keratinocyte growth factor induces expansion of murine peripheral CD4+Foxp3+ regulatory T cells and increases their thymic output. J Immunol. 2007 Dec 1;179(11):7424-30.

Miller RD, Caulfield MJ, Calkins CE. Expression and regulation of a recurrent anti-erythrocyte autoantibody idiotype in spleen cells from neonatal and adult BALB/c mice. J Immunol. 1992 Apr 15;148(8):2452-5.

Min D, Panoskaltsis-Mortari A, Kuro-O M, Holländer GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood. 2007 Mar 15;109(6):2529-37. Epub 2006 Nov 30.


Responsible Party:	Alasdair Coles, Principal Investigator, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:	NCT01712945 History of Changes
Other Study ID Numbers:	EudraCT 2011-005606-30
Study First Received:	October 19, 2012
Last Updated:	October 23, 2012
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Cambridge University Hospitals NHS Foundation Trust:


Alemtuzumab Palifermin Reconstitution Thymus

Additional relevant MeSH terms:


Sclerosis Multiple Sclerosis Autoimmune Diseases Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases	Demyelinating Diseases Immune System Diseases Mitogens Alemtuzumab Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents

ClinicalTrials.gov processed this record on September 27, 2016

Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY)