Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis

Multiple Sclerosis Clinical Trial

— CAM-THY  

Official title:

Keratinocyte Growth Factor - Promoting Thymic Reconstitution and Preventing Autoimmunity After Alemtuzumab (Campath-1H) Treatment of Multiple Sclerosis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01712945
• Other study ID #: EudraCT 2011-005606-30
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: June 2012
• Est. completion date: October 2017

Study information

• Verified date: April 2019
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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®).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 40
• Est. completion date: October 2017
• Est. primary completion date: August 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Months to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Autoimmune Diseases
• Multiple Sclerosis
• Sclerosis

Intervention

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.
• 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).

Locations

Country	Name	City	State
United Kingdom	Addenbrooke's Hospital	Cambridge	Cambridgeshire

Sponsors (1)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (7)

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. — 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

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 ß-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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time at which autoimmunity develops		Within 30 months after alemtuzumab
Other	Reconstitution of lymphocyte subsets	Percentage of naive, central memory, effector memory and effector memory RA cells within the CD4 and CD8 T cell populations	within 30 months of starting treatment with alemtuzumab
Other	T cell receptor (TCR) clonality	T cell receptor (TCR) clonality	within 30 months of starting treatment with alemtuzumab
Other	Thymic function	Thymic function - determined by measuring TRECs	within 30 months of starting treatment with alemtuzumab
Other	Thymic volume	Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.	within 30 months of starting treatment with alemtuzumab
Other	Thymic density	Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6.	within 30 months of starting treatment with alemtuzumab
Primary	incidence of clinical autoimmunity	The primary endpoint is incidence of clinical autoimmunity within 30 months of starting treatment with alemtuzumab	within 30 months of starting treatment with alemtuzumab
Secondary	Absolute numbers of naive T cells	Absolute numbers of naive T cells	within 30 months of starting treatment with alemtuzumab
Secondary	Safety events	Safety outcomes - incidence and nature of adverse events	within 30 months of starting treatment with alemtuzumab