Immune- and miRNA-response to Recombinant Interferon Beta in Healthy Volunteers and Patients With Relapsing Remitting Multiple Sclerosis

NCT02364986 | Unknown Phase 1

• 1 other identifier: NEU-201201-RESI
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 2

Brief Summary

There are two standard and a few second line treatments for RRMS. Since the disease cannot be cured by these existing treatments and all treatment options have significant limitations, there is the need to develop new treatment strategies to improve therapy of patients with RRMS. We developed a RIG-I ligand as a new therapeutic strategy for patients with MS. The RIG-I ligand functions partially via induction of Interferon beta (IFN-b), but has advantages over therapy with recombinant IFN-b. Identification of suitable biomarkers to monitor treatment with RIG-I ligand and to guide the dose steps would help to increase the safety of the volunteers in the early clinical trials with RIG-I ligand. The RESI study is designed to analyse immune readouts and potential biomarkers such as type I IFN levels, type I IFN dependent immune activation and miRNA expression following Rebif or Avonex (Interferon beta 1a) application. Rebif is applied s.c. at a dose of 44 µg three times a week (on day 1,3,5 and 8), and Avonex i.m. at a dose of 30µg once a week (on day 1 and 8), as they are routinely used in RRMS-therapy. The immune readouts are assessed on day 1, 3, 5 and 8 immediately before application of Rebif/Avonex and on day 1 and 8 at 1 / 6 / 12 /24 hrs after Rebif/Avonex application by analysing blood samples. Since studies of the RIG-I ligand will start in healthy volunteers and will be continued in MS patients we need data from both populations since they could show significant differences in response to IFN-b. Thus, the RESI study includes healthy volunteers, RRMS-patients already under Rebif/Avonex treatment, and RRMS-patients who have to yet started a therapy with Rebif/Avonex.

Conditions

Relapsing-remitting Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• Change of mRNA (IFN-b, CXCL10, IL-6, MxA and 5'-3'OAS) and protein expression (IFN-b, CXCL10, IL-6) in peripheral blood mononuclear cells/ serum

  PBMCs and Serum are isolated from the blood before and at different time points after the application of Rebif/Avonex on day 1, 3, 5, and 8 (before / after 1hr / 6 hrs / 12 hrs / 24 hrs) to assess the changes in mRNA and protein expression related to Rebif/Avonex administration

  before / after 1hr / 6 hrs / 12 hrs / 24 hrs

Secondary Outcomes (11)

• Change of mRNA and miRNA expression in peripheral blood mononuclear cells and serum in healthy volunteers as well as in patients with RRMS

  before / after 1hr / 6 hrs / 12 hrs / 24 hrs

• Correlation of Rebif/Avonex side effects in patients with RRMS and healthy volunteers with changes in IFN-b, CXCL10, MxA, 5'-3'OAS, IL-6 serum levels, gene- and miRNA expression pattern and functional immune tests

  day 1 (+1 hr / 6hrs /12 hrs after 1. Rebif/Avonex application)

• Correlation of Rebif/Avonex side effects in patients with RRMS and healthy volunteers with changes in IFN-b, CXCL10, MxA, 5'-3'OAS, IL-6 serum levels, gene- and miRNA expression pattern and functional immune tests

  day 2 (24 hrs after 1.Rebif/Avonex application)

• Correlation of Rebif/Avonex side effects in patients with RRMS and healthy volunteers with changes in IFN-b, CXCL10, MxA, 5'-3'OAS, IL-6 serum levels, gene- and miRNA expression pattern and functional immune tests

  day 3 (48 hrs after 1.Rebif/Avonex application)

• Correlation of Rebif/Avonex side effects in patients with RRMS and healthy volunteers with changes in IFN-b, CXCL10, MxA, 5'-3'OAS, IL-6 serum levels, gene- and miRNA expression pattern and functional immune tests

  day 5 (48 hrs after 2.Rebif/ 96 hrs after 1. Avonex application)

Study Arms (1)

Rebif/Avonex

EXPERIMENTAL

Rebif® 44µg (day 1, 3, 5 and 8) s.c. Avonex 30µg (day 1 and 8) i.m.

Drug: Rebif®; Drug: Avonex

Interventions

Rebif® DRUG

Rebif® 44µg (day 1, 3, 5 and 8) s.c.

Also known as: Interferon beta 1a

Rebif/Avonex

Avonex DRUG

Avonex 30µg (day 1 and 8) i.m.

Also known as: Interferon beta 1a

Rebif/Avonex

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Voluntary participation in this study as proven by written informed consent
• Female or male patients with relapsing remitting MS according to McDon-ald-criteria (2010 revision) and decision for IFN-b treatment according to routine clinical criteria (not applying for healthy volunteers)
• Expanded Disability Status Scale (EDSS) between 0.0 and 6.0 (not applying for healthy volunteers)
• Naïve for IFN-b therapy (not applying for RRMS patients already under treatment)
• Age between 18 and 65 years
• Ability to follow study instructions and likely to attend and complete all required visits
• Adequate organ function as described below:
• Adequate bone marrow reserve:
• White blood cell (WBC) count ≥ 3000/µl,
• granulocyte count \> 1500/µl,
• platelets ≥ 100000/µl,
• haemoglobin ≥ 10 g/dl
• Adequate liver function
• bilirubin \< 1.5 times above upper limit of normal range (ULN) (the higher concentrations are only allowed for patients with RRMS)
• alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/SGOT) \< 3 times ULN (the higher concentrations are only allowed for patients with RRMS)

You may not qualify if:

• Subjects not able to give consent
• Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial
• Patients suffering from a form other than relapsing remitting Multiple Sclerosis (not applying for healthy volunteers)
• EDSS \>6.0 (not applying for healthy volunteers)
• Patients with known allergy or hypersensitivity to Interferon-beta or ingredients of the injection solution
• Subjects with a physical or psychiatric condition/ a systemic disease which at the investigator's discretion may compromise safety of the subject, may confound the trial results, may interfere with the subject's participation in this clinical trial or may prevent sufficient compliance
• Known or persistent abuse of medication, drugs or alcohol
• Prior malignancy (unless adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer). If prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence the subject can be enrolled at the discretion of the investigator
• Prior chemotherapy, systemic or local treatment with DNA-damaging and immune-modulating agents, tyrosine kinase inhibitors or anti-angiogenic agents for any cancer
• History of major depression, suicide attempt in the past, ongoing suicidal thoughts
• Cardiac insufficiency (NYHA III or IV), cardiomyopathy, significant cardiac dysrhythmia, unstable or advanced ischemic heart disease, or significant hypertension at rest (BP \> 180/110 mmHg)
• HIV, Hepatitis B or C infection or any relevant infectious disease which might interfere with the study procedures and results (at the discretion of the investigator)
• Women who are pregnant or breast-feeding
• Comedication with corticosteroids
• Female Patients with reproductive potential who do not accept to use contraception during the trial and 3 months thereafter

Sponsors & Collaborators

• PD Dr. Marcus Müller: lead
• BfARM, Bonn: collaborator
• DZNE, Bonn: collaborator

Study Sites (2)

Department of Neurology

Bonn, 53105, Germany

RECRUITING

Phase I Unit

Bonn, 53105, Germany

RECRUITING

Related Publications (1)

• Coenen M, Hinze AV, Mengel M, Fuhrmann C, Ludenbach B, Zimmermann J, Dykstra V, Fimmers R, Viviani R, Stingl J, Holdenrieder S, Muller M, Hartmann G, Coch C. Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies. BMC Pharmacol Toxicol. 2015 Sep 22;16:25. doi: 10.1186/s40360-015-0025-x.

  PMID: 26392348 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Interferon beta-1a

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Interferon-beta; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Marcus Müller, PD Dr.

  Department of Neurology University Hospital Bonn

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Verena Dykstra, Dr.

CONTACT

+49 (0) 228 287 16360; verena.dykstra@ukb.uni-bonn.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: PD Dr. Marcus M Müller

Study Record Dates

• First Submitted: December 10, 2014
• First Posted: February 18, 2015
• Study Start: January 1, 2015
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: June 3, 2016

Record last verified: 2016-06

Locations

DE (2)