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

June 2, 2016 updated by: PD Dr. Marcus Müller

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.

Study Overview

Status

Unknown

Intervention / Treatment

Detailed Description

Study subjects receive either Rebif or Avonex. Rebif is applied s.c. at a dose of 44 µg on day 1, day 3, day 5 and day 8, Avonex i.m. at a dose of 30µg on day 1 and 8. Blood samples are taken before application and on day 1 and 8 at 1 / 6 / 12 /24 hrs after Rebif/Avonex application to analyse the occuring immune response. The total duration of the trial for the individual subject are 9 days. An MRI ist performed before the first application of IMP and at the end of the study to investigate the correlation of Rebif/Avonex application and depression.

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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)
    • Adequate renal function: creatinine < 1.5 times ULN (the higher concentrations are only allowed for patients with RRMS)
    • TSH within normal limits
    • Adequate blood clotting:

      • INR and PTT within normal limits
  • Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after the trial (Pearl index <1; Oral hormonal contraception must be used in combination with a barrier device due to elevated risk of nausea. Use of an intrauterine device made of copper is not allowed for healthy volunteers due to MRI)
  • Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained prior to treatment start
  • MRI study: only healthy participants

Exclusion Criteria:

  • 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)
  • Patients with a MS relapse within 30 days before study inclusion
  • 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
  • Treatment in another clinical trial with therapeutic intervention or use of any other investigational medicinal product (IMP) during the trial or within the 30 days but at least 5 times the half life of the IMP before enrolment
  • Very poor peripheral veins and pronounced fear of blood drawings
  • Patients with history of epileptic seizures and / or under medical therapy with antiepileptic drugs
  • MRI study: Metal implants (eg pacemaker, inner-ear prosthesis, nerve stimulator, implanted defibrillator, infusion pump, artificial joints), wearing of magnetic or metallic objects that cannot be removed from the body (such as body piercing, dental prosthesis, implanted electrodes, contraceptive coil, acupuncture needle), tattoos & permanent makeup, claustrophobia, tinnitus, inability to lie on the back for an extended period of time, previous surgery on heart or head

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Rebif/Avonex
Rebif® 44µg (day 1, 3, 5 and 8) s.c. Avonex 30µg (day 1 and 8) i.m.
Rebif® 44µg (day 1, 3, 5 and 8) s.c.
Other Names:
  • Interferon beta 1a
Avonex 30µg (day 1 and 8) i.m.
Other Names:
  • Interferon beta 1a

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: before / after 1hr / 6 hrs / 12 hrs / 24 hrs
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of mRNA and miRNA expression in peripheral blood mononuclear cells and serum in healthy volunteers as well as in patients with RRMS
Time Frame: before / after 1hr / 6 hrs / 12 hrs / 24 hrs
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 change in mRNA and miRNA expression determined by Chip Array related to Rebif/Avonex administration
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
Time Frame: day 1 (+1 hr / 6hrs /12 hrs after 1. Rebif/Avonex application)
Rebif/Avonex side effects and the occuring immune response (measured by protein- / gene- / miRNA-levels from PBMCs and Serum) are correlated 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)
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
Time Frame: day 2 (24 hrs after 1.Rebif/Avonex application)
Rebif/Avonex side effects and the occuring immune response (measured by protein- / gene- / miRNA-levels from PBMCs and Serum) are correlated 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)
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
Time Frame: day 3 (48 hrs after 1.Rebif/Avonex application)
Rebif/Avonex side effects and the occuring immune response (measured by protein- / gene- / miRNA-levels from PBMCs and Serum) are correlated 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)
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
Time Frame: day 5 (48 hrs after 2.Rebif/ 96 hrs after 1. Avonex application)
Rebif/Avonex side effects and the occuring immune response (measured by protein- / gene- / miRNA-levels from PBMCs and Serum) are correlated 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)
day 5 (48 hrs after 2.Rebif/ 96 hrs after 1. 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
Time Frame: day 8 (72 hrs after 3. Rebif application, +1 hr / 6hrs /12 hrs after 4. Rebif/ 2. Avonex application)
Rebif/Avonex side effects and the occuring immune response (measured by protein- / gene- / miRNA-levels from PBMCs and Serum) are correlated 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)
day 8 (72 hrs after 3. Rebif application, +1 hr / 6hrs /12 hrs after 4. Rebif/ 2. 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
Time Frame: day 9 (24 hrs after 4. Rebif/ 2. Avonex application)
Rebif/Avonex side effects and the occuring immune response (measured by protein- / gene- / miRNA-levels from PBMCs and Serum) are correlated 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)
day 9 (24 hrs after 4. Rebif/ 2. Avonex application)
Psychometric testing: correlation between Rebif/Avonex administration and scores in depression and anxiety scales
Time Frame: before / day 9
Psychometric tests are performed before the first application of Rebif/Avonex and at the end of the study at day 9 (24 hrs after 4.Rebif application) and changes between the 2 time points are evaluated
before / day 9
MRI: Changes in regional cerebral blood flow at rest (arterial spin labeling) and their correlation with psychometric outcome variables and with transcriptome data
Time Frame: before / day 9
MRI is performed before the first application of Rebif/Avonex and at the end of the study at day 9 (24 hrs after 4.Rebif application) and changes between the 2 time points are evaluated
before / day 9
Changes in functional neuroimaging endophenotypes in the limbic system or prefrontal cortex that constitute possible markers of anxiety and depression and their correlation with psychometric outcome variables
Time Frame: before / day 9
Neuroimaging endophenotypes are assessed before the first application of Rebif/Avonex and at the end of the study at day 9 (24 hrs after 4.Rebif/ 2. Avonex application) and changes between the 2 time points are evaluated
before / day 9
Changes of IFN-b, CXCL10, MxA, 5'-3'OAS, IL-6 serum levels, gene- and miRNA-expression pattern and functional immune tests between healthy volunteers, RRMS-patients naïve to IFN-b and RRMS-patients with established IFN-b treatment
Time Frame: before / after 1hr / 6 hrs / 12 hrs / 24 hrs
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 protein- / gene- and miRNA expression related to Rebif administration
before / after 1hr / 6 hrs / 12 hrs / 24 hrs

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Marcus Müller, PD Dr., Department of Neurology University Hospital Bonn

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2015

Primary Completion (Anticipated)

January 1, 2017

Study Completion (Anticipated)

January 1, 2017

Study Registration Dates

First Submitted

December 10, 2014

First Submitted That Met QC Criteria

February 10, 2015

First Posted (Estimate)

February 18, 2015

Study Record Updates

Last Update Posted (Estimate)

June 3, 2016

Last Update Submitted That Met QC Criteria

June 2, 2016

Last Verified

June 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Relapsing-remitting Multiple Sclerosis

Clinical Trials on Rebif®

3
Subscribe