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Prediction of Response to Certolizumab Pegol Treatment by Functional MRI of the Brain (PreCePRA)

Primary Purpose

Rheumatoid Arthritis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Certolizumab Pegol
Placebo
Sponsored by
University of Erlangen-Nürnberg Medical School
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Rheumatoid arthritis, functional MRI, Prediction of Response, Certolizumab Pegol

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Understands and voluntarily signs an informed consent form
  • Male or female, aged ≥ 18 years at time of consent
  • Must be able to adhere to the study visit schedule and other protocol requirements
  • Must satisfy the 2010 ACR/EULAR classification criteria for rheumatoid arthritis plus a disease duration of at least 6 months.
  • Must have active RA with a DAS28 ≥3.2
  • Must be RF and/or ACPA positive
  • ≥ 3 swollen and/or tender joints of the hands
  • At screening- visit patients should have been treated without alterations of therapy for at least three months with DMARDS (i.e. Methotrexate) with or without concomitant use of steroids).

  • Glucocorticoids treatment up to 10mg prednisolone per day will be allowed at study entry.

    . Exclusion Criteria:

  • Individuals not able to understand and follow study protocol and not able to voluntarily sign informed consent
  • Individuals not willing to follow study protocol and sign informed consent
  • Individuals with claustrophobia, tattoos containing metal, magnetic endoprostheses, surgery on bone in between a time interval < 3 months.
  • Patients treated before with any biological or small molecule or medication under investigation for the treatment of RA.
  • Patients with serious or chronic infections within the previous 3 months
  • Opportunistic infections within the 6 months before screening
  • Cancer within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin)
  • History of severe congestive heart failure
  • Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal (a.e.diverticulitis), endocrine, pulmonary, cardiac, neurologic or cerebral disease
  • Transplanted organ (with the exception of corneal transplantation done more than 3 months before screening)
  • Evidence of active tuberculosis

Sites / Locations

  • Charité - Universitätsmedizin Berlin; Campus Charité Mitte Klinik für Rheumatologie und klinische Immunologie Studienambulanz
  • University of Erlangen-Nuremberg, Department of Internal Medicine 3, Rheumatology & Immunology
  • Medizinische Universitätsklinik Freiburg Abteilung Rheumatologie und Klinische Immunologie
  • Universitätsklinikum Leipzig AÖR Department Innere Medizin Sektion Rheumatologie
  • Hospitais da Universidade (SRHUC) Reumatologia
  • Belgrade University School of Medicine Director of the Institute Institute of Rheumatology

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Certolizumab Pegol

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Reaching low disease activity
Proportion of patients who reach low disease activity according to the DAS28 (DAS28 < 3.2) during the first 12 weeks of study participation according their screening CNS activity measured by functional MRI.

Secondary Outcome Measures

Remission
Proportion of subjects in each treatment group reaching remission (defined as DAS28 < 2.6) after 1, 12 and 24 weeks
Quality of Life
HAQ of zero after 12 and 24 weeks to baseline
SF36
Mean and median SF-36 after 1, 12 and 24 weeks
MRI
Proportion of subjects in each treatment group with normal functional MRI after screening, week 12 and 24 weeks
Normal fMRI
Proportion of subjects in each treatment group with normal functional MRI after screening, 12 and 24 weeks
Ultrasound score
Mean and median ultrasound synovitis score after 1, 12 and 24 weeks
Bold signal
Mean and median ultrasound synovitis score after 1, 12 and 24 weeks
Adverse events
Type, frequency, severity and relationship of adverse events, serious adverse events or suspected unexpected serious adverse reactions to drugs used in this study
Number of patients who discontinue Certolizumab-Pegol
Number of subjects who prematurely discontinue Certolizumab-Pegol due to any adverse event

Full Information

First Posted
May 21, 2013
Last Updated
March 9, 2020
Sponsor
University of Erlangen-Nürnberg Medical School
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1. Study Identification

Unique Protocol Identification Number
NCT01864265
Brief Title
Prediction of Response to Certolizumab Pegol Treatment by Functional MRI of the Brain
Acronym
PreCePRA
Official Title
Prediction of Response to Certolizumab Pegol Treatment by Functional MRI of the Brain. A Multi-center, Randomized Double-blind Controlled Study Prediction of Response to Certolizumab-Pegol in RA (PreCePRA)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
July 2013 (undefined)
Primary Completion Date
June 30, 2019 (Actual)
Study Completion Date
January 10, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Erlangen-Nürnberg Medical School

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
By using functional MRI the investigators have recently shown that TNFi elicit rapid changes in brain function linked to the perception of RA [5]. Functional MRI represents a method allowing detecting tiny changes in neuronal activity by measuring alterations of blood flow in the context of neuronal activation. TNFi rapidly reversed the widespread activation of brain centers involved in pain such as the thalamus and the somatosensoric cortex, as well as those involved in the control, of mood and emotions such as the limbic system. Moreover, as small phase I study with 10 patients with RA showed that high brain activity detected in the functional MRI predicts clinical response to Certolizumab Pegol after 1 month, suggesting the central nervous system activity may be used as a tool to predict response to TNFi [8]. The rationale of this study is to test whether response to TNFi can be predicted by using functional MRI.
Detailed Description
Randomized double-blinded controlled multi-centre, study over 12 weeks, followed by a 12 weeks single blinded multicenter trial in 156 patients with RA with inadequate response to DMARD therapy. The study is composed of 3 arms with a 1:1:1 randomization at baseline: High functional MRI/400mg Certolizumab Pegol on week 0,2 and 4 followed by Certolizumab Pegol 200mg every two weeks for a total of 24 weeks; low functional MRI/400mg Certolizumab Pegol on week 0,2 and 4 followed by Certolizumab Pegol 200mg every two weeks for a total of 24 weeks with the possibility of early escape at week 12. Patients who did not respond sufficiently according to EULAR response criteria (DAS28 reduction ≥ 1.2) to Certolizumab-Pegol (Treatment Arm A and Arm B) after 12 weeks will be off-Study and treated according to local guidelines. Patients in the Placebo group with an EULAR response ≥ 1.2 reaching remission (DAS28 ≤ 2.6) will also be off study and treated according to the local guidelines or will be followed while they are in clinical remission. Patients with an EULAR response (DAS28 reduction ≥ 1.2) but not fulfilling the clinical remission criteria (DAS28 ≤ 2.6) will receive Certolizumab Pegol in week 12,14 and 16 with Certolizumab Pegol 400mg s.c. followed by s.c.injection of 200mg Certolizumab Pegol every two weeks till week 24. In the situation that in one group sufficient patients will be randomized, fMRI done at screening, needs to be analyzed first to ensure that no further patient will be randomized with the randomization to the closed group. A blinded person, not involved either in the analysation of the fMRI nor in the treatment of the patients or the clinical assessments, will be responsible for the randomization list. If the next number on the randomization list represent the number of the closed group, the patient is not eligible for the study and will be treated according to local guidelines.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
Keywords
Rheumatoid arthritis, functional MRI, Prediction of Response, Certolizumab Pegol

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
156 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Certolizumab Pegol
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Certolizumab Pegol
Other Intervention Name(s)
Cimzia
Intervention Description
Certolizumab Pegol (Cimzia®) is an engineered, humanized antibody-Fab'-fragment with specificity for human TNF-α, that is conjugated to polyethylene glycol (PEG). Certolizumab Pegol (Cimzia®) is a humanized antibody-Fab'-fragment that is produced in Escherichia coli and subsequently PEGylated to prolong its circulating half-time to be similar to that of an intact mAB. Certolizumab Pegol has a high affinity for TNF α with a Kd90pM and is an effective TNF α inhibitor. Certolizumab pegol does not neutralize TNFß (lymphotoxin), a related cytokine, and does not activate complement or kill cells via antibody-dependent cellular toxicity.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo will be administered according to the label of the biological
Primary Outcome Measure Information:
Title
Reaching low disease activity
Description
Proportion of patients who reach low disease activity according to the DAS28 (DAS28 < 3.2) during the first 12 weeks of study participation according their screening CNS activity measured by functional MRI.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Remission
Description
Proportion of subjects in each treatment group reaching remission (defined as DAS28 < 2.6) after 1, 12 and 24 weeks
Time Frame
6 months
Title
Quality of Life
Description
HAQ of zero after 12 and 24 weeks to baseline
Time Frame
6 months
Title
SF36
Description
Mean and median SF-36 after 1, 12 and 24 weeks
Time Frame
6 months
Title
MRI
Description
Proportion of subjects in each treatment group with normal functional MRI after screening, week 12 and 24 weeks
Time Frame
6 months
Title
Normal fMRI
Description
Proportion of subjects in each treatment group with normal functional MRI after screening, 12 and 24 weeks
Time Frame
6 months
Title
Ultrasound score
Description
Mean and median ultrasound synovitis score after 1, 12 and 24 weeks
Time Frame
6 months
Title
Bold signal
Description
Mean and median ultrasound synovitis score after 1, 12 and 24 weeks
Time Frame
6 months
Title
Adverse events
Description
Type, frequency, severity and relationship of adverse events, serious adverse events or suspected unexpected serious adverse reactions to drugs used in this study
Time Frame
6 months
Title
Number of patients who discontinue Certolizumab-Pegol
Description
Number of subjects who prematurely discontinue Certolizumab-Pegol due to any adverse event
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Understands and voluntarily signs an informed consent form Male or female, aged ≥ 18 years at time of consent Must be able to adhere to the study visit schedule and other protocol requirements Must satisfy the 2010 ACR/EULAR classification criteria for rheumatoid arthritis plus a disease duration of at least 6 months. Must have active RA with a DAS28 ≥3.2 Must be RF and/or ACPA positive ≥ 3 swollen and/or tender joints of the hands At screening- visit patients should have been treated without alterations of therapy for at least three months with DMARDS (i.e. Methotrexate) with or without concomitant use of steroids). Glucocorticoids treatment up to 10mg prednisolone per day will be allowed at study entry. . Exclusion Criteria: Individuals not able to understand and follow study protocol and not able to voluntarily sign informed consent Individuals not willing to follow study protocol and sign informed consent Individuals with claustrophobia, tattoos containing metal, magnetic endoprostheses, surgery on bone in between a time interval < 3 months. Patients treated before with any biological or small molecule or medication under investigation for the treatment of RA. Patients with serious or chronic infections within the previous 3 months Opportunistic infections within the 6 months before screening Cancer within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin) History of severe congestive heart failure Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal (a.e.diverticulitis), endocrine, pulmonary, cardiac, neurologic or cerebral disease Transplanted organ (with the exception of corneal transplantation done more than 3 months before screening) Evidence of active tuberculosis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juergen Rech, MD
Organizational Affiliation
University of Erlangen-Nuremberg, Department of Internal Medicine 3, Rheumatology & Immunology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Georg Schett, MD, Prof.
Organizational Affiliation
University of Erlangen-Nuremberg, Department of Internal Medicine 3, Rheumatology & Immunology
Official's Role
Study Director
Facility Information:
Facility Name
Charité - Universitätsmedizin Berlin; Campus Charité Mitte Klinik für Rheumatologie und klinische Immunologie Studienambulanz
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
University of Erlangen-Nuremberg, Department of Internal Medicine 3, Rheumatology & Immunology
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
Medizinische Universitätsklinik Freiburg Abteilung Rheumatologie und Klinische Immunologie
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Facility Name
Universitätsklinikum Leipzig AÖR Department Innere Medizin Sektion Rheumatologie
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Hospitais da Universidade (SRHUC) Reumatologia
City
Coimbra
ZIP/Postal Code
3000-075
Country
Portugal
Facility Name
Belgrade University School of Medicine Director of the Institute Institute of Rheumatology
City
Belgrad
ZIP/Postal Code
11000
Country
Serbia

12. IPD Sharing Statement

Learn more about this trial

Prediction of Response to Certolizumab Pegol Treatment by Functional MRI of the Brain

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