Infliximab Therapy in Patients With Refractory Polymyalgia Rheumatica

August 25, 2011 updated by: Dr. Vicente Rodri-guez Valverde, Hospital Universitario Marqués de Valdecilla

Infliximab Therapy in Patients With Refractory Polymyalgia Rheumatica: a Double Blind Placebo Controlled Trial

Rheumatic Polymyalgia(PMR) is a relatively common chronic inflammatory disorder of unknown origin which predominantly develops in elderly subjects and presents with severe pain and stiffness in the neck, shoulder and pelvic girdles, along with increased acute phase reactants. Systemic manifestations such as fever, anorexia and weight loss are characteristic signatures of PMR.

Corticosteroids (CS) constitute the standard treatment of PMR. Although in most patients the symptoms of the disease disappear after one or two years of treatment, a proportion of patients remain CS-dependent with the subsequent CS toxicity. Open label studies have suggested that tumour necrosis factor (TNF) antagonists lead to sustained improvement and CS sparing effect in patients with refractory PMR.

The investigators conducted a randomised, double-blind, placebo controlled trial with infliximab in CS-dependent patients with PMR. Patients with CS-dependent PMR (defined as requiring ≥ 5 mg/day after at least 2 years of treatment to maintain remission or ≥ 7.5 mg/day after at least 6 months) were randomly assigned to receive Infliximab (5 mg/kg i.v) at 0, 2, 6, 14 and 22 weeks (n = 12) or placebo (n = 11) together with CS that were reduced according to a predefined schedule. The primary outcome was the proportion of responder patients -defined as individuals with both complete clinical and analytical remission without receiving CS for at least three months- at 24 weeks. Secondary outcomes were cumulative CS doses and adverse events proportion.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The duration of the study will be 1 year, and it will be divided in several phases:

A) Initial phase (double-blind trial): Between week 0 and week 24. Placebo or Infliximab at a dose of 3 mg/kg/day at weeks 0, 2 and 6.

After the screening process, patients who meet the inclusion/exclusion criteria of the protocol will be randomized to receive three infusions of placebo or infliximab as previously described.

After the first infusion (week 0), the prednisone dose will be tapered according to the following schedule: Prednisone (or equivalent) should be decreased at a rate of 1.25 mg per week until complete withdrawal of corticosteroids. In case of relapse, the dose of prednisone will be increased up to the previous dose that controlled the symptoms of PMR, and after 4 weeks of stable dose, prednisone will be again tapered but with a slower schedule: 1.25 mg every 2 weeks until complete withdrawal of corticosteroids. In case of a new relapse, the dose of prednisone will be managed according to the physician criteria.

B) Extension phase (open trial): Between week 24 and week 48. Infliximab at a dose of 3 mg/kg/day at weeks 24, 26 and 30.

At 24 weeks, all the patients included into the trial and still on corticosteroid therapy with or without clinical manifestations of PMR, will receive three infusions of infliximab according to the previous described schedule.

After the first infusion (week 24) the dose of prednisone will be decreased according to the same schedule previously described in the initial phase of the trial.

The schedule therapy proposed in the extension phase is going to be for:

  • (GROUP A) To evaluate time response to Infliximab in responders concerning active treatment group in phase 1.
  • (GROUP B). To incorporate patients placebo- treated to treatment who have showed efficacy (in case of favorable results in the interim analysis)
  • (GROUP C). To offer maintenance treatment to patients who have showed complete response during phase 1 and this treatment is associated to a significant corticosteroid tapering dose or maintenance response.
  • (GROUP D). Discontinuation of the treatment in patients who have been receiving active treatment during phase 1 and have not showed response in any time.

After the first infusion (week 24), it will be reduced prednisone dose following same regimen described in the clinical phase of the study.

Treatment duration.

•Study will be administrate for 24 + 24 weeks. In the end of the study the patient will continue treatment the most efficacy in the investigator opinion.

Objectives:

Primary objective: Proportion of responders (complete remission without corticosteroids) at 24 weeks.

Secondary objectives:

  • Proportion of responders at 48 weeks.
  • Time to response
  • Number of relapses / recurrences.
  • Response duration
  • Cumulative dose and side effects of steroids at 24 and 48 weeks.
  • Number of patients that should be re-treated with infliximab.
  • Side effects of Infliximab in this patient population.
  • Serum cytokine analysis

I) CLINICAL ASSESSMENT:

Evaluations will be performed at screening, baseline, every 2 weeks during the first 2 months of treatment and monthly thereafter.

The following data will be recorded at each visit:

  • A structured questionnaire on symptoms of PMR.
  • Global evaluation of disease activity by the patients and physicians (visual analogue scale, 0-100).
  • Global evaluation of pain by the patients (visual analogue scale, 0-100).
  • Acute phase reactants: ESR (Westergren) and CRP (nephelometry).
  • Complete blood cell count, glucose (glycosylated hemoglobin in case of diabetes), blood urea and creatinine, liver enzymes and albumin.
  • Steroid dosage. Cumulative steroid dosage during the study period.
  • Presence of relapse
  • Side effects, with special emphasis in infections and corticosteroid side effects.

All patients will have a PPD test and chest X-rays performed at screening following the current recommendations for anti-TNF therapy (50-52). Those patients with a positive PPD test (induration ≥ 5 mm) or with chest X-ray images showing lesions consistent with latent tuberculosis infection, will have prophylactic treatment with isoniazid, 300 mg daily during 9 months (in case of isoniazid toxicity: rifamycin, 600 mg/day during four months).

In addition, the patients will be instructed to the possible development of infections and other side effects, and new manifestations of GCA, which should be immediately reported to the attending physician.

II) SERUM CYTOKINE STUDY During the study period and after informed consent, patients will be asked to provide a serum sample (around 200 ml) at 7 different time points (week 0 or pre-treatment, and weeks 2, 6, 24, 26, 30 and 48). The blood will be obtained at the same time that the scheduled venipuncture for routine tests.

The analysis will be done using a Cytometric Bead Array (CBA) methodology. The investigators will use the CBA Flex Set system (Becton Dickinson) that includes the following cytokines: IL-1, IL-6, TGF-beta, TNF-alfa, IL-10, IL-12, IL-2, IL-4, IFN-gamma. Following acquisition of sample data using the FACSCalibur flow cytometer (Becton Dickinson), the sample results are generated in graphical and tabular format using the CBA Analysis Software (Becton Dickinson).

Group I:

Infliximab 5 mg/kg. i.v. at week 0, 2, 6, 14 and 22.

Group II:

Infliximab Placebo i.v. weeks 0, 2, 6, 14 and 22.

Extension Phase (weeks 24-48):

  1. Responders at week 24: Treatment discontinuation (GROUP A).

  2. No-responders at week 24:

    • Placebo group: infliximab (5 mg/kg) at weeks 24, 26, 30, 36 y 42 (GROUP B).
    • Infliximab group:
    • Patients who have lost response during phase 1 before week 24 will receive infliximab (5 mg/kg) at weeks 30, 36 and 42 (GROUP C).
    • Patients who never have fulfilled response criteria during Phase 1: will not receive treatment in extension phase. (GROUP D)

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
23

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

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

Study Locations

  • Spain
    • Cantabria
      • Santander, Cantabria, Spain, 39008
        • Reumatology division, Hospital Universitario Marques de Valdecilla

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • PMR patients that after 2 years of corticosteroid treatment are not able to reduce the dose of prednisone below 5 mg/day or equivalent.
  • PMR patients that after 6 months of corticosteroid treatment are not able to reduce the dose of prednisone below 7,5 mg/day or equivalent.

  • PMR patients should fulfill the criteria proposed by Chuang et al (8):

    • Age ≥ of 50 years.
    • Development of bilateral moderately/severe aching and stiffness persisting for 1 month or more, involving two of the following areas: neck or torso, shoulders or proximal regions of the arms, and hips or proximal aspects of the thighs.
    • ESR ≥ 40 mm/h.
    • Complete clinical response to low-dose of steroids (prednisone or equivalent ≤ 20mg/day)

Exclusion Criteria:

  • -Patients with biopsy-proven GCA or those with cranial symptoms or signs suggestive of GCA but without biopsy-proven arteritis.
  • Patients with clinical features suggestive of RA or other connective tissue disorders.
  • Chronic infections such as HIV, hepatitis B or C, active mycobacterial or fungal infections, etc.
  • Neoplasm or a history of malignancy in the preceding 5 years.
  • Patients with multiple sclerosis or other demilinizating disorders.
  • Patients with cytopenias: leukopenia (leukocytes ≤ 3.5x109/L.), thrombocytopenia (platelets ≤ 100x109/L.) and/or anemia (≤ 10 g./dl.)
  • Patients with cardiac failure (functional class III / IV).
  • Any other condition that contraindicates Infliximab therapy

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: infliximab
Drug: infliximab
Infliximab 5 mg/kg. i.v. at week 0, 2, 6, 14 y 22.
Other Names:
  • Remicade, anti-TNF monoclonal Therapy
Placebo Comparator: inactive powder
Drug: inactive powder
Inactive powder. i.v. at week 0, 2, 6, 14 y 22.
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Proportion of responders(complete remission without corticosteroids)
Time Frame: at 24 weeks
at 24 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Proportion of responders
Time Frame: at 48 weeks
at 48 weeks
Time to response
Time Frame: 48 weeks
48 weeks
Number of relapses / recurrences
Time Frame: 48 weeks
48 weeks
Response duration
Time Frame: 48 weeks
48 weeks
Cumulative dose and side effects of steroids
Time Frame: at 24 and 48 weeks
at 24 and 48 weeks
Number of patients that should be re-treated with infliximab
Time Frame: 48 weeks
48 weeks
Side effects of Infliximab in this patient population
Time Frame: 48 weeks
48 weeks

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Hospital Universitario Marqués de Valdecilla

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Schering-Plough

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Víctor M Martínez-Taboada,, Md, PhD, Servicio de Reumatología, Hospital Universitario Marques de Valdecilla
  • Principal Investigator: Vicente Rodriguez-Valverde, MD, PhD, Servicio de Reumatología, Hospital Universitario Marques de Valdecilla

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

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2007

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2010

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2011

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 19, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 25, 2011

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 26, 2011

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 26, 2011

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 25, 2011

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • P04578

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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.

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