Tocilizumab for the Treatment of Familial Mediterranean Fever

November 17, 2020 updated by: University Hospital Tuebingen

Tocilizumab for the Treatment of Familial Mediterranean Fever - A Randomized, Doubleblind, Phase II Proof of Concept Study

Adult patients with Familial Mediterranean Fever, who have active disease

Study Overview

Status

Status

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

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

FMF is a rare disease, which permanently affects daily life of the patients with severe pain and the risk of developing a life threatening amyloidosis. Today there are only very limited treatment options and an ongoing highly unmet medical need for improved treatment strategies. This study will be the first randomized, controlled trial to assess the benefit as well as the safety profile of IL6 receptor inhibition wirth TCZ in patients with FMF. Elevated tissue and serum levels of IL-6 have been implicated in the pathogenesis of FMF. FMF attacks are painfull during the period of the attack but are not life- or organthreatening and usually can be handeled by nonsteroidal and antipyretic treatment. Amyloidos is a longtime complication that appears after several years of uncontrolled disease. Placebo control trials' data are characterized as having greater ability to distinguish between effective and ineffective treatments (that is, greater assay sensitivity). The concerns about placebo use should revolve around the issue of risk to participants, rather than around denial of treatment, and that in the absence of a significant risk of harm, placebo treatment is acceptable. In general, it is easier to achieve statistical significance in placebo-controlled trials, where effects tend to be larger, such that smaller numbers of participants need to be exposed to the investigational medication (and research costs are lower.) This is especially important in rare diseases like FMF. If an active control was itself never evaluated in a placebo-controlled trial, using it in an equivalency study, begs the question of its efficacy. This is the case for Canakinumab as a potential active comparator in FMF. No randomized controlled trial is published for this indication by now. Therefore, a placebo controlled study over a period of 16 weeks seems to be justifiable without exposing our patients to risk of serious or irreversible harm. NSAR and antipyretic treatment, as a rescue therapy for attacks, is possible throughout the study. In addition, all patients with uncontrolled active disease despite NSAR or paracetamol will drop out and will be treated with escape therapy, especially Canakinumab. Based on the available safety data in the RA program, the adverse effects of TCZ have been shown to be manageable (e.g. cytopenia, liver encyme elevation), reversible and usually not treatment limiting . The safety profile and tolerability of TCZ are expected to be similar or even better in patients with FMF than in patients with rheumatoid arthritis or giant cell arteritis, as the cohort of FMF patients is, in general, younger and shows less concomitant diaseases. Overall, the benefit-risk ratio of FMF patients to be treated with TCZ is judged positive.

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.
30

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 2

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

  • Germany
      • Berlin, Germany, 10117
        • Charité Universitätsmedizin Berlin, Klinik für Rheumatologie und Klinische Immunologie, Abteilung -Neue Therapien & Studien
      • Tuebingen, Germany, 72076
        • University Hospital Tuebingen; Department of oncology, hematology, rheumatology, immunology and pulmology
    • NRW
      • Cologne, NRW, Germany, 50937
        • Universitatsklinikum Koln, Klinik I fur Innere Medizin

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 64 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years and written informed consent
  • FMF according to the Tel Hashomer Criteria; with at least one heterozygous or homozygous mutation of the MEFV gene
  • Inadequate response or intolerance to colchicine (inadequate response/intolerance:

disease activity despite colchicine with at least 2 x 0.5 mg/day or intolerance to colchicine)

  • Attack during the last 12 weeks, defined as episodes of fever and/or pericarditis and/or serositis and/or testis involvement and/or arthritis and/or erysipelas-like rash and

    • CRP > 0.5 mg/dl and/or ESR > 20mm/h and/or SAA > 10mg/dl
    • PGA >2
  • Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
  • Ability to adhere to the study visit schedule and other protocol requirements.
  • Females of childbearing potential (FCBP*) must agree to utilize two reliable forms of contraception simultaneously from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for 6 months after study treatment discontinuation and must agree to regular pregnancy testing during this timeframe to abstain from breastfeeding during study participation and 6 months after study drug discontinuation.
  • Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 6 months following discontinuation from this study, even if he has undergone a successful vasectomy to refrain from donating semen or sperm while on Tocilizumab/Placebo and 6 months after discontinuation from this study treatment.
  • All subjects must agree to refrain from donating blood while on study drug and 6 months after discontinuation from this study treatment.
  • All subjects must agree not to share medication.

A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

Subjects presenting with any of the following criteria will not be included in the trial:

  • Patient participating simultaneously in other clinical interventional trials
  • Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after randomization
  • Transplanted organs (except corneal transplant performed more than 3 months prior to screening)

Exclusions Related to Prior or Concomitant Therapy

  • Previous treatment with TCZ
  • Treatment with glucocorticosteroids >10mg/day within 1 week; prednisolone ≤ 10mg/day can be given on a stable dose throughout the study
  • Analgesic medication, other than paracetamol or ibuprofen or diclofenac or colchicine, which can be used at a stable dose throughout the study and/or for treatment of FMF attacks to the maximum allowed daily dose (paracetamol: 4000mg/day, ibuprofene: maximum 2400mg/day, diclofenac maximum 150mg/day; colchicine 12mg/day) .
  • Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
  • Treatment with Anakinra within the last 1 week prior to baseline (ptb), Canakinumab within the last 8 week prior to baseline
  • Treatment with etanercept within 2 weeks; certolizumab pegol, abatacept or adalimumab within 6 weeks; golimumab and infliximab within 8 weeks ptb
  • Rituximab within 24 weeks ptb
  • Leflunomide within 12 weeks ptb (washout possible),
  • azathioprine, cyclophosphamide within 12 weeks ptb
  • Immunization with a live/attenuated vaccine within ≤ 4 weeks ptb
  • Previous treatment with cell-depleting therapies, including investigational agents or approved therapies: anti-CD33, anti-CD52, anti-CD4, anti-CD5, anti- CD3 and anti-CD19
  • Treatment with intravenous gamma globulin within 6 months of baseline
  • Treatment with plasmapheresis within 6 months of baseline
  • Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation

Exclusions Related to General Safety

  • History of severe allergic or anaphylactic reactions to human, humanized, or murine antibodies
  • Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, psychiatric or gastrointestinal (GI) disease
  • History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
  • Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis (TB) and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
  • Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
  • Active TB requiring treatment within the previous 3 years; patients should be screened for latent TB and, if positive, treated according to local practice guidelines prior to initiating TCZ treatment; patients treated for TB with no recurrence within 3 years and patients treated for latent TB within 3 years are eligible.
  • Primary or secondary immunodeficiency (history of or currently active)
  • Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured)
  • FCBP who are not willing to use an effective method of contraception, such as condom, sterilization during the study and for a minimum of 6 months after study drug therapy and breast-feeding females
  • Pregnant women
  • Males of reproductive potential who are not willing to use an effective method of contraception, such as condom, sterilization, or true abstinence throughout study and for a minimum of 6 months after study drug therapy
  • History of alcohol, drug, or chemical abuse within 1 year prior to screening

Laboratory Exclusions (at Screening)

  • Serum creatinine >1.4 mg/dL in female patients and >1.6 mg/dL (in male patients
  • ALT or AST > 2 ×ULN
  • Total bilirubin > 2 x ULN
  • Platelet count < 100 × 109/L
  • Hemoglobin < 8.5 g/dL
  • White blood cells < 3.0 ×109/L
  • Absolute neutrophil count < 2.0 × 109/L
  • Absolute lymphocyte count < 0.5 × 109/L
  • Positive hepatitis B surface antigen, anti-HBc, HIV or hepatitis C antibody

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: Tocilizumab
Tocilizumab Infusion RoAcemtra (EU) or Actemra (Rest of the world)
Drug: Tocilizumab Infusion RoAcemtra (EU)
Experimental arm's patients will obtain TCZ intravenously once every 4 weeks for 28 weeks
Other Names:
  • Actemra
Placebo Comparator: Placebo
0,9% physiological Saline
Drug: Tocilizumab Infusion RoAcemtra (EU)
Experimental arm's patients will obtain TCZ intravenously once every 4 weeks for 28 weeks
Other Names:
  • Actemra
Drug: 0.9% physiological saline
Experimental arm's patients will obtain saline intravenously once every 4 weeks for 16 weeks. If necessary, patients will get "rescue medication" after week 16 to week 28.

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
Measure Description
Time Frame
Efficacy: measured change of Physician's Global Assessment of disease activity (PGA)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

Efficacy: measured by Physician's Global Assessment of disease activity (PGA) will be assessed at every visit

The PGA will be based on a 5 point-scale (from 0 to 4):

0=none (no) disease associated clinical signs and symptoms*

  1. minimal disease associated clinical signs and symptoms*
  2. mild disease associated clinical signs and symptoms*
  3. moderate disease associated clinical signs and symptoms*
  4. severe disease associated clinical signs and symptoms* *sign and symptoms for evaluation of PGA: chest pain, abdominal pain, arthralgia, arthritis, skin rash, fever (body temperature ≥ 38.0°C). Patient are asked to fill out a patient's diary to help the physician to judge the PGA primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR or CRP (the one that led to inclusion must be normalized) + normalized SAA
at week -4,0,4,8,12,16,20,24,28,32

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
Measure Description
Time Frame
Incidence of Treatment-Emergent Adverse Events-Determination of Erytthro Sedimentation Rate (ESR)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

To evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard). Clinical laboratory testing for all study-relevant evaluations will be performed at all visits.

Laboratory testing has to include:

• ESR [mm after 1hour]
at week -4,0,4,8,12,16,20,24,28,32
serological remission
Time Frame: at week 16, 28
To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP < 0.5 mg/dl)
at week 16, 28
SAA level
Time Frame: at week 16 + 28
To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA < 10mg/l)
at week 16 + 28

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of Treatment-Emergent Adverse Events -Determination of the C-reactive protein
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

CRP [mg/L]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of the blood cell count
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

complete blood cell count with differential [cells/µl]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of serum parameters (Creatinine)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

serum chemistry function tests :

Creatinine [mg/dl]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of renal parameters (Uric Acid)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

renal function tests :

Uric Acid [mg/dl]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of serum and renal parameters (Glomerular Filtration Rate)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

renal function tests :

GFR [ml/min]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters (Gamma Glutamyltransferase (GGT))
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

GGT[IU/L]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters ( Alanine- (ALT) -Aminotransferase)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

ALT [IU/L]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters ( Alanine-Aminotransferase (AST))
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

Safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

AST[IU/L]
at week -4,0,4,8,12,16,20,24,28,32
Incidence of Treatment-Emergent Adverse Events -Determination of liver parameters (Biliribun)
Time Frame: at week -4,0,4,8,12,16,20,24,28,32

to evaluate the safety of TCZ in subjects with FMF Safety of participating subjects will be assessed by regular clinical examinations, laboratory tests and reporting of adverse events. In case of a relapse the physician will discuss further treatment options with the patient and will initiate further treatment (according to local standard).

Bilirubin [mg/dl]
at week -4,0,4,8,12,16,20,24,28,32

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.
University Hospital Tuebingen

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 (Actual)

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.
April 23, 2018

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.
October 30, 2020

Study Completion (Actual)

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.
October 30, 2020

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).
December 11, 2017

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.
February 19, 2018

First Posted (Actual)

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.
February 26, 2018

Study Record Updates

Last Update Posted (Actual)

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.
November 18, 2020

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.
November 17, 2020

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.
April 1, 2019

More Information

Terms related to this study

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.
  • TOFFIFE 1.1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

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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