Familial Mediterranean FeverPhase 2NCT03446209
Tocilizumab for the Treatment of Familial Mediterranean Fever
A Phase 2 study testing Tocilizumab Infusion RoAcemtra (EU) and 0.9% physiological saline in people with Familial Mediterranean Fever, run by University Hospital Tuebingen at 3 sites in Germany.
Trial summary
Adult patients with Familial Mediterranean Fever, who have active disease Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Familial Mediterranean Fever
- What is being tested?
- Tocilizumab Infusion RoAcemtra (EU) and 0.9% physiological saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 3 sitesGermany
- Study dates
- 23 Apr 2018to 30 Oct 2020
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Show all 14Show fewer
- 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).
Who cannot join
- 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
Show all 42Show fewer
- 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
Trial locations and contacts
3 sites in 1 country.
Germany3 sites
Charité Universitätsmedizin Berlin, Klinik für Rheumatologie und Klinische Immunologie, Abteilung -Neue Therapien & Studien
Berlin, 10117
Universitätsklinikum Köln, Klinik I für Innere Medizin
Cologne, North Rhine-Westphalia, 50937
University Hospital Tuebingen; Department of oncology, hematology, rheumatology, immunology and pulmology
Tübingen, 72076
About this study
Official title: 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
Read the 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.
- Conditions
- Familial Mediterranean Fever
- Being tested
- Tocilizumab Infusion RoAcemtra (EU), 0.9% physiological saline
- Medical subject headings
- Familial Mediterranean Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tocilizumab Infusion RoAcemtra (EU)Drug
Also called Actemra
Experimental arm's patients will obtain TCZ intravenously once every 4 weeks for 28 weeks
0.9% physiological salineDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Tocilizumab | Experimental | Tocilizumab Infusion RoAcemtra (EU) or Actemra (Rest of the world) Receives: Drug: Tocilizumab Infusion RoAcemtra (EU) |
| Placebo | Placebo comparator | 0,9% physiological Saline Receives: Drug: Tocilizumab Infusion RoAcemtra (EU); Drug: 0.9% physiological saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy: measured change of Physician's Global Assessment of disease activity (PGA)
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*
- minimal disease associated clinical signs and symptoms*
- mild disease associated clinical signs and symptoms*
- moderate disease associated clinical signs and symptoms*
- 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
Measured: at week -4,0,4,8,12,16,20,24,28,32
Secondary outcomes (3)
Incidence of Treatment-Emergent Adverse Events-Determination of Erytthro Sedimentation Rate (ESR)
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]
Measured: at week -4,0,4,8,12,16,20,24,28,32
serological remission
To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP < 0.5 mg/dl)
Measured: at week 16, 28
SAA level
To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA < 10mg/l)
Measured: at week 16 + 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2018
- Study start23 Apr 2018
- Primary completion30 Oct 2020
- Study completion30 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Familial Mediterranean FeverStudies of the same condition, open and under way.
- More trials run by University Hospital TuebingenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Multi-center, phase II, randomized, placebo-controlled, double blind proof of concept trial
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital Tuebingen
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03446209
- Sponsor's protocol ID
- TOFFIFE 1.1
- Status last verified
- Apr 2019
- First submitted
- 11 Dec 2017
- Last updated
- 18 Nov 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Tocilizumab for the Treatment of Familial Mediterranean Fever - A Randomized, Doubleblind, Phase II Proof of Concept Study
- ClinicalTrials.gov ID
- NCT03446209
- Acronym / sponsor ID
- TOFFIFE 1.1
- Conditions
- Familial Mediterranean Fever
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University Hospital TuebingenUniversity, hospital or other
- Study start
- 23 Apr 2018 (actual)
- Primary completion
- 30 Oct 2020 (actual)
- Study completion
- 30 Oct 2020 (actual)
- First posted
- 26 Feb 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Adult patients with Familial Mediterranean Fever, who have active disease
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Multi-center, phase II, randomized, placebo-controlled, double blind proof of concept trial
| Arm | Type | Receives |
|---|---|---|
| Tocilizumab | Experimental | Drug: Tocilizumab Infusion RoAcemtra (EU)Tocilizumab Infusion RoAcemtra (EU) or Actemra (Rest of the world) |
| Placebo | Placebo comparator | Drug: Tocilizumab Infusion RoAcemtra (EU), Drug: 0.9% physiological saline0,9% physiological Saline |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (14 listed)
- 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
Key exclusion criteria (42 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tocilizumab Infusion RoAcemtra (EU)Also: ActemraExperimental arm's patients will obtain TCZ intravenously once every 4 weeks for 28 weeks | Drug | Placebo, Tocilizumab |
| 0.9% physiological salineExperimental 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. | Drug | Placebo |
Primary outcome
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
3 secondary outcomes
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
serological remission
Time frame: at week 16, 28
SAA level
Time frame: at week 16 + 28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tocilizumab Infusion RoAcemtra (EU) and 0.9% physiological saline in people with Familial Mediterranean Fever, run by University Hospital Tuebingen at 3 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2020.