Clinical trial NCT03704610: Efficacy of Remission-induction Regimen With Infliximab for Severe Extrathoracic Sarcoidosis (EFIRTES)
Official title: Efficacy of Remission-induction Regimen With Infliximab for Severe Extrathoracic Sarcoidosis (EFIRTES STUDY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Extrathoracic Sarcoidosis
Keywords: sarcoidosis
extra-thoracic
infliximab
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-10-15
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The present study was designed to assess the efficacy of infliximab in a 2-period study :

* An initial period with comparison of infliximab versus placebo and allowing the determination of the primary criteria
* Then an extension period in which the 2 arms will receive infliximab (in the placebo group : 5 perfusions and in the experimental group 3 supplemental perfusions). Finally, the 2 groups will receive 5 injections of infliximab There is little evidence in the literature of when and how infliximab should be administered in sarcoidosis. We hypothesized, from our personal experience in 30 cases (18 of which were reported in a retrospective trial (14), that infliximab would have a very quick activity. So it appeared reasonable to evaluate the primary criterion at 6 weeks after initiation of the treatment.

Detailed description: Sarcoidosis is a multisystemic granulomatous disease of unknown cause . Sarcoidosis is chronic and progressive in 25 % of the patients. Although mediastinal lymph nodes and lung are the most frequently sites affected, extrathoracic localizations may occur. In particular, cardiac or neurological localizations are frequently associated with a chronic disease, with subsequent morbidity and mortality. Such patients require long term therapy to avoid organ dysfunction which may occur with fibrosis.

If cyclophosphamide remains the "historical" treatment to treat resistant sarcoidosis, it can present serious adverse effects such as infections and gonadic toxicity which may be a problem in young people. As infliximab has demonstrated a real efficacy in resistant sarcoidosis, we challenged that it could be a valuable option for resistant extra-thoracic sarcoidosis.

The population studied will be the patients with clinical and radiological presentation concordant with sarcoidosis

This study is a phase 3, randomized, controlled, parallel group trial, designed to assess the efficacy of infliximab in a 2-period study :

In the first part, patients will be randomly assigned in a 1:1 ratio to receive either infliximab or placebo. Both patients and investigators will be blind regarding study treatment. Concomitantly, patients will be treated with usual care (i.e. steroids at the dose of 0.5 mg/kg/d with a program of tapering dose).

In the second open-labelled part, all the patients will receive infliximab treatment, steroids tapering regimen and low-dose methotrexate left to the investigator choice or, in case of contra-indication, azathioprine.

Finally, the 2 groups will receive 5 injections of infliximab

Infliximab will be used at a dose of 5 mg/kg at D1,D15 then every 4 weeks because in our experience, extrathoracic severe localization require such dosage and may be resistant to the low dosage (3 mg/kg). This dosage is also the dose usually recommended for extra-thoracic localizations.

Disease activity and ePOST score will be evaluated at the inclusion, W6 and after 5 injections (2 weeks after W20 for placebo group or W14 for experimental group). Severity assessment score (ePOST score) will be assessed by the physician in charge of the patient. This score reflects the sarcoidosis activity in 17 organs and has been validated in previous studies.

Remission at week 6 will be defined as: Percentage of patients who have a severity assessment score (ePOST score) inferior to 1 in all organs and absence of hypercalcemia at W6, whatever the corticosteroid dosage received.

Eligibility criteria: Inclusion Criteria:

* Clinical and radiological presentation confirming sarcoidosis
* Presence of non caseating granuloma in at least one organ
* Presence of at least one extrathoracic localization, including hypercalcemia
* Exclusion of other causes of granuloma
* Presence of serious organ involvement or relapse/apparition of a new localization despite a first-line immunosuppressive drug
* Age superior or equal to 18 years

Exclusion Criteria:

* Pregnancy or breast feeding or women in age of pregnancy without efficient contraception
* Patients with multiple sclerosis
* Patients with prior history of any cancer in the 5 years before inclusion (except for cutaneous basocellular cancers),
* Patients with a history of hypersensitivity to infliximab to other murine proteins, or to any of the excipients
* Patients with untreated tuberculosis or current other severe infections such as sepsis, abscesses, and opportunistic infections• Patients with moderate or severe heart failure (NYHA class III/IV)
* Concurrent vaccination with live vaccines during therapy
* Inability to understand information about the protocol
* Adult subject under legal protection or unable to consent.
* No informed consent
* Absence of affiliation to National French social security system
* Patients with severe renal failure, severe hepatic impairment, hepatocellular insufficiency, chronic respiratory insufficiency, risk of angle closure glaucoma, risk of urinary retention related to urethroprostatic disorders, certain evolving viral diseases (including hepatitis, herpes, varicella, zoster), psychotic states still not controlled by treatment

Primary outcomes:
measure: Percentage of patients
timeFrame: week 6
Secondary outcomes:
measure: Percentage of patients
timeFrame: week 16 for experimental arm ; week 22 for control arm
measure: Mean variation in severity assessment score measured by extrapulmonary Physician Organ Severity Tool (ePOST)
timeFrame: Week 6
measure: Pulmonary sarcoidosis involvement
timeFrame: Week 6
measure: Pulmonary sarcoidosis involvement 2 weeks after the 5th injection
timeFrame: week 16 for experimental arm ; week 22 for control arm
measure: Severity assessment score measured by ePOST 2 weeks after the 5th injection
timeFrame: week 16 for experimental arm ; week 22 for control arm
measure: Mean variation in the severity assessment score measured by ePOST from 1st injection (W0 or W6) to 2 weeks after the 5th injection
timeFrame: week 16 for experimental arm ; week 22 for control arm
measure: Mean variation of quality of life measured by SF-36
timeFrame: Week 6
measure: Mean variation of fatigue, measured by the Fatigue Scale (FAS)
timeFrame: Week 6
measure: Mean variation of quality of life measured by SF-36
timeFrame: week 16 for experimental arm ; week 22 for control arm
measure: Mean variation of fatigue, measured by the Fatigue Scale (FAS)
timeFrame: week 16 for experimental arm ; week 22 for control arm
measure: Rate of relapses
timeFrame: week 16 for experimental arm ; week 22 for control arm
Other outcomes:
Locations:
city: Bobigny
country: France
facility: Hopital Avicenne - service de pnaumologie
city: Créteil
country: France
facility: Hopital Henri Mondor- service de Médecine Interne
city: Lille
country: France
facility: Hopital Claude Huriez- service de Médecine Interne
city: Lyon
country: France
facility: Hopital de la Croix Rousse- service de Médecine Interne
city: Marseille
country: France
facility: Hopital de la Timone- service de Médecine Internne
city: Nantes
country: France
facility: CHU Hotel Dieu - service de Médecine Interne
city: Paris
country: France
facility: GH la Pitié Salpêtrière. Service de Médecine interne
city: Paris
country: France
facility: Hopital BICHAT - Médecine Interne
city: Paris
country: France
facility: Hopital Bichat- service de pneumologie
city: Strasbourg
country: France
facility: Nouvel Hopital Civil- service de Médecine Interne
Study officials:
affiliation: APHP - Hôpital Pitié-Salpêtriere, Paris,France
name: Fleur COHEN AUBART, MCU-PH
role: STUDY_DIRECTOR
References: