Efficacy and Safety of RPH-104 for Resolution and Prevention of Recurring Attacks in Adult Subjects With Familial Mediterranean Fever With Resistance to or Intolerance of Colchicine
- Conditions
- Familial Mediterranean FeverFMF
- Interventions
- Drug: Placebo
- Registration Number
- NCT05092776
- Lead Sponsor
- R-Pharm International, LLC
- Brief Summary
Study purpose is an evaluation of efficacy and safety of RPH-104 in the population of subjects with Familial Mediterranean Fever (FMF) with colchicine resistance or intolerance(i.e. colchicine resistant (crFMF).. Primary objective is to determine proportion of subjects with complete response to treatment with RPH-104 compared to placebo among FMF subjects with colchicine resistance or intolerance.
- Detailed Description
The study is supposed to enroll (randomize) (n= not less than 28, not less than 14 per group), so that not less than 24 to complete study in full (including all the treatment period visits and follow-up period visits - Visit 11 for patients who agreed to participate in the Open-label extension (OLE) study; Visit 11 and Visit 12 for those who do not wish to participate in the OLE study; given potential withdrawal at screening the number of screened subjects (signed Informed Consent Form (ICF) is planned to be up to 84.
The study will consists of three following periods:
1. Screening period (up to 12 weeks); Throughout the screening the subjects will be monitored to identify "marker" attacks and verify the subject eligibility. The subjects having an attack during screening period and meeting inclusion/exclusion criteria will be enrolled into treatment period.
2. Double-blind randomized placebo-controlled treatment period (16 weeks);
The subjects enrolled will be randomized to one of the treatment groups in 1:1 ratio:
* RPH-104 group to receive subcutaneous (SC) injections according to the following regimen: 160 mg on Day 0, 80 mg on Day 7, Day 14 and once every 2 weeks (q2w) thereafter;
* placebo group to receive matching SC injections on Day 0, Day 7, Day 14 and q2w thereafter.
Efficacy assessment will be performed at Visit 2 and Visit 3, and subsequently every 2 weeks up to Visit 10 inclusive; safety assessment will be performed throughout the study (Visit 1 - Visit 12). In a case of adverse event (AE) development (or other safety reasons), additional unscheduled safety visits could be performed throughout the study. Starting from Visit 2, additional unscheduled visits due to suspected development of FMF attack could be performed. In a case of a recurrent attack, the patient should come to the study site within 2 days from the attack onset for the attack registration.
The treatment response (i.e. the resolution of FMF "marker" attack/absence of recurrent attacks) will be assessed throughout the treatment period with the investigational products administered both blind and open-label. Responders will continue the study treatment with the assigned investigational products (RPH-104 or placebo as a single SC 2 mL injection q2w, based on the randomization group) in a blinded manner. In non-responders, the following treatment modifications are possible:
* In a case the "marker" attack has not resolved by Visit 2 - the treatment group will be unblinded:
* patients from placebo group will be switched to active treatment with RPH-104 in SC injections at a dose of 160 mg (single dose, first injection) followed by administration of 80 mg in 7 days at the Attack + 7 days Visit (with procedures corresponding to Visit 2), and 80 mg at the next scheduled Visit performed 1 week later than initially scheduled (with procedures corresponding to this Visit) after the Attack + 7 days Visit.
* patients from RPH-104 group will receive planned RPH-104 80 mg administration.
* In a case of recurrent FMF attack confirmation at a scheduled visit - the treatment group will be unblinded (if still blinded):
* patients from placebo group will be switched to active treatment with RPH-104 in SC injections at a dose of 160 mg (single dose, first injection) followed by administration of 80 mg in 7 days at the Attack + 7 days Visit (with procedures corresponding to Visit 2), and then at the next scheduled Visit (with procedures corresponding to the further study schedule) and all the next scheduled visits every 2 weeks thereafter;
* patients from RPH-104 group or patients who were switched from placebo group and receiving RPH-104 80 mg will receive RPH-104 160 mg administration at the visit and thereafter 160 mg q2w;
* patients already receiving RPH-104 160 mg q2w in unblinded manner can continue treatment or can discontinue treatment at the discretion of Investigator, based on the risk/benefit assessment of the further RPH-104 treatment.
* In a case of recurrent FMF attack confirmation at an unscheduled visit - the treatment group will be unblinded (if still blinded):
* if a recurrent FMF attack is recorded and the subject visits the study site within 3 days before the next scheduled visit (starting from Visit 3), the subject will undergo all the next scheduled visit procedures including the unblinded RPH-104 administration and blood sampling provided for at this scheduled visit. The treatment rules for a scheduled visit described above are applicable in this case;
* in a case of a recurrent attack and subject's arrival to the site more than 3 days before the next scheduled visit but not less than 7 days after the previous scheduled visit (starting from Visit 2), the unscheduled visit will be performed on the day of arrival to the study site (and the administration will be shifted from the planned next scheduled visit). The treatment rules for a scheduled visit described above are applicable in this case. Further the subject will not attend the next scheduled visit and all the visit procedures per Protocol should be performed as an unscheduled visit. Afterwards, the initially planned visits schedule for a patient will be kept;
* in a case of unscheduled visit within 7 days after administration of the scheduled blinded RPH-104 80 mg dose or placebo all procedures planned for unscheduled visit to be performed. If at such unscheduled visit development of a recurrent attack is confirmed the subject will be unblinded:
* patients from placebo group will be switched to active treatment with RPH-104 in SC injections at the unscheduled visit at a dose of 160 mg (single dose, first injection) followed by administration of 80 mg in 7 days at the Attack + 7 days Visit (with procedures corresponding to Visit 2), and 80 mg at the next scheduled Visit performed 1 week later (with procedures corresponding to this Visit) after the Attack + 7 days Visit;
* patients from RPH-104 group or patients who were switched from placebo group and receiving RPH-104 80 mg q2w will receive RPH-104 80 mg administration at the visit and thereafter 160 mg q2w starting from the next scheduled visit;
* patients already receiving RPH-104 160 mg q2w will not receive RPH-104 at this unscheduled visit and can continue treatment or can discontinue treatment at the discretion of Investigator, based on the risk/benefit assessment of the further RPH-104 treatment.
For patients receiving RPH-104 at a dose of 160 mg q2w no further dose escalation is carried out. In a case of consequent recurrent attacks this patient may continue treatment with RPH-104 at a maximum dose of 160 mg q2w according to the Investigator's reasonable decision until the end of the study treatment period. No dose reduction of the investigational products could be made throughout the study.
Maximum treatment duration is 16 weeks.
Subjects receiving both blinded and unblinded therapy will undergo regular evaluation of efficacy and safety; the visits will be performed every 2 weeks for this purpose.
At the last visit of the treatment period (Visit 10) after completion of all visit procedures the patients will be invited to proceed in a long-term open-label extension (OLE) study to evaluate the safety and efficacy study of RPH-104 (CL04018071).
3. Follow-up period (8 weeks) that includes safety monitoring for 8 weeks after the last dosing with the investigational products.
In case of lacking relevant clinical response and if the subjects do not wish to participate in the open-label study, they should complete all safety follow-up visits.
Therefore, the total maximum duration of participation of one patient in the study will be 37 weeks, id est (i.e.) about 9 months (1 additional week could be added to the overall study duration in case of switching from the placebo to the RPH-104 treatment for a subject due to the disease attack).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 84
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RPH-104 RPH-104 Test product group receiving RPH-104 subcutaneous (s.c.) injections:160 mg on Day 0, 80 mg on Day 7, Day 14 and every 2 weeks (q2w) thereafter. In case "marker" attack does not resolve at Visit 2 - the treatment group will be unblinded: patients will receive planned RPH-104 80 mg administration. In case of a new attack on further days of treatment period until Visit 10 inclusive - the treatment group will be unblinded: the dose of RPH-104 could be escalated to 160 mg q2w; The patients already receiving RPH-104 160 mg q2w will continue to receive RPH-104 at this dose. Further dose escalation is forbidden. Placebo Placebo Placebo group receiving the equivalent placebo dose also as s.c. injections on Day 0, Day 7, Day 14 and q2w thereafter. In case the "marker" attack does not resolve at Visit 2 - the treatment group will be unblinded: patients will be switched to active treatment with RPH-104 in SC injections at a dose of 160 mg followed by administration of 80 mg in 7 days at the Attack + 7 days Visit, and 80 mg at the next Visits. In a case of a new attack the patients switching from placebo and receiving RPH-104 at 80 mg dose could be escalated to RPH-104 160 mg q2w; Further dose escalation is forbidden.
- Primary Outcome Measures
Name Time Method Proportion of subjects with complete response during 16 week therapy with RPH-104 vs. placebo in FMF subjects with colchicine inefficacy or intolerance. Up to 16 weeks Complete response defined as resolution of "marker" attack by Visit 2 (Day 7) and lack of recurrent attacks during the treatment period up to Visit 10 (Day 112).
Criteria of resolution of a "marker" FMF attack include simultaneous clinical and laboratory signs of the attack resolution:
* Physician Global Assessment (PGA) score \< 2 (i.e. minimum or complete lack of clinical signs and symptoms) AND
* C-reactive protein (CRP) level ≤ 10 mg/L OR CRP reduction by ≥ 70% compared to baseline defined at enrollment to treatment period (Visit 1).
Criteria of a recurrent FMF attack development after resolution of "marker" attack include simultaneous development of clinical and laboratory signs of the attack:
* PGA score ≥ 2 assuming mild, moderate or severe disease activity (i.e. clinical signs), AND
* CRP level ≥ 30 mg/L (serological signs).
PGA is a 5-point scale: from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.
- Secondary Outcome Measures
Name Time Method Time to the development of a recurrent FMF attack in patients with resolved "marker" attacks from Day 7 to the development of a recurrent FMF attack, up to 16 weeks Criteria of a recurrent FMF attack development after resolution of "marker" attack include simultaneous development of clinical and laboratory signs of the attack:
* PGA score ≥ 2 assuming mild, moderate or severe disease activity (i.e. clinical signs), AND
* CRP level ≥ 30 mg/L (serological signs).
PGA is a 5-point scale: from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.Proportion of subjects with Physician Global Assessment (PGA) score < 2 during the study Up to 16 weeks PGA score \< 2 during the treatment period with RPH-104 compared to placebo in FMF subjects with colchicine inefficacy or intolerance.
PGA is a 5-point scale from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.Proportion of subjects with partial response to treatment Up to 16 weeks Partial response defined as Resolution of "marker" attack by Visit 2 (Day 7) but with development of recurrent attacks up to Visit 10 (Day 112).
Criteria of resolution of a "marker" FMF attack include simultaneous clinical and laboratory signs of the attack resolution:
* Physician Global Assessment (PGA) score \< 2 (i.e. minimum or complete lack of clinical signs and symptoms) AND
* CRP level ≤ 10 mg/L OR CRP reduction by ≥ 70% compared to baseline defined at enrollment to treatment period (Visit 1).
Criteria of a recurrent FMF attack development after resolution of "marker" attack include simultaneous development of clinical and laboratory signs of the attack:
* PGA score ≥ 2 assuming mild, moderate or severe disease activity (i.e. clinical signs), AND
* CRP level ≥ 30 mg/L (serological signs).
PGA is a 5-point scale: from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.Proportion of subjects with serological remission Up to 16 weeks Proportion of subjects with serological remission (CRP ≤ 10 mg/L) throughout the study.
Proportion of subjects with normalized Serum Amyloid A (SAA) level Up to 16 weeks Proportion of subjects with normalized serum amyloid A level (SAA \< 10 mg/L) throughout the study
Proportion of subjects escalated to RPH-104 160 mg q2w dose Up to 16 weeks In patients whose treatment group has been unblinded because of a confirmed attack or no "marker" attack resolution: the patients from RPH-104 group and those switching from placebo and receiving RPH-104 at 80 mg dose will be escalated to RPH-104 160 mg q2w.
Proportion of subjects receiving additional symptomatic therapy with Nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol or glucocorticoids due to FMF Up to 16 weeks Proportion of subjects receiving additional symptomatic therapy with NSAIDs, paracetamol or glucocorticoids due to FMF
Change in inflammation parameters vs. baseline (CRP) From baseline (Day 0) up to 18 weeks Change in CRP levels vs. baseline (Day 0)
Change in inflammation parameters vs. baseline (SAA) From baseline (Day 0) up to 18 weeks Change in SAA levels vs. baseline (Day 0)
PGA score change compared to baseline From baseline (Day 0) up to 18 weeks PGA score change compared to baseline (Day 0) during the study. PGA is a 5-point scale from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.
Changes in patients' quality of life during the treatment period with RPH-104 From baseline (Day 0) up to 18 weeks Change in quality of life vs. baseline (Day 0) based on Medical Outcome Short Form (12) Health Survey (SF-)12® questionnaire throughout the study.
Trial Locations
- Locations (14)
Saint-Petersburg Pasteur Institute
🇷🇺Saint-Petersburg, Russian Federation
Terafarm, Llc
🇷🇺Stavropol, Russian Federation
Hacettepe University Faculty of Medicine
🇹🇷Ankara, Turkey
Multidisciplinary Scientific and Clinical Center named after S.P. Botkin
🇷🇺Moscow, Russian Federation
Gazi University Faculty of Medicine
🇹🇷Ankara, Turkey
Akdeniz University Faculty of Medicine
🇹🇷Antalya, Turkey
Istanbul University Istanbul Faculty of Medicine
🇹🇷Istanbul, Turkey
Istanbul University Cerrahpasa Faculty of Medicine
🇹🇷Istanbul, Turkey
Center of Medical Genetics and Primary Health Care
🇦🇲Yerevan, Armenia
Mikaelyan Institute Of Surgery CJSC
🇦🇲Yerevan, Armenia
Inova LLC
🇬🇪Tbilisi, Georgia
The First Medical Center Ltd.
🇬🇪Tbilisi, Georgia
Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)
🇷🇺Moscow, Russian Federation
Medical Technologies Ltd
🇷🇺Saint Petersburg, Russian Federation