Randomized, Double-Blind, Placebo-Controlled Study of Canakinumab in Patients with Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome
- Trial ID
- 2024-517155-13-00
- Protocol
- PAPA-Can
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to provide the first evidence of the actual efficacy of **IL-1 blockade** in a potentially devastating inflammatory condition, using canakinumab. This is clinically relevant as it aims to address the therapeutic potential of canakinumab in managing PAPA syndrome, a rare autoinflammatory disorder characterized by pyogenic sterile arthritis, pyoderma gangrenosum, and acne. The study is designed as a double-blind, placebo-controlled, randomized withdrawal trial to rigorously evaluate the treatment's impact on this condition.
Participants
The clinical trial involves participants diagnosed with **PAPA syndrome**, a rare inflammatory condition. The study population includes both male and female subjects, with an age range encompassing children, adolescents, and adults. Participants are required to have a clinical diagnosis of PAPA syndrome with an active flare at the time of enrollment and a mutation of the PSTPIP1 gene. The trial includes a vulnerable population, indicating that special considerations are in place for the protection of these participants. The sponsor has not provided information regarding the total number of participants. The selection process ensures that all participants have provided written informed consent, with additional consent from a parent or legal guardian for those under 18 years of age. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion of both genders and a wide age range aims to provide comprehensive data on the efficacy of IL-1 blockade using canakinumab in this potentially devastating condition.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **canakinumab** in patients with PAPA syndrome. The trial aims to provide evidence of the efficacy of IL-1 blockade in this inflammatory condition. Participants will be randomly assigned to receive either canakinumab or a placebo, both administered as a **solution for injection**. The trial is structured to include an initial screening visit, followed by regular follow-up visits every four weeks, and concludes with an end-of-study visit. The primary endpoint is to assess whether canakinumab can prevent disease flares compared to placebo in canakinumab-responder patients.
The trial is expected to last until July 31, 2027, with recruitment starting on January 30, 2024. Participants will be involved in the study for a maximum treatment period of 18 months. Inclusion criteria require a clinical diagnosis of PAPA syndrome with an active flare at enrollment, a mutation of the PSTPIP1 gene, and informed consent from participants or their guardians. The study will include both male and female patients. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that compromise participant safety.
Treatment
The clinical trial involves the administration of **Canakinumab**, marketed under the name Ilaris, which is a **solution for injection** with a concentration of 150 mg/ml. This experimental medication is provided by Novartis Europharm Limited. The active substance, Canakinumab, is a protein of other origin, classified under the ATC code L04AC08. The medication is administered via the **subcutaneous** route. The dosing schedule allows for a maximum daily dose of 16 mg, with a total maximum dose of 450 mg over the treatment period. The maximum treatment period is 18 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
The study also includes a **placebo** control, which is a solution for injection with the same concentration of 150 mg/ml, provided in vials identical to those of Canakinumab. The placebo is also administered subcutaneously and is designed to be indistinguishable from the test product to maintain the double-blind nature of the trial. The placebo is supplied by Novartis Pharma. The use of a placebo is critical in assessing the efficacy of Canakinumab by providing a baseline for comparison.
Efficacy
The efficacy of canakinumab in the treatment of **pyogenic sterile arthritis pyoderma gangrenosum and acne (PAPA) syndrome** will be assessed in a double-blind, placebo-controlled, randomized withdrawal study. The primary endpoint for evaluating efficacy is the ability of canakinumab, administered every 4 weeks, to prevent disease flares in patients who have previously responded to the treatment, compared to a placebo. This endpoint will be measured by monitoring the occurrence of disease flares in participants receiving canakinumab versus those receiving the placebo.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Clinical diagnosis of PAPA with active flare at the time of enrolment.
- Mutation of the PSTPIP1 gene.
- Patient’s written informed consent from those ≥ 18 years of age must be obtained before any assessment is performed. Parent or legal guardian’s written informed consent and child’s assent, if appropriate, are required before any assessment is performed for patients < 18 years of age.
- Male and female patients.
Exclusion Criteria
- Use of the following therapies: a. Glucocorticoids (prednisone equivalent > 0.2 mg/kg/day [or greater than the maximum of 10 mg/ day for children over 60 kg]) within 1 week prior to Baseline b. Anakinra within 72 hours prior to Baseline c. Other biologics (including canakinumab) or immunosuppressants 2 half-life prior to Baseline.
- Any conditions or significant medical problems which in the opinion of the investigator immunocompromises the patient and/ or places the patient at unacceptable risk for immunomodulatory therapy such as: a. Absolute neutrophil count <1.0 x 109/L or below b. Thrombocytopenia Platelets <10.0 x 109/L c. Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral infection. At least 1 month should elapse between the complete resolution of a severe infection, requiring hospitalization or systemic antibiotic therapy before the inclusion in the study d. Presence of Human Immunodeficiency Virus (HIV) infection, Hepatitis B (HBsAg) or Hepatitis C (HCV) infections based on screening lab results specific hepatitis serology that leads to exclusion. e. Clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty’s syndrome
- History or evidence of tuberculosis (TB) (active or latent) infection or one of the risk factors TB such as but not limited or exclusive to: a. History of any of the following: residence in a congregate setting (e.g. jail or prison, homeless shelter, or chronic care facility), substance abuse (e.g. injection or non-injection); health-care workers with unprotected exposure to patients who are at high risk of TB or patients with TB disease before the identification and correct airborne precautions of the patient, or b. Close contact (i.e. share the same air space in a household or other enclosed environment for a prolonged period (days or weeks, not minutes or hours) with a person with active pulmonary TB disease within the last year, or c. Evidence of TB infection (active or latent) determined by positive QuantiFERON (QFT-TB G In-Tube) test or positive Purified Protein Derivative (PPD) test (≥5 mm induration) at screening or within 2 months prior to the screening visit, according to the national guidelines. If presence of TB infection (active or latent) is established then treatment for TB as per national guidelines must have been initiated or completed prior to randomization. In the absence of national guidelines, the following has been demonstrated: TB has been treated adequately by antibiotics, cure can be demonstrated and risk factors resulting in TB exposure and contracting have been removed.
- Elevated alanine aminotransferase (ALT) ≥3x ULN (if ALT at screening is >3x but <5x ULN, a re-test will be allowed. If ALT at re-test is <3x ULN and confirmed at another re-test, the patient will be eligible for participation).
- Elevated aspartate aminotransferase (AST) ≥3x ULN (if AST at screening is >3x but <5x ULN, a re-test will be allowed. If AST at re-test is <3x ULN and confirmed at another re-test, the patient will be eligible for participation)
- Increase in total bilirubin (TBL) defined as per CTC Grade ≥2: TBL >1.5x ULN
- Administration of any investigational drug or implantation of investigational device, or participation in another trial, within 30 days before screening.
- Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose
- Donation or loss of blood (amount depending on age and weight, 10-20% or more of volume, within 8 weeks prior to first dosing, or longer if required by local regulation). Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
- Female adolescents (≤18 years of age) of childbearing potential who do not agree to abstinence or, if sexually active, do not agree to the use of contraception as defined in the exclusion criterion for women of child bearing potential.
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
- Known allergy or hypersensitivity to any component the IMP
- History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 30 Jan 2024 | 24 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo is solution for injection (150 mg/ml) contained in vials equal to those of Canakinumab and appears identical to the Test product. Placebo is provided by Novartis pharma. | Placebo | N/A | — | — | — | N/A |
Ilaris 150 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 16 | 18 | PRD4821251 |