Efficacy and Tolerance of the Association of ANIFROLUMAB (300mg) IV Every Four Weeks and Phototherapy Versus Phototherapy in Adults With Progressive Vitiligo

Efficacy and Tolerance of the Association of ANIFROLUMAB (300mg) IV Every Four Weeks and Phototherapy Versus Phototherapy in Adults With Progressive Vitiligo: a Randomized Double Blind Prospective, Non Comparative Proof of Concept Phase II Study

The purpose of this phase 2 study is to evaluate the effect and the safety of the combination of ANIFROLUMAB in combination with phototherapy in adult participants with non-segmental progressive vitiligo

Treatment Strategy: Multicentric, parallel double blind randomized phase 2 prospective study comparing ANIFROLUMAB (300mg/month) + narrowband UVB TL01 versus placebo + narrowband UVB TL01 Follow-up of the study: patients included in this study will start ANIFROLUMAB 3 months before starting narrowband UVB TL01. Phototherapy will be performed twice a week during 6 months. Follow-up visit will be done at week 12, 24, 36 and 48.

Inclusion Criteria:

• Subject: male or female aged ≥ 18 years and ≤ 65 years
• Subject with body weight ≥ 40kg
• Diagnosis of non-segmental (symmetrical) vitiligo with a body surface area involved >5% excluding hands and feet
• Active non-segmental vitiligo is defined by:

Non-segmental vitiligo with new patches or extension of old lesions during the last 6 months AND Presence of hypochromic aspect under Wood's lamp examination and/or perifollicular hypopigmentation under Wood's lamp examination.

• Able to read, understand, and give documented (electronic or paper signature) informed consent
• Registered in the French Social Security
• Agree to discontinue the use of the following excluded medications/treatments for at least 4 weeks prior to randomization (Visit 2) and throughout the study: systemic steroids, phototherapy, methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.
• Agree to discontinue the use of the following excluded medications for at least 2 weeks prior to randomization (Visit 2) and throughout the study:

TCS or topical immune modulators (e.g., tacrolimus or pimecrolimus) Topical phosphodiesterase type 4 (PDE-4) inhibitor (e.g. crisaborole) Topical JAK inhibitor (e.g., tofacitinib or ruxolitinib) and/or any other investigational topical treatments.

• Patient characteristics

• Are male or nonpregnant, nonbreastfeeding female patients:

  1. Male patients must agree to use 2 forms of birth control (1 must be highly effective, see below) while engaging in sexual intercourse with female partners of childbearing potential while enrolled in the study and for at least 4 weeks following the last dose of investigational product.

  2. Female patients of childbearing potential must agree to use 2 forms of birth control, when engaging in sexual intercourse with a male partner while enrolled in the study and for at least 12 weeks following the last dose of investigational product.

     The following birth control methods are considered acceptable (the patient should choose 2 to be used with their male partner, and 1 must be highly effective):

     Highly effective birth control methods: oral, injectable, or implanted hormonal contraceptives (combined estrogen/progesterone or progesterone only, associated with inhibition of ovulation); intrauterine device (containing copper) or intrauterine system (e.g., progestin-releasing coil); or vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate). Effective birth control methods: condom with a spermicidal foam, gel, film, cream, or suppository; occlusive cap (diaphragm or cervical/vault caps) with a spermicidal foam, gel, film, cream, or suppository; or oral hormonal contraceptives.

  3. Females of non-childbearing potential are not required to use birth control and they are defined as:

Women ≥60 years of age or women who are congenitally sterile, or Women ≥40 and <60 years of age who have had a cessation of menses for ≥12 months and a folliculostimulating hormone (FSH) test confirming non-childbearing potential (≥40 mIU/mL or ≥40 IU/L), or women who are surgically sterile (i.e., have had a hysterectomy or bilateral oophorectomy or tubal ligation).

• Patients fully vaccinated against COVID-19. A patient is considered fully vaccinated ≥2 weeks after receipt of the second dose in a 2-dose series (Pfizer-BioNTech and Moderna).
• Signed informed consent form (ICF)

Exclusion Criteria:

General exclusion criteria

• Segmental or mixed vitiligo
• Patients that are currently experiencing or have a history of other concomitant skin conditions (e.g., psoriasis or lupus erythematosus) that would interfere with evaluations of the effect of study medication on vitiligo
• Patients who are currently experiencing a skin infection that requires treatment, or who are currently being treated with topical or systemic antibiotics.
• Patients that have any serious concomitant illness that is anticipated to require the use of systemic corticosteroids or otherwise interfere with study participation or require active frequent monitoring. (e.g., unstable chronic asthma).
• Patients with history of basal cell or squamous epithelial skin cancer or melanoma
• Presence of significant uncontrolled neuropsychiatric disorder, are clinically judged by the investigator to be at risk for suicide.
• Current alcohol, drug, or chemical abuse

Exclusion criteria related to concomitant medications

• Patients that have been treated with the following therapies:

  1. monoclonal antibody (e.g., ustekinumab, omalizumab, dupilumab) for less than 5 half-lives prior to randomization.
  2. received prior treatment with any oral JAK inhibitor (e.g., tofacitinib, ruxolitinib)
  3. received any systemic corticosteroid administered within 4 weeks prior to planned randomization or are anticipated to require systemic corticosteroids during the study.
  4. received any systemic treatment with Methotrexate, Azathioprine, Cyclosporine within 12 weeks prior to planned randomization
  5. have had an intra-articular corticosteroid injection within 4 weeks prior to planned randomization.
  6. have received more than 250 UV lights sessions

• Patients that are largely or wholly incapacitated permitting little or no self-care, such as being bedridden.

Exclusion criteria related to infection and malignancy risk factors

• Any underlying condition that predisposes the subject to infection, including history of/current human immunodeficiency virus (HIV) infection
• An HIV test must be performed. The result should be available within 30 days of randomisation, but prior to the second dose of investigational product administration (Visit 2/Week 4).

Confirmed positive test for hepatitis B serology for:

1. Hepatitis B surface antigen, OR

2. Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA detected above the lower limit of quantitation Note: Patients who were HBcAb positive at screening were tested every 3 months for HBV DNA. To remain eligible for the study, the patient's HBV DNA levels must have remained below the limit of quantitation

   • Positive test for hepatitis C antibody

   • Any of the following:

     1. Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis, etc) within 8 weeks prior to Inclusion Visit (chronic nail infections not causing open skin lesions are allowed)
     2. Any infection requiring hospitalisation or treatment with IV anti-infectives not completed at least 4 weeks prior to Inclusion visit

   • Any infection requiring IV or oral anti-infectives (including antivirals) within 2 weeks prior to Inclusion visit

   • Have evidence of active TB or latent TB:

     1. have evidence of active TB, defined in this study as the following: Documented by a positive PPD test (≥5 mm induration between approximately 48 and 72 hours after application, regardless of vaccination history), medical history, clinical features, and abnormal chest x-ray at screening. The QuantiFERON®-TB Gold test or TSPOT®.TB test (as available and if compliant with local TB guidelines) may be used instead of the PPD test. Patients are excluded from the study if the test is not negative and there is clinical evidence of active TB.

        Exception: Patients with a history of active TB who have documented evidence of appropriate treatment, have no history of re-exposure since their treatment was completed, and have a screening chest x-ray with no evidence of active TB may be enrolled if other entry criteria are met. Such patients would not be required to undergo the protocol-specific TB testing for PPD, QuantiFERON®-TB Gold test, or T-SPOT® TB test but must have a chest x-ray at screening.

     2. have evidence of untreated/inadequately or inappropriately treated latent TB, defined in this study as the following: documented to have a positive PPD test (≥5 mm induration between approximately 48 and 72 hours after application, regardless of vaccination history), no clinical features consistent with active TB, and a chest x-ray with no evidence of active TB at screening; or PPD test is positive and the patient has no medical history or chest x-ray findings consistent with active TB, the patient may have a QuantiFERON®-TB Gold test or TSPOT® TB test (as available and if compliant with local TB guidelines). If the test results are not negative, the patient will be considered to have latent TB (for purposes of this study); or QuantiFERON®-TB Gold test or T-SPOT® TB test (as available and if compliant with local TB guidelines) may be used instead of the PPD test. If the test results are positive, the patient will be considered to have latent TB. If the test is not negative, the test may be repeated once within approximately 2 weeks of the initial value. If the repeat test results are again not negative, the patient will be considered to have latent TB (for purposes of this study). Exception: Patients who have evidence of latent TB may be enrolled if he or she completes at least 4 weeks of appropriate treatment prior to randomization and agrees to complete the remainder of treatment while in the trial.

Exception: Patients with a history of latent TB who have documented evidence of appropriate treatment, have no history of re-exposure since their treatment was completed, and have a screening chest x-ray with no evidence of active TB may be enrolled if other entry criteria are met.

Such patients would not be required to undergo the protocol specific TB testing for PPD, QuantiFERON®-TB Gold test, or TSPOT® TB test but must have a chest x-ray at screening.

• Safety exclusions labs

• At Screening (within 4 weeks before Week 0 [Day 1]), any of the following:

  1. Aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN).
  2. Alanine aminotransferase (ALT) >2.0 × ULN.
  3. Total bilirubin >1.5ULN (unless due to Gilbert's syndrome)
  4. Serum creatinine >2.0 mg/dL (or >181 μmol/L)
  5. Neutrophil count <1000/μL (or <1.0 × 109/L)
  6. Platelet count <25000/μL (or <25 × 109/L)
  7. Haemoglobin <8 g/dL (or <80 g/L),
  8. Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening (diabetic subjects only) Note: Abnormal screening laboratory tests may be repeated ONCE on a separate sample before subject is declared a screen failure.

• Confirmed COVID-19: The Baseline Visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, defined as resolution of fever without use of antipyretics and improvement in symptoms;

• Suspected COVID-19: Subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., polymerase chain reaction [PCR]) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure. Perioperative management of investigational product Surgery should be avoided during the study if clinically feasible, but is permitted. If a surgery becomes necessary during the study, it should be scheduled at least 4 weeks after the previous administration of investigational product.

For non-major surgery, the decision to withhold investigational product administration is at the Investigator's discretion.

For major surgery, investigational product administration can be resumed at the Investigator's discretion after all of the following criteria are met:

• External wound healing is complete, and
• Any postoperative antibiotic course is completed, and
• All acute surgical complications have resolved Blood donations Subjects should not donate whole blood, blood components or sperm until the completion of the follow-up period.

Other non-inclusion criteria

• Have hypersensitivity to anifrolumab or to any of the excipients.
• Are unable or unwilling to make themselves available for the duration of the study and/or are unwilling to follow study restrictions/procedures.
• Are currently enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
• Have participated within the last 30 days in a clinical study involving an investigational product. If the previous investigational product has a long half-life (2 weeks or longer), at least 3 months or 5 half-lives (whichever is longer) should be allowed between the end of the previous treatment and the inclusion.
• Have previously been randomized in this study or any other study investigating anifrolumab.
• Are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.