chronic pruritus of unknown origin (CPUO)

This master trial proposal includes two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials, one for 24 weeks of treatment (Trial A) and the other for 12 weeks of treatment (Trial B), designed to evaluate the efficacy and safety of dupilumab in male and female subjects aged 18 to 90 years for CPUO. Trial B will begin staggered after recruitment for Trial A. Each trial will assess the effect of dupilumab on improvement of pruritus, as well as its effects on patients' quality of life (QoL), sleep quality, anxiety and depression, and overall health.

injection

dupilumab

230

300mg/2ml

The primary endpoint is the proportion of participants whose weekly mean WI-NRS score improved (decreased) by 4 or more (≥4) from baseline to week 24.

• The primary analysis will be performed using the Cochran-Mantel-Haenszel (CMH) test, stratified by factors including type 2 biomarker (yes/no; "yes" defined as eosinophil count ≥300/mm3 and/or total IgE ≥150 IU/mL), region (pooled into three strata: North America, Asia, and other regions), and age group (65 years [≥65] years or younger [<65] years). The odds ratio and response rate differences between dupilumab and placebo, along with 95% confidence intervals and p-values, will be provided. For subjects who discontinued trial treatment before week 24 (Trial A) or week 12 (Trial B), their data up to week 24 (Trial A) or week 12 (Trial B) will be included in the analysis. Subjects who used rescue medication during treatment (before week 24 [Trial A] or week 12 [Trial B]), or who had missing data at week 24 (Trial A) or week 12 (Trial B), will be considered non-responders.

Age

I 01. At the time of signing the participant consent form, participants must be between 18 years of age (or the legal age of consent in the jurisdiction where the trial is conducted) and 90 years of age (inclusive).

Participant Type and Disease Characteristics

I 02. Participants with chronic pruritus (CP) for at least 6 months prior to return visit will be screened.

I 03. Chronic pruritus of unknown origin will be considered based on the trial administrator's assessment at the baseline period. The following primary causes must be specifically excluded (dry skin is not considered a primary cause of pruritus):

• Chronic pruritus secondary to skin conditions, including but not limited to Alzheimer's disease (AD), psoriasis, lichen planus, prurigo nodosa (PN), herpetic dermatitis, and bullous pemphigoid (including direct immunofluorescence skin biopsy when latent bullous pemphigoid is suspected).

• Chronic pruritus secondary to systemic conditions, including but not limited to chronic kidney disease, hepatobiliary disease, malignancies/hematologic disorders, endocrine disorders, and infections (e.g., HIV, scabies, parasitic infections).

• Chronic pruritus of neurological origin, including but not limited to notalgia paraesthetica and brachioradialis pruritus.

• Chronic pruritus of psychogenic origin (e.g., pruritus associated with mental illness or stressful life events, psychogenic pain or other somatic symptoms, or a mental illness including parasitic parasitic disease). Eligibility is also given if the patient experiences anxiety or depression secondary to the pruritus.

• Chronic pruritus secondary to medications (e.g., opioids, chloroquine, angiotensin-converting enzyme [ACE] inhibitors, statins).

I 04. Chronic pruritus must affect at least two of the following body parts: legs, arms, or trunk.

I 05. A history of poor control of CP with prior treatment.

I 06. Subjects should receive optimal treatment for comorbidities that may affect pruritus (e.g., diabetes, iron deficiency).

I 07. Subjects must have a history of severe pruritus and a WI-NRS maximum pruritus score of ≥7 (range 0 to 10, higher scores indicate more severe pruritus) at screening, and a PGIS score of "severe" for pruritus at screening.

I 08. Subjects must have an average WI-NRS maximum pruritus score of ≥7 (range 0 to 10) within 7 days prior to the introductory follow-up visit and within 7 days prior to Day 1.

Note: The average pruritus NRS score for maximum pruritus intensity will be determined based on the average daily NRS score for maximum pruritus intensity (range 0 to 10) within 7 days prior to the introductory follow-up visit and randomization. Daily scores for at least 4 out of 7 days are required to calculate the average score. For patients who do not have at least 4 daily scores within 7 days prior to the scheduled introductory period date, the introductory period follow-up should be postponed until this requirement is met, but not exceeding the maximum screening period of 28 days. For patients who do not report at least 4 daily scores within 7 days prior to the scheduled randomization date, randomization may be postponed until this requirement is met, but not exceeding an additional 7 days.

I 09. Subject's PGIS score for pruritus on Day 1 is "Severe".

Weight
Not applicable.

Sex, Contraception/Barrier Method, and Pregnancy Testing Requirements/Breastfeeding

I 10. All (Men and Women)

Women should use contraceptive methods that comply with local regulations regarding contraceptive methods for participation in clinical studies.

a) Female Subjects

• Female subjects are eligible to participate if they are not pregnant or breastfeeding and meet at least one of the following criteria:

-Be a woman who is infertile (WONCBP), the definition of which can be found in Appendix 4 (Section 10.4 Guidelines for Contraception and Barrier Methods).

Or

- For women of childbearing age (WOCBP) who agree to use highly effective (failure rate less than 1% [<1%]) contraception during the trial treatment and for at least 12 weeks after the last dose of the investigational drug, as described in Appendix 4 (Section 10.4 Guidelines for Contraception and Barrier Methods).

• WOCBPs must have negative results on a highly sensitive pregnancy test at screening (serum testing), during the lead-up visit, and before the first dose of the investigational drug on day 1 (urine testing), see Section 8.2.5 (Pregnancy Testing).

• If the urine test is not definitively negative (e.g., the result is indeterminate), a serum pregnancy test is required. In this case, if the serum pregnancy test result is positive, the subject must be excluded.

The trial administrator is responsible for reviewing medical history, menstrual history, and recent sexual activity to reduce the risk of including women with undetected early pregnancy in the trial.

Participant Consent Form

I 11. Able to sign the participant consent form as described in Appendix 1 (Section 10.1.3), including compliance with the Participant Consent Form (ICF) and the requirements and restrictions listed in this trial protocol. In countries where the legal age of adulthood is over 18 years, the participant's legal guardian must also sign a specific ICF.

Other Inclusion Criteria

I 12. Apply a topical emollient (moisturizer) for at least 80% of the days during the introductory period.

Note: For restrictions on emollient (moisturizer) treatment, please refer to the trial protocol.

I 13. Receive non-sedated antihistamine treatment for at least 80% of the days during the introductory period.

I 14. Participants must be willing and able to complete a daily symptom electronic log during the trial. The trial administrator will review this for the screening and introductory periods.

Medical Conditions
E 01. The presence of a serious medical condition that, in the assessment of the trial administrator, would adversely affect the patient's participation in this trial. Examples include, but are not limited to, subjects with a short life expectancy, uncontrolled diabetes (heme A1c ≥ 9%), cardiovascular disease (e.g., New York Heart Association class III or IV heart failure), severe kidney disease (e.g., subjects undergoing dialysis), hepatobiliary disease (e.g., Child-Pugh B or C), neurological disorders (e.g., demyelinating diseases), autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), and other serious endocrine, gastrointestinal, metabolic, pulmonary, psychiatric, or lymphatic diseases. The specific reasons for exclusion based on this criterion will be recorded in the trial documentation (medical records, eCRFs, etc.).

E 02. Patients with active tuberculosis (TB) or nontuberculous mycobacterial infection, or a history of incompletely treated TB, will be excluded from the trial unless a specialist has a complete record of adequate treatment and the subject may now begin biologic therapy based on the medical judgment of the trial administrator and/or the infectious disease specialist. If required by regulatory authorities or ethics committees, or if the trial administrator suspects TB, TB testing will be conducted in each country according to local guidelines.

E 03. Patients diagnosed with, suspected of having, or at high risk of endoparasitic infection, and/or using antiparasitic drugs within 2 weeks prior to the screening follow-up visit (first follow-up visit) or during screening or induction.

E 04. History of HIV infection.

E 05. Severe renal failure (dialysis).

E 06. Patients with active chronic or acute infection within 2 weeks prior to the induction follow-up visit (second follow-up visit), requiring systemic antibiotic, antiviral, or antifungal treatment.

E 07. Known or suspected immunodeficiency, including a history of invasive opportunistic infections (e.g., histoplasmosis, listeriosis, coccidioidomycosis, Pneumocystis, and aspergillosis) regardless of remission, or recurrent infections of unusual frequency or duration, which the trial administrator determines are suspected of causing immunodeficiency.

E 08. History of active malignancy or malignant tumors within 5 years prior to the baseline return visit, excluding completely cured cervical carcinoma in situ and remissioned non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin.

E 09. History of allergy or intolerance to non-sedated antihistamines.

E 10. History of systemic anaphylaxis or anaphylactic shock to any excipient or component of IMP.

E 11. Known or suspected alcohol and/or drug abuse.

E 12. The trial administrator believes that the patient has any other medical or psychological condition, including relevant laboratory tests or ECG abnormalities at screening, indicating a possible new and/or unexplained illness, which may pose an unreasonable risk to the trial participants due to participation in this clinical trial, may make the patient's participation unreliable, or may interfere with the trial assessment. The specific reasons for exclusion based on this criterion will be recorded in the trial documentation (medical record, eCRF, etc.).

Previous/Concomitant Treatments

E 13. Any of the following treatments used within 4 weeks prior to the lead-up follow-up visit (or 5 half-lives, whichever is longer) or during the lead-up period:

- Systemic immunosuppressive/immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolate-mofetil, interferon-gamma, JAK inhibitors, azathioprine, methotrexate, thalidomide, lenalidomide, dapsone).

- Phototherapy, including tanning beds.

- Opium antagonists or agonists, such as naltrexone or butorphanol

- Gabapentin, pregabalin

E 14. Start using one of the following antidepressants or change the dose of such medication within 3 months prior to the introductory period follow-up visit, or anticipate changing the dose during the trial. Subjects who have discontinued these medications for at least 4 weeks (or 5 half-lives, whichever is longer) prior to the introductory period follow-up visit may be included.

- Paroxetine, fluvoxamine, or other selective serotonin reuptake inhibitors (SSRIs).

- Serotonin and norepinephrine reuptake inhibitors (SNRIs)

- Amitriptyline or other tricyclic or tetracyclic antidepressants (e.g., mirtazapine).

E 15. Use of a TCS/topical calcineurin inhibitor (TCI) (of any potency) or any skin-directed topical treatment other than a moisturizer within one week prior to the Day 1 follow-up visit (including prescription moisturizers or moisturizers containing additives, topical doxepin, menthol, crotamiton cream, capsaicin, calamine, pramoxine, polidocanol, lidocaine, prilocaine, N-palmitoylethanolamine).

E 16. Use of a sedative or non-sedative antihistamine other than (or at a different dose than) fexofenadine or loratadine background treatment within one week prior to the Day 1 follow-up visit.

E 17. Use of a serotonin (5-HT3) receptor antagonist (e.g., ondansetron) or neurokinase receptor 1 antagonist (e.g., aprepitant) within one week prior to the Day 1 follow-up visit.

E 18. Use of a leukotriene antagonist/modulator or H2 receptor antagonist within one week prior to the Day 1 follow-up visit, unless a stable dose is being used for other non-CPUO diseases starting from the screening follow-up visit.

E 19. Previous treatment with biologics within the following timeframes:

- Any cell elimination drug, including but not limited to rituximab: within 6 months prior to the introduction follow-up visit.

- Immunomodulatory biologics, including omalizumab: within 5 half-lives (if known) or 16 weeks prior to the introduction follow-up visit, whichever is longer.

E 20. Received an active (attenuated) vaccine within 4 weeks prior to the screening follow-up visit (Day 1 follow-up visit).

Note: For subjects scheduled to receive the live attenuated vaccine during the trial (according to the national vaccination program/local guidelines), a physician will be consulted to determine whether vaccination can be postponed until after the EOS (Emergency Opportunity) or brought forward to before the start of the trial without affecting the subject's health:

- Patients who can safely postpone receiving the live (attenuated) vaccine will be eligible to participate in the trial.

- If a patient is vaccinated in advance, they can only participate in the trial 4 weeks after vaccination.

E 21. Planned or anticipated use of any prohibited drugs (Section 6.8) and procedures during screening, introduction, and trial treatment.

Previous/Concurrent Clinical Trial Experience

E 22. Previous participation in a previous dupilumab clinical trial or prior treatment with commercially available dupilumab.

E 23. Currently participating in or having participated in any investigational drug or device clinical trial within 3 months prior to the screening follow-up visit or within 5 half-lives of the investigational compound (whichever is longer).

E 24. Trial B only: Trial A participants in this trial.

Diagnostic Assessment

E 25. Applicable to subjects who have no history of HIV infection prior to the screening follow-up visit but test positive for HIV serological testing at the time of screening.

E 26. Patients with the following findings at screening:

- Platelet count ≤ 100 × 10³/μL

- Neutrophil count ≤ 1.0 × 10³/μL

- Creatinine clearance ≤ 60 mL/min/1.73 m², calculated using the Chronic Kidney Disease Epidemiological Study (CKD-EPI) formula (44)

- Total serum bilirubin > 2.5 times the upper limit of normal (ULN)

- Ferritin < (<) the lower limit of normal (LLN) or > 600 (>600) ng/mL

- TSH < (<) LLN or > 8 (>8) mIU/L

E 27. Patients with any of the following test results at the screening follow-up visit (first follow-up visit):

- HBsAg positive (or indeterminate), or

- Total HBc Ab Positive for HBV DNA, or positive for HCV Ab and confirmed by HCV RNA.

Other Exclusion Criteria

E 28. Subjects detained in an institution due to regulatory or legal orders; prisoners or subjects legally detained.

E 29. Subjects deemed unfit to participate in the trial by the trial administrator, for any reason, including medical or clinical conditions, or who may be at risk of non-compliance with trial procedures.

E 30. Subjects who are employees of the clinical trial facility, or other persons directly involved in the execution of the trial, or immediate family members of such persons (see Section 1.61 of ICH - Good Clinical Practice (GCP) Regulation E6).

E 31. Any specific circumstances that may raise ethical considerations during the execution of the trial.

E 32. Subjects who are allergic to any of the trial treatments or their components, or who have had other allergic reactions, should not participate in the trial in the opinion of the trial administrator.