The main objective of the study is to assess efficacy and safety of dupilumab given up to 24 weeks in adults with CPUO This is a master protocol which includes 2 parallel-treatment, double-blind, 2- arm Phase 3 staggered studies of similar design (Study A and Study B) in male and female participants aged 18 to 90 years with CPUO. Study A results at week 12 will inform study B.

For both Study A and B, after an up-to-4-week screening period, participants with severe pruritus (worst-itch numerical rating scale [WI-NRS ≥7) will enter a 4-week run-in period during with a non-sedative antihistamine and an emollient (moisturizer). Participants with severe pruritus (WI-NRS ≥7) at baseline will be randomized (1:1) to be treated for 24 weeks (Study A) or 12 weeks (Study B) with either dupilumab or matching placebo in addition to their antihistamine and emollient regimen. The treatment period will be followed by a 12-week follow-up period.

Inclusion Criteria:

• Participant must be 18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 90 years of age inclusive, at the time of signing the informed consent.
• Participants with chronic pruritus for at least 6 months before the screening visit.
• Chronic pruritus considered of unknown origin as assessed by the investigator at baseline (excluding chronic pruritus secondary to dermatological or systemic conditions, of neuropathic or psychogenic origin or secondary to drugs).
• Chronic pruritus must affect at least 2 of the following body areas: legs, arms, or trunk.
• History of insufficient control of the chronic pruritus with prior treatment.
• Participants should receive optimal treatment for concomitant conditions that could impact pruritus (eg, diabetes, iron deficiency).
• Participants must have a history of severe itch and a worst itch score of ≥7 at screening on the WI-NRS (score scale ranges from 0 to 10; higher score indicates worse itch) and Patient global impression of severity (PGIS) of pruritus scored "severe" at screening.
• Participants must have an average worst itch score of ≥7 in the 7 days prior to run-in visit and in the 7 days prior to Day 1 on the WI-NRS.
• Participants scored "severe" in the PGIS of pruritus on Day 1.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the patient's participation in the study.
• Patients with active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis, unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent.
• Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drug within 2 weeks before the screening visit.
• HIV infection.
• Severe renal failure (dialysis).
• Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the run-in visit.
• Known or suspected immunodeficiency.
• Active malignancy or history of malignancy within 5 years before the baseline visit, except completely treated in situ carcinoma of the cervix and completely treated and resolved non metastatic squamous or basal cell carcinoma of the skin.
• History of hypersensitivity or intolerance to non-sedative antihistamines.
• Participation in prior dupilumab clinical study or have been treated with commercially available dupilumab.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.