Table 2.

Approved therapies and current or completed double-blind placebo-controlled studies or RCTs for CNPG

Target	Agent	Approved (+/−) for CNPG [other approved indications]	Clinical trials for CNPG			Adverse events (excerpt)
			ClinicalTrials.gov or other identifier [short name of the study (if applicable); phase; status as reported by ClinicalTrials.gov]	Dosage	Number of patients (n) and changes in Patient-reported outcomes (excerpt)
Topical therapies
Janus kinase (JAK) receptors
JAK1/2	Ruxolitinib	– [Non-segmental vitiligo in patients aged ≥ 12 years with face involvement] [USA: mild to moderate AD in non-immunocompromised patients aged ≥ 12 years when topical treatment is not advisable or insufficiently effective as short-term therapy]	NCT05755438 [TRuE-PN1; III; recruiting] NCT05764161 [TRuE-PN2; III; not yet recruiting]	Ruxolitinib 1.5% cream twice daily on the affected areas for 12 weeks and during the open-label treatment period (up to 40 weeks)	n.a.	Not yet applicable for PN Vitiligo: application site acne (~ 6%) and pruritus, nasopharyngitis, headache [89] AD: nasopharyngitis, upper respiratory tract infection, headache, application site burning and pruritus [81]
Calcineurin receptor
Calcineurin receptor	Pimecrolimus vs topical hydrocortisone	– [Mild to moderate AD in patients aged ≥ 3 months]	NCT00507832 [CASM981CDE21; II; completed [58]]	Pimecrolimus 1% cream twice daily on the affected areas of one arm for 8 weeks; hydrocortisone 1% cream on the affected areas of the other arm for 8 weeks [58]	n = 30 Reduction of pruritus intensity (VAS; 0–10) and scratch lesions: no significant difference between pimecrolimus and hydrocortisone (p = 0.394) [58] Mean percentual pruritus reduction after 57 ± 3 days: 35.7% (pimecrolimus) vs 36.7% (hydrocortisone) (p > 0.1) [58]	Suspected AE related to the study medication: worsening of the disease (1 patient) [58]
Systemic therapies
Th2 cytokines and receptors
IL-4R/IL-13R	Dupilumab	+ [AD, asthma (add-on), CRSwNP (add-on), EoE]	NCT04183335 [LIBERTY-PN PRIME; III; completed [56]] NCT04202679 [PRIME2; III; completed [56]]	Dupilumab 300 mg (loading dose 600 mg) SC Q2W for 24 weeks; background therapy with TCS/TCI [56]	n = 151 (PRIME); n = 160 (PRIME2) [56] Pruritus reduction (PP-NRS) ≥ 4 points at week 12 in 37.2% of patients vs in 22.0% of patients in the placebo arm (95% CI 2.3–31.2; p = 0.022) in PRIME2, at week 24 in 60.0% of patients vs. in 18.4% of patients in the placebo arm (95% CI 27.8–57.7; p < 0.001) in PRIME [56] IGA PN-S score of 0 or 1 (‘clear’/’almost clear’) at week 12/24: 32%/48% of patients (dupilumab) vs 11.8%/18.4% (placebo) (PRIME); 25.6%/44.9% of patients (dupilumab) vs 12.2%/15.9% (placebo) (PRIME2) [56] (95% CI for the difference at week 24: PRIME: 13.4–43.2, p < 0.001; PRIME 2: 16.4–45.2, p < 0.001) (95% CI for the difference at week 12: PRIME: 7.8–34.0, p = 0.003; PRIME 2: 2.6–27.0, p = 0.019)	Nasopharyngitis, conjunctivitis, herpes viral infections (PRIME2) [56]
IL-31RA	Nemolizumab (CD14152)	– [Japan: pruritus in AD patients aged ≥ 13 years, when treatment is insufficiently effective]	NCT03181503 [II; completed [72]] NCT04501679 [III; completed] NCT05052983 [III; recruiting] NCT04204616 [III; enrolling by invitation] NCT04501666 [III; active, not recruiting]	Nemolizumab 0.5 mg/kg SC at baseline, week 4 and week 8 [72]	n = 70 [72] Pruritus reduction (PP-NRS) within 48 h (nemolizumab: − 19.5%; placebo: − 5.8%; p = 0.014) [73] Pruritus reduction (reduction of PP-NRS ≥ 4) at week 12: achieved by 52.9% of patients (nemolizumab) vs 8.3% of patients (placebo) (p < 0.001) [73] ≥ 75% healed lesions at week 4 (24% of patients with nemolizumab vs 11% of patients with placebo) [72] n = 183 Pruritus reduction (weekly average PP-NRS) at week 16: achieved by 56.3% of patients (nemolizumab) vs 20.9% of patients (placebo) (p < 0.0001) [71] IGA success (score 0 or 1, that is clear or almost clear, and a ≥ 2 grade improvement): 37.7% (nemolizumab) vs 11.0% (placebo) (p < 0.0001) [71]	Abdominal pain, diarrhea, musculoskeletal symptoms, bronchitis, nasopharyngitis [72]
OSMRβ	Vixarelimab (KPL-716)	–	NCT03816891 [II; active, not recruiting [74]] NCT03858634 [II; completed]	Vixarelimab 360 mg SC weekly (loading dose 720 mg SC) [74]	n = 50 [74] Pruritus reduction (reduction of weekly PP-NRS) at week 8: − 50.6% (vixarelimab) vs − 29.4% (placebo) (95% CI for the difference − 40.8 to − 1.6, p = 0.03) Pruritus reduction (reduction of PP-NRS ≥ 4) at week 8: achieved by 52.2% (vixarelimab) vs 30.8% (placebo) of patients (p = 0.11) [74]	Upper respiratory tract infections, nasopharyngitis, headache, urticaria, nummular eczema [74]
Janus kinase (JAK) and Tyrosine kinase KIT receptors
JAK1	Abrocitinib	– [Moderate-to-severe AD in adult patients (Europe, USA) and in patients ≥12 years (UK, Japan)]	NCT05038982 [II; completed]	Abrocitinib 200 mg orally daily	n.a.	Not yet applicable for PN AD: nasopharyngitis, headache, nausea, acne [90]
JAK1	Povorcitinib (INCB054707)	–	NCT05061693 [II; recruiting]	n.a. (dose A, B or C)	n.a.	n.a.
Tyrosine kinase KIT receptor	Barzolvolimab (CDX-0159)	–	NCT04944862 [I; active, not recruiting]	One dose intravenously	n.a.	n.a.
Opioid receptors
KOR/MOR	Nalbuphine	– (Severe pain when alternate treatment is insufficiently effective; pre- and postoperative analgesia)	NCT02174419 [II/III; completed [68]] NCT02174432 [II/III; completed] NCT03497975 [II/III; completed]	Nalbuphine 81 mg and 162 mg orally BID [68]	n = 62 [68] Pruritus reduction (weekly PP-NRS) ≥ 30% from baseline at week 10 in 44.4% of patients treated with 162 mg (p = 0.32) and 27.3% (p = 0.78) of patients treated with 81 mg (vs 36.4% of patients in the placebo arm) [68]	Road traffic accident and thoracic vertebral fracture (1 patient) Nausea, headache, fatigue, dizziness
Substance P/Neurokinin 1 receptor (NK1R)
NK1R	Serlopitant	–	NCT02196324 [II; completed [91]] NCT03677401 [III; completed] NCT03546816 [III; completed] NCT03540160 [III; terminated]	Serlopitant 5 mg orally once daily [91]	n = 128 [91] Pruritus reduction (mean average VAS score) at week 8: − 48.3% (serlopitant) vs − 26.3% (placebo) (p < 0.05) Pruritus reduction ≥ 4 cm (mean average VAS score) at week 8 in 54.4% of patients (serlopitant arm) vs 25.0% of patients (placebo arm) (p = 0.002) [91] Pruritus reduction (PP-NRS) at week 8: − 37.2% (serlopitant) vs − 26.4% (placebo) (p < 0.05) Pruritus reduction ≥ 4 points (PP-NRS) at week 8 in 46.5% of patients treated with serlopitant vs in 25.6% of patients treated with placebo (p = 0.045) [91]	Nasopharyngitis, diarrhea, fatigue, dizziness, fatigue [91]
NK1R	Aprepitant	– (Vomiting, postoperative nausea and vomiting, cancer)	EudraCT Number: 2013-001601-85 [APREPRU; II; completed [92]]	Aprepitant 80 mg orally once daily [97]	n = 58 patients [97] Aprepitant was not superior to placebo and did not reduce the pruritus intensity in patients with prurigo nodularis (p = 0.7 respectively 0.8) [92]	None [92]

AD atopic dermatitis, AE adverse event, BID twice daily, CI confidence interval, CNPG chronic prurigo of nodular type, CRSwNP chronic rhinosinusitis with nasal polyps, EoE eosinophil esophagitis, IGA PN-S Investigator Global Assessment for PN–Stage, IL interleukin, JAK Janus kinase, KOR κ-opioid receptor, MOR μ-opioid receptor, n.a. not applicable, NK1R neurokinin 1 receptor, OSMRβ oncostatin M receptor β, PN prurigo nodularis, PP-NRS peak pruritus numeric rating scale, Q2W every 2 weeks, Q4W every 4 weeks, R receptor, RA receptor antagonist, RCT randomized controlled trial, SC subcutaneously, UK United Kingdom, VAS visual analog scale