A Randomized, Double-blind, Vehicle-controlled, Multicenter, Parallel-Design, Phase 2 Study to Assess the Efficacy and Safety of CLE-400 Topical Gel for the Treatment of Chronic Pruritus in Adult Subjects With Notalgia Paresthetica
Phase: PHASE2
Conditions: Chronic Pruritus in Adult Subjects With Notalgia Paresthetica (NP)
Sponsor: Clexio Biosciences Ltd.

 
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Protocol Title: 
A Randomized, Double-Blind, Vehicle-Controlled, Multicenter, Parallel-Design, Phase 2 
Study to Assess the Efficacy and Safety of CLE-400 Topical Gel for the Treatment of 
Chronic Pruritus in Adult Subjects with Notalgia Paresthetica 
NCT06262607 
 
22 July 2024 
 
 

 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), and applicable local regulations. The 
principal investigator will assure that no planned deviation from, or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
institutional review board (IRB)/research ethics board (REB), except where necessary to eliminate 
an immediate hazard(s) to the trial subjects. All personnel involved in the conduct of this study 
have completed ICH GCP training. 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB/REB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any subject is enrolled. Any amendment to the protocol will require 
review and approval by the IRB/REB before the changes are implemented to the study. All changes 
to the consent form will be IRB/REB approved. 

 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this trial will be conducted according to this protocol, applicable local regulations, and ICH 
GCP guidelines. 

 
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PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE 
I have carefully read and understand the foregoing protocol and agree it contains all the 
necessary information for conducting this study safely.  
I will agree to personally conduct this study in strict accordance with this protocol, International 
Conference on Harmonization (ICH) guidelines for Good Clinical Practice (GCP), the Code of 
Federal Regulations, local regulatory and ethical principles that have their origin in the 
Declaration of Helsinki. I will attempt to complete the study within the time designated.  
I will ensure the rights, safety, and welfare of subjects under my care are protected. I will ensure 
control of the drugs under investigation in this study.  
I will provide access to the protocol and all other study-related information supplied by the 
sponsor to all personnel who participate in the study. I will discuss this information with them 
to assure that they are adequately informed regarding the drug and conduct of the study.  
I agree to keep records on all Subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) and drug disposition in accordance 
with Food and Drug Administration (FDA) regulations. I agree to retain and maintain strict 
accountability of the Investigational Medicinal Products supplied to the study site.  
I will not enroll any subjects into this study, until Institutional Review Board/Research Ethics 
Board (IRB/REB) approval and sponsor’s approval are obtained for the protocol. 
 
 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
10. For female subject of childbearing potential involved in any sexual intercourse that 
could lead to pregnancy: the subject must agree to use a highly effective contraceptive 
method from at least 4 weeks prior to Day 1 until at least 4 weeks after the last study 
treatment administration. Highly effective contraceptive methods include oral, 
intravaginal, or transdermal combined estrogen and progesterone, oral, injectable, or 
implantable progesterone-only, intrauterine devices or intrauterine hormone-releasing 
system, double barrier methods of contraception (e.g., male condom with cervical cap, 
male condom with diaphragm) in conjunction with spermicide, vasectomized partner(s) 
(provided his vasectomy was performed ≥ 4 months prior to Screening), and bilateral 
tubal occlusion.   
Note: Subjects using hormonal contraceptives must have been on a stable dose for at 
least 4 weeks before Day 1.  
Note: The above list of contraceptive methods does not apply to subjects who are 
abstinent for at least 4 weeks before Day 1 and will continue to be abstinent from penile-
vaginal intercourse throughout the study. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods) is not acceptable. 
Note: A female subject of nonchildbearing potential is defined as follows:  
– 
Female subject who has had surgical sterilization (hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy). 
– 
Female subject who has had a cessation of menses for at least 12 months prior to 
the screening visit without an alternative medical cause, and a follicle-stimulating 
hormone (FSH) test confirming nonchildbearing potential (refer to laboratory 
reference ranges for confirmatory levels).  
Note: Female subjects must agree to not have egg retrieval throughout the study and 
for 4 weeks after the last study treatment application. 
11. For male subject involved in any sexual intercourse that could lead to pregnancy, subject 
must agree to use a condom throughout the study (and for at least 2 weeks after the last 
study treatment application). 
Note: Subjects must agree to refrain from donating sperm throughout the study and for 
2 weeks after the last study treatment application.  
12. Subject is willing to participate and is capable of giving informed consent.  
Note: Consent must be obtained prior to any study-related procedures. 
13. Subjects must be willing to comply with all study procedures and must be available for 
the duration of the study. 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
Exclusion Criteria:    
A subject who meets any of the following criteria at the screening and/or Day 1 visits, as 
applicable, will be excluded from participation in this study: 
1. Subject has chronic pruritus that is related to a condition other than NP, and is either 
generalized, widespread on a large area, or is located in the trunk/arms, and/or it is 
assessed by the investigator that the subject is not able to differentiate it from the pruritus 
of NP (for example, chronic pruritus associated with dermatologic diseases, allergic 
conditions, systemic diseases, psychogenic or medication-induced pruritus). 
2. Subject has acute pruritus at any area other than the predefined typical areas of the 
disease (as per Inclusion Criterion 2).  
3. Subject with previous finding of macular amyloidosis or lichen amyloidosis in skin 
biopsy of the affected area (if done). 
4. Subject has used gabapentin and/or pregabalin, systemic corticosteroids, or systemic 
sedative antihistamines within 4 weeks prior to the run-in period (Day -7).  
Note: Oral non-sedative H1 antihistaminic will be permitted during the study only if the 
subject has been on a stable dose for at least 2 weeks prior to run-in and continues to use 
the same agent at the same frequency throughout the study.   
5. Subject has received the following treatments for NP: 
– 
Capsaicin patch on the affected skin area within 12 weeks prior to the run-in period 
(Day -7). 
– 
Topical corticosteroids or capsaicin cream on the affected skin area within 2 weeks 
prior to the run-in period (Day -7). 
– 
Treatment with any other topical medication for pruritus on the affected skin area 
(including emollients containing active components such as urea, polidocanol, 
lidocaine, pramoxine, amitriptyline, ketamine, menthol, camphor, cannabidiol 
[CBD] oils), topical calcineurin inhibitors, phosphodiesterase-4 [PDE-4] and Janus 
Kinase [JAK] / signal transducer and activator of transcription [STAT] inhibitors, 
or cold/hot packs) within 1 week prior to the run-in period (Day -7).  
Note: Application of emollients without active components on the affected skin area 
should be avoided during the study starting at Day -7, unless regularly applied for 
at least 4 weeks before screening and subject continues to apply at the same 
frequency throughout the study. 
– 
Subject has used thalidomide for the treatment of NP within 6 weeks prior to the 
run-in period (Day -7). 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
– 
Subject has had cryolipolysis, or cervical or thoracic spine surgery (e.g., discectomy 
with or without fusion, spinal fusion, etc.) for the treatment of NP within 6 months 
prior to the run-in period (Day -7). 
– 
Subject has received transcutaneous electrical nerve stimulation (TENS), electrical 
muscle stimulation (EMS), spinal manipulation, osteopathic manipulative therapy, 
or acupuncture for the treatment of NP within 2 weeks prior to the run-in period 
(Day -7). 
– 
Subject has used intralesional corticosteroids, has received paravertebral local 
anesthetic block or trigger point injections, or has had cervical traction for the 
treatment of NP within 4 weeks prior to the run-in period (Day -7). 
– 
Subject has used botulinum toxin injections for the treatment of NP within 12 weeks 
prior to the run-in period (Day -7). 
– 
Subject has received biological agent (e.g., or dupilumab) within 12 weeks or 5 half-
lives (whichever is longer) prior to the run-in period (Day -7). 
– 
Subject has undergone surgical decompression for the treatment of NP within 12 
weeks prior to the run-in period (Day -7). 
– 
Subject has had phototherapy (including tanning beds), laser therapy, or psoralen-
UV-A (PUVA) treatment to the back to treat NP within 4 weeks prior to the run-in 
period (Day -7).  
6. Subject has a clinically significant skin disorder affecting the planned area of application 
or within 3 cm from it (e.g., atopic dermatitis, lymphedema, immature scar) that is 
chronic or currently active, or may interfere with the study assessments, including open 
wounds or sores or otherwise non-intact skin. Subjects with only typical pigmentation 
changes or scratch lesions may be included.  
7. Subject has received hair removal treatments such as waxing, epilation, or laser 
treatments at the affected skin area within 2 weeks prior to the run-in period (Day -7). 
Note: Subject should not remove hair throughout the study in the affected skin area.  
8. Subject has clinical signs of skin atrophy (parchment-like skin appearance and/or visible 
telangiectasia) on the planned area of application (e.g., in subjects on long-term 
treatment with corticosteroids). 
9. Subject has received treatment with or nonmedical use of any of the below within 4 
weeks or 5 half-lives (whichever is longer) prior to the run-in period (Day -7): 
• 
α2-adrenoreceptor (AR) antagonists (e.g., mirtazapine);  
• 
Other α2-AR agonists (e.g., clonidine, guanabenz, methyldopa);  
• Sedating medications including sedative antihistamines, sedatives (benzodiazepines, 
benzodiazepine-like drugs, barbiturates), hypnotics, opioid-receptor agonists, and 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
over-the-counter (OTC) products with sedating properties (e.g., Benadryl 
[Diphenhydramine], Doxilamine [Unisom], Melatonin, Valerian supplement, CBD, 
or cannabis). 
• Medications that are known to prolong the QT interval (e.g., antimicrobial agents 
such as fluoroquinolones, macrolides, and antifungal agents; antipsychotic agents 
that prolong QT; antidepressants such as tricyclic antidepressants [TCAs] and 
selective serotonin reuptake inhibitors [SSRIs]). 
10. Subject has a known hypersensitivity to detomidine, or any other α2-AR agonists, or to 
any of the excipients in CLE-400. 
11. Subject has been diagnosed with hypotension or is at risk of hypotension based on 
investigator judgement (e.g., has experienced repeated episodes of symptomatic 
hypotension, repeated drops in systolic blood pressure [SBP] below 90 mmHg or in 
diastolic blood pressure [DBP] below 60 mmHg, repeated episodes of orthostatic 
hypotension, fainting spells, or blackouts in the past). 
12. Subject has SBP < 90 mmHg or > 160 mmHg or bradycardia with heart rate (HR) 
< 55 bpm at screening (physically fit subjects with a HR < 55 bpm, but no less than 45 
bpm, may be enrolled with sponsor approval in cases where clinically significant 
bradycardia can be ruled out); symptomatic hypotension during screening period, or 
orthostatic hypotension at screening defined as a SBP decrease ≥ 20 mmHg or DBP 
decrease ≥ 10 mmHg when standing up from the seated or supine position. 
13. Subject has received treatment with HR lowering medications (e.g., amiodarone, beta-
blockers, non-dihydropyridines calcium channel-blockers [diltiazem and verapamil], 
digoxin) within 2 weeks prior to the run-in period (Day -7).  
14. Subject is receiving an anti-hypertensive treatment which has not been stable for at least 
4 weeks prior to screening. 
15. Subject has a history of bradycardia with HR < 55 bpm and no reasonable explanation, 
or a history of sick sinus syndrome or sinoatrial (SA) block unless treated with 
pacemaker, or evidence of sick sinus syndrome or SA block in ECG at screening. 
16. Subject has any clinically significant abnormality identified on the screening 12-lead 
ECG: prolonged QRS duration (QRS > 120 ms), QTcF > 480 ms, first degree 
atrioventricular (AV) block with PQ > 240 ms (PR where there is no Q wave), second- 
or third-degree AV block.  
17. Subject has a current angina pectoris, or history of stable or unstable angina or 
myocardial infarction (MI) in the past 6 months, and/or heart failure with reduced 
ejection fraction (EF ≤ 45%) and/or symptomatic heart failure (New York Heart 
Association Criteria Class ≥ III) at screening. 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
18. Subject has clinically significant peripheral vascular disease (as evidenced by a history 
of intermittent claudication, limb ischemia, or ischemic limb ulcers), active Raynaud’s 
phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. 
19. Subject has uncontrolled diabetes mellitus with hemoglobin A1c (HbA1C) > 10% or 
repeated episodes of symptomatic hypoglycemia in the last 6 months, or evidence of 
severe Diabetic Neuropathy. 
20. Subject has a history of cerebrovascular disorders: stroke of any kind, transient ischemic 
attack (TIA) unless subject had revascularization for internal carotid artery stenosis with 
no TIA since revascularization or known hemodynamically significant carotid artery 
stenosis. 
21. Subject has a current major depression  episode or history of significant uncontrolled 
psychiatric disorders in the last year prior to the run-in period (Day -7). 
22. Subject has a known history of clinically significant drug or alcohol abuse in the last 
year prior to the run-in period (including recreational substance use judged by the 
investigator not to be compatible with study participation). 
23. Subject has current symptoms of depression with a PHQ-8 score ≥ 10 at screening. 
24. Subject has an active malignancy or history of malignancy within 5 years prior to 
screening, with the exception of adequately treated localized carcinoma in situ of the 
cervix, and of successfully resected basal cell carcinoma or skin squamous cell 
carcinoma not located in the affected skin area or < 10 cm away. 
25. Subject has a current thoracic spinal tumor or lesion. 
26. Subject has aspartate transaminase (AST) or alanine transaminase (ALT) or total 
bilirubin ≥ 2.5 times the upper limit of normal or known moderate-severe hepatic 
insufficiency. 
27. Subject has estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 or known 
chronic kidney disease (CKD) stage ≥ 3. 
28. Subject has a known history of human immunodeficiency virus (HIV), hepatitis B virus 
(HBV), or hepatitis C virus (HCV; however, a subject with documented proof of cure 
from HCV can be enrolled). 
29. Subject has a known active COVID-19 infection during the screening period 
(rescreening may occur 10 days or greater after the onset of COVID-19, provided that 
symptoms have resolved). 
30. Subject is a female who is breastfeeding, pregnant, or who is planning to become 
pregnant during the study. 
31. Subject with known or suspected history of a clinically significant systemic disease, 
unstable medical disorders, life-threatening disease, including 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
physical/laboratory/ECG/vital signs abnormality that would, in the opinion of the 
investigator, put the subject at undue risk or interfere with interpretation of study 
results. 
32. Subject has received a nonbiological investigational product or device within 4 weeks 
prior to the run-in period (Day -7) or has received any investigational biological agent 
within 12 weeks or 5 half-lives (whichever is longer) prior to the run-in period (Day -
7). 
33. Planned major surgery during the clinical study. 
34. Sponsor or CRO employees or employees under the direct supervision of the 
investigator and/or involved directly in the trial, or their family members/subjects in 
same household. 
35. In the opinion of the investigator, the subject is unsuitable for participating in the study. 
Statistical methods:  
The significance level of this study will be 0.05, 2-sided.  
A fixed sequence gatekeeping (hierarchical) approach will be applied to adjust for multiplicity 
and to control type I error due to multiple efficacy endpoints testing of the primary and 
secondary endpoints. The sequence order is according to the defined order of the primary and 
secondary endpoints. If the primary analysis is statistically significant at the 2-sided 0.05 level, 
the secondary endpoints will be analyzed sequentially according to the order of the secondary 
endpoints as listed above. A secondary endpoint will only be considered statistically significant 
at the 2-sided 0.05 level if the previous secondary or primary endpoint in the hierarchy is 
significant at the 2-sided 0.05 level. 
. 
Analysis sets: 
The Intent-To-Treat (ITT) Analysis Set will include all randomized subjects. In this analysis 
set, treatment is assigned based on the treatment to which subjects were randomized, regardless 
of which treatment they actually received. 
The Full Analysis Set (FAS), which is a subset of the ITT Analysis Set, will include all 
randomized subjects who received at least 1 dose of study treatment and have both baseline and 
at least one postbaseline WI-NRS evaluation. In this analysis set, treatment is assigned based 
on the treatment to which subjects were randomized, regardless of which treatment they actually 
received.  
The Safety Analysis Set includes all subjects who receive at least 1 dose of study treatment. 
The ITT Analysis Set will be used for summaries of subject demographics and baseline 
variables. 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
The FAS Analysis Set will serve as the principal analysis set for efficacy inference. 
The Safety Analysis Sets will be used for analyses of safety variables. 
Efficacy Analyses: 
Efficacy will be evaluated on the basis of the FAS analysis set. 
For all WI-NRS endpoints (% change and change from baseline and proportion of subjects), the 
weekly mean of the 24-hour WI-NRS will be defined as the sum of the daily 24-hour WI-NRS 
score reported during a specific week of the study (e.g., Days 1 to 7, Days 8 to 14, Days 15 to 
21, etc.) divided by the number of days with nonmissing scores for that week. For all WI‑NRS 
endpoints, the baseline score will be defined as the average of all nonmissing daily 24-hour 
WI-NRS scores over the run-in period (Day -7 to Day -1); at least 4 completed WI-NRS 
assessments will be required during the run-in period.  
For the primary efficacy endpoint, the percent change from baseline in weekly mean of daily 
24-hour WI-NRS, the statistical model to be used for inference will be the Mixed Models 
Repeated Measures (MMRM) analysis using the SAS® MIXED procedure with the 
REPEATED subcommand. The model will include terms for treatment, categorical Week in 
study (1, 2, 3, and 4), treatment by week interaction, pooled sites, Baseline weekly mean WI-
NRS and Baseline weekly mean WI-NRS by week interaction. The percent change from 
baseline in the weekly mean of daily 24-hour WI-NRS score will be the response variable in 
the model. The model derived least squares means of percent changes at Week 4 will be 
compared between the CLE-400 group and the vehicle group. The model will use the 
unstructured covariance matrix, the Restricted Maximum Likelihood (REML) estimation 
method, and the Kenward Roger adjustment method for the degrees of freedom. In the case that 
the model does not converge, the Maximum-Likelihood estimation method will be used instead 
of the default REML. If the model still does not converge, then a simpler covariance structure 
with fewer parameters will be used according to the following order: heterogeneous 
autoregressive (1), heterogeneous compound symmetry, autoregressive (1), and compound 
symmetry.  
Safety Analyses:  
Safety analyses will include TEAEs, LTA, laboratory tests, vital signs, ESS scores, and ECGs. 
No inferential statistics will be done on safety variables. 
Pharmacokinetic Analyses: 
Detomidine concentration data will be listed per subject and summarized by visit, dose and 
nominal timepoints using descriptive statistics. 

 
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Name of 
Sponsor/Company:  
Clexio Biosciences Ltd. 
Name of Study Treatment: 
CLE-400 or Vehicle 
Name of Active Ingredient: 
Detomidine HCl monohydrate 
Sample Size Consideration: 
The sample size was determined based on the following assumptions: a difference of 24% in 
the percent change from baseline to Week 4 in WI-NRS between CLE-400 and vehicle, a 
randomization ratio of 1:1, a standard deviation (SD) of 30%, a power of 81%, a 2-sided alpha 
level of 0.05, and an overall drop-out rate of 5%. 
Under the above assumptions, the estimated number of subjects required for this study is 54 
subjects (27 subjects per treatment arm).