Assess the Efficacy and Safety in Volunteers of DCF100, TIB200 and SPR300 vs. Placebo and Control(s) in a UV Pain Model

Study Overview
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Brief Summary
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This is a randomised, double blind, cross over clinical study in healthy human volunteers (including pharmacokinetic [PK] sampling and laser Doppler assessment of local blood flow in a subset of up to 6 subjects per cohort of 20) to assess the efficacy and safety of three different topical analgesics (DCF100, TIB200 and SPR300) versus placebo and active control(s) in a model of UV-induced inflammatory pain.

Detailed Description
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This is a randomised, double blind, cross over clinical study in healthy human volunteers, including pharmacokinetic (PK) sampling and laser Doppler assessment of local blood flow in a subset of up to 6 subjects per cohort, to assess the efficacy and safety of three different topical analgesics (DCF100, TIB200 and SPR300) versus placebo and active control(s) in a model of UV-induced inflammatory pain. The study will consist of 3 cohorts of subjects (n=20 subjects per cohort). Subjects of each cohort will receive test and reference products (no reference product for Cohort 3) of one investigational medicinal product (IMP) and a placebo. Test Products: Cohort 1: Ibuprofen, TIB200 gel (10%, w/w) Cohort 2: Diclofenac, DCF100 gel (2% or 4%, w/w) Cohort 3: Methyl-salicylate and Menthol, SPR300 gel (15%:7%, w/w; ratio of Methylsalicylate to Menthol) Reference Products: Cohort 1: Ibuprofen, Nurofen Max Strength gel (10%, w/w), Ibuprofen, Nurofen, oral tablet (400 mg) Cohort 2: Voltaren Emulgel (2%), Voltarol oral tablet (50 mg) Placebo: All Cohorts:Test product matching vehicle gel. Pharmacodynamic tests and PK blood draws will be performed at: pre-dose, 1, 2, 4, and 6 hours post dose for all treatment cohorts and treatment days (PK blood sampling in up to 6 subjects per cohort only). Safety will be evaluated by the incidence of local and systemic treatment-emergent adverse events (TEAEs) reported after each treatment. Safety assessments will also include vital signs, 12-Lead Electrocardiograms (ECGs), laboratory tests and a physical examination at Screening and the Follow-up visit.

Official Title
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A Randomised, Double Blind, Cross Over Clinical Study in Healthy Human Volunteers to Assess the Efficacy and Safety of Three Different Topical Analgesics (DCF100, TIB200 And SPR300) Versus in a Model of UV-Induced Inflammatory Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Ibuprofen
* Drug: Diclofenac
* Drug: Methyl-salicylate / Menthol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Were able to provide written informed consent. Male between 18 and 65 years old, inclusive, at the time of screening. Good general health as ascertained by detailed medical history and physical examination. Body mass index (BMI) ≥18 and ≤29 kg/m2 (BMI = weight/height2), at the time of screening. No clinically relevant abnormalities in 12-lead ECG as per PI's judgement, e.g., absence of cardiac rhythm disorder, in particular bradycardia (<40 beats per minute), conduction abnormalities such as atrioventricular block, absence of active ischemia (such as unstable angina pectoris) or recent myocardial infarction, no QTcF interval >450 milliseconds, no QRS complex ≥120 milliseconds, at Screening. No clinically relevant abnormalities in results of laboratory tests as per PI's judgement; in particular, no significant liver impairment defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT) 1.5x upper limit of normal (ULN); no significant kidney impairment defined as serum creatinine 2x ULN; abnormal thyroid function as defined by thyroid-stimulating hormone (TSH) and total thyroxin (T4) (TSH within range 0.27 to 4.2 mIU/L, total T4 within range 59 to 154 nmol/L). Had a skin type II or III (Fitz Patrick classification). Non-smokers or ex-smokers for at least 6 months prior to the Screening Visit, as confirmed by a urine cotinine test. Subjects were able to communicate well with the PI/designee. - Exclusion Criteria: History of hypersensitivity to the IMP or any of the excipients or to medicinal products with similar chemical structures. Presence of any clinically relevant acute or chronic disease which could interfere with the subject safety during the study, expose the subject to undue risk, limit the biological sampling (e.g., blood collection), interfere with the absorption of the IMP (e.g., active dermatological conditions at the application sites, or ulcers, irritable bowel syndrome) or interfere with the study objectives. Skin type I, IV, V or VI (Fitzpatrick Classification). History of chronic pain symptoms (>6 months) or ongoing pain. Any condition that required regular concomitant medication including herbal products, or predicted need of any concomitant medication from Screening Visit until the end of the study. Intake of any medication including over the counter (OTC) medication (in particular any pain killers), herbal and dietary supplements such as St John's Wort, vitamins and minerals that could affect the outcome of the study, within 48 hours before the first administration of the investigational product and for the duration of the study. Use of photosensitising medication, such as phenothiazines, tetracyclines, quinolones, sulphonamides, nalidixic acid, non-steroidal anti-inflammatories, furosemides, hydrochlorothiazides, fibrate, phytotherapeutic drugs (herbal supplements), phenothiazines, quinidines, psoralens and amiodarone within 4 weeks before the first UVB irradiation and for the duration of the study. Any skin disease, acute or chronic (e.g., psoriasis vulgaris, neurodermatitis) or auto immune diseases associated with increased light sensitisation. Any active dermatological conditions, local pigmentary disorders, body art (e.g., tattoos), or excessive hair growth at the lower back that might interfere with the study assessments or absorption of the IMP. History of skin cancer (i.e., melanoma, squamous cell carcinoma or basal cell carcinoma). History of conditions that increase risk for melanoma (e.g., dysplastic nevus [>5 nevi], xeroderma pigmentosum, Fanconi anaemia, Bloom's syndrome, Werner syndrome, Cockayne syndrome, trichothiodystrophy, or familial mole melanoma syndrome). History of bleeding disorders, peptic ulceration or gastro intestinal bleeding, heart burn, cardiovascular disease, myocardial infarction or stroke. Inability to give reproducible HPPT ratings on naïve skin at screening, (defined as HPTT test re-test difference ≥1.0 °C) Heat pain perception threshold <40°C or >51°C on naïve skin at Screening. Supine systolic blood pressure (SBP) <90 mmHg or >140 mmHg, or supine diastolic blood pressure (DBP) <50 mmHg or >90 mmHg after 5 minutes supine, at the Screening Visit. Positive test results for HBsAg, HCVAb or HIV-1 and/or -2 antibodies at Screening. Excessive use of caffeine-containing beverages exceeding 500 mg caffeine/day (5 cups of coffee) and the inability to refrain from the use of caffeine-containing beverages during confinement in the Clinical Unit. Excessive alcohol consumption (regular alcohol intake ≥21 units per week). Use of alcohol 48 hours before any study visit, as confirmed by urine alcohol testing at Screening, Day -2, and with any additional tests at the discretion of the PI. History in the last year or presence of drug addiction (positive urine drug screen) at Screening and Day -2. Presence or history of alcohol abuse in the last year, as confirmed by subject's general practitioner (GP). Blood donation within 8 weeks before the first IMP administration. Participation in another study with an experimental drug within 3 months before the first dosing day. Any psychological, emotional problems, any disorder or resultant therapy that was likely to invalidate informed consent, or limited the ability of the subject to comply with the protocol requirements. Unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g., uncooperative attitude, inability to return for Follow-up visits and improbability of completing the clinical study. Planned surgery, dental procedure, or hospitalisation from the Screening Visit until the end of the study. Inability to give written informed consent or to comply fully with the protocol. Subjects who, in the opinion of the PI, were considered unsuitable for any other reason. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: TIB200 gel 10%<br>All Cohort 1 participants: TIB200 gel (10%, w/w ibuprofen) | Drug: Ibuprofen<br> <br> * Other names: TIB200 gel 10%, Nurofen gel 10%, Nurofen tablets;|
| Active Comparator: Cohort 1: Nurofen gel 10%<br>All Cohort 1 participants: Nurofen Max Strength gel (10%, w/w ibuprofen) | Drug: Ibuprofen<br> <br> * Other names: TIB200 gel 10%, Nurofen gel 10%, Nurofen tablets;|
| Active Comparator: Cohort 1: Nurofen tablets<br>All Cohort 1 participants: Nurofen oral tablets (2 x 400 mg ibuprofen) | Drug: Ibuprofen<br> <br> * Other names: TIB200 gel 10%, Nurofen gel 10%, Nurofen tablets;|
| Placebo Comparator: Cohort 1: TIB200 Placebo gel<br>All Cohort 1 Participants: TIB200 matching placebo gel | Drug: Placebo<br> <br> * Other names: TIB200 placebo gel, DCF100 placebo gel and SPR300 placebo gel;|
| Active Comparator: Cohort 2: DCF100 gel 2%<br>All Cohort 2 Participants: DCF100 gel (2% w/w diclofenac) | Drug: Diclofenac<br> <br> * Other names: DCF100 gel 2%, DCF100 gel 4%, Voltaren gel 2%, Voltaren oral tablet;|
| Experimental: Cohort 2: DCF100 gel 4%<br>All Cohort 2 Participants: DCF100 gel (4% w/w diclofenac) | Drug: Diclofenac<br> <br> * Other names: DCF100 gel 2%, DCF100 gel 4%, Voltaren gel 2%, Voltaren oral tablet;|
| Active Comparator: Cohort 2: Voltaren gel 2%<br>All Cohort 2 Participants: Voltaren Emulgel (2% diclofenac) | Drug: Diclofenac<br> <br> * Other names: DCF100 gel 2%, DCF100 gel 4%, Voltaren gel 2%, Voltaren oral tablet;|
| Active Comparator: Cohort 2: Voltarol oral tablet<br>All Cohort 2 Participants: Voltarol oral tablet (50 mg - diclofenac) | Drug: Diclofenac<br> <br> * Other names: DCF100 gel 2%, DCF100 gel 4%, Voltaren gel 2%, Voltaren oral tablet;|
| Placebo Comparator: Cohort 2: DCF100 Placebo gel<br>All Cohort 2 Participants: DCF100 matching placebo gel | Drug: Placebo<br> <br> * Other names: TIB200 placebo gel, DCF100 placebo gel and SPR300 placebo gel;|
| Active Comparator: Cohort 3: SPR300 gel (15%:7%)<br>All Cohort 3 Participants: Methyl-salicylate / Menthol, SPR300 gel (15%:7%, w/w; ratio of Methylsalicylate / Menthol) | Drug: Methyl-salicylate / Menthol<br> <br> * Other names: SPR300 gel (15%/7%);|
| Placebo Comparator: Cohort 3: SPR300 Placebo gel<br>All Cohort 3 Participants: SPR300 matching placebo gel | Drug: Placebo<br> <br> * Other names: TIB200 placebo gel, DCF100 placebo gel and SPR300 placebo gel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heat Pain Tolerance Test (HPTT) Measured the Point at Which the Heat Became Painful - Degrees Centigrade - | To assess the pharmacodynamic effect by Heat Pain Tolerance Test (HPTT) which measured the point at which the heat became painful (degrees centigrade) of three topical analgesics, DCF100, TIB200, and SPR300 versus topical placebo and active topical reference products in a model of UV-induced inflammatory pain. | 15 minutes before to 6 hours post administration | 
| Intensity of the UVB-induced Erythema (Determined by Assessment of Skin Blood Flow by Laser Doppler Imaging [Flux Units]) | Intensity of the Ultra Violet B radiation (UVB)-induced erythema (determined by assessment of skin blood flow by laser Doppler imaging [flux units], up to 8 subjects per cohort) - Change from baseline | 15 minutes before to 6 hours post administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) | Maximum observed plasma concentration (Cmax), time corresponding to occurrence of Cmax (tmax) (up to 6 subjects per cohort only) laser Doppler imaging [flux units], up to 6 subjects per cohort) | 15 minutes before and 1, 2, 4 and 6 hours post administration | 
| Area Under the Plasma Concentration Versus Time Curve | Area under the concentration vs. time curve from time zero to 6 hours (AUC0-6h) (up to 6 subjects per cohort only) laser Doppler imaging [flux units], up to 6 subjects per cohort) | 15 minutes before and 1, 2, 4 and 6 hours post administration | 
| Number of Recorded Abnormal Clinical Assessments | Laboratory assessments - standard clinical trial assessments for clinical chemistry and haematology Listing of individual laboratory measurements by subjects and evaluation of each laboratory parameter | Estimated study duration for each subject will be approximately 6 weeks | 
| Physical Exams to Ensure Safety and Well Being of the Subjects | Physical examinations - including assessments of the application site. examination. | Estimated study duration for each subject will be approximately 6 weeks | 
| Adverse Events (AEs) | Local and systemic Adverse Events (AEs). | Estimated study duration for each subject will be approximately 6 weeks | 
| To Determine Vital Signs and Electrocardiograms (ECGs) That Were Abnormal to Ensure Safety and Well Being of the Subjects | To determine Vital Signs and Electrocardiograms (ECGs) that were abnormal to ensure safety and well being of the subjects | Estimated study duration for each subject will be approximately 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PK, UVB Pain Model, Topical, NSAIDs