Safety, Tolerability, and Pharmacokinetics of Ascending Topical Doses of TCP-25 Applied to Epidermal Suction Blister Wounds

Study Overview
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Brief Summary
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This is a Phase I, double-blind, placebo-controlled, randomized first-in-human study including healthy volunteers with acute epidermal wounds formed by the suction blister technique designed to evaluate the safety, tolerability, and potential systemic exposure of multiple topical doses of TCP-25.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Male and Female Volunteers to Investigate the Safety, Tolerability, and Pharmacokinetics of Ascending Topical Doses of TCP-25 Applied to Epidermal Suction Blister Wounds

Conditions
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Blister, Wound of Skin

Intervention / Treatment
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* Drug: TCP-25 gel 0.86 mg/ml or placebo gel
* Drug: TCP-25 gel 2.9 mg/ml or placebo gel
* Drug: TCP-25 gel 8.6 mg/ml or placebo gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study. Healthy male or female subject 18-60 years (inclusive) of age at the time of signing the informed consent. Body Mass Index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2. Healthy and intact skin where the blister suction wounds will be induced. Women of childbearing potential (WOCBP) must have a documented negative serum pregnancy test done at the screening visit, within 4 weeks prior to suction blister formation and the start of study treatment. WOCBP must practice abstinence (only allowed when this is the preferred and usual lifestyle of the subject) or must agree to use a highly effective method of contraception with a failure rate of < 1% to prevent pregnancy (combined [oestrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD] or intrauterine hormone-releasing system [IUS]) from at least 4 weeks prior to dose to 4 weeks after last dose. Female subjects must refrain from donating eggs from the date of dosing until 3 months after dosing with the IMP. Their male partner must agree to use a condom during the same time frame if he has not undergone vasectomy. Women of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone [FSH] 25-140 IE/L is confirmatory). Male subjects must be willing to use condom or be vasectomised or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of last dosing until 3 months after the last dosing with the IMP. Their female partner of child-bearing potential must use contraceptive methods with a failure rate of < 1% to prevent pregnancy (see above). Clinically relevant medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. Disease that may interfere with wound healing, e.g., diabetes type I/II, arterial-, renal-, liver, or cardiac insufficiency, chronic obstructive lung disease, cancer, autoimmune disease, edema at the study site, severe obesity, or previous known wound healing problems, as judged by the investigator. Active skin disease, e.g., dermatitis, psoriasis and wounds, and/or tattoos in the areas where suction blister wounds will be induced, as judged by the investigator. Any planned major surgery within the duration of the study. After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges: Systolic blood pressure <90 or >160 mmHg, or Diastolic blood pressure <50 or >100 mmHg, or Pulse <40 or >90 beats per minute (bpm) Any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit. Female subjects who are pregnant or lactating or planning a pregnancy. Systemic immunosuppressive treatment. Subjects who are currently receiving or have received the following treatments within 2 weeks prior to screening are excluded from the study: - systemic corticosteroids or immunosuppressant agents; or - antibiotics via any route Regular use of anticoagulants (i.e., heparin, warfarin, coumarins, other anticoagulants per Investigator's judgement) or non-steroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to the (first) administration of IMP, at the discretion of the Investigator. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TCP-25 or to any excipients of the hydrogel. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator. Presence or history of drug abuse, as judged by the Investigator Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening. Involvement in the planning and/or conduct of the study. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Interventional Model Description: Multiple topical doses of TCP-25 will be administered in 3 sequential dose groups, each of 8 subjects. Within each cohort, the subjects will receive TCP-25 on one wound on each thigh and placebo on one wound on each thigh in a randomized fashion as topical treatment.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose group 1<br>0.15 mL of TCP-25 gel (0.86 mg/mL) or 0.15 mL placebo gel per wound applied as topical treatment on days 1, 2, 3, 5, and 8 | Drug: TCP-25 gel 0.86 mg/ml or placebo gel<br>* TCP-25 gel (0.86 mg/mL) applied to two wounds per patient and placebo gel applied to two wounds per patient<br>|
| Experimental: Dose group 2<br>0.15 mL of TCP-25 gel (2.9 mg/mL) or 0.15 mL placebo gel per wound applied as topical treatment on days 1, 2, 3, 5, and 8 | Drug: TCP-25 gel 2.9 mg/ml or placebo gel<br>* TCP-25 gel (2.9 mg/mL) applied to two wounds per patient and placebo gel applied to two wounds per patient<br>|
| Experimental: Dose group 3<br>0.15 mL of TCP-25 gel (8.6 mg/mL) or 0.15 mL placebo gel per wound applied as topical treatment on days 1, 2, 3, 5, and 8 | Drug: TCP-25 gel 8.6 mg/ml or placebo gel<br>* TCP-25 gel (8.6 mg/mL) applied to two wounds per patient and placebo gel applied to two wounds per patient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Frequency, intensity and seriousness of adverse events (AEs) | 15 days | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 1 | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 2 | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 3 | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 5 | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 8 | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 11 | 
| Incidence of abnormal local reactions (Local tolerability) | Incidence of abnormal local reactions as compared to expected wound healing outcome, by direct assessment by Investigator: Skin and wound erythema (abnormal reaction noted) Skin and wound oedema and swelling (abnormal reaction noted) Wound necrosis, crusting, and hemorrhage (abnormal reactions noted) Wound purulent discharge as sign of excessive bacterial colonization and/or infection | Day 15 | 
| Number of patients with clinically significant changes from baseline in electrocardiogram (ECG) | Systolic and diastolic blood pressure and pulse will be measured. Any abnormalities will be specified and documented as clinically significant or not clinically significant by the investigator. | During screening (baseline) and on day 11 | 
| Number of patients with clinically significant changes from baseline in vital signs. | Vital signs include systolic/diastolic blood pressure and pulse rate. Any vital signs outside the normal ranges will be judged as not clinically significant or clinically significant by the investigator. | During screening (baseline) and on day 11 | 
| Number of patients with clinically significant changes from baseline in physical examinations | A physical examination will include assessments of general condition, lymph nodes, throat, heart, lungs and abdomen. Any abnormalities will be specified and documented as clinically significant or not clinically significant by the investigator. | During screening (baseline) and on day 11 | 
| Number of patients with clinically significant changes from baseline in safety laboratory parameters | Safety laboratory parameters include haematology, clinical chemistry and coagulation. Any lab values outside the normal ranges will be judged as not clinically significant or clinically significant by the investigator. Haematology parameters to be measured are: Haematocrit Haemoglobin Erythrocytes Mean corpuscular volume Mean corpuscular haemoglobin Mean corpuscular haemoglobin concentration Thrombocytes Leukocytes Eosinophils Neutrophils Basophils Lymphocytes Monocytes Clinical chemistry parameters to be measured are: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Creatinine C-reactive protein (CRP) Glucose Haemoglobin A1c (HbA1C) Coagulation parameters to be measured are: Activated partial thromboplastin time (APTT) Prothrombin complex/International Normalised Ratio (PK/INR) | During screening (baseline) and on day 2 | 
| Number of patients with clinically significant changes from baseline in safety laboratory parameters | Safety laboratory parameters include haematology, clinical chemistry and coagulation. Any lab values outside the normal ranges will be judged as not clinically significant or clinically significant by the investigator. Haematology parameters to be measured are: Haematocrit Haemoglobin Erythrocytes Mean corpuscular volume Mean corpuscular haemoglobin Mean corpuscular haemoglobin concentration Thrombocytes Leukocytes Eosinophils Neutrophils Basophils Lymphocytes Monocytes Clinical chemistry parameters to be measured are: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Creatinine C-reactive protein (CRP) Glucose Haemoglobin A1c (HbA1C) Coagulation parameters to be measured are: Activated partial thromboplastin time (APTT) Prothrombin complex/International Normalised Ratio (PK/INR) | During screening (baseline) and on day 3 | 
| Number of patients with clinically significant changes from baseline in safety laboratory parameters | Safety laboratory parameters include haematology, clinical chemistry and coagulation. Any lab values outside the normal ranges will be judged as not clinically significant or clinically significant by the investigator. Haematology parameters to be measured are: Haematocrit Haemoglobin Erythrocytes Mean corpuscular volume Mean corpuscular haemoglobin Mean corpuscular haemoglobin concentration Thrombocytes Leukocytes Eosinophils Neutrophils Basophils Lymphocytes Monocytes Clinical chemistry parameters to be measured are: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Creatinine C-reactive protein (CRP) Glucose Haemoglobin A1c (HbA1C) Coagulation parameters to be measured are: Activated partial thromboplastin time (APTT) Prothrombin complex/International Normalised Ratio (PK/INR) | During screening (baseline) and on day 5 | 
| Number of patients with clinically significant changes from baseline in safety laboratory parameters | Safety laboratory parameters include haematology, clinical chemistry and coagulation. Any lab values outside the normal ranges will be judged as not clinically significant or clinically significant by the investigator. Haematology parameters to be measured are: Haematocrit Haemoglobin Erythrocytes Mean corpuscular volume Mean corpuscular haemoglobin Mean corpuscular haemoglobin concentration Thrombocytes Leukocytes Eosinophils Neutrophils Basophils Lymphocytes Monocytes Clinical chemistry parameters to be measured are: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Creatinine C-reactive protein (CRP) Glucose Haemoglobin A1c (HbA1C) Coagulation parameters to be measured are: Activated partial thromboplastin time (APTT) Prothrombin complex/International Normalised Ratio (PK/INR) | During screening (baseline) and on day 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of TCP-25 | Measurement of TCP-25 concentration in plasma | Day 1 (measured before blister formation) | 
| Plasma concentration of TCP-25 | Measurement of TCP-25 concentration in plasma | Day 2 (measured before administration of the intervention and 0.5 and 1 hours after administration of the intervention) | 
| Plasma concentration of TCP-25 | Measurement of TCP-25 concentration in plasma | Day 3 (measured before administration of the intervention 1 hour after administration of the intervention) | 
| Plasma concentration of TCP-25 | Measurement of TCP-25 concentration in plasma | Day 5 (measured before administration of intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute epidermal wounds, suction blister, healthy volunteers