Clinical Trials/NCT05956314

NCT05956314

Completed

Phase 1

Phase 1b, Open Label Study to Evaluate the Safety, Tolerability, and Efficacy of a 1% Topical Formulation of KM-001 for the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenita

Kamari Pharma Ltd1 site in 1 country18 target enrollmentMarch 6, 2023

Overview

Phase: Phase 1
Intervention: Urinalysis
Conditions: Punctate Palmoplantar Keratoderma Type 1
Sponsor: Kamari Pharma Ltd
Enrollment: 18
Locations: 1
Primary Endpoint: Safety endpoint will be assessed through collection and analysis of adverse events.
Status: Completed
Last Updated: last year

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases. In this study 2 cohorts will be recruited:

Cohort 1: up to 11 eligible patients, will be enrolled to be treated twice daily, for 12 weeks, with 1% topical KM-001, on the plantar surfaces (2 feet).
Cohort 2: up to 8 eligible patients, will be enrolled to be treated twice daily, for 16 weeks, with 1% topical KM-001, on the plantar surfaces (2 feet).

Safety (AEs, blood work [at specific visits], vital signs), tolerability, and efficacy parameters (overall lesion improvement) will be assessed during in-clinic visits (Cohort 1: during Screening, Enrolment, and on Days 7, 28, 42, 63, 84 [end of treatment, EoT], 112 [End of Study, EoS] post first investigational medicinal product (IMP) administration; Cohort 2: during Screening, Enrolment, and on Days 7, 28, 42, 63, 84, 112 [EoT], 140 [EoS] post first investigational medicinal product (IMP) administration).

PK samples will be collected to assess plasma levels of KM-001 on

Screening (Day -14 to -0): any time during the visit. (or on Day 1 up to 30 minutes pre-dose if missed during Screening)
Day 7 and at EoT (Cohort 1: Day 84; Cohort 2: Day 112) up to 30 minutes pre-dose, and at 1 h, 2 h, 3 h, 6 h (+15 min) post-dose
Days 28, 42 for both Cohorts, and Day 84 for Cohort 2: 1 sample after the first dose, before the second dose, as late as possible in the visit.
End of Study (EoS, Day 112 (Cohort 1) or Day 140 (cohort 2)), or at Early Termination (ET): at any time during the visit.

The patient will complete a patient-reported diary, consisting of treatment compliance and self-assessments for efficacy.

Follow up- 2 weeks after EoT by phone call, and 4 weeks after EoT in clinic visit.

Detailed Description

The palmoplantar keratoderma (PPK) group of skin disorders results from various mutations in several epidermal genes and is characterized by thickening of the skin on the palms and soles. Punctate palmoplantar keratoderma (PPKP1) is a rare autosomal, dominant, inherited skin disease characterized by bilateral asymptomatic, tiny, hyperkeratotic punctate papules and plaques on the palmoplantar surface. Pachyonychia congenita (PC) is a rare group of autosomal dominant skin disorders that are caused by a mutation in one of five different keratin genes. PC is often associated with thickened toenails, plantar keratoderma, and plantar pain. Its manifestations include bilateral PPK on palms and soles pattern with sharp margins and a yellow tone. A common characteristic of these skin diseases is the impaired differentiation of keratinocytes, often caused by defective calcium homeostasis. Normal calcium homeostasis is regulated by calcium ion channels, including the transient receptor potential cation channel subfamily V, member 3 (TRPV3), which has been implicated in regulation of keratinocyte proliferation, differentiation, and apoptosis. As a result, it has been suggested as a drug target for a variety of dermatological conditions and itch. It has therefore been suggested that inhibition of TRPV3 by specific antagonists can address the above-mentioned conditions.KM-001, developed by Kamari Pharma, is a potent and selective TRPV3 antagonist. Kamari has demonstrated that KM-001 reduces Ca+2flux in keratinocytes and decreases cell proliferation accompanied by normalization of keratinocyte differentiation markers. Efficacy was demonstrated in in vivo studies, using the DS-Nh mice model, where it was able to normalize epidermal hyperkeratosis. In addition, the compound significantly reduced pruritus which is characteristic of this model and of many types of PPK. KM-001 topical formulation demonstrates favorable safety profile in rodents and minipigs and significant efficacy in animal models.

Registry

clinicaltrials.gov

Start Date

March 6, 2023

End Date

November 7, 2024

Last Updated

last year

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

Kamari Pharma Ltd

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Read, understood, and signed an informed consent form (ICF) before any investigational procedure(s) are performed.
•Male and female and aged 18 - 75 years (inclusive) at the time of screening.
•Clinical diagnosis of:
•Punctate palmoplantar keratoderma type I disease with confirmed heterozygous mutation in AAGAB gene.
•PC with confirmed heterozygous mutation in either KRT16, KRT17, KRT6A, KRT6B or KRT6C mutations.
•The target treatment region is 0.5% to 4% BSA including target lesion.
•CGI-S score (as assessed by the CI at the screening visit) of ≥
•Female patients of childbearing potential1 must use a highly effective birth control method2 (failure rate ˂1% per year when used consistently and correctly) (28) throughout the trial and for at least 4 weeks after last application of IMP.
•In addition to the hormonal contraception, female patients must agree to use a supplemental barrier method during intercourse with a male partner (i.e., male condom) throughout the trial and for at least 4 weeks after last application of IMP.
•Female patients must be having regular menstrual periods (interval of 21 to 35 days, duration of 2 to 7 days for several months) at the baseline visit (as reported by the patient); exception: patients using hormonal contraceptives that preclude regular menstrual periods, menopausal or hysterectomised patients.

Exclusion Criteria

•History of drug or alcohol abuse in the past 2 years.
•Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine).
•Positive hepatitis B surface antigen \[HbsAg\], hepatitis B core antibody \[HbcAb\], hepatitis C antibody, or human immunodeficiency virus (HIV) antibody serology results at the screening visit.
•Known hypersensitivity or any suspected cross-allergy to the API and/or excipients.
•Any medical or active psychological condition or any clinically relevant laboratory abnormalities, such as, but not limited, to elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (\>3 × upper limit of normal \[ULN\]) in combination with elevated bilirubin (\>2 × ULN), at the screening/baseline visit.
•Planned or expected major surgical procedure during the clinical trial.
•Patient is unwilling to refrain from using prohibited medications during the clinical trial.
•Currently participating or participated in any other clinical trial of an IMP or device, within the past 4 months before the screening visit.
•Cutaneous infection or another underlying condition of the skin which may impact the assessments or trial participation.
•Cutaneous infection of the area to be treated with IMP within 2 weeks before the screening visit or any infection of treatment area requiring treatment with oral, parenteral antibiotics, antivirals, antiparasitics or antifungals or any topical within 2 weeks before the screening visit.

Arms & Interventions

KM-001 cream 1% 12 weeks treatment.

KM-001 1% cream will be applied to the affected area, twice daily for 12 consecutive weeks. KM-001 will be supplied in glass jars (30 g) and will be provided to patients with spatulas and polyethylene gloves.

Intervention: Urinalysis

KM-001 cream 1% 12 weeks treatment.

Intervention: KM-001 cream 1% 12 weeks treatment.

KM-001 cream 1% 12 weeks treatment.

Intervention: Physical Examination

KM-001 cream 1% 12 weeks treatment.

Intervention: Vital Signs

KM-001 cream 1% 12 weeks treatment.

Intervention: Serum chemistry

KM-001 cream 1% 12 weeks treatment.

Intervention: Hematology

KM-001 cream 1% 12 weeks treatment.

Intervention: Serology

KM-001 cream 1% 12 weeks treatment.

Intervention: ECG test

KM-001 cream 1% 12 weeks treatment.

Intervention: Pharmacokinetics Assessments

KM-001 cream 1% 12 weeks treatment.

Intervention: Clinical global impression of severity (CGI-S)

KM-001 cream 1% 12 weeks treatment.

Intervention: Visual Analogue Scale (VAS) pain scale

KM-001 cream 1% 12 weeks treatment.

Intervention: Lesion photography

KM-001 cream 1% 12 weeks treatment.

Intervention: Peak pruritus-numerical rating scale (PP-NRS)

KM-001 cream 1% 12 weeks treatment.

Intervention: Patient global impression of change (PGI-C) scoring

KM-001 cream 1% 12 weeks treatment.

Intervention: Patient global impression of severity (PGI-S) scoring

KM-001 cream 1% 16 weeks treatment.

KM-001 1% cream will be applied to the affected area, twice daily for 16 consecutive weeks. KM-001 will be supplied in glass jars (30 g) and will be provided to patients with spatulas and polyethylene gloves.

Intervention: Physical Examination

KM-001 cream 1% 16 weeks treatment.

Intervention: Vital Signs

KM-001 cream 1% 16 weeks treatment.

Intervention: Serum chemistry

KM-001 cream 1% 16 weeks treatment.

Intervention: Hematology

KM-001 cream 1% 16 weeks treatment.

Intervention: Serology

KM-001 cream 1% 16 weeks treatment.

Intervention: Urinalysis

KM-001 cream 1% 16 weeks treatment.

Intervention: ECG test

KM-001 cream 1% 16 weeks treatment.

Intervention: Pharmacokinetics Assessments

KM-001 cream 1% 16 weeks treatment.

Intervention: Clinical global impression of severity (CGI-S)

KM-001 cream 1% 16 weeks treatment.

Intervention: Visual Analogue Scale (VAS) pain scale

KM-001 cream 1% 16 weeks treatment.

Intervention: Peak pruritus-numerical rating scale (PP-NRS)

KM-001 cream 1% 16 weeks treatment.

Intervention: Patient global impression of change (PGI-C) scoring

KM-001 cream 1% 16 weeks treatment.

Intervention: Patient global impression of severity (PGI-S) scoring

KM-001 cream 1% 16 weeks treatment.

Intervention: Lesion photography

KM-001 cream 1% 16 weeks treatment.

Intervention: KM-001 cream 1% 16 weeks treatment.

Outcomes

Primary Outcomes

Safety endpoint will be assessed through collection and analysis of adverse events.

Time Frame: Up to 112 days

Incidence rate of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) grouped by body system up to the patient´s end of trial (Day 112 \[Visit 12\]) or early termination \[ET\] visit\]).

Safety endpoint-will be assessed by the % of change from normal range in the collection of Hematology- laboratory blood test profile.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in clinical Hematology blood test profile from baseline (Day 1) up to day 112. Data management team will assess and review the laboratory blood test results (Hematology). Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: WBC (K/µl) and platelet count (K/µl), neutrophils (absolute \[abs.\])(K/µl), lymphocytes (abs.)(K/µl), monocytes (abs.) (K/µl), eosinophiles (abs.)(K/µl) and basophiles (abs.) (K/µl) and reticulocyte count (K/µl).

Safety endpoint-will be assessed by the % of change from normal range in the collection of MCH result in laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in MCH (pg) blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the MCH lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.

Safety endpoint-will be assessed by the % of change from normal range in the collection of MCV result in laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in MCV(fl) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the MCV lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.

Safety endpoint-will be assessed by the % of change from normal range in the collection of haematocrit result in laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in haematocrit (%) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the haematocrit lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.

Safety endpoint-will be assessed by the % of change from normal range in the collection of hemoglobin result in laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in hemoglobin (g/dL) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the hemoglobin lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.

Safety endpoint-will be assessed by the % of change from normal range in the collection of RBC result in laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in RBC (M/µl) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the RBC lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.

Safety endpoint-will be assessed by the % of change from normal range in the collection of Sodium, potassium and chloride results in chemistry laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in chemistry laboratory blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Sodium (mmol/L), potassium (mmol/L) and chloride (mmol/L).

Safety endpoint-will be assessed by the % of change from normal range in the collection of: Glucose fasting , BUN/Ur, creatinine, bilirubin total and direct, calcium, uric acid, and bilirubin result, in chemistry laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in chemistry laboratory blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Glucose fasting (mg/dL), BUN/Ur (mg/dL), creatinine (mg/dL), bilirubin total (mg/dL) and direct (mg/dL), calcium (mg/dL), uric acid (mg/dL), and bilirubin (mg/dL).

Safety endpoint-will be assessed by the % of change from normal range in the collection of Alkaline phosphatase, AST, ALT and GGT result in chemistry- laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in chemistry laboratory blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Alkaline phosphatase (U/L), AST (U/L), ALT (U/L) and GGT (U/L).

Safety endpoint-will be assessed by the % of change from normal range in the collection of Albumin and total protein result in chemistry- laboratory blood test.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in chemistry blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Albumin (g/dL) and total protein (g/dL).

Safety endpoint-will be assessed by the % of change from normal range in the collection of Serology -in laboratory blood test profile.

Time Frame: Up to 112 days

Safety will be assessed by the % of change from normal range in serology clinical blood test profile, from baseline (Day 1) up to Day 112. Data management team will assess and review the serology lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: HBsAg (positive/negative), HBcAb (positive/negative), hepatitis C antibody (positive/negative), or HIV antibody (positive/negative).

Safety endpoint-will be assessed by the % of change from normal range in the collection of urine laboratory profile.

Time Frame: Up to 112 days

Safety will be assessed by the % of change in clinical urine laboratory profile from baseline (Day 1) up to Day 112. Data management team will assess and review the urine lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. the following values will be assessed: Glucose (mg/dl), protein (mg/ml),urobilinogen (mg/ml) and ketones (mg/ml).

Safety endpoint-will be assessed by the % of change from normal range in the collection of Specific gravity , pH, blood and nitrites result in urine laboratory profile.

Time Frame: Up to 112 days

Safety will be assessed by the % of change in clinical urine laboratory profile from baseline (Day 1) up to Day 112. Data management team will assess and review the urine lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Specific gravity , pH, blood and nitrites.

Safety endpoint-Mean change in body temperature measurement from baseline.

Time Frame: Up to 112 days

Mean changes in body temperature from baseline (Day 1) up to Day 112.

Safety endpoint-Mean change in pulse measurement from baseline.

Time Frame: Up to 112 days

Mean changes in pulse (unites: beats per minute) measurements from baseline (Day 1)up to Day 112.

Safety endpoint- Mean change in blood pressure measurement from baseline.

Time Frame: Up to 112 days

Mean changes in blood pressure (systolic and diastolic blood pressure \[unites: mm Hg\]) measurements from baseline (Day 1) up to Day 112.

Safety endpoint-ECG

Time Frame: Up to 112 days

Mean changes in ECG parameters from baseline (Day 1) up to Day 112. the following ECG parameters will be recorded: heart rate (HR), PR, QT, and QTC interval and QRS complex.

Secondary Outcomes

Efficacy end point - will be assessed by Patient global impression of change (PGI-C) questionaries(Up to 84 days)
Efficacy end point - will be assessed by Clinical global impression of severity (CGI-S) questionaries(Up to 84 days)
Efficacy end point - will be assessed by Patient global impression of change (PGI-S) questionaries(Up to 84 days)