Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human... Show moreMycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm2 on 400 cm2, with a mean Cavg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs. Show less
Wind, S.S.; Jansen, M.A.A.; Rijsbergen, M.; Esdonk, M.J. van; Ziagkos, D.; Cheng, W.C.; ... ; Rissmann, R. 2022
Simple Summary Primary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and... Show moreSimple Summary Primary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and translational research augmented our understanding of the pathogenesis and pathophysiology of different subtypes of CTCL, enabling the identification of novel therapeutic drug targets. In this study, the primary focus is on bimiralisib gel 2%, a dual pan-class PI3K/mTOR inhibitor, and its potential to inhibit the PI3K/AKT/mTOR signaling pathway as a novel therapeutic target in CTCL. Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 mu g/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm(2) on 400 cm(2), with a mean C-avg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean C-avg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 mu g/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs. Show less
Rijsbergen, M.; Rijneveld, R.; Todd, M.; Feiss, G.L.; Kouwenhoven, S.T.P.; Quint, K.D.; ... ; Poelgeest, M.I.E. van 2020
AIMS\nMETHODS\nRESULTS\nCONCLUSION\n To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous... Show moreAIMS\nMETHODS\nRESULTS\nCONCLUSION\n To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL).\nTwo randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire.\nTwenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval -99.9 to -7.4%; P = .045) in AGW patients only.\nTopical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients. Show less
Rijsbergen, M.; Rijneveld, R.; Todd, M.; Feiss, G.L.; Kouwenhoven, S.T.P.; Quint, K.D.; ... ; Poelgeest, M.I.E. van 2020
Aims To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL).... Show moreAims To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high-grade squamous intraepithelial lesions (HSIL). Methods Two randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow-up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self-reported pain, itch and quality of life were assessed by an electronic diary and questionnaire. Results Twenty-four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n =27) were mild, transient and self-limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient-reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (-96.6%; 95% confidence interval -99.9 to -7.4%;P =.045) in AGW patients only. Conclusion Topical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients. Show less
Niemeyer-van der Kolk, T.; Assil, S.; Buters, T.P.; Rijsbergen, M.; Klaassen, E.S.; Feiss, G.; ... ; Moerland, M. 2020
Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a... Show moreOmiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%-30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%-2.83; P = 0.02). Interferon regulatory factor-driven and NF kappa B-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFN gamma), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases. Show less
Rijsbergen, M.; Niemeyer-van der Kolk, T.; Rijneveld, R.; Pinckaers, J.H.F.M.; Meshcheriakov, I.; Bavinck, J.N.B.; ... ; Rissmann, R. 2020
BackgroundAssessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have... Show moreBackgroundAssessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have limited reliability, particularly for outpatient trials.ObjectivesTo investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials.MethodsAn e-diary application was developed and technically validated. Treatment adherence was defined as topical administration by the patient, and patient-reported outcomes, i.e. pain and itch, were evaluated by the e-diary in six clinical trials on newly tested topical drugs. Additionally, the proportion of patients capturing the applied topical drug by camera and filling in the pain and itch scores was defined as e-diary adherence, and patients' perception of usefulness and acceptability of the e-diary were evaluated.ResultsTreatment adherence rates of the included 256 patients were high (median 98%, range 97-99%). E-diary adherence was also high with a median of 93% (range 87-97%) for capturing the applied drug by camera, and 89% (range 87-96%) and 94% (range 87-96%) for entering respectively the itch and pain score. Daily symptom scores provided good insights into the disease burden, and patients rated the e-diary as good to excellent with respect to user acceptability.ConclusionsThe results suggest that the e-diary is an excellent way to ensure proper treatment administration, indicated by both the high user acceptability scores and high treatment adherence. Moreover, the e-diary may also be valuable for frequent and reliable monitoring of patient-reported outcomes in daily clinical practice. Show less
Rijsbergen, M.; Niemeyer-van der Kolk, T.; Rijneveld, R.; Pinckaers, J.H.F.M.; Meshcheriakov, I.; Bavinck, J.N.B.; ... ; Rissmann, R. 2020
BackgroundAssessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have... Show moreBackgroundAssessment of treatment effects in clinical trials requires valid information on treatment adherence, adverse events and symptoms. Paper-based diaries are often inconvenient and have limited reliability, particularly for outpatient trials.ObjectivesTo investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials.MethodsAn e-diary application was developed and technically validated. Treatment adherence was defined as topical administration by the patient, and patient-reported outcomes, i.e. pain and itch, were evaluated by the e-diary in six clinical trials on newly tested topical drugs. Additionally, the proportion of patients capturing the applied topical drug by camera and filling in the pain and itch scores was defined as e-diary adherence, and patients' perception of usefulness and acceptability of the e-diary were evaluated.ResultsTreatment adherence rates of the included 256 patients were high (median 98%, range 97-99%). E-diary adherence was also high with a median of 93% (range 87-97%) for capturing the applied drug by camera, and 89% (range 87-96%) and 94% (range 87-96%) for entering respectively the itch and pain score. Daily symptom scores provided good insights into the disease burden, and patients rated the e-diary as good to excellent with respect to user acceptability.ConclusionsThe results suggest that the e-diary is an excellent way to ensure proper treatment administration, indicated by both the high user acceptability scores and high treatment adherence. Moreover, the e-diary may also be valuable for frequent and reliable monitoring of patient-reported outcomes in daily clinical practice. Show less
This thesis provides an overview of the application of clinical pharmacology to the field of gynecology in general and early phase clinical trials in particular. The first part describes the... Show moreThis thesis provides an overview of the application of clinical pharmacology to the field of gynecology in general and early phase clinical trials in particular. The first part describes the development of novel tools and biomarkers for intervention trials in HPV-induced disorders, i.e. common and plantar warts, anogenital warts and vulvar high grade intraepithelial lesion is described. The second part of the thesis focuses on the application and implementation of the tools and biomarkers into intervention trials with different investigational medicinal products. Show less
Rijsbergen, M.; Rijneveld, R.; Todd, M.; Pagan, L.; Feiss, G.; Koning, M.N.C. de; ... ; Poelgeest, M.I.E. van 2019
Background The quantification of human papilloma virus (HPV)-induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical... Show moreBackground The quantification of human papilloma virus (HPV)-induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical assessments that measure dimensions of lesions using a caliper do not provide complete insight into three-dimensional (3D) lesions, and its inter-rater variability is often poor. Objective The aim of this study was to validate a stereophotogrammetric 3D camera system for the quantification of HPV-induced lesions. Methods The camera system was validated for accuracy, precision and interoperator and inter-rater variability. Subsequently, 3D photographs were quantified and compared to caliper measurements for clinical validation by Bland-Altman modelling, based on data from 80 patients with cutaneous warts (CW), 24 with anogenital warts (AGW) patients and 12 with high-grade squamous intraepithelial lesions of the vulva (vulvar HSIL) with a total lesion count of 220 CW, 74 AGW and 31 vulvar HSIL. Results Technical validation showed excellent accuracy [coefficients of variation (CV) <= 0.68%] and reproducibility (CVs <= 2%), a good to excellent agreement between operators (CVs <= 8.7%) and a good to excellent agreement between different raters for all three lesion types (ICCs >= 0.86). When comparing 3D with caliper measurements, excellent biases were found for diameter of AGW (long diameter 5%), good biases were found for diameter of AGW (short diameter 10%) and height of CW (8%), and acceptable biases were found for the diameter of CW (11%) and vulvar HSIL (short diameter 14%, long diameter 16%). An unfavourable difference between these methods (bias 25%) was found for the assessment of height of AGWs. Conclusion Stereophotogrammetric 3D imaging is an accurate and reliable method for the clinical visualization and quantification of HPV-induced skin lesions. Show less
Rijsbergen, M.; Pagan, L.; Niemeyer-van der Kolk, T.; Rijneveld, R.; Hogendoorn, G.; Lemoine, C.; ... ; Rissmann, R. 2019
Background The quantification of human papilloma virus (HPV)-induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical... Show moreBackground The quantification of human papilloma virus (HPV)-induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical assessments that measure dimensions of lesions using a caliper do not provide complete insight into three-dimensional (3D) lesions, and its inter-rater variability is often poor. Objective The aim of this study was to validate a stereophotogrammetric 3D camera system for the quantification of HPV-induced lesions. Methods The camera system was validated for accuracy, precision and interoperator and inter-rater variability. Subsequently, 3D photographs were quantified and compared to caliper measurements for clinical validation by Bland-Altman modelling, based on data from 80 patients with cutaneous warts (CW), 24 with anogenital warts (AGW) patients and 12 with high-grade squamous intraepithelial lesions of the vulva (vulvar HSIL) with a total lesion count of 220 CW, 74 AGW and 31 vulvar HSIL. Results Technical validation showed excellent accuracy [coefficients of variation (CV) <= 0.68%] and reproducibility (CVs <= 2%), a good to excellent agreement between operators (CVs <= 8.7%) and a good to excellent agreement between different raters for all three lesion types (ICCs >= 0.86). When comparing 3D with caliper measurements, excellent biases were found for diameter of AGW (long diameter 5%), good biases were found for diameter of AGW (short diameter 10%) and height of CW (8%), and acceptable biases were found for the diameter of CW (11%) and vulvar HSIL (short diameter 14%, long diameter 16%). An unfavourable difference between these methods (bias 25%) was found for the assessment of height of AGWs. Conclusion Stereophotogrammetric 3D imaging is an accurate and reliable method for the clinical visualization and quantification of HPV-induced skin lesions. Show less
