Mobile e-diary application facilitates the monitoring of patient-reported outcomes and a high treatment adherence for clinical trials in dermatology.

BACKGROUND: Assessment 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. OBJECTIVES: To investigate the utility of an electronic diary (e-diary) application for patients with skin diseases in outpatient clinical trials. METHODS: An 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. RESULTS: Treatment 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. CONCLUSIONS: The 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.

Stereophotogrammetric three-dimensional photography is an accurate and precise planimetric method for the clinical visualization and quantification of human papilloma virus-induced skin lesions.

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 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.

A randomized controlled proof-of-concept trial of digoxin and furosemide in adults with cutaneous warts.

BACKGROUND: Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts. OBJECTIVES: To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT. METHODS: Treatment with ICVT was assessed for efficacy, safety and tolerability in a single- centre, randomized, double-blind, placebo-controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed-model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643. RESULTS: Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (-3·0 mm, 95% confidence interval -4·9 to -1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (-94%, 95% confidence interval -100 to -19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts. CONCLUSIONS: This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

Topical ionic contra-viral therapy comprised of digoxin and furosemide as a potential novel treatment approach for common warts.

BACKGROUND: DNA viruses such as HPV rely on K+ influx for replication. Both digoxin and furosemide inhibit the K+ influx by interacting with cell membrane ion co-transporters (Na+ /K+ -ATPase and Na+ -K+ -2Cl- co-transporter-1, respectively). We therefore hypothesized that these two compounds in a topical formulation may be valuable in the treatment of HPV-induced warts. This new approach is called Ionic Contra-Viral Therapy (ICVT). OBJECTIVE: To evaluate systemic exposure, safety and tolerability of ICVT with a combination of furosemide and digoxin after repeated topical application in subjects with common warts. Furthermore, we aimed to evaluate pharmacodynamics effects of ICVT. METHODS: Twelve healthy subjects with at least four common warts on their hands were included in the study and treated with a fixed dose of 980 mg topical gel containing 0.125% (w/w) digoxin and 0.125% (w/w) furosemide for 7 consecutive days on their lower back to assess safety and systemic exposure. Two warts were treated with 10 mg each and two served as negative controls to obtain preliminary evidence of treatment effect. RESULTS: ICVT was well tolerated topically, and there was no evidence of systemic exposure of digoxin or furosemide. There were no clinical relevant safety findings and no serious adverse events (SAEs). A rapid and statistically significant reduction in diameter, height and volume of the warts was already observed at day 14. CONCLUSION: ICVT was found to be safe for administration to humans and 7 days of active treatment showed a statistical significant wart reduction compared to untreated control lesions, clearly indicating pharmacological activity.

Dose-ranging study of the clinical efficacy of twice-daily triamcinolone acetonide inhalation aerosol in moderately severe asthma.

OBJECTIVES: This multicenter, double-blind, placebo-controlled study evaluated the dose response to 6 weeks of triamcinolone acetonide inhalation aerosol (TAA, 100 microg per puff) in patients with moderately severe asthma. STUDY DESIGN: A total of 285 patients were randomly assigned to treatment with 1, 2, 4, or 8 puffs TAA (total daily doses of 200, 400, 800, and 1,600 microg, respectively), administered twice daily, or matching placebos. Efficacy was assessed by changes in FEV1, asthma symptom scores, albuterol use, and peak flow rates. RESULTS: Linear trend analyses showed a dose response for all efficacy variables across the dose range of 200 to 1,600 microg daily. Therapeutic activity was evident at a dose of 200 microg daily for all variables, with significant clinical efficacy (p<0.05) demonstrated for all doses except for reduction in inhaled albuterol use which achieved statistical significance at 400 microg/d. Daily doses of 400 microg and higher showed response plateaus at 3 weeks of treatment that were maintained for the remainder of the trial. The incidence of adverse events was similar in all treatment groups, although more patients treated with TAA reported pharyngitis in a dose-related manner. CONCLUSIONS: Our findings suggest that most patients with chronic, moderately severe asthma can be treated adequately with doses of TAA between 200 microg (1 puff bid) and 800 microg (4 puffs bid) daily. At this dose range, clinically significant improvements are evident in symptoms, pulmonary function, and rescue medication use.

Long-term safety and efficacy of triamcinolone acetonide aqueous nasal spray for the treatment of perennial allergic rhinitis.

This 12-month, multicenter, open-label study to assess the long-term safety and efficacy of triamcinolone acetonide (TAA) aqueous nasal spray for perennial allergic rhinitis (PAR) symptom relief was a continuation of a 4-week, double-blind study. Patients who received TAA Aqueous (220 micrograms/day) during the 4-week, double-blind study continued with the same treatment for the open label study; those randomized to placebo during the 4-week, double-blind study received TAA Aqueous (220 micrograms/day) for the open-label study. Dose reduction to 110 micrograms/day was allowed if it was felt that symptom relief would be maintained. Safety was assessed by daily diary entries and clinical laboratory results. Long-term efficacy was assessed by visual analog scale (VAS). Of the 172 patients who began the open-label study, 94.2 percent completed 3 months of treatment, 83.6 percent completed 6 months, and 62 percent completed 12 months. PAR symptom relief improved progressively throughout the study. Adverse events were generally mild or moderate and consistent with long-term use and winter symptoms. The most common adverse events were pharyngitis (32 percent of patients), rhinitis (28.5 percent), headache (22.1 percent), and epistaxis (18 percent). Adverse events related to the local effects of the study medication were similar to those observed in long-term studies with TAA aerosol. The aqueous nasal spray formulation of triamcinolone acetonide was well tolerated and continued to relieve nasal symptoms with long-term use in adolescent and adult patients with PAR.

Efficacy and safety of triamcinolone acetonide aqueous nasal spray in patients with seasonal allergic rhinitis.

BACKGROUND: In order to accommodate increasing patient preferences a new aqueous formulation of triamcinolone acetonide nasal spray was developed for the relief of symptoms associated with seasonal and perennial allergic rhinitis. OBJECTIVE: This multicenter, randomized, double-blind study was designed to compare the efficacy and safety of once-daily triamcinolone acetonide aqueous nasal spray (220 micrograms/day) with placebo in relieving the symptoms of seasonal allergic rhinitis due to ragweed. METHODS: One hundred forty patients received either a once daily 220-microgram dose of triamcinolone acetonide aqueous nasal spray or placebo for 2 weeks. Patients evaluated the severity of seasonal allergic rhinitis symptoms daily for 2 weeks according to a 4-point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Physician and patient global evaluations of overall treatment effectiveness were assessed at the end of the treatment period. RESULTS: Patients receiving triamcinolone acetonide aqueous nasal spray, 220 micrograms/day, had significantly (P < .05) greater improvements in all rhinitis symptoms at weeks 1 and 2 and overall for the 2-week treatment period compared with the placebo group. A significant (P = .006) improvement in the nasal index occurred as early as 12 hours after the first dose of triamcinolone acetonide aqueous nasal spray. Both patients and physicians reported a greater overall improvement in symptoms for the triamcinolone acetonide aqueous nasal spray group. There were no differences between the two treatment groups in the incidence of adverse events. CONCLUSIONS: This study confirmed that a 220-microgram dose of triamcinolone acetonide aqueous nasal spray, administered once daily for 2 weeks, is well tolerated and reduces effectively the severity of symptoms of seasonal allergic rhinitis due to ragweed.

A comparison of effects of triamcinolone acetonide aqueous nasal spray, oral prednisone, and placebo on adrenocortical function in male patients with allergic rhinitis.

BACKGROUND: One of the risks associated with the use of oral corticosteroids is suppression of adrenocortical function. Triamcinolone acetonide (TAA) aqueous nasal spray administered once daily (110 micrograms and 220 micrograms) has been shown to reduce allergic rhinitis symptoms. OBJECTIVE: This multicenter, placebo-controlled, double-blind study determined the effects of TAA aqueous nasal spray, placebo, and oral prednisone on adrenocortical function in patients with allergic rhinitis. METHODS: Sixty-four patients received TAA aqueous nasal spray (220 micrograms or 440 micrograms), oral prednisone (10 mg), or placebo once daily for 6 weeks. Adrenocortical function was assessed after cosyntropin stimulation for 6 hours before treatment and after 6 weeks of treatment. RESULTS: There was no statistically significant effect on adrenocortical function in patients who received either dose of TAA aqueous nasal spray compared with placebo. In contrast, prednisone produced statistically significant (p < 0.001) reductions in adrenocortical function compared with placebo; reductions occurred in both the mean 6-hour plasma cortisol levels and mean change in 6-hour plasma cortisol levels from pretreatment. CONCLUSION: This study demonstrated that, unlike oral prednisone, TAA aqueous nasal spray, in therapeutic doses, did not alter adrenocortical function and was comparable to treatment with placebo in its absence of measurable effects on adrenocortical function.

Placebo-controlled, double-blind study of the efficacy and safety of triamcinolone acetonide aerosol nasal inhaler in pediatric patients with seasonal allergic rhinitis.

Triamcinolone acetonide (TAA) aerosol nasal inhaler has been shown to effectively relieve the symptoms of seasonal allergic rhinitis in adults and adolescents. We conducted a study to evaluate the efficacy and safety of once-daily administration of TAA aerosol nasal inhaler in pediatric patients aged 6 to 11 years with grass seasonal allergic rhinitis. This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled 116 children who were treated with either TAA aerosol nasal inhaler (220 micrograms/d) or placebo once daily for 2 weeks. Patients evaluated the severity of rhinitis symptoms (nasal stuffiness, discharge, sneezing, and itching) daily according to a four-point scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). Patients' and physicians' global evaluations of overall treatment efficacy were assessed at the end of the 2-week treatment period. Patients treated with TAA aerosol nasal inhaler had significantly greater reductions in all nasal symptom scores overall and in virtually all symptoms at the end of week 1 and week 2 compared with those in the placebo group. Both patients' and physicians' global evaluations of efficacy favored TAA aerosol nasal inhaler over placebo. This study demonstrated that once-daily administration of 220 micrograms of TAA aerosol nasal inhaler was well tolerated and effectively reduced the symptoms of seasonal allergic rhinitis in pediatric patients.

Effect of RG 12525, a new leukotriene antagonist, on pulmonary function of asthmatic adults.

RG 12525 is a new oral leukotriene D4 (LTD4) antagonist with proven activity in animal and human models of leukotriene-induced bronchoconstriction. In this randomized, double-blind, parallel-group, placebo-controlled study the bronchodilator effects of single oral doses of RG 12525 of 25 and 200 mg or placebo were evaluated in 62 adult asthmatic patients. All patients had previously demonstrated 20% reversibility of FEV1 with an inhaled beta-agonist. They had an unmedicated FEV1 less than 80% of predicted value at the time of the study. Bronchodilator activity was assessed by spirometry before and at multiple time points after dosing for eight hours. A single 200-mg dose of RG 12525 of mg resulted in statistically significantly greater increases in mean maximum change above baseline for FEV1 and FEF25-75% than placebo. The peak effect was observed four to five hours after dosing. The RG 12525 dose of 25 mg dose induced better bronchodilation than placebo but the differences were not significant. Adverse clinical experiences or laboratory abnormalities were not noted.

A comparative study of the effects of intranasal triamcinolone acetonide aerosol (ITAA) and prednisone on adrenocortical function.

A comparison of adrenocortical function before and after treatment with either intranasal triamcinolone acetonide aerosol (ITAA), prednisone, or placebo was done. Sixty-two male subjects with allergic rhinitis were treated for 6 weeks with either ITAA (220 or 440 micrograms/day), oral prednisone (10 mg/day), or placebo in double-blind, parallel-group fashion. Adrenocortical function was assessed by 6-hour cosyntropin stimulation before and at the end of the treatment period. The placebo-treated and two ITAA-treated groups produced no changes in adrenocortical function with treatment, and the ITAA-treated groups were not different from the placebo-treated group with mean +/- SEM changes in stimulated plasma cortisol (micrograms per deciliter) as follows: placebo, -2.68 +/- 1.77; ITAA 220 micrograms, -2.69 +/- 1.18; ITAA 440 micrograms, -2.96 +/- 1.81. The prednisone-treated group had a mean reduction in adrenocortical function (mean +/- SEM change in stimulated plasma cortisol of -19.8 +/- 1.77 micrograms/dl) that was significant (p less than 0.0001) compared with that of the placebo-treated group. The results of this study indicate that 6 weeks of treatment with 220 micrograms/day or 440 micrograms/day of ITAA has no effect on adrenocortical function, but prednisone, at a dosage of 10 mg/day for 6 weeks, produces partial adrenocortical suppression.

Inspiratory pressure generation: comparison of subjects with COPD and age-matched normals.

We continuously monitored esophageal (Pes) and gastric (Pga) pressures and used these measurements in a three-component model to estimate instantaneous diaphragmatic (DIA), inspiratory accessory muscle (IAM), and postexpiratory recoil (PER) pressures at various times during inspiration. We validated our model both by volume-pressure relationships of the respiratory system (Vrc-Pga and Vab-Pga, where Vrc and Vab are the rib cage and abdominal volumes, respectively) as well as electromyography of the respiratory muscles. Measurements were carried out at rest and during graded treadmill exercise in 11 subjects with chronic obstructive pulmonary disease (COPDs) and 8 age-matched normal subjects (AMNs). AMNs were 59 +/- 2 (SE) yr and had a forced expiratory volume at 1 s (FEV1.0) of 3.6 +/- 0.2 liters; COPDs were 66 +/- 2 yr and had a FEV1.0 of 1.0 +/- 0.1 liters. We noted the following. At rest, both AMNs and COPDs exhibited an increasing DIA pressure (PDIA) across inspiratory time (TI) at rest. As expired minute ventilation increased with exercise intensity, AMNs continued to maintain this PDIA ramp across inspiration; in contrast, COPDs exhibited higher values of PDIA during the first half of TI than during the second half. At all intensities of exercise, COPDs exhibited higher IAM and PER pressures than the AMNs.