Pudexacianinium (ASP5354) chloride for ureter visualization in participants undergoing laparoscopic, minimally invasive colorectal surgery.

BACKGROUND: Intraoperative ureteral injury, a serious complication of abdominopelvic surgeries, can be avoided through ureter visualization. Near-infrared fluorescence imaging offers real-time anatomical visualization of ureters during surgery. Pudexacianinium (ASP5354) chloride is an indocyanine green derivative under investigation for intraoperative ureter visualization during colorectal or gynecologic surgery in adult and pediatric patients. METHODS: In this phase 2 study (NCT04238481), adults undergoing laparoscopic colorectal surgery were randomized to receive one intravenous dose of pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg. The primary endpoint was successful intraoperative ureter visualization, defined as observation of ureter fluorescence 30 min after pudexacianinium administration and at end of surgery. Safety and pharmacokinetics were also assessed. RESULTS: Participants received pudexacianinium 0.3 mg (n = 3), 1.0 mg (n = 6), or 3.0 mg (n = 3). Most participants were female (n = 10; 83.3%); median age was 54 years (range 24-69) and median BMI was 29.3 kg/m2 (range 18.7-38.1). Successful intraoperative ureter visualization occurred in 2/3, 5/6, and 3/3 participants who received pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg, respectively. Median intensity values per surgeon assessment were 1 (mild) with the 0.3-mg dose, 2 (moderate) with the 1.0-mg dose, and 3 (strong) with the 3.0-mg dose. A correlation was observed between qualitative (surgeon's recognition/identification of the ureter during surgery) and quantitative (video recordings of the surgeries after study completion) assessment of fluorescence intensity. Two participants experienced serious adverse events, none of which were drug-related toxicities. One adverse event (grade 1 proteinuria) was related to pudexacianinium. Plasma pudexacianinium concentrations were dose-dependent and the mean (± SD) percent excreted into urine during surgery was 22.3% ± 8.0% (0.3-mg dose), 15.6% ± 10.0% (1.0-mg dose), and 39.5% ± 12.4% (3.0-mg dose). CONCLUSIONS: In this study, 1.0 and 3.0 mg pudexacianinium provided ureteral visualization for the duration of minimally invasive, laparoscopic colorectal procedures and was safe and well tolerated.

Evaluation and performance of a newly developed patient-reported outcome instrument for diarrhea-predominant irritable bowel syndrome in a clinical study population.

BACKGROUND: To evaluate the psychometric properties of the newly developed seven-item Irritable Bowel Syndrome - Diarrhea predominant (IBS-D) Daily Symptom Diary and four-item Event Log using phase II clinical trial safety and efficacy data in patients with IBS-D. This instrument measures diarrhea (stool frequency and stool consistency), abdominal pain related to IBS-D (stomach pain, abdominal pain, abdominal cramps), immediate need to have a bowel movement (immediate need and accident occurrence), bloating, pressure, gas, and incomplete evacuation. METHODS: Psychometric properties and responsiveness of the instrument were evaluated in a clinical trial population [ClinicalTrials.gov identifier: NCT01494233]. RESULTS: A total of 434 patients were included in the analyses. Significant differences were found among severity groups (p < 0.01) defined by IBS Patient Global Impression of Severity (PGI-S) and IBS Patient Global Impression of Change (PGI-C). Severity scores for each Diary and Event Log item score and five-item, four-item, and three-item summary scores were calculated. Between-group differences in changes over time were significant for all summary scores in groups stratified by changes in PGI-S (p < 0.05), two of six Diary items, and three of four Event Log items; a one-grade change in PGI-S was considered a meaningful difference with mean change scores on all Diary items -0.13 to -0.86 [standard deviation (SD) 0.79-1.39]. Similarly, for patients who reported being 'slightly improved' (considered a clinically meaningful difference) on the PGI-C, mean change scores on Diary items ranged from -0.45 to -1.55 (SD 0.69-1.39). All estimates of clinically important change for each item and all summary scores were small and should be considered preliminary. These results are aligned with the previous standalone psychometric study regarding reliability and validity tests. CONCLUSIONS: These analyses provide evidence of the psychometric properties of the IBS-D Daily Symptom Diary and Event Log in a clinical trial population.

Diarrhea-predominant irritable bowel syndrome: creation of an electronic version of a patient-reported outcome instrument by conversion from a pen-and-paper version and evaluation of their equivalence.

BACKGROUND: Subjects with diarrhea-predominant irritable bowel syndrome (IBS-D) experience abdominal cramping, bloating, pressure, and pain. Due to an absence of clinical biomarkers for IBS-D severity, evaluation of clinical therapy benefits depends on valid and reliable symptom assessments. A patient-reported outcome (PRO) instrument has been developed, comprising of two questionnaires - the IBS-D Daily Symptom Diary and IBS-D Symptom Event Log - suitable for clinical trials and real-world settings. This program aimed to support instrument conversion from pen-and-paper to electronic format. MATERIALS AND METHODS: Digital technology (Android/iOS) and a traditional mode of administration study in the target population were used to migrate or convert the validated PRO IBS-D pen-and-paper measure to an electronic format. Equivalence interviews, conducted in three waves, each had three parts: 1) conceptual equivalence testing between formats, 2) electronic-version report-history cognitive debriefing, and 3) electronic version usability evaluation. After each inter-view wave, preliminary analyses were conducted and modifications made to the electronic version, before the next wave. Final revisions were based on a full analysis of equivalence interviews. The final analysis evaluated subjects' ability to read, understand, and provide meaningful responses to the instruments across both formats. Responses were classified according to conceptual equivalence between formats and mobile-format usability assessed with a questionnaire and open-ended probes. RESULTS: Equivalence interviews (n=25) demonstrated conceptual equivalence between formats. Mobile-application cognitive debriefing showed some subjects experienced difficulty with font/screen visibility and understanding or reading some report-history charts and summary screens. To address difficulties, minor revisions/modifications were made and landscape orientation and zoom-in/zoom-out features incorporated. CONCLUSION: This study indicates that the two administration modes are conceptually equivalent. Since both formats are conceptually equivalent, both are psychometrically reliable, as established in the pen-and-paper version. Subjects found both mobile applications (Android/iOS) offered many advantages over the paper version, such as real-time assessment of their experience.

Cultural adaptation: translatability assessment and linguistic validation of the patient-reported outcome instrument for irritable bowel syndrome with diarrhea.

BACKGROUND AND OBJECTIVE: Following a 2009 US Food and Drug Administration guidance, a new patient-reported outcome (PRO) instrument was developed to support end points in multinational clinical trials assessing irritable bowel syndrome with diarrhea (IBS-D) symptom severity. Our objective was to assess the translatability of the IBS-D PRO instrument into ten languages, and subsequently perform a cultural adaptation/linguistic validation of the questionnaire into Japanese and US Spanish. MATERIALS AND METHODS: Translatability assessments of the US English version of the IBS-D PRO were performed by experienced PRO translators who were native speakers of each target language and currently residing in target-language countries. Languages were Chinese (People's Republic of China), Dutch (the Netherlands), French (Belgium), German (Germany), Japanese (Japan), Polish (Poland), Portuguese (Brazil), Russian (Russia), Spanish (Mexico), and Spanish (US). The project team assessed the instrument to identify potential linguistic and/or cultural adaptation issues. After the issues identified were resolved, the instrument was translated into Spanish (US) and Japanese through a process of two forward translations, one reconciled translation, and one backward translation. The project team reviewed the translated versions before the instruments were evaluated by cognitive debriefing interviews with samples of five Spanish (US) and five Japanese IBS-D patients. RESULTS: Linguistic and cultural adaptation concerns identified during the translatability assessment required minor revisions, mainly the presentation of dates/times and word structure. During the cognitive debriefing interviews, two of five Spanish respondents misunderstood the term "bowel movement" to mean only diarrhea in the Spanish version. Consequently, the term was changed from "movimiento intestinal" to "evacuaciones". None of the Japanese respondents identified issues with the Japanese version. CONCLUSION: The translatability of the IBS-D PRO instrument into ten target languages was confirmed, with only minor changes made to the translations of the instrument. The translation and linguistic validation into Spanish (US) and Japanese provide evidence that this instrument can be used in multinational trials and clinical settings.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T-Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients.

ASP2408 is a next-generation anti-cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was 36.3%-56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single-dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose-dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose-limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12-lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.

Psychometric assessment of the IBS-D Daily Symptom Diary and Symptom Event Log.

PURPOSE: Diarrhea-predominant irritable bowel syndrome (IBS-D) can considerably impact patients' lives. Patient-reported symptoms are crucial in understanding the diagnosis and progression of IBS-D. This study psychometrically evaluates the newly developed IBS-D Daily Symptom Diary and Symptom Event Log (hereafter, "Event Log") according to US regulatory recommendations. METHODS: A US-based observational field study was conducted to understand cross-sectional psychometric properties of the IBS-D Daily Symptom Diary and Event Log. Analyses included item descriptive statistics, item-to-item correlations, reliability, and construct validity. RESULTS: The IBS-D Daily Symptom Diary and Event Log had no items with excessive missing data. With the exception of two items ("frequency of gas" and "accidents"), moderate to high inter-item correlations were observed among all items of the IBS-D Daily Symptom Diary and Event Log (day 1 range 0.67-0.90). Item scores demonstrated reliability, with the exception of the "frequency of gas" and "accidents" items of the Diary and "incomplete evacuation" item of the Event Log. The pattern of correlations of the IBS-D Daily Symptom Diary and Event Log item scores with generic and disease-specific measures was as expected, moderate for similar constructs and low for dissimilar constructs, supporting construct validity. Known-groups methods showed statistically significant differences and monotonic trends in each of the IBS-D Daily Symptom Diary item scores among groups defined by patients' IBS-D severity ratings ("none"/"mild," "moderate," or "severe"/"very severe"), supporting construct validity. CONCLUSIONS: Initial psychometric results support the reliability and validity of the items of the IBS-D Daily Symptom Diary and Event Log.

A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy.

ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143.

Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure.

BACKGROUND: This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF). METHODS: We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment. The primary endpoint was a composite that evaluated changes in clinical status during the first 5 days after randomization. RESULTS: In the 600-patient trial, more levosimendan than placebo patients (58 vs. 44) were improved at all 3 pre-specified time points (6 h, 24 h, and 5 days), whereas fewer levosimendan patients (58 vs. 82) experienced clinical worsening (p = 0.015 for the difference between the groups). These differences were apparent, despite more frequent intensification of adjunctive therapy in the placebo group (79 vs. 45 patients). Improvements in patient self-assessment and declines in B-type natriuretic peptide levels with levosimendan persisted for 5 days and were associated with reduced length of stay (p = 0.009). Similar findings were present in the 100-patient pilot trial. Levosimendan was associated with more frequent hypotension and cardiac arrhythmias during the infusion period and a numerically higher risk of death across the 2 trials (49 of 350 on a regimen of levosimendan vs. 40 of 350 on a regimen of placebo at 90 days, p = 0.29). CONCLUSIONS: In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425).

Effects of intravenous ABT-870 (iron (III)-hydroxide oligosaccharide) on mean arterial pressure and heart rate in the anaesthetized beagle: comparison with other iron-containing haematinic agents.

Iron-deficiency anaemia, a complication of end-stage renal disease (ESRD), is often treated with parenteral iron therapies that have been shown to produce dose-limiting hypotension in patients. ABT-870 (iron-(III)-hydroxide-oligosaccharide) is comprised of elemental iron complexed with oligosaccharide, a composition that we hypothesised would allow the hypotensive effects of parenteral iron therapy to be overcome, thus allowing a rapid rate of infusion to be well tolerated. Mean arterial pressure (MAP) and heart rate (HR) were monitored in anaesthetized dogs following the infusion of ABT-870 and iron sucrose administered at doses of 7.1 and 21.3 mg/kg using a rapid 30 s infusion. ABT-870 and iron sucrose were also monitored at doses of 7.1, 21.3 and 50 mg/kg administered over a 10 min period. Sodium ferric gluconate complex (SFGC) was administered in an identical fashion at doses of 12.5 and 31.2 mg/kg. A 30 s rapid infusion of ABT-870 at doses of 7.1 and 14.3 mg/kg or a 10 min infusion of ABT-870 at doses of 7.1 and 21.3 mg/kg produced little effect on MAP and HR. Infusion of the highest dose of ABT-870 (50 mg/kg) produced no consistent hypotension, but did produce an increase in HR (maximal increase 35 +/- 9 b.p.m.), an effect that lasted only 15 min. A 30 s rapid infusion of iron sucrose at 7.1 mg/kg produced modest increases in MAP and HR (5 +/- 1 mmHg and 5 +/- 2 b.p.m., respectively). However, rapid infusion of iron sucrose at 14.3 mg/kg produced hypotension (to -8 +/- 1 mmHg below baseline) and exerted variable, biphasic effects on HR ranging from -16 to +50 b.p.m. Although 10 min infusion of iron sucrose at 7.1 mg/kg exerted little effect on MAP and HR, at doses of 21.3 and 50 mg/kg iron sucrose elicited a profound dose-dependent decrease in MAP (-34 +/- 11 and -83 +/- 5 mmHg, respectively) and a pronounced increase in HR ranging from 32 to 49 b.p.m. above baseline. A 10 min infusion of SFGC at doses of 12.5 and 31.2 mg/kg produced a dose-dependent decrease in MAP (-28 +/- 18 and -67 +/- 12 mmHg below baseline) and a marked increase in HR (26 +/- 11 and 94 +/- 15 b.p.m. above baseline). In conclusion, unlike iron sucrose and SFGC, high doses of ABT-870 failed to exert consistent hypotensive effects. These data demonstrate that ABT-870 may have a substantial therapeutic window and considerable clinical potential for iron-replacement therapy.

A model for the interim analysis process: a case study.

To evaluate data from a clinical trial before its completion, researchers routinely perform interim analyses. However, if not performed carefully, interim analyses can compromise the integrity of a clinical trial. In the last 10-15 years, regulatory authorities and the pharmaceutical industry have developed procedures and guidelines to allow trial sponsors access to unblinded data in an ongoing clinical trial without affecting the outcome. In December 1996, Abbott Laboratories was codeveloping a drug for treatment of an autoimmune disease. The pivotal phase II/III trial for the new drug application was very expensive, large, long term, and slow-accruing. The trial was initiated with a great deal of uncertainty concerning the safety and efficacy of the proposed treatment. An interim analysis was a logical part of the trial design. Two interim analyses were performed; the second analysis resulted in early termination of the trial. This article describes the interim analysis, including the process used for planning and execution and the lessons learned from the experience. In addition, the methodology for performing an interim analysis and the roles and responsibilities of involved members are discussed.