Safety and Outcomes in Infants Born to Mothers Participating in Retosiban Treatment Trials: ARIOS Follow-up Study.

OBJECTIVE: Retosiban, an oxytocin receptor antagonist, was developed for treating spontaneous preterm labor (sPTL) in women with intact membranes. This ARIOS follow-up study aimed to characterize clinical safety, morbidity, and mortality of infants exposed to retosiban or comparator over 2 years. STUDY DESIGN: ARIOS prospectively assessed outcomes in infants whose mothers received at least one dose of retosiban or comparator (placebo/atosiban) in two Phase 3 sPTL trials. Both trials were terminated prematurely owing to poor enrolment. Infants could be enrolled into ARIOS from 28 days after estimated due date until hospital discharge or up to 9 months (corrected age). An internally developed questionnaire detailing medical conditions, mortality and resource use (Child Health Inventory; CHI), Ages and Stages Questionnaire-3 (ASQ-3), Modified Checklist for Autism in Toddlers-Revised with Follow-Up, and Child Behavior Checklist for Ages 1.5 to 5 were completed remotely by parents or legal guardians at prespecified intervals. Serious adverse events (SAEs) were primarily captured via CHI. No comparative statistical analysis was conducted between treatment arms. RESULTS: A total of 49 (86%) infants who had received retosiban and 49 (78%) infants who had received a comparator were enrolled in ARIOS. No deaths occurred during the study. Nine infants experienced SAEs: 6/49 (12.2%) infants in the comparators group and 3/49 (6.1%) in the retosiban group. Of the nine SAEs, seven were due to infections, three, and four in the retosiban and comparators groups, respectively. Based on ASQ-3 score, the incidence of neurodevelopmental delay at 18 and 24 months were 0/18 (0%) and 2/25 (8%) with retosiban and 7/22 (31.8%) and 3/21 (14.3%) with comparator, respectively. CONCLUSION: The current study showed no unexpected adverse outcome or impairment with retosiban based on safety monitoring and neurodevelopment assessments. No further follow-up is intended owing to the discontinuation of clinical development of retosiban. KEY POINTS: · There is a need for an effective and safe treatment for sPTL.. · ARIOS was a follow-up study of two Phase 3 trials in sPTL.. · There were no safety concerns with retosiban treatment.. · Slow recruitment led to termination of the Phase 3 trials..

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.

Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor.

OBJECTIVE: The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). STUDY DESIGN: Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 336/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. RESULTS: The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016-July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015-August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n = 10) and 30.5 weeks (placebo, n = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n = 47, and atosiban, n = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. CONCLUSION: Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL.

A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials.

Objective To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother-neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ≥24 weeks' GA. Results Among 17,912 mother-neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at <31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately.

A Phase 1 Randomized, Placebo-Controlled Study Assessing the Pharmacokinetics, Safety, and Tolerability of Retosiban in Healthy, Nonpregnant Japanese Subjects.

This study characterized the pharmacokinetics, safety, and tolerability of retosiban in healthy, nonpregnant Japanese women prior to the enrollment of Japanese women in preterm labor in phase 3 trials. This study had 2 cohorts. Cohort 1 was a double-blind, sponsor-open, randomized study in Japanese women. Cohort 2 was an open-label study in white women to compare the pharmacokinetics with those of Japanese women. Retosiban was administered as a 6 mg/h infusion for 24 hours, followed by a 12 mg/h infusion over the next 24 hours; each infusion was preceded by a 6 mg loading dose administered over 5 minutes. Plasma concentrations of retosiban and its major metabolite, GSK2847065, were determined with an informal comparison of pharmacokinetics between Japanese and white women. There was minimal difference in exposure to retosiban or GSK2847065 between Japanese and white women (ratio of 1.03 in retosiban AUC and Cmax ). The 2 doses of retosiban were well tolerated across both populations, and no ethnic difference was observed in the safety profile. Given the results of this study and the known safety profile and dosing flexibility in the phase 3 trials, ethnic-specific dose adjustment of retosiban is not considered necessary for the Japanese and general Asian population.

Assessing a composite end point for new tocolytics in clinical trials: Data from 4 US integrated delivery networks.

PURPOSE: A composite end point (CE) measuring neonatal benefit was created for use in tocolytic randomized controlled trials with rates assessed using data from one referral hospital. The goal of this study was to assess wider generalizability of the CE, using data from multiple integrated delivery networks, creating a cohort of linked mother-neonate pairs to understand neonatal outcomes in a broad population. METHODS: Retrospective data on births (2001-2012) were collected from 4 US integrated delivery networks in the COMparative effectiveness PAtient Safety and Surveillance (COMPASS) Research Network, and linked mother-neonate pairs were identified. The CE was analyzed for all in-hospital singleton neonates at ≥24 weeks of gestational age (GA) born to mothers aged ≤45 years at a referral hospital or hospital with >2000 annual births. RESULTS: The CE analyses included 56 485 eligible mother-neonate pairs; frequency of the CE decreased from 89% to 66% between GA weeks 24 and 29 and further decreased to <14% for infants born >34 weeks of GA. Composite end point rates were 20% to 30% lower at 24 to 30 weeks of GA in COMPASS compared with Medical University of South Carolina but were similar by 31 weeks. CONCLUSIONS: The COMPASS Network enabled evaluation of the CE across a large population demonstrating that the CE findings could be replicated beyond a single hospital and the potential for lower CE frequency. Based on this, an adaptive design was adopted for randomized controlled trials, specifically sample size reestimation to mitigate against the risk of lower outcome rates, highlighting the use of real-world data in drug development.

Institutionalizing Sex Education in Diverse U.S. School Districts.

PURPOSE: This paper describes the Working to Institutionalize Sex Education (WISE) Initiative, a privately funded effort to support ready public school districts to advance and sustain comprehensive sexuality programs, and examines the degree to which WISE has been successful in increasing access to sex education, removing barriers, and highlighting best practices. METHODS: The data for this study come from a set of performance indicators, guidance documents, and tools designed for the WISE Initiative to capture changes in sex education institutionalization at WISE school districts. The evaluation includes the analysis of 186 school districts across 12 states in the U.S. RESULTS: As a result of the WISE Initiative, 788,865 unique students received new or enhanced sex education in school classrooms and 88 school districts reached their sex education institutionalization goals. In addition to these school district successes, WISE codified the WISE Method and toolkit-a practical guide to help schools implement sex education. CONCLUSIONS: Barriers to implementing sexuality education can be overcome with administrative support and focused technical assistance and training, resulting in significant student reach in diverse school districts nationwide.

Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study.

AIM: The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. METHODS: This was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 30(0/7) and 35(6/7) weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety. RESULTS: Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups. CONCLUSIONS: Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile.

Effects of aggregation of drug and diagnostic codes on the performance of the high-dimensional propensity score algorithm: an empirical example.

BACKGROUND: The High-Dimensional Propensity Score (hd-PS) algorithm can select and adjust for baseline confounders of treatment-outcome associations in pharmacoepidemiologic studies that use healthcare claims data. How hd-PS performance is affected by aggregating medications or medical diagnoses has not been assessed. METHODS: We evaluated the effects of aggregating medications or diagnoses on hd-PS performance in an empirical example using resampled cohorts with small sample size, rare outcome incidence, or low exposure prevalence. In a cohort study comparing the risk of upper gastrointestinal complications in celecoxib or traditional NSAIDs (diclofenac, ibuprofen) initiators with rheumatoid arthritis and osteoarthritis, we (1) aggregated medications and International Classification of Diseases-9 (ICD-9) diagnoses into hierarchies of the Anatomical Therapeutic Chemical classification (ATC) and the Clinical Classification Software (CCS), respectively, and (2) sampled the full cohort using techniques validated by simulations to create 9,600 samples to compare 16 aggregation scenarios across 50% and 20% samples with varying outcome incidence and exposure prevalence. We applied hd-PS to estimate relative risks (RR) using 5 dimensions, predefined confounders, ≤ 500 hd-PS covariates, and propensity score deciles. For each scenario, we calculated: (1) the geometric mean RR; (2) the difference between the scenario mean ln(RR) and the ln(RR) from published randomized controlled trials (RCT); and (3) the proportional difference in the degree of estimated confounding between that scenario and the base scenario (no aggregation). RESULTS: Compared with the base scenario, aggregations of medications into ATC level 4 alone or in combination with aggregation of diagnoses into CCS level 1 improved the hd-PS confounding adjustment in most scenarios, reducing residual confounding compared with the RCT findings by up to 19%. CONCLUSIONS: Aggregation of codes using hierarchical coding systems may improve the performance of the hd-PS to control for confounders. The balance of advantages and disadvantages of aggregation is likely to vary across research settings.

Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data.

PURPOSE: To evaluate the incidence, phenotypes, and outcomes of drug-associated liver injury identified in electronic medical record (EMR) data using standardized criteria for drug-induced liver injury (DILI). METHODS: This retrospective cohort study used EMR data from a large integrated healthcare system. Study inclusion required 18 years of age or older, ≥1 prescription fill for any of 14 medications associated with hepatotoxicity between 1 January 2003 and 30 June 2009, and ≥12 months of membership prior to the drug exposure. Patients with underlying non-drug causes of liver injury were excluded to minimize capture of liver injury events unrelated to drugs. Drug-associated liver injuries were identified by liver chemistry elevations temporally associated with drug use based on standardized criteria for DILI. Cases were classified by clinical pattern and severity. Outcomes of liver transplant and all-cause and liver-related death were examined. RESULTS: A total of 1 053 979 drug exposures were identified in 601 125 patients. We identified 265 drug-associated liver injuries (32.8 per 100 000 persons) occurring in 250 patients. Isoniazid exhibited the highest incidence rate of 606 per 100 000 persons. Of the 265 cases, 41% were mild; 12% exhibited moderate drug-associated liver injury (with concomitant ALT ≥ 5× ULN and bilirubin ≥2× ULN); and 17% exhibited coagulopathy, ascites, encephalopathy, or other organ failure. Last, seven cases (3%) were associated with death, and there were no liver transplants. CONCLUSIONS: Study results align with earlier prospective studies, supporting the value of standardized methodology to identify drug-associated liver injury in the EMR. These methods can potentially enhance safety and clinical outcomes.

Performance of a semi-automated approach for risk estimation using a common data model for longitudinal healthcare databases.

Different structures and coding schemes may limit rapid evaluation of a large pool of potential drug safety signals using multiple longitudinal healthcare databases. To overcome this restriction, a semi-automated approach utilising common data model (CDM) and robust pharmacoepidemiologic methods was developed; however, its performance needed to be evaluated. Twenty-three established drug-safety associations from publications were reproduced in a healthcare claims database and four of these were also repeated in electronic health records. Concordance and discrepancy of pairwise estimates were assessed between the results derived from the publication and results from this approach. For all 27 pairs, an observed agreement between the published results and the results from the semi-automated approach was greater than 85% and Kappa coefficient was 0.61, 95% CI: 0.19-1.00. Ln(IRR) differed by less than 50% for 13/27 pairs, and the IRR varied less than 2-fold for 19/27 pairs. Reproducibility based on the intra-class correlation coefficient was 0.54. Most covariates (>90%) in the publications were available for inclusion in the models. Once the study populations and inclusion/exclusion criteria were obtained from the literature, the analysis was able to be completed in 2-8 h. The semi-automated methodology using a CDM produced consistent risk estimates compared to the published findings for most selected drug-outcome associations, regardless of original study designs, databases, medications and outcomes. Further assessment of this approach is useful to understand its roles, strengths and limitations in rapidly evaluating safety signals.

Semi-automated risk estimation using large databases: quinolones and Clostridium difficile associated diarrhea.

PURPOSE: The availability of large databases with person time information and appropriate statistical methods allow for relatively rapid pharmacovigilance analyses. A semi-automated method was used to investigate the effect of fluoroquinolones on the incidence of C. difficile associated diarrhea (CDAD). METHODS: Two US databases, an electronic medical record (EMR) and a large medical claims database for the period 2006-2007 were evaluated using a semi-automated methodology. The raw EMR and claims datasets were subject to a normalization procedure that aligns the drug exposures and conditions using ontologies; Snowmed for medications and MedDRA for conditions. A retrospective cohort design was used together with matching by means of the propensity score. The association between exposure and outcome was evaluated using a Poisson regression model after taking into account potential confounders. RESULTS: A comparison between quinolones as the target cohort and macrolides as the comparison cohort produced a total of 564,797 subjects exposed to a quinolone in the claims data and 233,090 subjects in the EMR. They were matched with replacement within six strata of the propensity score. Among the matched cohorts there were a total of 488 and 158 outcomes in the claims and the EMR respectively. Quinolones were found to be twice more likely to be significantly associated with CDAD than macrolides adjusting for risk factors (IRR 2.75, 95%CI 2.18-3.48). CONCLUSIONS: Use of a semi-automated method was successfully applied to two observational databases and was able to rapidly identify a potential for increased risk of developing CDAD with quinolones.

Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database.

BACKGROUND: The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database. DESIGN AND METHODS: Using the General Practice Research Database, 1,070 adults (>or=18 years) with coded records for primary immune thrombocytopenia first referenced between January 1(st) 1992 and November 30(th) 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox's proportional hazards regression. RESULTS: Over a median 47.6 months of follow-up (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48), 1.37 (95% CI, 0.94-2.00), and 1.41 (95% CI, 1.04-1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia. CONCLUSIONS: Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.

Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy.

PURPOSE: The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1-specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy. EXPERIMENTAL DESIGN: ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-DL-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 microg every other week for up to 12 doses. RESULTS: Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year. CONCLUSIONS: The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.

Dynamics of human papillomavirus infection between biopsy and excision of cervical intraepithelial neoplasia: results from the ZYC101a protocol.

BACKGROUND: Little is known about the dynamics of human papillomavirus (HPV) during the follow-up of cervical intraepithelial neoplasia (CIN) 2/3 after biopsy. METHODS: A total of 127 women with biopsy-confirmed CIN2/3 were enrolled in a phase 2 double-blinded, randomized, placebo-controlled clinical trial of ZYC101a. Colposcopic, cytologic, and HPV testing were performed over the course of 6 months, before a loop electrical surgical excision procedure was performed at study exit. RESULTS: Of the women tested, 99% were found to be HPV positive at study entry, 50% were found to be HPV type 16 positive at study entry, 22% were found to be positive for multiple HPV types at study entry, and 37% were found to be positive for additional HPV types during follow-up. Of those with a histologic outcome of CIN1 at study exit, 78% were found to be positive for additional HPV types; in 39%, the original type was replaced with a new HPV type. Virus load at study entry did not predict outcome, but pre-study-exit virus load correlated with a histologic outcome of any CIN, and changes in virus load correlated with risk for an outcome of CIN2/3 at study exit. CONCLUSIONS: The type and number of HPVs at study entry, detection of additional viral types, and virus load changes during follow-up influence histologic outcome at study exit. An outcome of CIN1 at study exit is most likely due to additional HPV infections, rather than morphologic reversion of CIN2/3 to CIN1. Knowledge of the dynamics of HPV infection during the biopsy-to-excision period is critical to understanding the natural history of HPV infection, its contribution to disease outcome, and interpretations of drug efficacy.

ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA-encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles. METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 microg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy. RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P =.12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P =.007). ZYC101a activity was not restricted to HPV-16-or HPV-18-positive lesions. CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years. LEVEL OF EVIDENCE: I

Production of pathogen-inactivated RBC concentrates using PEN110 chemistry: a Phase I clinical study.

BACKGROUND: Despite extensive reductions in risk, donor selection and testing cannot eliminate pathogen transmission. The objective of this study was to evaluate clinically the viability of pathogen-inactivated RBCs. STUDY DESIGN AND METHODS: Twelve healthy subjects each donated two units of blood that were handled as additive system control units or were inactivated using the PEN110 process (INACTINE, V.I. Technologies) in randomized order. PEN110, which inactivates pathogens by reacting with nucleic acid bases, was incubated with RBCs for 6 hours, followed by washing and quenching with sodium thiosulfate. Radiolabeled RBC recovery and survival determinations were undertaken after 28 days of storage; biochemical and hematologic variables were assessed over 42 days. RESULTS: After 28 days, treated units had a 24-hour double-label ((51)Cr/(99m)Tc) recovery (85.0 +/- 5.0%) that was indistinguishable from control units (85.9 +/- 2.7%); the times required for reduction of radioactivity of labeled cells to half the Day 1 activity (T(50)) were similar for both groups (treated, 31.9 +/- 8.2 days; control, 32.9 +/- 3.3 days). No deleterious effects of PEN110 treatment were found on RBC antigens tested. Treatment reduced 2,3-DPG levels by half and slightly lowered pH levels. Throughout the 42-day storage period, treated RBCs had a lower level of lactate production and a trend toward lower glucose consumption. Hemolysis remained below 1 percent; supernatant potassium and ATP levels were lower than those seen in control RBCs. CONCLUSION: PEN110-treated RBCs stored for 28 days meet all critical requirements for therapeutically useful units.