AIDE: Adaptive intrapatient dose escalation designs to accelerate Phase I clinical trials.

Designing Phase I clinical trials is challenging when accrual is slow or sample size is limited. The corresponding key question is: how to efficiently and reliably identify the maximum tolerated dose (MTD) using a sample size as small as possible? We propose model-assisted and model-based designs with adaptive intrapatient dose escalation (AIDE) to address this challenge. AIDE is adaptive in that the decision of conducting intrapatient dose escalation depends on both the patient's individual safety data, as well as other enrolled patient's safety data. When both data indicate reasonable safety, a patient may perform intrapatient dose escalation, generating toxicity data at more than one dose. This strategy not only provides patients the opportunity to receive higher potentially more effective doses, but also enables efficient statistical learning of the dose-toxicity profile of the treatment, which dramatically reduces the required sample size. Simulation studies show that the proposed designs are safe, robust, and efficient to identify the MTD with a sample size that is substantially smaller than conventional interpatient dose escalation designs. Practical considerations are provided and R code for implementing AIDE is available upon request.

Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study.

BACKGROUND & AIMS: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive disorders that lead to energy depletion and major clinical events (MCEs), such as acute metabolic crises of hypoglycemia, cardiomyopathy, and rhabdomyolysis. The aim of this study was to report a post hoc analysis of diet diary data from the phase 2 UX007-CL201 study (NCT01886378). METHODS: In the single-arm, open-label, phase 2 UX007-CL201 study, the safety and efficacy of 78 weeks of treatment with triheptanoin, an odd-carbon, medium-chain triglyceride consisting of three 7-carbon fatty acids on a glycerol backbone, was investigated in subjects with LC-FAOD versus a retrospective 78-week period when subjects were optimally managed under published dietary guidelines. Subject dietary reports were collected to analyze the relationship between diet, triheptanoin treatment, and MCEs. Referring metabolic physicians completed a survey on patient management and clinical outcomes before and after initiation of triheptanoin. Before initiating triheptanoin, subjects received a mean daily caloric intake (DCI) of 17.4% from medium-chain triglycerides (MCT). During the study, subjects received a mean of 27.5% DCI from triheptanoin. Protein (13.7% vs 14.5% DCI), long-chain fat (13.1% vs 10.5% DCI), and carbohydrate (55.3% vs 47.1% DCI) intake were consistent between the pre-triheptanoin and triheptanoin treatment periods, respectively. RESULTS: Following 78 weeks of treatment, mean annualized MCE rate decreased by 48.1% (p = 0.021) and mean annualized MCE event-day rate decreased by 50.3% (p = 0.028). A weak association existed between improvement in annualized MCE rate and change in percent DCI from MCT (Spearman rank correlation: r = -0.38; 95% CI: -0.675, 0.016). However, there was large variability in the association and no specific pattern of change for larger or smaller changes in dose. Seventy-two percent of physicians reported that triheptanoin had a clinically meaningful benefit on medical management of their patients. CONCLUSIONS: Treatment with triheptanoin at the protocol-specified dose decreased the rate of MCEs in patients with LC-FAOD independently from other dietary changes between the pre-triheptanoin and triheptanoin treatment periods. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01886378.

Healthcare costs among patients with hemophilia A treated with factor replacement or bypassing agents.

Objective: To assess real-world costs for patients with hemophilia A treated with bypassing agents versus factor VIII (FVIII) replacement. Methods: Claims data from a large US health insurer during 1 January 2006-30 September 2014 were used for analysis. Treated patients with hemophilia A were identified based on ≥1 medical claim with a diagnosis code for hemophilia A (ICD-9-CM 286.0) and ≥1 medical or pharmacy claim for bypassing therapy and/or FVIII replacement during 1 January 2007-31 August 2014. The bypassing therapy cohort comprised patients with ≥1 claim for bypassing therapy; all others were assigned to the factor replacement therapy cohort. Post-index hemophilia-related costs were computed as combined health plan plus patient paid amounts for medical claims with hemophilia A diagnosis code or hemophilia therapy procedure code (bypassing therapy, FVIII replacement therapy, desmopressin, antifibrinolytic therapy), as well as pharmacy claims for hemophilia therapy. Results: The study sample represented 580 patients: 50 (8.6%) in the bypassing therapy cohort (mean age: 38.5 years; mean post-index period: 2.1 years) and 530 (91.4%) in the factor replacement therapy cohort (mean age: 29.3 years; mean post-index period: 2.7 years). Compared with the factor replacement therapy cohort, mean per-patient-per-month hemophilia-related total costs were 4.8-fold higher in the bypassing therapy cohort ($57,232 vs. $11,899), comprising 4.4-fold higher medical costs ($45,911 vs. $10,352) and 7.3-fold higher outpatient pharmacy costs ($11,321 vs. $1547). Conclusions: Patients with hemophilia A treated with bypassing agents between 2007 and 2014 incurred substantially higher monthly hemophilia-related medical and pharmacy costs than patients treated only with FVIII replacement.

Clinical and Economic Burden of Commercially Insured Patients with Acromegaly in the United States: A Retrospective Analysis.

BACKGROUND: Acromegaly is a chronic disorder characterized by excess growth hormone secretion and elevated insulin-like growth factor-1 levels most often caused by a pituitary adenoma. Clinical presentation of the disease includes coarsening of the facial features, soft-tissue swelling of the hands and feet, and overgrowth of the frontal skull and protrusion of the jaw, as well as joint symptoms. Acromegaly is associated with several comorbidities, including diabetes, cardiovascular disease, and arthropathy, which, if left untreated, can lead to early mortality. Surgery to remove the adenoma is the first-line treatment for many patients, but more than 50% of patients will require additional pharmacologic or radiation therapy. OBJECTIVES: To (a) determine the clinical and economic burden of illness among patients with acromegaly using administrative claims data from a large, commercially insured population in the United States and (b) estimate the most frequent acromegaly-related comorbidities and health care resource utilization and costs among these patients. METHODS: This retrospective, observational cohort study used administrative claims data from the HealthCore Integrated Research Database, containing a geographically diverse spectrum of longitudinal claims data from the largest database of commercially insured patients in the United States. Patients were aged ≥ 20 years and fulfilled ≥ 1 of the following criteria during the intake period (March 31, 2008-July 31, 2012): ≥ 2 independent diagnostic codes for acromegaly, ≥ 1 acromegaly diagnosis code and ≥ 1 acromegaly-related procedure code, or ≥ 1 acromegaly diagnosis code and ≥ 1 medical claim for acromegaly-related therapy. The index date was defined as the date of the first medical claim for acromegaly within the intake period. Assessed outcomes included prevalence of acromegaly diagnosis and incidence of new acromegaly diagnoses during the study period (January 1, 2008-July 31, 2013), acromegaly-related comorbidities, and pharmacotherapy use. Because 2008 and 2012 data were incomplete, incidence rates were only reported for 2009, 2010, and 2011. Total and acromegaly-related health care resource utilization and annual health care costs were analyzed during a 12-month post-index observational period. RESULTS: In total, 757 patients with acromegaly met the selection criteria for this study, with a mean age of 49.3 years (53.6% female). The total prevalence of acromegaly was 41.7 cases per million. Acromegaly incidence was 15.0, 13.3, and 9.5 cases per million in 2009, 2010, and 2011, respectively. The top 5 acromegaly-related comorbidities were hypertension, diabetes, hypothyroidism, arthropathy/arthralgia/synovitis, and sleep apnea. During the study period, 51% of patients (n = 385) used acromegaly-related pharmacologic therapy, with the most common being cabergoline and octreotide (used by 12.4% and 12.2% of patients, respectively). Overall, 18.8% of patients incurred an acromegaly-related inpatient stay; 97.0% used outpatient services other than emergency room (ER) or physician visits; 74.8% had a physician office visit; and 1.8% visited the ER for acromegaly-related reasons. In the 12-month post-index period, 37.0% of patients filed claims for acromegaly-related prescription drugs, and patients with greater than 1 claim had an average of 7.6 prescriptions. The most expensive acromegaly-related costs in this study population were inpatient hospitalizations ($6,754) and prescription drugs ($6,147). CONCLUSIONS: Consistent with previous studies, this study confirms that acromegaly is a rare condition associated with multiple comorbidities. Notably, 18.8% of this study population required an inpatient hospital admission during the 12-month post-index period, possibly because of severe comorbidities. Because acromegaly-related costs were driven by hospitalizations and pharmacotherapy, improved management of the disease may reduce the clinical and economic burden experienced by patients with acromegaly.

Comparison of statistical and operational properties of subject randomization procedures for large multicenter clinical trial treating medical emergencies.

Large multicenter acute stroke trials demand a randomization procedure with a high level of treatment allocation randomness, an effective control on overall and within-site imbalances, and a minimized time delay of study treatment caused by the randomization procedure. Driven by the randomization algorithm design of A Study of the Efficacy and Safety of Activase (Alteplase) in Patients with Mild Stroke (PRISMS) (NCT02072226), this paper compares operational and statistical properties of different randomization algorithms in local, central, and step-forward randomization settings. Results show that the step-forward randomization with block urn design provides better performances over others. If the concern on the potential time delay is not serious and a central randomization system is available, the minimization method with an imbalance control threshold and a biased coin probability could be a better choice.