Judith Hey-Hadavi

Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease LEADe

Background: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. Methods: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13–25), were aged 50–90 years, and were taking donepezil 10 mg daily for ≥3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were >95 and <195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimers Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimers Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. Results: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. Conclusions: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50–90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimers Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimers Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY.

CONTEXT Pegvisomant is a GH receptor antagonist. The ACROSTUDY is a global safety surveillance study of long-term treatment of acromegaly with pegvisomant. OBJECTIVE The objective of the study was to monitor long-term safety and treatment outcomes. DESIGN ACROSTUDY is open to all patients with acromegaly who are treated with pegvisomant. We report an interim analysis of data captured from 1288 subjects enrolled before a database freeze of December 31, 2009. SETTING This was a global noninterventional surveillance study. MAIN OUTCOME MEASURE(S) Long-term monitoring of safety, including central magnetic resonance imaging (MRI) reading and treatment outcomes, was measured. RESULTS Subjects (n = 1288) were treated with pegvisomant for a mean of 3.7 yr and followed up in ACROSTUDY for a mean of 2.1 yr. A total of 1147 adverse events (AE) were recorded in 477 subjects (37%), among which 192 AE in 124 subjects (9.6%) were considered to be related to pegvisomant. Serious AE were recorded in 159 subjects (12.3%), whereas pegvisomant-related Serious AE were recorded in 26 subjects (2%). No deaths (15 subjects; 1.2%) were attributed to pegvisomant use. The incidence of increase in pituitary tumor size in the subset with confirmed MRI increases on central reading represented 3.2% of the overall cohort with at least two available MRI (n = 936). Injection-site reactions were reported in 28 cases (2.2%). In 30 patients (2.5%), an elevated aspartate aminotransferase or alanine aminotransferase of more than 3 times the upper level of normality was reported. There were no reports of liver failure. After 5 yr of pegvisomant treatment, 63.2% of subjects had normal IGF-I levels at a mean dose of 18 mg/d. CONCLUSIONS Data entered and evaluated in ACROSTUDY indicate that pegvisomant is an effective and safe medical treatment in patients with acromegaly. The reported low incidence of pituitary tumor size increase, liver enzyme elevations, and lipodystrophy at the injection site are reassuring.

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics

Growing evidence suggests that elevated cholesterol levels in mid‐life are associated with increased risk of developing Alzheimers disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitors Effect in Alzheimers Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily).

Sub-antimicrobial doxycycline for periodontitis reduces hemoglobin A1c in subjects with type 2 diabetes: a pilot study.

In vitro and animal studies suggest a possible role for the tetracycline class of drugs in the inhibition of non-enzymatic protein glycation. We conducted a 3-month, randomized placebo-controlled pilot clinical trial of conventional sub-gingival debridement (periodontal therapy), combined with either a three month regimen of sub-antimicrobial-dose doxycycline (SDD), a two week regimen of antimicrobial-dose doxycycline (ADD), or placebo in 45 patients with long-standing type 2 diabetes (mean duration 9 years) and untreated chronic periodontitis. Subjects were taking stable doses of oral hypoglycemic medications and/or insulin. Treatment response was assessed by measuring hemoglobin A1c (HbA1c), plasma glucose, and clinical periodontal disease measures. At one-month and three-month follow-up, clinical measures of periodontitis were decreased in all groups (data to be presented elsewhere). At three months, mean HbA1c levels in the SDD group were reduced 0.9% units from 7.2% units±2.2 (±SD), to 6.3% units±1.1, which represents a 12.5% improvement. In contrast, there was no significant change in HbA1c in the ADD (7.5%±2.0 to 7.8%±2.1) or placebo (8.5%±2.0 to 8.5%±2.6) groups. Mean HbA1c change from baseline was significantly greater in the SDD group compared with the ADD group (p=0.04) but not placebo (p=0.22). Moreover, a larger proportion of subjects in the SDD group experienced improvement (p<0.05) compared to the ADD or placebo groups. Mean plasma glucose levels were not significantly different between or within the groups. The results of this pilot study suggest that the treatment of periodontitis with sub-gingival debridement and 3-months of daily sub-antimicrobial-dose doxycycline may decrease HbA1c in patients with type 2 diabetes taking normally prescribed hypoglycemic agents.

AUDIT study. Evidence of global undertreatment of dyslipidaemia in patients with type 2 diabetes mellitus

The Analysis and Understanding of Diabetes and Dyslipidaemia: Improving Treatment (AUDIT) study was a confidential, web-based, cross-sectional survey involving 2,043 diabetes specialists in 50 countries. The study investigated the attitudes of physicians specialising in the treatment of patients with type 2 diabetes mellitus towards the management of dyslipidaemia and other cardiovascular risk factors in these patients. Physicians reported obtaining lipid profiles in 91% of patients with type 2 diabetes and estimated that 62% of type 2 diabetic patients have dyslipidaemia. Across all regions, stated low-density lipoprotein cholesterol (LDL-C), triglyceride and total cholesterol targets were lower for type 2 diabetic patients with than without cardiovascular disease (CVD). Fewer physicians reported having an LDL-C target of < 2.6 mmol/L (< 100 mg/dL) for patients without CVD (59%) than with CVD (85%). Physicians reported that 54% of patients achieve LDL-C targets, with significantly more estimated to achieve their LDL-C goal in North America (69%) than in any other region (43‐61%; p<0.001). When setting targets, 58% of physicians stated that they were most influenced by lipid management guidelines, although a large proportion of physicians from Eastern Europe (54%) and Africa/Middle East (50%) cited a personal read of the literature. Patient compliance was the most commonly perceived barrier to lipid goal attainment in most regions (42‐61%); financial constraints were cited most often in South America (76%), Africa/Middle East (65%) and Eastern Europe (63%). The AUDIT study revealed a disparity between lipid screening and control in type 2 diabetic patients. Physicians reported that they treated patients without CVD less intensively than patients with CVD, suggesting that type 2 diabetes was not widely considered a coronary heart disease risk equivalent. A reassessment of guideline implementation is needed for physicians worldwide to improve lipid control to decrease cardiovascular risk in type 2 diabetes. Br J Diabetes Vasc Dis 2006;6:31‐40

Psychometric Assessment of the Injection Pen Assessment Questionnaire (IPAQ): measuring ease of use and preference with injection pens for human growth hormone

PurposeTo examine the psychometric properties of the Injection Pen Assessment Questionnaire (IPAQ) including the following: 1) item and scale characteristics (e.g., frequencies, item distributions, and factor structure), 2) reliability, and 3) validity.MethodsFocus groups and one-on-one dyad interviews guided the development of the IPAQ. The IPAQ was subsequently tested in 136 parent–child dyads in a Phase 3, 2-month, open-label, multicenter trial for a new Genotropin® disposable pen. Factor analysis was performed to inform the development of a scoring algorithm, and reliability and validity of the IPAQ were evaluated using the data from this two months study. Psychometric analyses were conducted separately for each injection pen.ResultsConfirmatory factor analysis provides evidence supporting a second order factor solution for four subscales and a total IPAQ score. These factor analysis results support the conceptual framework developed from previous qualitative research in patient dyads using the reusable pen. However, the IPAQ subscales did not consistently meet acceptable internal consistency reliability for some group level comparisons. Cronbach’s alphas for the total IPAQ score for both pens were 0.85, exceeding acceptable levels of reliability for group comparisons.ConclusionsThe total IPAQ score is a useful measure for evaluating ease of use and preference for injection pens in clinical trials among patient dyads receiving hGH. The psychometric properties of the individual subscales, mainly the lower internal consistency reliability of some of the subscales and the predictive validity findings, do not support the use of subscale scores alone as a primary endpoint.

A four-year, open-label, multi-center, randomized, two-arm study of Genotropin® in patients with idiopathic short stature: comparison of an individualized, target-driven treatment regimen to standard dosing of Genotropin® - analysis of two-year data.

Background: Several models have been developed to predict growth response to growth hormone (GH) based on auxological and biochemical parameters for children with non-GH-deficient, idiopathic short stature (ISS). Objective: To demonstrate if an individualized, formula-based, target-driven GH regimen for children with ISS would lead to a height (Ht) gain to -1.3 SDS during the first 24 months of treatment of this 4-year study, with less variability than with standard weight-based dosing. Methods: A 4-year, open-label, multi-center, randomized, two-arm study comparing formula-based dosing of Genotropin® GH from 0.18 to 0.7 mg/kg/week versus standard FDA-approved ISS dosing of Genotropin® (0.37 mg/kg/week). Subjects (n = 316, 89 females) were prepubertal, 3-14 years of age, bone age 3-10 years (m) and 3-9 years (f), naive to GH treatment, Ht SDS -3 to -2.25, Ht velocity <25th percentile for bone age, and peak GH >10 ng/ml. Results: The majority (83%) of subjects had Ht SDS within the normal range by 2 years. All subjects displayed catch-up growth consistent with other studies of GH treatment of ISS. Conclusion: The formula-based therapy did not meet the primary endpoint achieving targeted gain with lower variability. No new safety concerns were found.

SAT0221 Efficacy and Safety of PF-04171327, a Novel Dissociated Agonist of the Glucocorticoid Receptor (DAGR): Results of a Phase 2, Randomized, Double-Blind Study

Background Glucocorticoids (GC) are widely used to treat rheumatic and other diseases, but adverse effects limit their full potential. Improvement of their benefit-risk ratio represents both a current need and an ongoing challenge. One promising option includes dissociated agonists of the glucocorticoid receptor (DAGR) with the efficacy of higher dose GCs and the safety profile of lower dose GCs. Objectives PF-04171327, a DAGR, represents a first-in-class compound under investigation for the treatment of rheumatoid arthritis. The aim was to test the above hypothesis that this novel drug preferentially exerts transrepression mediated effects thereby inducing potent therapeutic activity with reduced adverse effects. Methods 323 adult patients with active RA (≥6 TJC and 6 SJC plus CRP ≥0.7 mg/dL) receiving MTX were randomized to receive DAGR 1, 5, 10 or 15 mg, prednisone (pred) 5 or 10 mg, or placebo (PBO) QD for 8 weeks followed by a 4-week taper period, and an ACTH stimulation test at Week 13. Use of GCs within 6 weeks of screening was prohibited. Efficacy analyses included characterization of dose-response at Week 8 for primary and secondary efficacy endpoints: ACR20 and DAS28-4(CRP). Effects on bone formation (P1NP, osteocalcin) and resorption (uNTX/uCr, sCTX) biomarkers, fasting plasma glucose and HbA1c were assessed for safety in addition to AEs and laboratory tests. Results Based on ACR20 responses, DAGR 10 and 15 mg QD were superior (by 20% with 80% confidence) to PBO; and DAGR 15 mg QD was non-inferior (by a margin of 5% with 80% confidence) to pred 10 mg QD. DAS28-4(CRP) results were consistent with ACR20 responses. 1, 5, 10 and 15 mg QD doses of DAGR were comparable to pred 5mg QD in bone formation; with small decreases in HbA1c in these predominantly non-diabetes patients. No clear trends or dose-response were seen in bone resorption markers. Prompt HPA axis recovery was evident at Week 13 in all patients. All DAGR doses were well-tolerated (comparable to PBO and pred doses), with no safety signal identified. Conclusions The aggregate efficacy analysis demonstrated that both DAGR 10 and 15 mg QD have efficacy superior to PBO and comparable to pred 10 mg QD, with bone and glucose effects comparable to pred 5 mg QD. All DAGR doses were safe and well-tolerated. This 8-week RCT provides first clinical evidence to demonstrate that PF-04171327 increases the transrepression/transactivation ratio, thereby improving the GC benefit-risk ratio compared with prednisone in RA patients. Disclosure of Interest F. Buttgereit Grant/research support from: Pfizer, V. Strand Consultant for: Pfizer, E. Lee Grant/research support from: Pfizer, D. McCabe Employee of: Pfizer, S. Kolluri Employee of: Pfizer, B. Tammara Employee of: Pfizer, R. Rojo Employee of: Pfizer, J. Hey-Hadavi Employee of: Pfizer

A 4-Year, Open-Label, Multicenter, Randomized Trial of Genotropin® Growth Hormone in Patients with Idiopathic Short Stature: Analysis of 4-Year Data Comparing Efficacy, Efficiency, and Safety between an Individualized, Target-Driven Regimen and Standard Dosing.

Background/Aims: Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment. Methods: This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week. Results: At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain. Conclusion: Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens.

Disease progression of cognitive impairment in Alzheimer's disease: A model-based approach

P1-260 DISEASE PROGRESSION OF COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE: A MODEL-BASED APPROACH Susan Willavize, Miia Kivipelto, D. Larry Sparks, Roy W. Jones, Andrei Breazna, David A. DeMicco, Judith Hey-Hadavi, Rachel J. Schindler, Brian Corrigan, Pfizer Global Research and Development, New London, CT, USA; Aging Research Centre, Karolinska Institute, Stockholm, Sweden; Ralph & Muriel Roberts Laboratory for Neurodegenerative Research, Sun Health Research Institute, Sun City, AZ, USA; The Research Institute for the Care of Older people, Royal United Hospital, Bath, United Kingdom; Pfizer Global Pharmaceuticals, New York, NY, USA. Contact e-mail: susan. a.willavize@pfizer.com