A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares.

OBJECTIVE: To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. METHODS: Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response. RESULTS: One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction. CONCLUSION: Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy.

PURPOSE: To explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study. METHODS: Patients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5 yrs of PEGV treatment. RESULTS: Among 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.0 ± 58.7 mg/dl at baseline, 116.4 ± 44.8 mg/dl at year 1 and 120.0 ± 44.3 mg/dl at yr 4. Mean HbA1c was 6.6 ± 1.2 % at yr 1 vs. 7.0 ± 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n = 109), mean blood glucose decreased by 20.2 mg/dl at yr 4, mean HbA1c was 7.0 ± 1.5% at baseline vs. 6.8 ± 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs. CONCLUSIONS: Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

Social, educational and vocational outcomes in patients with childhood-onset and young-adult-onset growth hormone deficiency.

OBJECTIVE: Hypopituitarism diagnosed in childhood, adolescence and young adulthood has the potential to affect growth and somatic development. Less is known about the impact of such a diagnosis on other aspects of development. DESIGN: An analysis of the KIMS database (Pfizer International Metabolic Database) was performed to explore social, educational and vocational outcomes of adult patients diagnosed in childhood, adolescence and young adulthood compared with adult-onset controls. PATIENTS: A total of 2952 adult patients diagnosed with hypothalamic pituitary conditions before the age of 25 were divided into two groups: childhood-onset [<16 years (CO)] (n = 1782) and young-adult-onset [16 to <25 years (YAO)] (n = 1170). A total of 1617 adult patients diagnosed with a nonfunctioning pituitary adenoma at the age of 25 or older formed the adult-onset control group (AO). MEASUREMENTS: KIMS Patient Life Situation Form which provided information on social, educational and vocational outcomes. RESULTS: Compared with the AO control group, CO and YAO patients were between 4·5 and 8·0 times more likely to live with their parents in adulthood; CO and YAO patients were also less likely to live in partnership and to have children. The impact on educational and vocational outcomes was less marked than on social outcomes with no significant differences compared with the AO control group. Educational and vocational outcomes showed the lowest level in male and female CO and YAO patients who had been previously diagnosed with a brain tumour. CONCLUSIONS: Social outcomes were more affected than educational and vocational outcomes. Although CO patients are more adversely affected, YAO patients were also failing to achieve social milestones. This has consequences for the delivery of endocrine care in both paediatric and adult services.

Treatment with high doses of pegvisomant in 56 patients with acromegaly: experience from ACROSTUDY.

OBJECTIVE: To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I. DESIGN: ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the 'high'-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35-60 (10-90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the 'low'-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3-10 (10-90%)). RESULTS: Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m(2)). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups. CONCLUSIONS: Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

Pregnancy outcomes in women with growth hormone deficiency.

OBJECTIVE: To study pregnancies in a large group of patients with growth hormone deficiency and hypopituitarism; and to investigate potential factors determining pregnancy outcomes and pregnancy complications. DESIGN: We analyzed pregnancies reported in KIMS, the Pfizer International Metabolic Database, of adult patients with growth hormone deficiency treated with growth hormone. SETTING: Outpatient clinics. PATIENT(S): A total of 201 pregnancies were reported: 173 in female patients and 28 in partners of male patients. INTERVENTION(S): Growth hormone replacement therapy (GHRT) was prescribed according to the local clinical practice. MAIN OUTCOME MEASURE(S): Pregnancy outcomes (live births, gestational week at delivery, and birth weight), pregnancy complications, and their relationship to use of GHRT during pregnancy were analyzed with regression models. RESULT(S): Two-thirds of women underwent fertility treatment to achieve pregnancy. Growth hormone replacement therapy was stopped before pregnancy in 7.5% of the female patients, as soon as pregnancy was confirmed in 40.1%, and at the end of the second trimester in 24.7% of the patients, whereas 27.6% continued GHRT throughout pregnancy. Birth of a healthy child was reported in 79% of the female pregnancies, nonelective abortions occurred mainly in the first trimester, and one fetal malformation (cystic hygroma) was diagnosed in the second trimester. Pregnancy outcomes and pregnancy complications were not related to GHRT treatment patterns, method of conception, or number of additional pituitary deficiencies. CONCLUSION(S): These data on pregnancy outcomes in a large group of women with hypopituitarism revealed no relationship between GHRT regimens and pregnancy outcomes.

Pregnancy in acromegaly patients treated with pegvisomant.

To summarize all available data on pregnancy outcome of acromegaly patients exposed to the growth hormone receptor antagonist pegvisomant (PEGV) during pregnancy as present in the Pfizer's Global Safety Database. Pfizer's Global Safety Database contains adverse event data obtained from the following sources: spontaneous reports, health authorities, Pfizer-sponsored post-marketing surveillance program (ACROSTUDY), customer engagement programs, and clinical studies, reported regardless of outcome. The safety database was searched up to 10th March 2014. From the 35 pregnancy cases, 27 involved maternal [mean age (range) 33.3 years (23-41) and 8 paternal (33.7 years (32-38)] PEGV exposure. Two female patients were reported with two pregnancy cases each. Fetal outcome was normal in 14 (4 paternal) of the 18 reported as live birth, while 4 cases (1 paternal) did not specify the birth outcome. At conception, PEGV mean dose (range) was 15.3 mg/d (4.3-30). In 3 cases of maternal exposure of the 18 cases reporting live birth, PEGV was continued throughout the pregnancy in a dose of 12.1 mg/d (10-15). In 5 cases (all maternal) an elective termination of the pregnancy was performed with no reported fetal abnormalities, 2 cases (maternal) reported a non-PEGV-related spontaneous abortion and in 1 maternal case an ectopic pregnancy occurred. In 9 cases (3 paternal), the fetal outcome was not reported. Three women reported gestational diabetes; one woman continued PEGV treatment during pregnancy. Although the number of reported pregnancies with exposure to PEGV is very small, the presented data reflect the largest series of data available to date and do not suggest adverse consequences of PEGV on pregnancy outcome. Nevertheless, it should be stressed that PEGV should not be used during pregnancy unless absolutely necessary.

The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients.

OBJECTIVE: Quality of life (QoL) is impaired in hypopituitary patients and patients with primary adrenal insufficiency. The aim of this study was to analyse the impact of glucocorticoid (GC) replacement on QoL. The main hypothesis was that ACTH-insufficient patients experience a dose-dependent deterioration in QoL. DESIGN, PATIENTS AND METHODS: This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Data from 2737 adult GH-deficient (GHD) hypopituitary patients were eligible for analysis. Thirty-six per cent were ACTH sufficient and 64% ACTH insufficient receiving a mean±s.d. hydrocortisone equivalent (HCeq) dose of 22.3±8.7 mg (median 20.0). QoL at baseline and 1 year after commencement of GH replacement was assessed by the QoL-assessment of GHD in adults. RESULTS: At baseline, no significant difference in QoL was observed between ACTH-sufficient and -insufficient patients. Increasing HCeq dose was associated with worse QoL. Patients on HCeq≤10 mg had the best and patients receiving ≥25 mg demonstrated the poorest QoL. At 1 year of GH replacement, the improvement in QoL did not differ between ACTH-sufficient and -insufficient patients, and no association was observed between HCeq dose and QoL improvement. CONCLUSION: Adult hypopituitary patients with untreated GHD receiving GC replacement have similar QoL as ACTH-sufficient patients. Among ACTH-insufficient patients, there is a dose-dependent association between increasing dose and impaired QoL. This association may be explained by supraphysiological GC exposure although it remains plausible that clinicians may have increased GC doses in order to address otherwise unexplained QoL deficits.

Overall and cause-specific mortality in GH-deficient adults on GH replacement.

OBJECTIVE: Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. DESIGN: In KIMS (Pfizer International Metabolic Database) 13,983 GH-deficient patients with 69,056 patient-years of follow-up were available. METHODS: This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. RESULTS: All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). CONCLUSIONS: GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

Identification of primary care patients at risk of nonadherence to antidepressant treatment.

INTRODUCTION: Poor adherence to antidepressant treatment is common, and results in increased disability and costs. Several factors are thought to influence patients' ability and willingness to adhere. So far, however, consensus is lacking regarding patient characteristics that predict nonadherence. The purpose of this study was to identify predictors of nonadherence to antidepressant treatment that can be ascertained at treatment start. METHOD: The present study used data from a randomized controlled trial with the main objective of studying the effect of two different compliance-enhancing programs on treatment adherence and treatment response in 1031 primary care patients with major depression. In this study, logistic regression analyses were performed to examine patient- and illness-related characteristics potentially associated with nonadherence. RESULTS: Nonadherence to antidepressant treatment was predicted by age under 35 or over 64 years, presence of personality disorder, sensation-seeking personality traits, substance abuse, and absence of concomitant medications. CONCLUSION: Certain patient- and illness-related characteristics may imply an increased risk of nonadherence to antidepressant treatment. Giving special attention to subjects with such characteristics may improve adherence.

Response, remission and relapse in relation to adherence in primary care treatment of depression: a 2-year outcome study.

Non-adherence to antidepressant drug treatment is common. In a recent study in depressed primary care patients, we reported a strong relationship between adherence and response after 6 months. With the use of a naturalistic design, the patients in that study were prospectively followed for 2 years. The purpose of the present study was to investigate the patients' long-term outcome and, in particular, to examine the impact of patients' treatment adherence on response, remission and relapse. Of the 1031 patients in the intent-to-treat (ITT) sample, 835 completed the study. After 2 years, the overall remission rate defined as a Montgomery-Asberg Depression Rating Scale score of nine or less was 68% in the ITT sample analysed with the last observation carried forward (LOCF) technique, and 75% in observed cases. In total, 34% of the responders experienced at least one relapse. Response rates (LOCF) were significantly higher in adherent compared to non-adherent patients at week 24 [95% confidence interval (CI) = 21.4-32.1], year 1 (95% CI = 12.3-22.2) and year 2 (95% CI = 9.2-19.0). Remission rates (LOCF) were also significantly higher in the group of adherent patients at week 24 (95% CI = 9.6-21.5), year 1 (95% CI = 10.0-21.5) and year 2 (95% CI = 11.0-22.0). No relationship between adherence and relapse rate was observed, although the mean time from response to first sign of relapse was significantly longer in the adherent patients (95% C I= 9-97 days). In conclusion, this 2-year follow-up study showed superior long-term recovery in patients who were adherent to antidepressant medication compared to non-adherent patients.

Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations.

BACKGROUND: A recent estimation in a psychiatric cohort showed numbers of noncompliance between 10% and 60%. Therapeutic drug monitoring (TDM) is one method assessing compliance by analysis of drug concentration in the blood. METHOD: During a 24-week phase IV clinical trial, five repeated serum samples of sertraline (SERT) and N-desmethylsertraline (DSERT), trough values in steady state, were collected per patient. Previous results show that the intraindividual variation over time of the ratio DSERT/SERT is low. Hence, we hypothesized that significant partial noncompliance could be scrutinized further by an assessment of the DSERT/SERT ratio. The main aim was to test the applicability of a novel type of TDM procedure based on repeated metabolite/parent compound ratio measurements. RESULT: 9.4% of the per-protocol population in the trial (n = 96) were in either hidden total (n = 4) or hidden partial (n = 5) noncompliance. Only by using the novel TDM ratio screening method could a majority of these patients be identified.

Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression.

Sertraline and paroxetine are frequently prescribed SSRIs for long-term treatment of major depression. Nevertheless, continuous follow-ups of drug concentrations prevailing in patients during the whole treatment period are not available. Hence, in a large phase IV clinical trial, a total of 353 patients with major depression were enrolled for a 6-month comparison of sertraline (50-150 mg daily) and paroxetine (20-60 mg daily). The present study reports the pharmacokinetic results of up to eight serum samples per patient. 1. A profound variability was found in the interindividual steady state and trough serum levels of sertraline, desmethylsertraline and paroxetine: the coefficient of variation (CV) was 59% for sertraline, 51% for desmethylsertraline, 27% for the ratio desmethylsertraline/sertraline (50 mg/day), and 71% for paroxetine (20 mg/day). The intraindividual CV for the ratio desmethylsertraline/sertraline was only 19%, indicating intraindividual metabolizing stability over time. Both sertraline and paroxetine displayed sex differences in the dose-concentration correlation. 2. It was possible to predict sertraline, but not paroxetine, steady state levels. 3. The terminal elimination t(1/2) for both drugs after 6 months of treatments was similar to data previously reported from short-term withdrawal studies. 4. No correlation between serum drug concentrations and clinical effect was detected for either sertraline or paroxetine. For the future, continuous efforts are warranted to perform PK investigations in the natural clinical setting in which the drugs are usually prescribed.

Effects of an educational compliance enhancement programme and therapeutic drug monitoring on treatment adherence in depressed patients managed by general practitioners.

Medication non-adherence is a major obstacle in the treatment of affective disorders. The primary objective of this study was to evaluate two different interventions to improve adherence to antidepressant drugs. Secondary objectives included response to treatment, relation between adherence and response, patient satisfaction and tolerability. A randomized controlled design was used to assess the effect of a patient educational compliance enhancing programme (CP) and therapeutic drug monitoring in 1031 major depressed patients treated with sertraline for 24 weeks and managed by their general practitioner. Adherence was measured by questioning, measurable serum levels of sertraline and desmethylsertraline, appointments kept and a composite index including all three methods. Treatment adherence was found in 37-70% of patients, depending on the method used. Neither of the interventions resulted in a significant increase in adherence rate. However, significantly more patients in the CP group had responded at week 24 compared to patients in the control group. Overall, significantly more adherent patients responded to treatment compared to non-adherent patients, regardless of method used to determine adherence. This large study demonstrates that treatment response increases when using an educational compliance programme and that a strong relationship between treatment adherence and response exists.