Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338).

BACKGROUND: Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18-34 kg/m2) with stable health and diet. The study comprised seven treatment groups (Cohorts 1-7). Participants received bimagrumab or placebo treatment every 4 weeks for three doses (Cohorts 1 [700 mg] and 2 [210 mg] intravenous infusion; Cohorts 3 [1500 mg] and 4 [525 mg] subcutaneous infusion), or every week for 12 doses (Cohorts 5 [300 mg], 6 [150 mg], and 7 [52.5 mg] subcutaneous bolus injection) and were followed up until week 20. Blood samples were collected for bimagrumab PK analysis. PD were assessed by dual energy X-ray absorptiometry to quantify the change from baseline in lean body mass (LBM) and fat body mass (FBM) compared with placebo. Safety was assessed throughout the study. RESULTS: Eighty-four of 91 (92.3%) randomized participants (mean age 74.5 years; BMI 28.0 kg/m2) completed the study. Demographic characteristics were generally balanced across the groups. A target-mediated drug disposition profile was observed following both intravenous and subcutaneous administration. The absolute subcutaneous bioavailability was estimated at approximately 40%. LBM increased by 4-6% (1.5-2 kg) from baseline throughout the treatment period for intravenous and subcutaneous regimens, except for the 52.5 mg subcutaneous dose, which did not differ from placebo. Concurrently, there was a decrease in FBM (approximately 2-3 kg) for all intravenous and subcutaneous regimens. Bimagrumab was generally safe and well tolerated; adverse events were mostly mild to moderate in severity. CONCLUSIONS: Dose levels of bimagrumab administered weekly subcutaneously resulted in PK profiles and PD effects comparable with monthly intravenous dosing, which supports the feasibility of the subcutaneous route of administration for bimagrumab for future clinical development.

Longitudinal Changes in MRI Muscle Morphometry and Composition in People With Inclusion Body Myositis.

BACKGROUND AND OBJECTIVES: Limited data suggest that quantitative MRI (qMRI) measures have potential to be used as trial outcome measures in sporadic inclusion body myositis (sIBM) and as a noninvasive assessment tool to study sIBM muscle pathologic processes. Our aim was to evaluate changes in muscle structure and composition using a comprehensive multiparameter set of qMRI measures and to assess construct validity and responsiveness of qMRI measures in people with sIBM. METHODS: This was a prospective observational cohort study with assessments at baseline (n = 30) and 1 year (n = 26). qMRI assessments include thigh muscle volume (TMV), inter/intramuscular adipose tissue (IMAT), muscle fat fraction (FF), muscle inflammation (T2 relaxation time), IMAT from T2* relaxation (T2*-IMAT), intermuscular connective tissue from T2* relaxation (T2*-IMCT), and muscle macromolecular structure from the magnetization transfer ratio (MTR). Physical performance assessments include sIBM Physical Functioning Assessment (sIFA), 6-minute walk distance, and quantitative muscle testing of the quadriceps. Correlations were assessed using the Spearman correlation coefficient. Responsiveness was assessed using the standardized response mean (SRM). RESULTS: After 1 year, we observed a reduction in TMV (6.8%, p < 0.001) and muscle T2 (6.7%, p = 0.035), an increase in IMAT (9.7%, p < 0.001), FF (11.2%, p = 0.030), connective tissue (22%, p = 0.995), and T2*-IMAT (24%, p < 0.001), and alteration in muscle macromolecular structure (ΔMTR = -26%, p = 0.002). A decrease in muscle T2 correlated with an increase in T2*-IMAT (r = -0.47, p = 0.008). Deposition of connective tissue and IMAT correlated with deterioration in sIFA (r = 0.38, p = 0.032; r = 0.34, p = 0.048; respectively), whereas a decrease in TMV correlated with a decrease in quantitative muscle testing (r = 0.36, p = 0.035). The most responsive qMRI measures were T2*-IMAT (SRM = 1.50), TMV (SRM = -1.23), IMAT (SRM = 1.20), MTR (SRM = -0.83), and T2 relaxation time (SRM = -0.65). DISCUSSION: Progressive deterioration in muscle quality measured by qMRI is associated with a decline in physical performance. Inflammation may play a role in triggering fat infiltration into muscle. qMRI provides valid and responsive measures that might prove valuable in sIBM experimental trials and assessment of muscle pathologic processes. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that qMRI outcome measures are associated with physical performance measures in patients with sIBM.

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Bimagrumab to improve recovery after hip fracture in older adults: a multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial.

BACKGROUND: Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. METHODS: This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15-35 kg/m2 who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. FINDINGS: Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p<0·0001) and in the bimagrumab 700 mg group 2·8 kg [2·2]; p<0·0001) but not in the bimagrumab 70 mg group (0·6 kg [SD 2·2]; significance not assessed). Changes in habitual gait speed and short physical performance battery scores between baseline and week 24 were not significantly different across the treatment groups, suggesting no enhancement of physical recovery with bimagrumab over placebo. Bimagrumab was safe and well tolerated. The most frequently reported treatment-emergent adverse events were falls (six [18%] of 34 participants in the bimagrumab 70 mg group; 12 [17%] of 69 participants in the bimagrumab 210 mg group; 14 [19%] of 75 participants in the bimagrumab 700 mg group; and 13 [18%] of 72 participants in the placebo group), muscle spasms (two [6%] in the bimagrumab 70 mg group; 17 [25%] in the bimagrumab 210 mg group; 12 [16%] in the bimagrumab 700 mg group; and six [8%] in the placebo group), and arthralgia (five [15%] in the bimagrumab 70 mg group; six [9%] in the bimagrumab 210 mg group; nine [12%] in the bimagrumab 700 mg group; and five [7%] in the placebo group). Six deaths were reported during the study, none of which were considered by investigators as related to the study drug. INTERPRETATION: Bimagrumab treatment for 24 weeks led to dose-dependent, significant increases in lean body mass in older patients recovering from hip fracture surgery when compared with placebo. However, no functional benefit was observed in recovery of mobility or lower extremity function following bimagrumab treatment compared with placebo. FUNDING: Novartis Pharma.

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes.

BACKGROUND: Bimagrumab is a human monoclonal antibody inhibitor of activin type II receptors (ActRII), with anabolic action on skeletal muscle mass by blocking binding of myostatin and other negative regulators of muscle growth. Bimagrumab is under evaluation for muscle wasting and associated functional loss in hip fracture and sarcopenia, and in obesity. Bimagrumab also blocks other endogenous ActRII ligands, such as activins, which act on the neurohormonal axes, pituitary, gonads and adrenal glands. AIM: To evaluate the effect of bimagrumab on the pituitary-gonadal and pituitary-adrenal axes in humans. METHODS: Healthy men and women, aged 55 to 75 years, received bimagrumab intravenously 10 mg/kg or placebo on Day 1 and Day 29. Pituitary-gonadal and pituitary-adrenal functions were evaluated with basal hormone measurement and standard gonadotropin-releasing hormone (GnRH) and adrenocorticotropic hormone (ACTH) stimulation tests at baseline, Week 8 and at the end of study (EOS)-Week 20. RESULTS: At Week 8, follicle-stimulating hormone (FSH) levels were reduced by 42.16 IU/L (P < .001) and luteinizing hormone (LH) levels were increased by 2.5 IU/L (P = .08) over placebo in response to bimagrumab in women but not in men. Effects that were reversible after bimagrumab was cleared. Gonadal and adrenal androgen levels were not affected by exposure to bimagrumab. CONCLUSION: Bimagrumab alters the function of pituitary gonadotroph cells, consistent with blockade of activin on local ActRII. This effect is reversible with clearance of bimagrumab. Bimagrumab did not impact gonadal and adrenal androgen secretion.

Evaluation of etoricoxib in patients undergoing total knee replacement surgery in a double-blind, randomized controlled trial.

BACKGROUND: Optimal postoperative pain management is important to ensure patient comfort and early mobilization. METHODS: In this double-blind, placebo- and active-controlled, randomized clinical trial, we evaluated postoperative pain following knee replacement in patients receiving placebo, etoricoxib (90 or 120 mg), or ibuprofen 1800 mg daily for 7 days. Patients ≥18 years of age who had pain at rest ≥5 (0-10 Numerical Rating Scale [NRS]) after unilateral total knee replacement were randomly assigned to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen 1800 mg (N = 224) postoperatively. Co-primary endpoints included Average Pain Intensity Difference at Rest over Days 1-3 (0- to 10-point NRS) and Average Total Daily Dose of Morphine over Days 1-3. Pain upon movement was evaluated using Average Pain Intensity Difference upon Knee Flexion (0- to 10-point NRS). The primary objective was to demonstrate analgesic superiority for the etoricoxib doses vs. placebo; the secondary objective was to demonstrate that the analgesic effect of the etoricoxib doses was non-inferior to ibuprofen. Adverse experiences (AEs) including opioid-related AEs were evaluated. RESULTS: The least squares (LS) mean (95% CI) differences from placebo for Pain Intensity Difference at Rest over Days 1-3 were -0.54 (-0.95, -0.14); -0.49 (-0.89, -0.08); and -0.45 (-0.85, -0.04) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.05 for etoricoxib vs. placebo). Differences in LS Geometric Mean Ratio morphine use over Days 1-3 from placebo were 0.66 (0.54, 0.82); 0.69 (0.56, 0.85); and 0.66 (0.53, 0.81) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.001 for etoricoxib vs. placebo). Differences in LS Mean Pain Intensity upon Knee Flexion were -0.37 (-0.85, 0.11); -0.46 (-0.94, 0.01); and -0.42 (-0.90, 0.06) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. Opioid-related AEs occurred in 41.8%, 34.7%, 36.5%, and 36.3% of patients on placebo, etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. CONCLUSIONS: Postoperative use of etoricoxib 90 and 120 mg in patients undergoing total knee replacement is both superior to placebo and non-inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption. CLINICAL TRIAL REGISTRATION: NCT00820027.

MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study.

Most elderly patients admitted for hip fracture suffer functional decline. Previous studies with MK-0677 in hip fracture patients suggested possible benefits to functional recovery. This is a randomized, double-blind study of 123 elderly hip fracture patients assigned to receive 25mg/day of MK-0677 (n = 62) or placebo (n = 61). Primary outcomes were a rank analysis of change during the study in objective functional performance measurements and insulin-like growth factor-1 (IGF-1) levels in blood. At 24-weeks, the mean stair climbing power increased by 12.5 W in the MK-0677 group (95% confidence interval (CI) = -10.95-35.88; p = 0.292) compared with placebo. Gait speed increased by a 0.7-score difference in the means (95% CI = 0.17-1.28; p = 0.011). There was no improvement in MK-0677 treated patients in several other functional performance measures. The MK-0677 group experienced fewer falls during the study compared to placebo and smaller number of patients who had any falls (p = 0.096). Levels of IGF-1 in treated patients increased by 51.4 ng/ml (95% CI = 34.42-68.44; p < 0.001) compared to placebo. Trial was terminated early due to a safety signal of congestive heart failure in a limited number of patients. In hip fracture patients treated with 25mg/day MK-0677, the increase in plasma IGF-1 levels was not paralleled by improvement in most functional performance measures. MK-0677 has an unfavorable safety profile in this patient population.

Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency.

BACKGROUND: Vitamin D insufficiency, which is prevalent in older individuals, is associated with bone and muscle weakness and falls. OBJECTIVE: We examined the effects of a weekly dose of 8400 IU vitamin D(3) on postural stability, muscle strength, and safety. DESIGN: In this double-blind trial, subjects aged > or =70 y with serum 25-hydroxyvitamin D [25(OH)D] concentrations < or =20 but > or =6 ng/mL were randomly assigned to receive a weekly dose of 8400 IU vitamin D(3) (n = 114) or a placebo (n = 112). Mediolateral body sway with eyes open (assessed with the AccuSway(PLUS) platform; Advanced Medical Technology Inc, Watertown, MA) was the primary endpoint. Secondary endpoints included the short physical performance battery (SPPB) and serum 25(OH)D concentrations. An analysis of covariance model was used for treatment comparisons. Safety and tolerability were monitored. RESULTS: Serum 25(OH)D concentrations rose significantly (from 13.9 to 26.2 ng/mL, P < 0.001) in patients treated with 8400 IU vitamin D(3) but not in patients treated with the placebo. After 16 wk, neither mediolateral sway nor SPPB differed significantly between treatment groups. However, in the post hoc analysis of patients subgrouped by baseline sway (> or = 0.46 compared with <0.46 cm), treatment with 8400 IU vitamin D(3) significantly reduced sway compared with treatment with placebo (P = 0.047) in patients with elevated baseline sway but not in patients with normal baseline sway. Adverse experiences and incidences of hypercalcemia, hypercalciuria, and elevated creatinine were similar with both treatments. In patients treated with 8400 IU vitamin D(3), but not in placebo-treated patients, parathyroid hormone decreased significantly. CONCLUSIONS: Weekly treatment with 8400 IU vitamin D(3) raised 25(OH)D concentrations in elderly, vitamin D-insufficient individuals. Treatment with 8400 IU vitamin D(3) did not reduce mediolateral sway significantly compared with treatment with placebo in this population, although in post hoc analysis, treatment with 8400 IU vitamin D(3) reduced sway in the subgroup of patients who had elevated sway at baseline. Weekly treatment with 8400 IU vitamin D(3) was well tolerated. This trial was registered at clinicaltrials.gov as NCT00242476.

Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone.

BACKGROUND: When vitamin C intake is from foods, fasting plasma concentrations do not exceed 80 micromol/L. We postulated that such tight control permits a paracrine function of vitamin C. OBJECTIVE: The purpose of this study was to determine whether paracrine secretion of vitamin C from the adrenal glands occurs. DESIGN: During diagnostic evaluation of 26 patients with hyperaldosteronism, we administered adrenocorticotrophic hormone intravenously and measured vitamin C and cortisol in adrenal and peripheral veins. RESULTS: Adrenal vein vitamin C concentrations increased in all cases and reached a peak of 176 +/- 71 micromol/L at 1-4 min, whereas the corresponding peripheral vein vitamin C concentrations were 35 +/- 15 micromol/L (P<0.0001). Mean adrenal vein vitamin C increased from 39 +/- 15 micromol/L at 0 min, rose to 162 +/- 101 micromol/L at 2 min, and returned to 55 +/- 16 micromol/L at 15 min. Adrenal vein vitamin C release preceded the release of adrenal vein cortisol, which increased from 1923 +/- 2806 nmol/L at 0 min to 27 191 +/- 16 161 nmol/L at 15 min (P<0.0001). Peripheral plasma cortisol increased from 250 +/- 119 nmol/L at 0 min to 506 +/- 189 nmol/L at 15 min (P<0.0001). CONCLUSIONS: Adrenocorticotrophic hormone stimulation increases adrenal vein but not peripheral vein vitamin C concentrations. These data are the first in humans showing that hormone-regulated vitamin secretion occurs and that adrenal vitamin C paracrine secretion is part of the stress response. Tight control of peripheral vitamin C concentration is permissive of higher local concentrations that may have paracrine functions.

Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study.

CONTEXT: Chronic fatigue syndrome (CFS) is an important public health problem. The causes of CFS are unknown and effective prevention strategies remain elusive. A growing literature suggests that early adverse experience increases the risk for a range of negative health outcomes, including fatiguing illnesses. Identification of developmental risk factors for CFS is critical to inform pathophysiological research and devise targets for primary prevention. OBJECTIVE: To examine the relationship between early adverse experience and risk for CFS in a population-based sample of clinically confirmed CFS cases and nonfatigued control subjects. DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 43 cases with current CFS and 60 nonfatigued controls identified from a general population sample of 56 146 adult residents from Wichita, Kan. MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical, and emotional abuse and emotional and physical neglect) and psychopathology (depression, anxiety, and posttraumatic stress disorder) by CFS status. RESULTS: The CFS cases reported significantly higher levels of childhood trauma and psychopathology compared with the controls. Exposure to childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types. There was a graded relationship between the degree of trauma exposure and CFS risk. Childhood trauma was associated with greater CFS symptom severity and with symptoms of depression, anxiety, and posttraumatic stress disorder. The risk for CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology. CONCLUSIONS: This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with nonfatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS.

Increased plasma interleukin 6 concentrations and exaggerated adipose tissue interleukin 6 content in severely obese patients after operative trauma.

BACKGROUND: The cytokine response to operative trauma may be altered in obesity. Thus, we monitored changes in systemic and adipose tissue content of interleukin 6 (IL-6) and in insulin resistance in nonobese versus severely obese patients before and immediately after abdominal operations. METHODS: At the beginning and the end of operation, blood samples and biopsies consisting of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were collected from 13 nonobese and 33 severely obese patients. Systemic concentrations of glucose, insulin, and IL-6, as well as adipose tissue content of IL-6, were determined. RESULTS: Plasma IL-6 concentration and adipose tissue content of IL-6 increased, compared with baseline in patients after operation (plasma, 13- and 5.7-fold; VAT, 270- and 210-fold; SAT, 79- and 8.2-fold in severely obese vs nonobese patients, respectively). The increase in IL-6 in plasma and in both VAT and SAT was exaggerated in severely obese patients, compared with nonobese patients. Increases after operation in plasma IL-6 concentrations were correlated positively to the corresponding increases in both SAT and VAT IL-6 content (r = 0.57 and 0.66, respectively). Also, we found a positive correlation between the worsening of insulin resistance and increases in both plasma and SAT IL-6 concentrations (r = 0.40 and 0.51, respectively). CONCLUSIONS: Circulating IL-6 concentrations both at baseline and after operation are related strongly to abdominal adipose tissue content of content of IL-6 and are exaggerated in severely obese persons. After operation, worsening of insulin resistance is associated with increasing plasma and adipose tissue content of IL-6.

Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS.

OBJECTIVE: Studies of primary and tertiary care patients suggest that maladaptive coping styles contribute to the pathogenesis and maintenance of chronic fatigue syndrome (CFS). We assessed coping styles in persons with unexplained fatigue and nonfatigued controls in a population-based study. METHODS: We enrolled 43 subjects meeting the 1994 Research Case Definition of CFS, matching them with 61 subjects with chronic unexplained fatigue who did not meet criteria for CFS [we term them insufficient symptoms or fatigue (ISF)] and 60 non-ill (NI) controls. Coping styles and clinical features of CFS were assessed using standard rating scales. RESULTS: Subjects with CFS and ISF reported significantly more escape-avoiding behavior than NI controls. There were no differences between the CFS and ISF subjects. Among participants with CFS, escape-avoiding behavior was associated with fatigue severity, pain, and disability. CONCLUSIONS: We demonstrate significantly higher reporting of maladaptive coping in a population-based sample of people with CFS and other unexplained fatiguing illnesses defined by reproducible standardized clinical empirical means in comparison to NI controls.

Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome.

Patients with chronic fatigue syndrome (CFS) frequently complain of cognitive dysfunction. However, evidence of cognitive impairment in CFS patients has been found in some, but not other, studies. This heterogeneity in findings may stem from the relative presence of mental fatigue in the patient populations examined. The present study assessed this possibility in a population-based sample of CFS patients. In all, 43 patients with CFS defined by the criteria of the 1994 research case definition using measurements recommended by the 2003 International CFS Study Group, and 53 age-, sex-, and race/ethnicity-matched nonfatigued subjects were included in the study. Mental fatigue was assessed using the mental fatigue subscale of the multidimensional fatigue inventory. Cognitive function was evaluated using an automated battery of computerized tests (Cambridge neuropsychological test automated battery (CANTAB)) that assessed psychomotor function, planning and problem-solving abilities, and memory and attentional performance. CFS patients with significant complaints of mental fatigue (score of mental fatigue 2 standard deviations above the mean of nonfatigued subjects) exhibited significant impairment in the spatial working memory and sustained attention (rapid visual information processing) tasks when compared to CFS patients with low complaints of mental fatigue and nonfatigued subjects. In CFS patients with significant mental fatigue, sustained attention performance was impaired only in the final stages of the test, indicating greater cognitive fatigability in these patients. CFS patients with low mental fatigue displayed performance comparable to nonfatigued subjects on all tests of the CANTAB battery. These findings show strong concordance between subjective complaints of mental fatigue and objective measurement of cognitive impairment in CFS patients and suggest that mental fatigue is an important component of CFS-related cognitive dysfunction.

Chronic fatigue syndrome--a clinically empirical approach to its definition and study.

BACKGROUND: The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria. METHODS: This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms). RESULTS: One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm. CONCLUSION: The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.

Orthostatic instability in a population-based study of chronic fatigue syndrome.

PURPOSE: Autonomic nervous system dysfunction has been suggested as involved in the pathophysiology of chronic fatigue syndrome. This population-based case control study addressed the potential association between orthostatic instability (one sign of dysautonomia) and chronic fatigue syndrome. SUBJECTS AND METHODS: Fifty-eight subjects who fulfilled criteria of the 1994 chronic fatigue syndrome research case definition and 55 healthy controls participated in a 2-day inpatient evaluation. Subjects had been identified during a 4-year population-based chronic fatigue syndrome surveillance study in Wichita, Kan. The present study evaluated subjects' current medical and psychiatric status, reviewed past medical/psychiatric history and medication use, used a stand-up test to screen for orthostatic instability, and conducted a head-up tilt table test to diagnose orthostatic instability. RESULTS: No one manifested orthostatic instability in the stand-up test. The head-up tilt test elicited orthostatic instability in 30% of eligible chronic fatigue syndrome subjects (all with postural orthostatic tachycardia) and 48% of controls (50% with neurally mediated hypotension); intolerance was present in only nonfatigued (n=7) subjects. Neither fatigue nor illness severity were associated with outcome. CONCLUSIONS: Orthostatic instability was similar in persons with chronic fatigue syndrome and nonfatigued controls subjects recruited from the general Wichita population. Delayed responses to head-up tilt tests were common and may reflect hydration status. These findings suggest reappraisal of primary dysautonomia as a factor in the pathogenesis of chronic fatigue syndrome.

Changes in C-reactive protein predict insulin sensitivity in severely obese individuals after weight loss surgery.

The production of inflammatory mediators by abdominal adipose tissue may link obesity and insulin resistance. We determined the influence of systemic levels of interleukin-6 and C-reactive protein on insulin sensitivity after weight loss via Roux-en-Y gastric bypass surgery. Severely obese individuals (n = 15) were evaluated at baseline and at 6 months after surgery. Insulin sensitivity was determined by frequently sampled intravenous glucose tolerance testing at the same time points. Visceral and subcutaneous adipose tissue volumes were quantified by computed tomography. Interleukin-6 and C-reactive protein were measured by enzyme-linked immunoassay in plasma and in adipose tissue biopsies. Correlation analysis was used to determine associations between insulin sensitivity and other outcome variables. Significance was set at P < 0.05. Plasma interleukin-6 concentrations were significantly correlated to the IL-6 content of subcutaneous adipose tissue (r = 0.71). At 6 months postsurgery, subcutaneous and visceral adipose tissue volumes were significantly reduced (34.7% and 44.1%, respectively) and insulin sensitivity had improved by 160.9%. Significant longitudinal correlations were found between insulin sensitivity and plasma C-reactive protein (r = -0.61), but not plasma interleukin-6 at 6 months. These findings offer insights that link obesity and insulin resistance via the activity of inflammatory mediators.

Immunologic aspects of chronic fatigue syndrome. Report on a Research Symposium convened by The CFIDS Association of America and co-sponsored by the US Centers for Disease Control and Prevention and the National Institutes of Health.

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800,000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the immune system. A symposium was organized in October 2001 to explore the possibility of an association between immune dysfunction and CFS, with special emphasis on the interactions between immune dysfunction and other abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting. Data suggest that persons with CFS manifest changes in immune responses that fall outside normative ranges, but current research does not provide definitive evidence on whether these immune abnormalities are a cause or result of the illness. It has become clear that CFS cannot be understood based on single measurements of immune, endocrine, cardiovascular, or autonomic nervous system dysfunction. This panel encourages a new emphasis on multidisciplinary research into CFS.

The effects of gastric surgery on systemic ghrelin levels in the morbidly obese.

HYPOTHESIS: Circulating ghrelin, produced primarily in the stomach, is a powerful orexigen. Ghrelin levels are elevated in states of hunger, but rapidly decline postprandially. Early alterations in ghrelin levels in morbidly obese patients undergoing weight reduction surgery may be attributed to gastric partitioning. DESIGN AND PATIENTS: Thirty-four patients underwent Roux-en-Y gastric bypass with a completely divided gastroplasty to create a 15-mL vertically oriented gastric pouch. Eight other patients underwent other gastric procedures that did not involve complete division of the stomach, including 4 vertical banded gastroplasties and 4 antireflux surgical procedures. Six additional patients undergoing antireflux surgery served as lean control subjects. Plasma samples were obtained before surgery and immediately after surgery. In a substudy, plasma was collected after Roux-en-Y limb formation and after dividing the stomach to identify any changes in plasma ghrelin levels. SETTING: Tertiary university medical center. MAIN OUTCOME MEASURES: Ghrelin levels at different stages of surgical intervention. RESULTS: Mean +/- SEM preoperative and postoperative ghrelin levels in the gastric bypass group were 355 +/- 20 and 246 +/- 13 pg/mL, respectively (P<.001). In the vertical banded gastroplasty group and in all patients undergoing antireflux surgery, ghrelin levels were not significantly changed. CONCLUSIONS: Compared with morbidly obese humans, lean controls had significantly higher plasma ghrelin levels at baseline. A divided gastroplasty creating a small proximal gastric pouch results in significant early declines in circulating ghrelin levels that are not observed with other gastric procedures. This may explain, in part, the loss of hunger sensation and rapid weight loss observed following gastric bypass surgery.