***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Clinical investigators are increasingly testing treatments that have the primary benefit of decreased burden or harms relative to an existing st and ard . The goal of the result ing r and omized trials -- called noninferiority trials -- is to establish that the novel treatment 's effectiveness is not substantially less than the existing st and ard . Conclusions from these trials are , however , based on noninferiority thresholds specified by authors whose judgments may not coincide with those of patients and clinicians . This article highlights issues related to validity , interpretation , and applicability of results specific to noninferiority trials . Suboptimal administration of st and ard treatment or exclusive reliance on the analyze-as-r and omized approach that is st and ard for conventional superiority trials may produce misleading results in noninferiority trials . Clinicians should judge whether the novel treatment 's impact on effectiveness outcomes --the prime reason for wanting to prescribe it -- is sufficiently close to that of st and ard treatment that they are comfortable substituting it for the existing st and ard . Trading off desirable and undesirable consequences is an individual decision : given the benefits of a novel treatment , some patients may perceive the uncertainty regarding a reduction in treatment effectiveness as acceptable while others may not Background : Individuals with type 2 diabetes mellitus have impairments in early insulin release , result ing in increased postpr and ial glucose excursions and suboptimal glycemic control . Studies with Technosphere ® Insulin ( TI ) indicate that it has rapid systemic absorption and a short duration of glucose-lowering activity , making it well suited for controlling postpr and ial glucose levels . Methods : The goal of this phase 2b , prospect i ve , multicenter , double-blind , placebo-controlled study was to characterize the dose response of four different doses ( equivalent to 3.6 , 7.3 , 10.9 , and 14.6 U subcutaneous regular human insulin ) of pr and ial TI or Technosphere powder alone administered before each of three meals daily , in combination with insulin glargine over an 11-week treatment period , in patients with type 2 diabetes and suboptimal glycemic control . Conclusions : This study demonstrated that , over 11 weeks , TI plus basal insulin glargine is well tolerated and results in dose-dependent reductions in postpr and ial glucose and HbA1c levels . Results : The study enrolled 227 patients . In all dose groups , TI demonstrated statistically significant dose-dependent reductions in hemoglobin A1c ( HbAlc ) versus baseline ( −0.4 , −0.5 , −0.5 , and −0.6 for 3.6 , 7.3 , 10.9 , and 14.6 U equivalents , respectively ; p < 0.05 in all groups ) , as well as versus placebo or Technosphere powder alone ( −0.40 , −0.67 , −0.70 , and −0.78 for 3.6 , 7.3 , 10.9 , and 14.6 U equivalents , respectively ; p < 0.04 in all groups ) . It reduced the postpr and ial maximum glucose concentration within each treatment group ( statistically significant in all but the TI 3.6 U-equivalent group ) and reduced the postpr and ial area under the glucose curve ( statistically significant for the TI 10.9 and 14.6 U-equivalent groups ) versus placebo . There were no cases of severe hypoglycemia , while mild/moderate hypoglycemia was observed most frequently in the highest dosage groups , as expected . Rates of cough were low and comparable among all groups . No clinical ly relevant changes in pulmonary function tests , body weight , or high-resolution computerized axial tomography and magnetic resonance imaging were observed Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more The development of pulmonary insulin formulation offers an attractive alternative to the current requirement of repeated subcutaneous ( s.c . ) injections for insulin administration . Technosphere/Insulin is a formulation of regular human insulin that was design ed to produce an efficient transport of insulin across the respiratory epithelium into the systemic circulation . Several studies using the euglycemic clamp technique were performed in healthy volunteers and patients with Type 2 diabetes to assess the pharmacokinetic and pharmacodynamic properties of Technosphere/Insulin . The investigations revealed a very rapid systemic insulin uptake ( insulin T(max ) approximately 12 - 14 min ) , a fast onset of action ( maximum activity approximately 20 - 30 min ) , and a short duration of action ( approximately 2 - 3 h ) in healthy volunteers and in patients with Type 2 diabetes . In the first study , employing a commercially available inhaler , the relative bioavailability ( compared with s.c . injections ) was initially reported to be 26 % for the first 3 h and 16 % for the entire observation period of 6 h. With the development of a specific inhaler adapted to the physical properties of Technosphere/Insulin , the MedTone Inhaler , relative bioavailability was 50 % for the first 3 h and 30 % over the entire 6-h period . A clear linearity of systemic insulin uptake was observed in a study employing 12 healthy volunteers inhaling doses of 25 , 50 , and 100 IU . Repeated inhalation of 100 IU of Technosphere/Insulin by 12 patients with Type 2 diabetes revealed a lower variability in comparison with published s.c . injection data from healthy volunteers . This new Technosphere/Insulin formulation was well tolerated , and no serious adverse events were reported in any of the investigations . Given its attractive time-action profile , Technosphere/Insulin may become a suitable alternative to s.c . injection for pr and ial insulin delivery , especially in patients with Type 2 diabetes , if the long-term safety , tolerability , and efficacy of this pulmonary insulin are established and confirmed in future studies AIMS This study assessed patient-reported outcomes in a multicenter study of adults with type 2 diabetes taking mealtime Technosphere ( ® ) inhaled insulin  ( MannKind Corp. , Valencia , CA ) and basal insulin ( insulin glargine ) or premixed aspart insulin 70/30 . METHODS Subjects were 618 non-smoking adults with starting hemoglobin A1c > 7.0 % : 302 in the Technosphere+glargine ( TI+G ) arm and 316 in the biphasic rapid-acting insulin arm ( premixed aspart insulin 70/30 ) . Subjects ( 47 % male ; mean age , 56 years ; mean duration of diagnosed diabetes , 13.4 years ) completed a measure of health-related quality of life ( the SF-36 ) and a measure of treatment satisfaction ( the Inhaled Insulin Treatment Question  naire [ IITQ ] ) before starting insulin treatment and approximately 45 weeks later . RESULTS There were no significant changes in either treatment arm for SF-36 Physical or Mental Component Summary measures . IITQ Diabetes Worries declined significantly in the TI+G arm ( P=0.008 ) , and Perceptions of Insulin Therapy , Treatment Satisfaction , and Treatment Preference improved in both arms ( all P<0.001 ) ; there were no significant between-arm differences in change on any of these measures . CONCLUSIONS Treatment with inhaled Technosphere insulin was implemented without a negative impact on health-related quality of life and with a reduction in diabetes worries . Improvements in perceptions of insulin therapy , treatment satisfaction , and treatment preference did not differ from treatment with premixed aspart insulin AIMS Development of inhaled insulin has increased the need to underst and its pulmonary safety . This study evaluated pulmonary function changes in diabetes patients receiving inhaled Technosphere Insulin ( TI ) or usual antidiabetes treatment ( usual care ) .  METHODS This r and omized , open-label study was conducted at 220 sites ( 25 July 2005 to 29 August 2008 ) .  Pulmonary function tests [ forced expiratory volume in 1 s ( FEV(1 ) ) , forced vital capacity ( FVC ) , total lung capacity ( TLC ) and lung diffusion capacity for carbon monoxide ( DL(CO ) ) ] were prospect ively followed over 2 years in patients with type 1 or type 2 diabetes receiving TI ( n = 730 ) or usual care ( n = 824 ) , along with a cohort without diabetes not receiving any specific therapy ( n = 145 ) . RESULTS Baseline demographics and pulmonary function were similar between diabetes treatment groups . Lung function declined from baseline in all groups . TI was non-inferior to usual care for mean change in FEV(1 ) from baseline to month 24 [ mean ( s.e.m . ) 0.037 ( 0.0119 ) l ; 95 % CI 0.014 to 0.060 ] using mixed-model repeated-measure with a pre-specified non-inferiority margin of 50 ml/year . After a greater initial decline at month 3 with TI , rate of change ( slope ) in FEV(1 ) , FVC and DL(CO ) ( months 3 - 24 ) was not statistically different between treatment groups . TI was well tolerated ; no serious safety concerns emerged . The most common respiratory event associated with TI was mild , transient cough , occurring within minutes of inhalation . CONCLUSIONS Observed changes in lung function with TI were small , occurred early after therapy initiation , remained non-progressive over 2 years and were unlikely to be clinical ly meaningful Background : Technosphere ® [ Bis-3 , 6(4-fumarylaminobutyl)-2 , 5-diketopiperazine ( FDKP ) ] microparticles , the integral component of the Technosphere inhalation system , deliver drugs to the deep lung and have been used to administer insulin and glucagon-like peptide-1 via inhalation in clinical studies . Three studies were conducted to characterize FDKP pharmacokinetics , including assessment s in subjects with diabetic nephropathy ( DNP ) , in subjects with chronic liver disease ( CLD ) , and in healthy subjects . Methods : An open-label , nonr and omized , two-period , fixed-sequence crossover absorption , distribution , metabolism , and excretion ( ADME ) study was conducted in six healthy nonsmoking men who received single intravenous and oral doses  of [14C]FDKP solution  , with serial sampling of blood , urine , feces , and expired air . Additionally , two single-dose , open-label , parallel- design studies with 20 mg of inhaled FDKP were conducted in ( 1 ) 12 diabetic subjects with normal renal function and 24 DNP subjects and ( 2 ) 12 healthy subjects and 21 CLD subjects . Results : In the ADME study , > 95 % of the intravenous dose and <3 % of the oral dose were recovered in urine , with no evidence of metabolism . No significant pharmacokinetic differences were observed between healthy subjects and CLD subjects [ geometric mean ( % coefficient of variation ) area under the curve from time 0 to 480 minutes ( AUC0 - 480 ) : 26,710 ( 34.8 ) and 31,477 ( 28.8 ) ng/ml·min , respectively ] . Maximum observed drug concentration ( C max ) and AUC0 - 480 were higher in DNP subjects than in subjects with normal renal function [ C max : 159.9 ( 59.4 ) ng/ml versus 147.0 ( 44.3 ) ng/ml ; AUC0 - 480 : 36,869 ( 47.2 ) ng/ml·min versus 30,474 ( 31.8 ) ng/ml·min ] . None of the differences observed were considered clinical ly significant . Conclusions : Fumaryl diketopiperazine is predominantly cleared unchanged by the kidney with essentially no oral bioavailability . Technosphere is a safe delivery vehicle for medications administered via inhalation AIM AFRESA [ Technosphere Insulin ( TI ) ; MannKind Corporation , Valencia , CA ] , a dry powder preparation of regular human insulin ( RHI ) , utilizes a novel and versatile drug carrier platform that enables pulmonary administration of medications typically administered by injection . The aim of this study was to compare the pharmacokinetic ( PK ) and pharmacodynamic ( PD ) parameters of three different inhaled doses of TI with those of subcutaneous ( s.c . ) RHI . METHODS This r and omized , open-label , four-way crossover study of 11 healthy , non-smoking volunteers evaluated PK and PD profiles following single inhalations of 25 , 50 or 100 U TI and 10 IU RHI administered subcutaneously using a euglycaemic clamp technique . RESULTS Following inhalation of TI , peak insulin concentrations ( C(max ) ) were achieved approximately 2 h earlier than with RHI ( 12 - 17 min for TI vs. 134 min for RHI ) . Area under the insulin concentration-time curve ( AUC ) and insulin C(max ) values increased with increasing TI dose . Insulin 
    Output:
    
INTERPRETATION Glycaemic  efficacy of Technosphere inhaled insulin is lower than that of subcutaneous insulin , but inhaled insulin has a lower risk of severe hypoglycaemia and weight gain .