Lung, FEV1 & Cardiovascular Risk Data
Oct 25, 2018 7:39:30 GMT -5
lakefox333, robbmo, and 9 more like this
Post by mango on Oct 25, 2018 7:39:30 GMT -5
These data were over the span of many years, I believe at least 4 on some studies. I personally believe that, collectively with real-life evidence, would suffice FDA's Lung, FEV1 & Cardiovascular risk data requirements. Over 600 chest scans, mountains of FEV1 data, and clear cut CV data. We still need MannKind to release the results of their clinical trial involving participants taking Afrezza while hooked up to an EKG. But, it might not be necessary, the data we already have is probably more than enough.
Logical thinking: the thousands of participants, the numerous years, and the real-life evidence have produced consistent, reliable, and verifiable results every time.
It's time to change the Standards of Care and it's time to help people with diabetes around the world with getting back their health.
Let's get these new clinical trials data out there and let's get the ball rolling.
I hope Dr. Kendall's moral compass is still functioning properly, I imagine he has been hitting the ground running since day 1. Maybe he should slit the veins of gold now and let it flow.
Pulmonary Safety of Inhaled Technosphere® Insulin Therapy in Adults with Diabetes Using High-Resolution Computerized Tomography of the Chest
Background and aims: Technosphere® Insulin (TI) is a rapid-acting inhaled insulin with pharmacokinetics well suited for control of postprandial plasma glucose. Because TI is intended to be administered via the pulmonary route, the TI clinical program was designed to assess possible radiological changes associated with the chronic use of TI therapy.
Materials and methods: Adult subjects with diabetes were evaluated with high-resolution computerized tomography (HRCT) of the chest during the clinical trials. In controlled clinical trials, MKC-TI-005 (N = 217; 174 TI group, 43 Technosphere® Inhalation Powder [T Powder] group) and PDC-INS-0008 (N = 121; 60 TI group, 61 T Powder group) subjects were randomized to receive TI or T Powder without insulin. Chest HRCTs were obtained at baseline and at the end of the 12-week treatment period. After completion of these two trials, 206 subjects continued in the uncontrolled open-label extension trial (MKC-TI-010) and underwent annual chest HRCTs (or magnetic resonance imaging [MRI] in Germany) for up to 4 years. In addition, subsets of subjects with type 1 or type 2 diabetes participating in trial MKC-TI-030 (n = 127; 55 TI group, 72 usual care [UC] group) were also randomized to an annual chest HRCT during the 24-month treatment period. All HRCT images were reviewed centrally following a prespecified adjudication protocol by an independent, blinded, board- certified radiologist. All images for any subject with HRCT findings other than normal underwent secondary joint review by an independent board-certified radiologist (different from the primary reviewer) and an independent board-certified pulmonologist, who were blinded to the treatment group.
Results: A total of 667 subjects had a baseline and at least one post-baseline chest HRCT or MRI examination. Of these, 494 subjects were treated with TI, 101 were exposed to T Powder and 72 were in the UC group with no exposure to TI or T Powder. Chest HRCTs for 94% of the TI group, 92% of the T Powder group, and 96% of the UC group showed normal findings or the findings were not clinically significant (Table 2). Radiological findings considered abnormal and clinically significant consisted of atelectasis, septal thickening, peri-bronchial thickening, bronchial dilatation or mild bronchiectasis, one or more new or non-enlarging nodules, and ground glass densities; these findings were seen with comparable frequency in all three treatment groups.
Conclusions: Overall, HRCT and MRI findings suggest that there were no clinically significant radiological changes from baseline in all three groups. Observed radiological findings were not suggestive of a safety signal with the long-term use of TI therapy.
www.mannkindcorp.com/Collateral/Documents/English-US/08-2009_EASD_HRCT_Poster_921.pdf
Pulmonary Functions (Over 2 Years) in Diabetic Subjects Treated with Technosphere® Insulin or Usual Antidiabetic Treatment
Background and aims: Technosphere® Insulin (TI) is a rapid-acting inhaled insulin with an action profile that mimics early meal-related insulin release. The goal of this multicenter study was to evaluate and compare changes in lung function in subjects with diabetes treated with TI or with usual antidiabetic treatment (UC).
Materials and methods: Pulmonary function tests (PFTs), including forced expiratory volume in 1 second (FEV1), forced vital capacity, total lung capacity, and carbon monoxide diffusing capacity (DLCO), were prospectively followed over a 2-year period in subjects with type 1 and type 2 diabetes mellitus receiving TI (n = 730) or UC (n = 824), along with a cohort of nondiabetes subjects who did not receive any specific therapy (n = 145).
Results: The treatment groups were similar for age (TI group: 50.8 ± 11.6 years; UC group: 50.4 ± 11.6 years; p = 0.40), gender distribution (p = 0.85), proportion of ethnic group composition (p = 0.93), and baseline PFT. Over 2 years, PFTs declined in all groups, including the non-diabetes group. TI was noninferior to UC for mean change in FEV1 from Baseline to 24 months using Mixed Model Repeated Measure analysis with a prespecified noninferiority margin of
50 mL/year. After a slightly larger initial decline at the first post-Baseline assessment visit, annual rate of change (slope) in PFTs from Month 3 to Month 24 was not statistically different between the TI- and UC-treated subjects. Annualized change in FEV1 between 3 to 24 months was -0.047 L/year for TI-treated subjects and -0.036 L/year for UC-treated subjects (difference between the treatment groups, 0.010 L/year [95% CI -0.003, 0.022]); DLCO was
-0.507 mL/min/mm Hg per year for TI-treated subjects and -0.455 mL/min/mm Hg per year for UC-treated subjects (difference between the treatment groups, 0.117 mL/min/mm Hg per year [95% CI -0.058, 0.292]).
Conclusion: Small declines from Baseline in PFTs were observed in subjects with diabetes treated with TI and UC and also in subjects without diabetes. Observed differences between the TI and UC groups in the change from Baseline in FEV1 and DLCO were small, noted at the first post- Baseline assessment visit (3 months) and thereafter remained nonprogressive over 2 years of continuous therapy.
www.mannkindcorp.com/Collateral/Documents/English-US/07-2009_EASD_030_Abstract_920.pdf
Technosphere® Insulin: Safety in Type 2 Diabetes Mellitus
ABSTRACT
We conducted a prespecified analysis review across all studies of subjects with type 2 diabetes mellitus (T2DM) from controlled Phase 2/3 clinical trials of Technosphere® Insulin (TI) and one uncontrolled long-term extension trial (for HRCT). In all, 1795 subjects received TI, and 1345 received comparator—either sc insulin (953) or oral agents (392). In the TI group, 838 subjects completed 1 year of treatment and 533 completed 2 years. In both groups, mean age was 56 years. Mean BMI was 31 kg/m2; 51% of subjects were male.
Hypoglycemia was the most common adverse event (AE) in all insulin-treated subjects. The incidences of hypoglycemia and severe hypoglycemia were significantly lower with TI than comparator sc injected insulins.
Mild cough occurred more frequently with TI (25.8% vs 5.4%). Only 2.6% of TI subjects withdrew due to cough. Small declines in FEV1 and DLCO occurred in both groups over 2 years of treatment, with greater initial decline in TI-treated subjects. Differences were small, nonprogressive, and disappeared within 3 months of stopping TI.
Of 667 subjects with HRCT, 494 received TI and 72 received comparator. There were no differences in the rates of clinically significant abnormal findings between groups.
In patients with T2DM who received TI:
* The most common AEs were hypoglycemia and mild transient cough.
* The incidence of hypoglycemia and of severe hypoglycemia was reduced compared with sc insulin.
* There was no increase in cardiovascular risk.
* There was a small reduction in pulmonary function that was nonprogressive and resolved on discontinuation. There was no difference in the rate of clinically significant radiological findings in HRCT between groups.
RESULTS
Seven Phase 2/3 trials contributed to the pooled analyses in patients with type 2 diabetes. In total, 1795 patients received Afrezza, and 1345 received comparator—either sc insulin (953) or oral agents (392). In the Afrezza group, 838 patients completed 1 year of treatment and 533 completed 2 years. A total of 206 patients entered into an uncontrolled open-label extension trial and received Afrezza with or without other antidiabetes treatment for up to 4 years.
General Safety
The incidence of AEs, including severe AEs, deaths, and special events was comparable between treatment groups (Table 1). Figure 1 summarizes treatment emergent adverse events (TEAE) reported in ≥5% of subjects. Hypoglycemia was the most common adverse event with incidence ≥5% in all insulin-treated patients (Table 2). The incidences and event rates (Figure 2) of total hypoglycemia and severe hypoglycemia were significantly lower with Afrezza- treated patients than comparator insulin treatment. Mild cough occurred more frequently with Afrezza (25.8% vs. 5.4%). Only 2.6% of Afrezza patients withdrew due to cough.
Pulmonary Function Testing
Small declines in FEV1 (Figure 3) occurred in both groups over 2 years of treatment, with greater initial decline in Afrezza-treated patients. Differences were small, non-progressive, and disappeared within 3 months of stopping Afrezza irrespective of the duration of exposure (Figure 4). Changes from baseline in FVC and DLCO also showed a similar pattern. There was no significant difference in change from baseline in TLC between Afrezza and comparator groups.
Chest HRCT Results
AFREZZA (Technosphere® Insulin) is a rapid acting inhaled insulin being developed for the treatment of adult subjects with diabetes mellitus. Afrezza contains recombinant human insulin adsorbed onto Technosphere® microparticles (T Powder). Technosphere microparticles are formed by the acid-induced self-assembly of fumaryl diketopiperazine (FDKP) molecules, a novel and metabolically inert excipient. Upon inhalation into deep lung, 100 Technosphere particles dissolve rapidly at the prevailing physiological pH in lungs allowing rapid absorption of 90 insulin in systemic circulation. The resultant insulin pharmacokinetic profile mimics the early mealtime insulin release observed in healthy subjects. The main objective of this review of the Phase 2/3 clinical trials was to 80 characterize the safety profile of Afrezza in patients with type 2 diabetes mellitus (T2DM). 70
www.mannkindcorp.com/Collateral/Documents/English-US/2010%20ADA%20Poster%20523-P%20–%20A.Rossiter%20LR.pdf
EXTRA
clinicaltrials.gov/ct2/show/results/NCT00754624?term=MannKind&recrs=e&rslt=With&type=Intr&rank=2§=X5401236#limit
clinicaltrials.gov/ct2/show/results/NCT00308737?term=Technosphere&rank=34§=X01256#all
Logical thinking: the thousands of participants, the numerous years, and the real-life evidence have produced consistent, reliable, and verifiable results every time.
It's time to change the Standards of Care and it's time to help people with diabetes around the world with getting back their health.
Let's get these new clinical trials data out there and let's get the ball rolling.
I hope Dr. Kendall's moral compass is still functioning properly, I imagine he has been hitting the ground running since day 1. Maybe he should slit the veins of gold now and let it flow.
Pulmonary Safety of Inhaled Technosphere® Insulin Therapy in Adults with Diabetes Using High-Resolution Computerized Tomography of the Chest
Background and aims: Technosphere® Insulin (TI) is a rapid-acting inhaled insulin with pharmacokinetics well suited for control of postprandial plasma glucose. Because TI is intended to be administered via the pulmonary route, the TI clinical program was designed to assess possible radiological changes associated with the chronic use of TI therapy.
Materials and methods: Adult subjects with diabetes were evaluated with high-resolution computerized tomography (HRCT) of the chest during the clinical trials. In controlled clinical trials, MKC-TI-005 (N = 217; 174 TI group, 43 Technosphere® Inhalation Powder [T Powder] group) and PDC-INS-0008 (N = 121; 60 TI group, 61 T Powder group) subjects were randomized to receive TI or T Powder without insulin. Chest HRCTs were obtained at baseline and at the end of the 12-week treatment period. After completion of these two trials, 206 subjects continued in the uncontrolled open-label extension trial (MKC-TI-010) and underwent annual chest HRCTs (or magnetic resonance imaging [MRI] in Germany) for up to 4 years. In addition, subsets of subjects with type 1 or type 2 diabetes participating in trial MKC-TI-030 (n = 127; 55 TI group, 72 usual care [UC] group) were also randomized to an annual chest HRCT during the 24-month treatment period. All HRCT images were reviewed centrally following a prespecified adjudication protocol by an independent, blinded, board- certified radiologist. All images for any subject with HRCT findings other than normal underwent secondary joint review by an independent board-certified radiologist (different from the primary reviewer) and an independent board-certified pulmonologist, who were blinded to the treatment group.
Results: A total of 667 subjects had a baseline and at least one post-baseline chest HRCT or MRI examination. Of these, 494 subjects were treated with TI, 101 were exposed to T Powder and 72 were in the UC group with no exposure to TI or T Powder. Chest HRCTs for 94% of the TI group, 92% of the T Powder group, and 96% of the UC group showed normal findings or the findings were not clinically significant (Table 2). Radiological findings considered abnormal and clinically significant consisted of atelectasis, septal thickening, peri-bronchial thickening, bronchial dilatation or mild bronchiectasis, one or more new or non-enlarging nodules, and ground glass densities; these findings were seen with comparable frequency in all three treatment groups.
Conclusions: Overall, HRCT and MRI findings suggest that there were no clinically significant radiological changes from baseline in all three groups. Observed radiological findings were not suggestive of a safety signal with the long-term use of TI therapy.
www.mannkindcorp.com/Collateral/Documents/English-US/08-2009_EASD_HRCT_Poster_921.pdf
Pulmonary Functions (Over 2 Years) in Diabetic Subjects Treated with Technosphere® Insulin or Usual Antidiabetic Treatment
Background and aims: Technosphere® Insulin (TI) is a rapid-acting inhaled insulin with an action profile that mimics early meal-related insulin release. The goal of this multicenter study was to evaluate and compare changes in lung function in subjects with diabetes treated with TI or with usual antidiabetic treatment (UC).
Materials and methods: Pulmonary function tests (PFTs), including forced expiratory volume in 1 second (FEV1), forced vital capacity, total lung capacity, and carbon monoxide diffusing capacity (DLCO), were prospectively followed over a 2-year period in subjects with type 1 and type 2 diabetes mellitus receiving TI (n = 730) or UC (n = 824), along with a cohort of nondiabetes subjects who did not receive any specific therapy (n = 145).
Results: The treatment groups were similar for age (TI group: 50.8 ± 11.6 years; UC group: 50.4 ± 11.6 years; p = 0.40), gender distribution (p = 0.85), proportion of ethnic group composition (p = 0.93), and baseline PFT. Over 2 years, PFTs declined in all groups, including the non-diabetes group. TI was noninferior to UC for mean change in FEV1 from Baseline to 24 months using Mixed Model Repeated Measure analysis with a prespecified noninferiority margin of
50 mL/year. After a slightly larger initial decline at the first post-Baseline assessment visit, annual rate of change (slope) in PFTs from Month 3 to Month 24 was not statistically different between the TI- and UC-treated subjects. Annualized change in FEV1 between 3 to 24 months was -0.047 L/year for TI-treated subjects and -0.036 L/year for UC-treated subjects (difference between the treatment groups, 0.010 L/year [95% CI -0.003, 0.022]); DLCO was
-0.507 mL/min/mm Hg per year for TI-treated subjects and -0.455 mL/min/mm Hg per year for UC-treated subjects (difference between the treatment groups, 0.117 mL/min/mm Hg per year [95% CI -0.058, 0.292]).
Conclusion: Small declines from Baseline in PFTs were observed in subjects with diabetes treated with TI and UC and also in subjects without diabetes. Observed differences between the TI and UC groups in the change from Baseline in FEV1 and DLCO were small, noted at the first post- Baseline assessment visit (3 months) and thereafter remained nonprogressive over 2 years of continuous therapy.
www.mannkindcorp.com/Collateral/Documents/English-US/07-2009_EASD_030_Abstract_920.pdf
Technosphere® Insulin: Safety in Type 2 Diabetes Mellitus
ABSTRACT
We conducted a prespecified analysis review across all studies of subjects with type 2 diabetes mellitus (T2DM) from controlled Phase 2/3 clinical trials of Technosphere® Insulin (TI) and one uncontrolled long-term extension trial (for HRCT). In all, 1795 subjects received TI, and 1345 received comparator—either sc insulin (953) or oral agents (392). In the TI group, 838 subjects completed 1 year of treatment and 533 completed 2 years. In both groups, mean age was 56 years. Mean BMI was 31 kg/m2; 51% of subjects were male.
Hypoglycemia was the most common adverse event (AE) in all insulin-treated subjects. The incidences of hypoglycemia and severe hypoglycemia were significantly lower with TI than comparator sc injected insulins.
Mild cough occurred more frequently with TI (25.8% vs 5.4%). Only 2.6% of TI subjects withdrew due to cough. Small declines in FEV1 and DLCO occurred in both groups over 2 years of treatment, with greater initial decline in TI-treated subjects. Differences were small, nonprogressive, and disappeared within 3 months of stopping TI.
Of 667 subjects with HRCT, 494 received TI and 72 received comparator. There were no differences in the rates of clinically significant abnormal findings between groups.
In patients with T2DM who received TI:
* The most common AEs were hypoglycemia and mild transient cough.
* The incidence of hypoglycemia and of severe hypoglycemia was reduced compared with sc insulin.
* There was no increase in cardiovascular risk.
* There was a small reduction in pulmonary function that was nonprogressive and resolved on discontinuation. There was no difference in the rate of clinically significant radiological findings in HRCT between groups.
RESULTS
Seven Phase 2/3 trials contributed to the pooled analyses in patients with type 2 diabetes. In total, 1795 patients received Afrezza, and 1345 received comparator—either sc insulin (953) or oral agents (392). In the Afrezza group, 838 patients completed 1 year of treatment and 533 completed 2 years. A total of 206 patients entered into an uncontrolled open-label extension trial and received Afrezza with or without other antidiabetes treatment for up to 4 years.
General Safety
The incidence of AEs, including severe AEs, deaths, and special events was comparable between treatment groups (Table 1). Figure 1 summarizes treatment emergent adverse events (TEAE) reported in ≥5% of subjects. Hypoglycemia was the most common adverse event with incidence ≥5% in all insulin-treated patients (Table 2). The incidences and event rates (Figure 2) of total hypoglycemia and severe hypoglycemia were significantly lower with Afrezza- treated patients than comparator insulin treatment. Mild cough occurred more frequently with Afrezza (25.8% vs. 5.4%). Only 2.6% of Afrezza patients withdrew due to cough.
Pulmonary Function Testing
Small declines in FEV1 (Figure 3) occurred in both groups over 2 years of treatment, with greater initial decline in Afrezza-treated patients. Differences were small, non-progressive, and disappeared within 3 months of stopping Afrezza irrespective of the duration of exposure (Figure 4). Changes from baseline in FVC and DLCO also showed a similar pattern. There was no significant difference in change from baseline in TLC between Afrezza and comparator groups.
Chest HRCT Results
AFREZZA (Technosphere® Insulin) is a rapid acting inhaled insulin being developed for the treatment of adult subjects with diabetes mellitus. Afrezza contains recombinant human insulin adsorbed onto Technosphere® microparticles (T Powder). Technosphere microparticles are formed by the acid-induced self-assembly of fumaryl diketopiperazine (FDKP) molecules, a novel and metabolically inert excipient. Upon inhalation into deep lung, 100 Technosphere particles dissolve rapidly at the prevailing physiological pH in lungs allowing rapid absorption of 90 insulin in systemic circulation. The resultant insulin pharmacokinetic profile mimics the early mealtime insulin release observed in healthy subjects. The main objective of this review of the Phase 2/3 clinical trials was to 80 characterize the safety profile of Afrezza in patients with type 2 diabetes mellitus (T2DM). 70
www.mannkindcorp.com/Collateral/Documents/English-US/2010%20ADA%20Poster%20523-P%20–%20A.Rossiter%20LR.pdf
EXTRA
clinicaltrials.gov/ct2/show/results/NCT00754624?term=MannKind&recrs=e&rslt=With&type=Intr&rank=2§=X5401236#limit
clinicaltrials.gov/ct2/show/results/NCT00308737?term=Technosphere&rank=34§=X01256#all