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Post by agedhippie on Jun 6, 2018 9:18:14 GMT -5
Agreed. Dr. Kendall will use data as opposed to luck to make Afrezza the standard of care but knowing the opposition from BPs that will certainly come will require both luck and some level of integrity from industry decision makers. as has been pointed out, the rules are the rules. Here is the killer, not sure I can dig it up. On my reading last night, it was in the standards of care, had to be, The RAA's were approved non inferior to NPH. Afrezza made from regular insulin/ NPH. NPH Human Insulin which has an onset of insulin effect of 1 to 2 hours, a peak effect of 4 to 6 hours, and duration of action of more than 12 hours. ... Pre-Mixed Insulin which is NPH pre-mixed with either regular human insulin or a rapid- acting insulin analog. I would be surprised if they compared RAA to NPH since NPH is a basal insulin and RAA is a bolus insulin. I would have expected them to compare RAA to Regular insulin. Afrezza is only Regular insulin.
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Post by peppy on Jun 6, 2018 9:31:25 GMT -5
as has been pointed out, the rules are the rules. Here is the killer, not sure I can dig it up. On my reading last night, it was in the standards of care, had to be, The RAA's were approved non inferior to NPH. Afrezza made from regular insulin/ NPH. NPH Human Insulin which has an onset of insulin effect of 1 to 2 hours, a peak effect of 4 to 6 hours, and duration of action of more than 12 hours. ... Pre-Mixed Insulin which is NPH pre-mixed with either regular human insulin or a rapid- acting insulin analog. I would be surprised if they compared RAA to NPH since NPH is a basal insulin and RAA is a bolus insulin. I would have expected them to compare RAA to Regular insulin. Afrezza is only Regular insulin. I will go back and find it. Let's see what RAA's were found to be non inferior to on approval.
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Post by brotherm1 on Jun 6, 2018 9:53:31 GMT -5
linkFollowing which Mannkind had to publish a retraction ( link) and reissue the press release - the results were not statistically significant: CORRECTING and REPLACING MannKind Reports Positive Data from a Phase 3 Clinical Study of AFREZZA in Patients with Type 1 Diabetes
CORRECTING and REPLACING MannKind Reports Positive Data from a Phase 3 Clinical Study of AFREZZA in Patients with Type 1 DiabetesVALENCIA, Calif.--(BUSINESS WIRE)--Aug. 14, 2013-- Second graph under Other Results subhead, second sentence should read: The event rate of severe hypoglycemia was also lower in the AFREZZA-Gen2 group (8.05 events per 100 subject-months) than in the insulin aspart group (14.45 events per 100 subject-months); however, this difference was not statistically significant (p=0.1022) (sted The event rate of severe hypoglycemia was also lower in the AFREZZA-Gen2 group (8.05 events per subject-month) than in the insulin aspart group (14.45 events per subject-month); however, this difference was not statistically significant (p=0.1022)).Then there was the whole corrected release under that but I will spare people that. So the HbA1c was statistically significantly higher with Afrezza and the hypo reduction with Afrezza was not statistically significant. Do I have this correct? But according to Dr. Kendall, we do not need any more studies and we are planning to somehow have Afrezza become the SOC ? I’m so confused.
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Post by peppy on Jun 6, 2018 9:57:17 GMT -5
I would be surprised if they compared RAA to NPH since NPH is a basal insulin and RAA is a bolus insulin. I would have expected them to compare RAA to Regular insulin. Afrezza is only Regular insulin. I will go back and find it. Let's see what RAA's were found to be non inferior to on approval. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM401612.pdf. page 3. As per the Agency’s Written Request, Trial 2126 was a 24-week, randomized, open- label, active-control study in children (6-18 years) with type 1 diabetes (n = 377) to assess the safety and efficacy of insulin aspart (IAsp) compared to regular human insulin (HI) and to insulin lispro when administered subcutaneously as the short/rapid acting insulin in a basal bolus regimen in which NPH provided the basal insulin component. IAsp and lispro were injected subcutaneously immediately before the meal while HI was injected 30 minutes prior to the meal. IAsp was noninferior to HI in terms of HbA1c change from baseline, based on a noninferiority margin of 0.4%. IAsp failed to demonstrate noninferiority to lispro, but the mean HbA1c change from baseline for the IAsp arm was not significantly different from that of the lispro arm. No notable differences in the occurrence of adverse events were interesting non inferiority margin aye? Love you. thank you for making me look. added, should we laugh that the testing has found them each non inferior to each other?
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Post by mango on Jun 6, 2018 9:58:37 GMT -5
linkFollowing which Mannkind had to publish a retraction ( link) and reissue the press release - the results were not statistically significant: CORRECTING and REPLACING MannKind Reports Positive Data from a Phase 3 Clinical Study of AFREZZA in Patients with Type 1 Diabetes
CORRECTING and REPLACING MannKind Reports Positive Data from a Phase 3 Clinical Study of AFREZZA in Patients with Type 1 DiabetesVALENCIA, Calif.--(BUSINESS WIRE)--Aug. 14, 2013-- Second graph under Other Results subhead, second sentence should read: The event rate of severe hypoglycemia was also lower in the AFREZZA-Gen2 group (8.05 events per 100 subject-months) than in the insulin aspart group (14.45 events per 100 subject-months); however, this difference was not statistically significant (p=0.1022) (sted The event rate of severe hypoglycemia was also lower in the AFREZZA-Gen2 group (8.05 events per subject-month) than in the insulin aspart group (14.45 events per subject-month); however, this difference was not statistically significant (p=0.1022)).Then there was the whole corrected release under that but I will spare people that. Did you even read the PR? The results are significant. 🙂
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Post by peppy on Jun 6, 2018 10:05:10 GMT -5
Here you go The starting HbA1c is 7.98% for Afrezza and 7.88% for Novolog. Over the 24 weeks of the trial the Afrezza HbA1c dropped by 0.21% to 7.77% and the Novolog dropped by 0.40% to 7.48%. That make 0.21/7.98 = 0.0263 or 2.63% drop vs. 0.40/7.88 = 0.0508 or 5.08%. The confusion is because HbA1c is measured in percentage of Hb so everything is measured in percentages, both the HbA1c change, and the amount of change. aged can you calculate the absolute value on this data please? Afrezza patients had fewer hypos than Aspart users (9.8 per subject-month vs 13.97 per subject-month) change in HbA1c over the treatment period (-0.21 % vs -0.4%).
agedhippie I know you are working on this for me, it there an absolute value here? Added: What do you make of this regarding data and what the data really said? IAsp was noninferior to HI in terms of HbA1c change from baseline, based on a noninferiority margin of 0.4%.
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Post by dh4mizzou on Jun 6, 2018 10:17:02 GMT -5
Aged,
I think you're confusing percentage with points.
The percentage drop would be calculated by taking the actual drop(.21) divided by the starting number (7.98) which gives you right at 2.63% But as you provided above (.21) was the actual point drop in the A1C.
As an aside the percentage drop for Novolog would be 5.08% rounded.
So you're right that Novolog drops the A1C at more than twice the rate of Afrezza but as someone else pointed out the difference is insignificant to the point of being ignored.
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Post by peppy on Jun 6, 2018 10:20:55 GMT -5
linkFollowing which Mannkind had to publish a retraction ( link) and reissue the press release - the results were not statistically significant: CORRECTING and REPLACING MannKind Reports Positive Data from a Phase 3 Clinical Study of AFREZZA in Patients with Type 1 Diabetes
CORRECTING and REPLACING MannKind Reports Positive Data from a Phase 3 Clinical Study of AFREZZA in Patients with Type 1 DiabetesVALENCIA, Calif.--(BUSINESS WIRE)--Aug. 14, 2013-- Second graph under Other Results subhead, second sentence should read: The event rate of severe hypoglycemia was also lower in the AFREZZA-Gen2 group (8.05 events per 100 subject-months) than in the insulin aspart group (14.45 events per 100 subject-months); however, this difference was not statistically significant (p=0.1022) (sted The event rate of severe hypoglycemia was also lower in the AFREZZA-Gen2 group (8.05 events per subject-month) than in the insulin aspart group (14.45 events per subject-month); however, this difference was not statistically significant (p=0.1022)).Then there was the whole corrected release under that but I will spare people that. now, my understanding, as explained in the video I have linked at nauseam, these numbers will be turned into ratios and given as a % reduction or increase, "So the public finds the numbers easier to understand. Can any turn the language?
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Post by mango on Jun 6, 2018 10:54:25 GMT -5
Hey ya'll look at that. Significant improvement in fasting blood glucose. That means stress on the pancreas is significantly diminished because glucose homeostasis is being restored. Afrezza has historically improved the fasting blood glucose, and the Affinity 1 clinical trial showed, once again, that Afrezza significantly improved fasting blood glucose. Who wants to be the first to curtail this demonstrable fact?
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Post by dreamboatcruise on Jun 6, 2018 11:15:40 GMT -5
Hey ya'll look at that. Significant improvement in fasting blood glucose. That means stress on the pancreas is significantly diminished because glucose homeostasis is being restored. Afrezza has historically improved the fasting blood glucose, and the Affinity 1 clinical trial showed, once again, that Afrezza significantly improved fasting blood glucose. Who wants to be the first to curtail this demonstrable fact? True, but I remember seeing some study that compared using fasting blood glucose as a target metric to A1c and A1c won out. Of course that was not within the context of comparing insulins with different pk/pd profiles (which is a significant point). I believe this is a meaningful piece of data. Most doctors, however, are trained to look at A1c over fasting levels. Increasing use of CGM will open the eyes of SOME doctors as to what is really going on. Hopefully STAT will open some eyes. It will be a process, however, in reaching the masses of doctors.
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Post by mango on Jun 6, 2018 11:19:36 GMT -5
Hey ya'll look at that. Significant improvement in fasting blood glucose. That means stress on the pancreas is significantly diminished because glucose homeostasis is being restored. Afrezza has historically improved the fasting blood glucose, and the Affinity 1 clinical trial showed, once again, that Afrezza significantly improved fasting blood glucose. Who wants to be the first to curtail this demonstrable fact? True, but I remember seeing some study that compared using fasting blood glucose as a target metric to A1c and A1c won out. Of course that was not within the context of comparing insulins with different pk/pd profiles (which is a significant point). I believe this is a meaningful piece of data. Most doctors, however, are trained to look at A1c over fasting levels. Increasing use of CGM will open the eyes of SOME doctors as to what is really going on. Hopefully STAT will open some eyes. It will be a process, however, in reaching the masses of doctors. 🏆 A1c is a proxy.
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Post by peppy on Jun 6, 2018 11:25:55 GMT -5
True, but I remember seeing some study that compared using fasting blood glucose as a target metric to A1c and A1c won out. Of course that was not within the context of comparing insulins with different pk/pd profiles (which is a significant point). I believe this is a meaningful piece of data. Most doctors, however, are trained to look at A1c over fasting levels. Increasing use of CGM will open the eyes of SOME doctors as to what is really going on. Hopefully STAT will open some eyes. It will be a process, however, in reaching the masses of doctors. 🏆 A1c is a proxy. In a recent report, mean glucose measured with CGM versus central labo- ratory–measured A1C in 387 participants in three randomized trials demonstrated that A1C may underestimate or overesti- mate mean glucose. Thus, as suggested, a patient’s CGM profile has considerable potential for optimizing his or her glyce- mic management (42). Recommendations - A reasonable A1C goal for many nonpregnant adults is ,7% (53 mmol/mol). A - Providers might reasonably suggest more stringent A1C goals (such as ,6.5% [48 mmol/mol]) for se- lected individual patients if this can be achieved without significant hypoglycemia or other adverse ef- fects of treatment (i.e., polyphar- macy). Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no signifi- cant cardiovascular disease. C - Less stringent A1C goals (such as ,8% [64 mmol/mol]) may be ap- propriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascu- lar or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve de- spite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. B Rapid-acting inhaled insulin used be- fore meals in patients with type 1 diabe- tes was shown to be noninferior when compared with aspart insulin for A1C low- ering, with less hypoglycemia observed with inhaled insulin therapy (21). How- ever, the mean reduction in A1C was greater with aspart (–0.21% vs. –0.40%, satisfying the noninferiority margin of 0.4%), and more patients in the insulin aspart group achieved A1C goals of #7.0% Read more: mnkd.proboards.com/thread/10068/ada-2018-standards-care#ixzz5HfBhMmh5
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Post by akemp3000 on Jun 6, 2018 11:40:05 GMT -5
This thread is great in that it shows how well educated many PB posters are with their abilities to dissect and discuss past studies and more. Now consider that Dr. Kendall, the former Chief Scientific Medical Officer for the ADA, has already done the same in much, much greater depth and concluded that the studies contain "veins of gold" and that Afrezza should be the standard of care. Mike too has said, "doctor's are shocked" when they hear the results. I'm hopeful the company's strategic plan is to bring clarity to these statements in a big way at the ADA and this will truly explode the scientific chatter that is the topic of this thread. If this chatter is paired with a new marketing push, it could be the game changer and paradigm shift we've waited over 10 years to see. IMO, I can't see how this is not going to happen. GL
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Post by mango on Jun 6, 2018 11:54:07 GMT -5
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Post by peppy on Jun 6, 2018 11:56:12 GMT -5
HbA1c is a proxy for average glucose and does not reflect glucose homeostasis. It is subject to significant limitations and drawbacks. That's why TIR is the primary endpoint with STAT, it more accurately assesses glucose homeostasis. I am not arguing for HbA1c over TIR. I am simply saying that the counter-argument to the lower hypos measure will be that there was also a worse HbA1c which is why there reduced hypos. My point is that this is not a slam dunk which is why it is a poster. so aged, and in the end, the love we take is equal to the love we make. Afrezza. 7.98% - 7.77% = .21 Hba1c which is measured in %. Novolog 7.88% - 7.48% = .40 hbA1c which is measured in %. -The Gen2 arm of the trial was non-inferior to Insulin Aspart in terms of change in HbA1c over the treatment period (-0.21 % vs -0.4%). - Afrezza patients had fewer hypos than Aspart users (9.8 per subject-month vs 13.97 per subject-month)
Afrezza patients lost weight while Aspart patients gained weight Fewer patients in the Afrezza arm achieved treatment goals of HbA1c < 7% or 6.5% compared to Aspart, this difference was statistically significant Rapid-acting inhaled insulin used be- fore meals in patients with type 1 diabe- tes was shown to be noninferior when compared with aspart insulin for A1C low- ering, with less hypoglycemia observed with inhaled insulin therapy (21). How- ever, the mean reduction in A1C was greater with aspart (–0.21% vs. –0.40%, satisfying the noninferiority margin of 0.4%), and more patients in the insulin aspart group achieved A1C goals of #7.0% In a recent report, mean glucose measured with CGM versus central labo- ratory–measured A1C in 387 participants in three randomized trials demonstrated that A1C may underestimate or overesti- mate mean glucose. Thus, as suggested, a patient’s CGM profile has considerable potential for optimizing his or her glyce- mic management (42). As per the Agency’s Written Request, Trial 2126 was a 24-week, randomized, open- label, active-control study in children (6-18 years) with type 1 diabetes (n = 377) to assess the safety and efficacy of insulin aspart (IAsp) compared to regular human insulin (HI) and to insulin lispro when administered subcutaneously as the short/rapid acting insulin in a basal bolus regimen in which NPH provided the basal insulin component. IAsp and lispro were injected subcutaneously immediately before the meal while HI was injected 30 minutes prior to the meal. IAsp was noninferior to HI in terms of HbA1c change from baseline, based on a noninferiority margin of 0.4%. IAsp failed to demonstrate noninferiority to lispro, but the mean HbA1c change from baseline for the IAsp arm was not significantly different from that of the lispro arm. No notable differences in the occurrence of adverse events were Now assuming the increase hypo's in RAA caused the greater hbA1c reduction, the ADA is saying, - Less stringent A1C goals (such as ,8% [64 mmol/mol]) may be ap- propriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascu- lar or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve de- spite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. B
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