Afrezza® INHALE-1 Study in Pediatrics (INHALE-1)

[mango]

The Peds Phase 3 clinical trial is officially posted with the abstract and objectives.

Collaborator: Jaeb Center for Health Research

Brief Summary:
INHALE-1 is a Phase 3, open-label, randomized clinical study evaluating the efficacy and safety of Afrezza in combination with a basal insulin (i.e., the Afrezza group) versus insulin aspart or insulin lispro in combination with a basal insulin (i.e., the RAA injection group) in pediatric subjects with type 1 or type 2 diabetes mellitus. Following 26 weeks of randomized treatment (i.e., Afrezza or RAA injection combined with a basal insulin), all subjects will enter a treatment extension where subjects will receive Afrezza until Week 52. The purpose of the treatment extension is to assess safety and efficacy with continued use of Afrezza.

Pediatric subjects ≥4 and <18 years of age will be enrolled in this study. Subjects will be randomly assigned in a 1:1 ratio to either the Afrezza group or the RAA injection group.

The study is composed of:
Up to 4-week screening/run-in period
26 week randomized treatment period
26-week treatment extension
4-week follow-up period



Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 264 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Official Title:
INHALE-1: A 26-week Primary Treatment Phase, With 26-week Extension, Open-label, Randomized Clinical Trial Evaluating the Efficacy and Safety of Afrezza® Versus Rapid-acting Insulin Analog Injections, Both in Combination With a Basal Insulin, in Pediatric Subjects With Type 1 or Type 2 Diabetes Mellitus

Estimated Study Start Date :
September 2021
Estimated Primary Completion Date :
April 2024
Estimated Study Completion Date :
April 2025


—————————————————————


Primary Outcome Measures :
Change in HbA1c After 26 Weeks [ Time Frame: 26 weeks ]
HbA1c change after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA)


Secondary Outcome Measures :
Change in Fasting Plasma Glucose (FPG) After 26 weeks [ Time Frame: 26 weeks ]
FPG change after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA)

Rate of Hypoglycemic Events After 26 weeks [ Time Frame: 26 weeks ]
Event rate of hypoglycemia (SMBG <70 mg/dL) after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA).


Other Outcome Measures:
Time in Range (70 - 180 mg/dL) [ Time Frame: 26 weeks ]
Time in Range after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived glucose values.

Change in Percent Time with Glucose <54 mg/dL [ Time Frame: 26 weeks ]
Percent Time with Glucose <54 mg/dL after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.

Time Below Range (glucose <70 mg/dL) [ Time Frame: 26 weeks ]
Time Below Range after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.

Time Above Range (glucose >180 mg/dL) [ Time Frame: 26 weeks ]
Percent Time with Glucose >180 mg/dL after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.

Percentage of Subjects with HbA1c <7.0% at Week 26 [ Time Frame: 26 weeks ]
Percentage of Subjects with HbA1c <7.0% after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA).

Change in DTSQ score After 26 Weeks of Afrezza [ Time Frame: 26 weeks ]
Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ) score from before the first dose of Afrezza until after 26 weeks of Afrezza therapy (Week 26 for the Afrezza arm, or Week 52 for the RAA Arm). Scores range from -18 to 18, with higher scores indicating greater treatment satisfaction.

Change in HbA1c During Extension - RAA arm [ Time Frame: During treatment extension at week 26 to week 52 ]
Change in HbA1c from Week 26 to Week 52 for the RAA arm only (the RAA arm switches to Afrezza at Week 26)

Change in HbA1c After 52 Weeks - Afrezza arm [ Time Frame: 52 weeks ]
Change in HbA1c from baseline to week 52, in subjects who received Afrezza in both the randomized treatment period and the treatment extension.

Event Rate of Hypoglycemic Events After 52 Weeks [ Time Frame: 52 weeks ]
Event rate of total, nocturnal, and severe hypoglycemic events; based on the International Society for Pediatric and Adolescent Diabetes criteria.

Incidence of Hypoglycemic Events After 52 Weeks [ Time Frame: 52 weeks ]
Incidence of total, nocturnal, and severe hypoglycemic events; based on the International Society for Pediatric and Adolescent Diabetes criteria.

Incidence and Severity of Adverse Events [ Time Frame: 52 weeks ]
Incidence and severity of adverse events (AEs): treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs).

Change in Percent Predicted Forced Expiratory Volume in 1 Second [ Time Frame: 56 weeks ]
Change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline to Weeks 13, 26, 39, 52, and 56.



www.clinicaltrials.gov/ct2/show/NCT04974528

[peppy]

Jul 23, 2021 7:55:10 GMT -5 mango said:

The Peds Phase 3 clinical trial is officially posted with the abstract and objectives.

Collaborator: Jaeb Center for Health Research

Brief Summary:
INHALE-1 is a Phase 3, open-label, randomized clinical study evaluating the efficacy and safety of Afrezza in combination with a basal insulin (i.e., the Afrezza group) versus insulin aspart or insulin lispro in combination with a basal insulin (i.e., the RAA injection group) in pediatric subjects with type 1 or type 2 diabetes mellitus. Following 26 weeks of randomized treatment (i.e., Afrezza or RAA injection combined with a basal insulin), all subjects will enter a treatment extension where subjects will receive Afrezza until Week 52. The purpose of the treatment extension is to assess safety and efficacy with continued use of Afrezza.

Pediatric subjects ≥4 and <18 years of age will be enrolled in this study. Subjects will be randomly assigned in a 1:1 ratio to either the Afrezza group or the RAA injection group.

The study is composed of:
Up to 4-week screening/run-in period
26 week randomized treatment period
26-week treatment extension
4-week follow-up period



Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 264 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Official Title:
INHALE-1: A 26-week Primary Treatment Phase, With 26-week Extension, Open-label, Randomized Clinical Trial Evaluating the Efficacy and Safety of Afrezza® Versus Rapid-acting Insulin Analog Injections, Both in Combination With a Basal Insulin, in Pediatric Subjects With Type 1 or Type 2 Diabetes Mellitus

Estimated Study Start Date :
September 2021
Estimated Primary Completion Date :
April 2024
Estimated Study Completion Date :
April 2025


—————————————————————


Primary Outcome Measures :
Change in HbA1c After 26 Weeks [ Time Frame: 26 weeks ]
HbA1c change after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA)


Secondary Outcome Measures :
Change in Fasting Plasma Glucose (FPG) After 26 weeks [ Time Frame: 26 weeks ]
FPG change after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA)

Rate of Hypoglycemic Events After 26 weeks [ Time Frame: 26 weeks ]
Event rate of hypoglycemia (SMBG <70 mg/dL) after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA).


Other Outcome Measures:
Time in Range (70 - 180 mg/dL) [ Time Frame: 26 weeks ]
Time in Range after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived glucose values.

Change in Percent Time with Glucose <54 mg/dL [ Time Frame: 26 weeks ]
Percent Time with Glucose <54 mg/dL after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.

Time Below Range (glucose <70 mg/dL) [ Time Frame: 26 weeks ]
Time Below Range after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.

Time Above Range (glucose >180 mg/dL) [ Time Frame: 26 weeks ]
Percent Time with Glucose >180 mg/dL after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.

Percentage of Subjects with HbA1c <7.0% at Week 26 [ Time Frame: 26 weeks ]
Percentage of Subjects with HbA1c <7.0% after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA).

Change in DTSQ score After 26 Weeks of Afrezza [ Time Frame: 26 weeks ]
Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ) score from before the first dose of Afrezza until after 26 weeks of Afrezza therapy (Week 26 for the Afrezza arm, or Week 52 for the RAA Arm). Scores range from -18 to 18, with higher scores indicating greater treatment satisfaction.

Change in HbA1c During Extension - RAA arm [ Time Frame: During treatment extension at week 26 to week 52 ]
Change in HbA1c from Week 26 to Week 52 for the RAA arm only (the RAA arm switches to Afrezza at Week 26)

Change in HbA1c After 52 Weeks - Afrezza arm [ Time Frame: 52 weeks ]
Change in HbA1c from baseline to week 52, in subjects who received Afrezza in both the randomized treatment period and the treatment extension.

Event Rate of Hypoglycemic Events After 52 Weeks [ Time Frame: 52 weeks ]
Event rate of total, nocturnal, and severe hypoglycemic events; based on the International Society for Pediatric and Adolescent Diabetes criteria.

Incidence of Hypoglycemic Events After 52 Weeks [ Time Frame: 52 weeks ]
Incidence of total, nocturnal, and severe hypoglycemic events; based on the International Society for Pediatric and Adolescent Diabetes criteria.

Incidence and Severity of Adverse Events [ Time Frame: 52 weeks ]
Incidence and severity of adverse events (AEs): treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs).

Change in Percent Predicted Forced Expiratory Volume in 1 Second [ Time Frame: 56 weeks ]
Change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline to Weeks 13, 26, 39, 52, and 56.



www.clinicaltrials.gov/ct2/show/NCT04974528

Criteria
Inclusion Criteria:
Assent from the pediatric subject, as appropriate, and fully informed consent from the parent(s) or legal guardian, as required by both state and federal laws and the local Institutional Review Board (IRB);
Subjects ≥4 and <18 years of age;
Clinical diagnosis of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) per the Investigator and have been using insulin for at least 6 months for T1DM, or at least 3 months for T2DM
Treatment with basal-bolus insulin therapy delivered by multiple daily injections for at least 2 weeks:
Acceptable bolus insulins are restricted to the RAAs insulin lispro or insulin aspart, including biosimilar products.
Basal insulins are restricted to 100-U/mL formulations of insulin glargine or insulin degludec, including biosimilar products.
HbA1c ≥7.0% and ≤11%
Average prandial dose of insulin ≥2 units per meal
Utilized continuous glucose monitor (CGM) for ≥70% of the time over a 14-day period preceding randomization.


Thank you Mango.

[mango]

About the collaborator:

www.jaeb.org/wp-content/uploads/JCHR-History.pdf


www.jaeb.org/projects/

[markado]

The Primary end point timing on this study appears to assume it will take 15 months to recruit the 264 patients. Maybe, but I would purport that full recruitment will take less than that. If so, that, in and of itself will be an indicator of target population (parents of PWD and PWD youth) interest in the solution. JMO.

[mango]

Looking at the outcome measures and the fact we are using CGMs—this clinical trial is set up to be absolutely monumental and game changing.



I truly believe Afrezza will prove to be the superior mealtime insulin therapy once and for all with this clinical trial.

[esstan2001]

Jul 23, 2021 11:18:57 GMT -5 mango said:

Looking at the outcome measures and the fact we are using CGMs—this clinical trial is set up to be absolutely monumental and game changing.



I truly believe Afrezza will prove to be the superior mealtime insulin therapy once and for all with this clinical trial.

Sadly the rate of forward Afrezza progress in this Co. is like watching an oil tanker being towed by a 2 person pedal boat as it traverses the Atlantic ocean.

[longliner]

Jul 23, 2021 12:18:25 GMT -5 esstan2001 said:

Jul 23, 2021 11:18:57 GMT -5 mango said:

Looking at the outcome measures and the fact we are using CGMs—this clinical trial is set up to be absolutely monumental and game changing.



I truly believe Afrezza will prove to be the superior mealtime insulin therapy once and for all with this clinical trial.

Sadly the rate of forward progress in this Co. is like watching an oil tanker being towed by a 2 person pedal boat as it traverses the Atlantic ocean.

And the reason for your post in this thread is?? 

Peds trial progress with CGM!! Outstanding!!!

[esstan2001]

Jul 23, 2021 12:21:32 GMT -5 longliner said:

Jul 23, 2021 12:18:25 GMT -5 esstan2001 said:

Sadly the rate of forward Afrezza progress in this Co. is like watching an oil tanker being towed by a 2 person pedal boat as it traverses the Atlantic ocean.

And the reason for your post in this thread is?? 

Peds trial progress with CGM!! Outstanding!!!

Peds trial progress with CGM!! Outstanding!!!  => 100% AGREE

And the reason for your post in this thread is?? => Because waiting for the protocol for this trial to finalize such that it may commence has been like waiting for GODOT

(in case you have not been involved since 2008, the excitement of 2014, the Sanofi debacle, etc. ...but for the most part, I think you have  )

[radgray68]

As I recall, we got around a .8% reduction in HbA1C and the investment community wanted a whole 1% and that's why the Sanofi deal was lacking real luster. At the CC, Al's reflexive response, and he was known to get ahead of himself with straight talk and would be corralled by Matt P., was that the doctors were afraid to treat aggressively enough to show Afrezza's true superiority. That's almost verbatim, again, to my recollection. I'm also recalling his laugh, for some reason. Great laugh.

I have no doubt that these shortcomings have been addressed. All these other small trials have been gathering evidence and frankly fine tuning experience with our drug/device combo to get the trials we want. It's about execution from here, IMO. Anybody NOT think this trial could prove Al's vision?

[mannmade]

The last of the original trials for FDA approval were after the first denials by the FDA. So the last trials were designed not to prove superiority but more to show not less inferior as I recall, as this was to be the last time they applied to the FDA and Mannkind wanted to ensure approval.

Aa a result, the dosing protocols were way off for the kinetic actions of fast in/fast out which was not a fair comparison in hind sight. Actually very suprising given the protocol desgins for using Afrezza and dosing the same way as RAA prandials that Afrezza did as well as it did.

Hopefully this new peds study repairs all that and the damage it caused.

[wsulylecoug]

That is what I'm most curious about. What are the dosing protocols for each arm? The only place "unit" is referenced on the clinicaltrials.gov page is under Inclusion Criteria "Average prandial dose of insulin ≥2 units per meal". In past comments about the upcoming Peds trial, it seems that MC made a concerted effort to make sure Afrezza users would be treating to target, not treating to carb ratios. Is there somewhere the trial design could be viewed?

A close friend has a 7 year-old T1D son that might be a great candidate for the trial. We spent a few days vacationing with them recently and in a span of three days (and possibly within the same day) his range was mid 40's to 480's and they seem pretty vigilant trying to keep up with a Dexcom and Omnipod. 

[mannmade]

Jul 23, 2021 14:57:05 GMT -5 wsulylecoug said:

That is what I'm most curious about. What are the dosing protocols for each arm? The only place "unit" is referenced on the clinicaltrials.gov page is under Inclusion Criteria "Average prandial dose of insulin ≥2 units per meal". In past comments about the upcoming Peds trial, it seems that MC made a concerted effort to make sure Afrezza users would be treating to target, not treating to carb ratios. Is there somewhere the trial design could be viewed?

A close friend has a 7 year-old T1D son that might be a great candidate for the trial. We spent a few days vacationing with them recently and in a span of three days (and possibly within the same day) his range was mid 40's to 480's and they seem pretty vigilant trying to keep up with a Dexcom and Omnipod. 

Good points, as I was actually referring to timing of the doses, where in the last FDA trial, dosing for Afrezza was 30 minutes before a meal with no follow up, same as RAA's. This lead to a real disadvantage in not being able to show how superior the fast in/fast out kinetics of Afrezza are for pwd.  Suprising that Afrezza did as well as it did in coming up non-inferior to RAA's given the above.

[peppy]

Jul 23, 2021 16:09:54 GMT -5 mannmade said:

Jul 23, 2021 14:57:05 GMT -5 wsulylecoug said:

That is what I'm most curious about. What are the dosing protocols for each arm? The only place "unit" is referenced on the clinicaltrials.gov page is under Inclusion Criteria "Average prandial dose of insulin ≥2 units per meal". In past comments about the upcoming Peds trial, it seems that MC made a concerted effort to make sure Afrezza users would be treating to target, not treating to carb ratios. Is there somewhere the trial design could be viewed?

A close friend has a 7 year-old T1D son that might be a great candidate for the trial. We spent a few days vacationing with them recently and in a span of three days (and possibly within the same day) his range was mid 40's to 480's and they seem pretty vigilant trying to keep up with a Dexcom and Omnipod. 

Good points, as I was actually referring to timing of the doses, where in the last FDA trial, dosing for Afrezza was 30 minutes before a meal with no follow up, same as RAA's. This lead to a real disadvantage in not being able to show how superior the fast in/fast out kinetics of Afrezza are for pwd.  Suprising that Afrezza did as well as it did in coming up non-inferior to RAA's given the above.

Afrezza: Timing is Everything
"The timing of the dose is more important than the dose its' self."
Matthew Bendall.

[sayhey24]

Well - here we go again, trying to show how afrezza over a long period of time is better than an RAA. Its not.
Primary Outcome Measures :
Change in HbA1c After 26 Weeks [ Time Frame: 26 weeks ]

They better be monitoring closely and properly second and third dosing or this is going to turn out to Affinty-1 all over again.

There is nothing better than repeated hypos to lower A1c. The Primary outcome should be non-inferior in A1C and fewer hypos.

[cedafuntennis]

Jul 23, 2021 18:40:53 GMT -5 sayhey24 said:

Well - here we go again, trying to show how afrezza over a long period of time is better than an RAA. Its not.
Primary Outcome Measures :
Change in HbA1c After 26 Weeks [ Time Frame: 26 weeks ]

They better be monitoring closely and properly second and third dosing or this is going to turn out to Affinty-1 all over again.

There is nothing better than repeated hypos to lower A1c. The Primary outcome should be non-inferior in A1C and fewer hypos.

With TIR superiority