A Study Designed to Compare 2 Dose Strengths of TI Inhalation Powder in Adults With Type 1 Diabetes Mellitus and to Compare One of Those Formulations (30Units) With an Injection of Insulin Lispro

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00662857
• Collaborator: (none)
• Enrollment: 29
• Locations: 2
• Arms: 3
• Duration (Months): 8
• Patients Per Site: 14.5
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

28 subjects to be enrolled for a screening period, 3 dosing visits & a follow-up visit. Visits 2 and 3 dosing of TI Inhalation Powder, cross over between two 15 U cartridges and one 30 U cartridge. Visit 4 dosing will be a sc injection of 10 IU of RAA (rapid-acting insulin analogue).

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus: Type 1	Drug: Technosphere® Insulin Inhalation Powder; Drug: Technosphere Insulin® Inhalation Powder; Drug: RAA Population	Phase 2

Detailed Description

28 eligible subjects were planned to be enrolled to determine bioequivalence and safety parameters of two 15 U TI Inhalation Powder cartridges versus one 30 U TI Inhalation Powder cartridge, according to a randomized, 2-way crossover design. Additionally, bioavailability of one 30 U TI Inhalation Powder cartridge to a single subcutaneous injection of 10 IU of RAA will be compared.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-Label, Randomized, 2-Way Crossover, Clinical Trial to Compare the Pharmacokinetics of 2 Formulations of "Intended Commercial Product" Technosphere® Insulin Inhalation Powder and to Determine the Bioavailability of a 30 Unit Cartridge of "Intended Commercial Product" Technosphere® Insulin Inhalation Powder Versus a 10 Unit Subcutaneous Injection of Insulin Lispro in Subjects With Type 1 Diabetes Mellitus
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1: TI Inhalation Powder A Technosphere® Insulin Inhalation Powder, two 15 U cartridges	Drug: Technosphere® Insulin Inhalation Powder; TI Inhalation Powder, two 15 U cartridges
Experimental: 2: TI Inhalation Powder B Technosphere® Insulin Inhalation Powder, one 30 U cartridge	Drug: Technosphere Insulin® Inhalation Powder; TI Inhalation Powder, one 30 U cartridge
Experimental: 3: RAA Population Rapid Acting Analogue subjects received 10 IU sc Insulin Lispro	Drug: RAA Population; RAA Population: All subjects received a single 10 IU sc injection of insulin lispro.

Outcome Measures

Primary Outcome Measures

1. Bioequivalence of Two 15 U Cartridges (TI Inhalation Powder A) and One 30 U Cartridge (TI Inhalation Powder B) Based on Baseline Corrected Insulin AUC0-360 [0 to 360 minutes post-dose]

   Dose-normalized baseline-corrected area under the serum insulin vs. time curve

2. Bioequivalence of Two 15 U Cartridges (TI Inhalation Powder A) and One 30 U Cartridge (TI Inhalation Powder B) Based on Baseline Corrected Insulin Cmax. [0 to 360 minutes post-dose]

   Maximum observed baseline-corrected serum insulin concentration

3. Bioequivalence of Two 15 U Cartridges (TI Inhalation Powder A) and One 30 U Cartridge (TI Inhalation Powder B) Based on Baseline Corrected Insulin Tmax [0 to 360 minutes post-dose]

4. Relative Bioavailability of 30 U of TI (TI Inhalation Powder B) Versus 10 U of sc Insulin Lispro [0 to 360 minutes post-dose]

   Dose-normalized baseline-corrected area under the serum insulin vs. time curve (time 0 to 360 minutes post-dose)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Males and Females > 18 and < 60 years of age Clinical diagnosis of type 1 diabetes mellitus with stable anti-diabetic regimen for at least 90 days prior to Screening BMI of < 30 kg/m2 Non-smokers (never smoked or former smokers (> 6 months since cessation) Pulmonary Function Testing (FEV1 > 70%, FEV1/FVC > 70%, TLC > 80% DLco [unc] > 70% of Predicted Written Informed consent

Exclusion Criteria:

Two or more severe hypoglycemic episodes within 6 months of Screening/Visit 1 Severe complications of diabetes Previous exposure to any inhaled insulin product other than TI inhalation Powder or similar formulation Inability to perform PFT maneuvers meeting recommended American Thoracic Society (ATS) standards of acceptability and repeatability criteria Respiratory tract infection within 8 weeks prior to Screening/Visit 1 History of chronic obstructive pulmonary disease (COPD), clinically proven asthma, and/or any other clinically important pulmonary disease (eg. Obstructive sleep apnea), confirmed by pulmonary function testing, and/or radiologic findings Major organ system diseases including seizures, heart failure, uncontrolled hypertension, cancer within the past 5 years, liver disease, anemia or autoimmune disorder Clinically significant abnormalities on screening laboratory evaluation Female subjects who are pregnant, lactating, or planning to become pregnant during the clinical trial period or not practicing adequate birth control Unable and/or unlikely to comprehend how to use the investigational device in this study or to follow study instructions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Profil Institute for Clinical Research Inc.	Chula Vista	California	United States	91911
2	Diabetes & Glandular Disease Research Assoc PA	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Mannkind Corporation

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT00662857
• Other Study ID Numbers: MKC-TI-116
• First Posted: Apr 21, 2008
• Last Update Posted: Oct 16, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Mannkind Corporation: Diabetic adult male, diabetic adult female
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc

Study Results

Participant Flow

Recruitment Details	This was a single site with first subject screened 24 Apr 2008
Pre-assignment Detail	Subjects assigned at Visit 2 to either: 2 15 U cartridges (TI Inhalation Powder A) or 1 30 U cartridge (TI Inhalation Powder B). At Visit 3 each subject was crossed over to the other treatment group. At Visit 4 subjects received a single sc injection of 10 IU of insulin lispro to 1 of 3 possible injection sites: arm, leg, or abdomen.

Arm/Group Title	TI - A (2x15 U)/TI - B (1x30 U)/10 U sc Insulin Lispro	TI - B (1x30 U)/TI - A (2x15 U)/10 U sc Insulin Lispro
Arm/Group Description	Treatment sequence: 30 U of Technosphere Insulin (TI) administered as 2 x 15 U cartridges as a single-dose, followed by 30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose, and then 10 U of insulin lispro administered subcutaneously (sc) during a glucose clamp procedure	Treatment sequence: 30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose, followed by 30 U of Technosphere Insulin (TI) administered as 2 x 15 U cartridges as a single-dose, and then 10 U of insulin lispro administered subcutaneously (sc) during a glucose clamp procedure
Period Title: TI Dosing Period 1 (1 Day)
STARTED	13	16
COMPLETED	13	16
NOT COMPLETED	0	0
Period Title: TI Dosing Period 1 (1 Day)
STARTED	13	16
COMPLETED	13	14
NOT COMPLETED	0	2
Period Title: TI Dosing Period 1 (1 Day)
STARTED	13	14
COMPLETED	13	14
NOT COMPLETED	0	0
Period Title: TI Dosing Period 1 (1 Day)
STARTED	13	14
COMPLETED	12	14
NOT COMPLETED	1	0
Period Title: TI Dosing Period 1 (1 Day)
STARTED	12	14
COMPLETED	12	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Safety Population
Arm/Group Description	Any subject that received at least one treatment with TI inhalation powder
Overall Participants	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.4 (12.71)
Sex: Female, Male (Count of Participants)
Female	10 34.5%
Male	19 65.5%
Body mass index (BMI) (kg/m squared) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m squared]	26.61 (2.772)

Outcome Measures

1. Primary Outcome

Title	Bioequivalence of Two 15 U Cartridges (TI Inhalation Powder A) and One 30 U Cartridge (TI Inhalation Powder B) Based on Baseline Corrected Insulin AUC0-360
Description	Dose-normalized baseline-corrected area under the serum insulin vs. time curve
Time Frame	0 to 360 minutes post-dose

Outcome Measure Data

Analysis Population Description

Per Protocol Population - All subjects who completed the crossover portion of the trial (through Visit 3), had serum insulin concentration data for both TI Inhalation Powder A and TI Inhalation Powder B and were deemed to be protocol compliant (no major protocol violations during the clinical trial).

Arm/Group Title	Techosphere Insulin - A (2 x 15 U)	Techosphere Insulin - B (1 x 30 U)
Arm/Group Description	30 U of Technosphere Insulin (TI) administered as 2 x 15 U cartridges as a single-dose during a glucose clamp procedure	30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose during a glucose clamp procedure
Measure Participants	25	25
Least Squares Mean (Standard Error) [(micro U)*min/mL]	3337.2 (1.096)	3396.6 (1.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Techosphere Insulin - A (2 x 15 U), Techosphere Insulin - B (1 x 30 U)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Means
	Estimated Value	0.982
	Confidence Interval	(2-Sided) 90%; 0.846 to 1.141
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio of serum insulin from a single 30 U cartridge to 2 x 15 U cartridges of TI. Based on pair-wise comparisons from analysis of covariance fitting the model: natural log of parameter = cohort, treatment, visit, subject (cohort).

2. Primary Outcome

Title	Bioequivalence of Two 15 U Cartridges (TI Inhalation Powder A) and One 30 U Cartridge (TI Inhalation Powder B) Based on Baseline Corrected Insulin Cmax.
Description	Maximum observed baseline-corrected serum insulin concentration
Time Frame	0 to 360 minutes post-dose

Outcome Measure Data

Analysis Population Description

Per Protocol Population - All subjects who completed the crossover portion of the trial (through Visit 3), had serum insulin concentration data for both TI Inhalation Powder A and TI Inhalation Powder B and were deemed to be protocol compliant (no major protocol violations during the clinical trial).

Arm/Group Title	Techosphere Insulin - A (2 x 15 U)	Techosphere Insulin - B (1 x 30 U)
Arm/Group Description	30 U of Technosphere Insulin (TI) administered as 2 x 15 U cartridges as a single-dose during a glucose clamp procedure	30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose during a glucose clamp procedure
Measure Participants	25	25
Least Squares Mean (Standard Error) [(micro U)/mL]	65.72 (1.098)	69.08 (1.098)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Techosphere Insulin - A (2 x 15 U), Techosphere Insulin - B (1 x 30 U)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Means
	Estimated Value	0.951
	Confidence Interval	(2-Sided) 90%; 0.823 to 1.099
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio of serum insulin from a single 30 U cartridge to 2 x 15 U cartridges of TI. Based on pair-wise comparisons from analysis of covariance fitting the model: natural log of parameter = cohort, treatment, visit, subject (cohort).

3. Primary Outcome

Title	Bioequivalence of Two 15 U Cartridges (TI Inhalation Powder A) and One 30 U Cartridge (TI Inhalation Powder B) Based on Baseline Corrected Insulin Tmax
Time Frame	0 to 360 minutes post-dose

Outcome Measure Data

Analysis Population Description

Per Protocol Population - All subjects who completed the crossover portion of the trial (through Visit 3), had serum insulin concentration data for both TI Inhalation Powder A and TI Inhalation Powder B and were deemed to be protocol compliant (no major protocol violations during the clinical trial).

Arm/Group Title	Techosphere Insulin - A (2 x 15 U)	Techosphere Insulin - B (1 x 30 U)
Arm/Group Description	30 U of Technosphere Insulin (TI) administered as 2 x 15 U cartridges as a single-dose during a glucose clamp procedure	30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose during a glucose clamp procedure
Measure Participants	25	25
Median (Full Range) [min]	10	10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Techosphere Insulin - A (2 x 15 U), Techosphere Insulin - B (1 x 30 U)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3531
	Comments
	Method	Signed Rank Test
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Relative Bioavailability of 30 U of TI (TI Inhalation Powder B) Versus 10 U of sc Insulin Lispro
Description	Dose-normalized baseline-corrected area under the serum insulin vs. time curve (time 0 to 360 minutes post-dose)
Time Frame	0 to 360 minutes post-dose

Outcome Measure Data

Analysis Population Description

Rapid-acting insulin Analogue (RAA) Population All subjects who had serum insulin concentration data for both TI Inhalation Powder B and insulin lispro and were deemed to be protocol compliant (no major protocol violations during the clinical trial).

Arm/Group Title	Techosphere Insulin - B (1 x 30 U)	10 U Subcutaneous (sc) Insulin Lispro
Arm/Group Description	30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose during a glucose clamp procedure	10 U of insulin lispro administered subcutaneously during a glucose clamp procedure
Measure Participants	25	25
Least Squares Mean (Standard Error) [(micro U)*min/mL]	3406.8 (1.095)	7404.0 (1.102)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Techosphere Insulin - A (2 x 15 U), Techosphere Insulin - B (1 x 30 U)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Means
	Estimated Value	0.460
	Confidence Interval	(2-Sided) 90%; 0.366 to 0.578
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio of serum insulin from a single 30 U cartridge of TI to 10 U sc insulin lispro. Based on pair-wise comparisons from analysis of covariance fitting the model: natural log of parameter = cohort, treatment, visit, subject (cohort).

Adverse Events

Time Frame	From time of first dose to 30d after last dose; Serious adverse event (SAE) = until resolution
Arm/Group Title	Techosphere Insulin - A (2 x 15 U)		Techosphere Insulin - B (1 x 30 U)		10 U Subcutaneous (sc) Insulin Lispro
Arm/Group Description	30 U of Technosphere Insulin (TI) administered as 2 x 15 U cartridges as a single-dose during a glucose clamp procedure		30 U of Technosphere Insulin (TI) administered as 1 x 30 U cartridges as a single-dose during a glucose clamp procedure		10 U of insulin lispro administered subcutaneously during a glucose clamp procedure
All Cause Mortality
	Techosphere Insulin - A (2 x 15 U)		Techosphere Insulin - B (1 x 30 U)		10 U Subcutaneous (sc) Insulin Lispro
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Techosphere Insulin - A (2 x 15 U)		Techosphere Insulin - B (1 x 30 U)		10 U Subcutaneous (sc) Insulin Lispro
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/29 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Techosphere Insulin - A (2 x 15 U)		Techosphere Insulin - B (1 x 30 U)		10 U Subcutaneous (sc) Insulin Lispro
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/27 (33.3%)		14/29 (48.3%)		5/26 (19.2%)
Gastrointestinal disorders
Nausea	2/27 (7.4%)		1/29 (3.4%)		1/26 (3.8%)
Investigations
Hepatic enzyme increased	0/27 (0%)		0/29 (0%)		2/26 (7.7%)
Metabolism and nutrition disorders
Hypoglycaemia	1/27 (3.7%)		4/29 (13.8%)		1/26 (3.8%)
Nervous system disorders
Headache	2/27 (7.4%)		5/29 (17.2%)		1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Cough	4/27 (14.8%)		7/29 (24.1%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

MannKind has right to 1st joint multicenter publication. After 1st publication PI may publish data only if PI submits proposed publication to MNKD for review 60 days prior to publication date. MNKD may remove any confidential information. If a multicenter publication is not submitted 12 months after conclusion, abandonment, or termination of the Study at all sites, or if MNKD confirms there will be no multicenter Study publication, PI may publish the Study results subject to MNKD rights herein.