Evaluate Safety of Technosphere® Insulin (TI) in Diabetic Subjects With Moderate Obstructive Pulmonary Disease

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00642616
• Collaborator: (none)
• Enrollment: 34
• Locations: 21
• Arms: 4
• Duration (Months): 68
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Examine the effects of TI in combination with an anti-diabetic regimen including inhaled insulin versus anti-diabetic treatment without inhaled insulin on lung function & pulmonary safety

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus; Moderate Chronic Obstructive Pulmonary Disease; Asthma	Drug: Technosphere® Insulin; Drug: Usual Care	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-label, Randomized Clinical Trial to Evaluate the Safety of Technosphere® Insulin Inhalation Powder in Type 1 or Type 2 Diabetic Subjects With Obstructive Pulmonary Disease (Asthma or Chronic Obstructive Pulmonary Disease) Over a 12 Months Treatment Period With a 2 Month Follow-up
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Technosphere® Insulin (Asthma) Technosphere® Insulin Inhalation Powder administered prandially in diabetic participants with Asthma	Drug: Technosphere® Insulin; Technosphere® Insulin delivered with Gen 2 inhaler with doses individualized for each participant in combination with an antidiabetic regimen of insulin and/or oral antidiabetic agents; Other Names: Afrezza
Active Comparator: Usual Care (Asthma) Usual anti diabetic care in Diabetic participants with Asthma	Drug: Usual Care; Type 1 diabetics: long-acting (basal) insulin plus rapid-acting insulin, or pre-mix insulin Type 2 diabetics: oral anti-diabetic medications with or without long-acting (basal) insulin
Experimental: Technosphere® Insulin (COPD) Technosphere® Insulin Inhalation Powder administered prandially in diabetic participants with Chronic Obstructive Pulmonary disease (COPD)	Drug: Technosphere® Insulin; Technosphere® Insulin delivered with Gen 2 inhaler with doses individualized for each participant in combination with an antidiabetic regimen of insulin and/or oral antidiabetic agents; Other Names: Afrezza
Active Comparator: Usual Care (COPD) Usual anti diabetic care in Diabetic participants with Chronic Obstructive Pulmonary disease (COPD)	Drug: Usual Care; Type 1 diabetics: long-acting (basal) insulin plus rapid-acting insulin, or pre-mix insulin Type 2 diabetics: oral anti-diabetic medications with or without long-acting (basal) insulin

Outcome Measures

Primary Outcome Measures

1. Change in Post-bronchodilator FEV1 From Baseline to Week 52 [52 Weeks]

   Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) is measured at the pulmonary function laboratory.

Secondary Outcome Measures

1. Number of Participants With Asthma Exacerbation by Treatment Arm [Baseline to Week 52]

   Number of participants who experienced worsening of asthma symptoms

2. Number of Participants With COPD Exacerbation by Treatment Arm [Baseline to Week 52]

   Number of participants who experienced worsening of COPD symptoms

3. Change in HbA1C From Baseline to Week 52 [Baseline, week 52]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Asthma

• Physician diagnosis of asthma with history of any or all of the following: recurrent wheezing, recurrent chest tightness, recurrent difficulty breathing, or cough, particularly worse at nighttime

• Never smoked or former smokers (= 6 months since cessation)

• ≥18 years of age

• Prebronchodilator Forced Expiratory Volume in 1sec (FEV1) ≥ 60% Third National Health and Nutrition Examination Survey (NHANES III) predicted, prebronchodilator total lung capacity (TLC) ≥ 80% predicted Intermountain Thoracic Society (ITS), and prebronchodilator single breath carbon monoxide diffusing capacity of the lung (DLco) (unc) ≥70% predicted (Miller)

• < 30% day-to-day variability in daily morning Peak expiratory Volume (PEF) during the 2-week run-in period

• Significant improvement in pre- to postbronchodilator spirometry (defined as an increase from baseline of ≥ 12% and ≥ 200 mL in FEV1 or Forced Vital Capacity [FVC]) at Screening/Visit 1 or documented significant improvement in pre- to postbronchodilator spirometry (as defined above) within past 12 months in subject's medical records or a documented positive methacholine challenge test within the past 12 months

COPD

• Physician diagnosis of COPD (including emphysema and/or chronic bronchitis), history of dyspnea and/or intermittent or daily chronic cough with or without sputum production, not attributable to any other known cause

• Former smoker (≥ 6 months since cessation) with smoking history of ≥ 10 pack years

• ≥40 years of age

• Postbronchodilator FEV1/FVC ratio < 70%

• Postbronchodilator FEV1 ≥ 50% NHANES III predicted, total lung capacity (TLC) ≥ 80% predicted ITS, and DLco (unc) ≥ 50% predicted (Miller)

Both

• Clinical diagnosis of Type1 or 2 diabetes mellitus for ≥ 12 months and no change in anti-diabetic regiment for at least 90-days prior to screening

• BMI of, < 39 kg/m2

• Urine cotinine level ≤ 100ng/dL

• Clinical diagnosis of obstructive lung disease

• HbA1C > 6.5% ≤ 11.5%

Exclusion Criteria:

• History of pulmonary exacerbation within 8 weeks of screening/V1 or between V1 and V2

• Use of systemic corticosteroids or antibiotics for respiratory illness within 8 weeks of screening/V1 OR between V1 and V2

• Increase from baseline in the use of short-acting bronchodilator or short-acting anticholinergic agents, or the combination of the 2, by ≥6 puffs or ≥3 nebulizer treatments per day for ≥ 2 days

• Treatment with supplemental oxygen therapy, room air oxygen saturation, 94% or history of intubation or ICU admission for respiratory illness in the past 5 yrs.

• Greater than 2 hospitalizations or ER or urgent care visits or required >3 courses of systemic steroid in the past 12 months for respiratory illness

• Use of Symlin® (pramlintide acetate) within the preceding 90 days

• Two or more severe hypoglycemic episodes within 6 months of screening or episode of severe hypoglycemia between Screening and Baseline

• Previous exposure to any inhaled insulin product

• Currently using an insulin delivery pump

• Requires significant change (define as initiation of a new medication or change in the dose or frequency of the controller medications) in the asthma or COPD therapeutic regimen within 8 weeks of Screening/Visit 1 (Week -4) or between Visit 1 and Baseline/Visit 2

• Severe complications of diabetes mellitus, in the opinion of the PI or sub-investigator, including symptomatic autonomic neuropathy; disabling peripheral neuropathy; active proliferative retinopathy; nephropathy with renal failure, renal transplant and/or dialysis; history of foot ulcers; nontraumatic amputations due to gangrene; and/or vascular claudication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mission Hills	California	United States	91345
2		San Diego	California	United States	92117
3		Palm Harbor	Florida	United States	34684
4		Flint	Michigan	United States	48504
5		Morehead City	North Carolina	United States	28557
6		Medford	Oregon	United States	97504
7		Greenville	South Carolina	United States	29615
8		Spartanburg	South Carolina	United States	29302
9		Dallas	Texas	United States	75225
10		Dallas	Texas	United States	75231
11		Federal Way	Washington	United States	98003
12		Tacoma	Washington	United States	98405
13		Yaroslavl	RUS	Russian Federation	150002
14		Kemerovo	RU	Russian Federation	650066
15		Moscow	RU	Russian Federation	105120
16		St Petersburg	RU	Russian Federation	198013
17		St. Petersburg	RU	Russian Federation	191015
18		St. Petersburg	RU	Russian Federation	191119
19		St. Petersburg	RU	Russian Federation	194354
20		Kiev	UA	Ukraine	04114
21		Kyiv	UA	Ukraine	01021

Sponsors and Collaborators

• Mannkind Corporation

Investigators

• Study Chair: Chief Medical Officer, Mannkind Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT00642616
• Other Study ID Numbers: MKC-TI-134
• First Posted: Mar 25, 2008
• Last Update Posted: Apr 14, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Asthma; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Insulin

Study Results

Participant Flow

Recruitment Details	A total of 517 participants were screened in 5 countries . First participant was screened in March 2009.
Pre-assignment Detail	2 week screening period followed by a 2 week run-in period. After the screening period, 51 participants were randomized and 34 participants met eligibility criteria after the 2 week run-in period and were treated . Study was terminated based on data safety monitoring board recommendations.

Arm/Group Title	Technosphere® Insulin (Asthma)	Usual Care (Asthma)	Technosphere® Insulin (COPD)	Usual Care (COPD)
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Asthma	Usual and anti diabetic care in diabetic participants with Asthma.	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Chronic Obstructive Pulmonary disease (COPD)	Usual and anti diabetic care in diabetic participants with Chronic Obstructive Pulmonary disease (COPD)
Period Title: Overall Study
STARTED	9	8	9	8
COMPLETED	0	1	0	1
NOT COMPLETED	9	7	9	7

Baseline Characteristics

Arm/Group Title	Technosphere® Insulin (Asthma)	Usual Care (Asthma)	Technosphere® Insulin (COPD)	Usual Care (COPD)	Total
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic patients with Asthma	Usual and anti diabetic care in diabetic participants with Asthma.	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic patients with COPD	Usual and anti diabetic care in diabetic participants with COPD.	Total of all reporting groups
Overall Participants	9	8	9	8	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.00 (7.26)	49.75 (15.73)	67.44 (8.38)	68.88 (8.20)	64.03 (12.71)
Sex: Female, Male (Count of Participants)
Female	6 66.7%	4 50%	2 22.2%	1 12.5%	13 38.2%
Male	3 33.3%	4 50%	7 77.8%	7 87.5%	21 61.8%

Outcome Measures

1. Primary Outcome

Title	Change in Post-bronchodilator FEV1 From Baseline to Week 52
Description	Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) is measured at the pulmonary function laboratory.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Only two participants completed both time points (one in the Usual Care (Asthma) Arm and one in the Usual Care (COPD) Arm); data are not provided due to privacy concerns.

Arm/Group Title	Technosphere® Insulin (Asthma)	Usual Care (Asthma)	Technosphere® Insulin (COPD)	Usual Care (COPD)
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Asthma	Usual and anti diabetic care in diabetic participants with Asthma.	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with COPD	Usual and anti diabetic care in diabetic participants with COPD
Measure Participants	0	0	0	0

2. Secondary Outcome

Title	Number of Participants With Asthma Exacerbation by Treatment Arm
Description	Number of participants who experienced worsening of asthma symptoms
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Safety population: Participants who received at least one dose of study medication. The outcome applies only to participants with underlying Asthma

Arm/Group Title	Technosphere® Insulin (Asthma)	Usual Care With Anti-diabetic Agents (Asthma)	Technosphere® Insulin (COPD)	Usual Care With Anti-diabetic Agents (COPD)
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Asthma	Usual anti diabetic care in diabetic participants with Asthma	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with COPD	Usual anti diabetic care in diabetic participants with COPD
Measure Participants	9	8	0	0
Exacerbation of Asthma	1 11.1%	1 12.5%
No Exacerbation of Asthma	8 88.9%	7 87.5%

3. Secondary Outcome

Title	Number of Participants With COPD Exacerbation by Treatment Arm
Description	Number of participants who experienced worsening of COPD symptoms
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Safety population: Participants who received at least one dose of study medication. The outcome applies only to participants with underlying COPD

Arm/Group Title	Technosphere® Insulin (Asthma)	Usual Care With Anti-diabetic Agents (Asthma)	Technosphere® Insulin (COPD)	Usual Care With Anti-diabetic Agents (COPD)
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Asthma	Usual anti diabetic care in diabetic participants with Asthma	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with COPD	Usual anti diabetic care in diabetic participants with COPD
Measure Participants	0	0	9	8
COPD Exacerbation	3 33.3%	1 12.5%
No Exacerbation	6 66.7%	7 87.5%

4. Secondary Outcome

Title	Change in HbA1C From Baseline to Week 52
Time Frame	Baseline, week 52

Outcome Measure Data

Analysis Population Description

Only two participants completed both time points (one in the Usual Care (Asthma) Arm and one in the Usual Care (COPD) Arm); data are not provided due to privacy concerns

Arm/Group Title	Technosphere® Insulin (Asthma)	Usual Care (Asthma)	Technosphere® Insulin (COPD)	Usual Care (COPD)
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Asthma	Usual and anti diabetic care in diabetic participants with Asthma.	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with COPD	Usual and anti diabetic care in diabetic participants with COPD
Measure Participants	0	0	0	0

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to 30 days after the last study visit or study related procedure was performed regardless of seriousness or relationship to investigational product
Adverse Event Reporting Description	Analysis was done on safety population
Arm/Group Title	Technosphere® Insulin (Asthma)		Usual Care With Anti-diabetic Agents (Asthma)		Technosphere® Insulin (COPD)		Usual Care With Anti-diabetic Agents (COPD)
Arm/Group Description	Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with Asthma		Usual anti diabetic care in diabetic participants with Asthma		Technosphere® Insulin Inhalation Powder in combination with an antidiabetic regimen in diabetic participants with COPD		Usual anti diabetic care in diabetic participants with COPD
All Cause Mortality
	Technosphere® Insulin (Asthma)		Usual Care With Anti-diabetic Agents (Asthma)		Technosphere® Insulin (COPD)		Usual Care With Anti-diabetic Agents (COPD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Technosphere® Insulin (Asthma)		Usual Care With Anti-diabetic Agents (Asthma)		Technosphere® Insulin (COPD)		Usual Care With Anti-diabetic Agents (COPD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Gastrointestinal disorders
Intestinal obstruction	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Hypoglycaemia	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/9 (11.1%)		0/8 (0%)	0	0/9 (0%)	0	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	Technosphere® Insulin (Asthma)		Usual Care With Anti-diabetic Agents (Asthma)		Technosphere® Insulin (COPD)		Usual Care With Anti-diabetic Agents (COPD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/9 (88.9%)		7/8 (87.5%)		4/9 (44.4%)		6/8 (75%)
Blood and lymphatic system disorders
Lymphadenopathy	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Nausea	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Diarrhoea	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		1/8 (12.5%)
General disorders
Influenza like illness	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Asthenia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Chest discomfort	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Oedema peripheral	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Immune system disorders
Seasonal allergy	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Infections and infestations
Bronchitis	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Influenza	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Respiratory tract infection	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Respiratory tract infection viral	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Nasopharyngitis	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/8 (12.5%)
Pharyngitis	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Pyelonephritis chronic	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Tracheitis	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Upper respiratory tract infection	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Urinary Tract Infection	0/9 (0%)		2/8 (25%)		0/9 (0%)		0/8 (0%)
Viral infection	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Herpes zoster	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Sinusitis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Staphylococcal infection	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Investigations
Pulmonary function test decreased	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Monocyte count increased	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Metabolism and nutrition disorders
Hypoglycemia	2/9 (22.2%)		0/8 (0%)		1/9 (11.1%)		3/8 (37.5%)
Diabetes mellitus inadequate control	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Diabetes mellitus	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Dyslipidaemia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Hypertriglyceridaemia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Obesity	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Type 1 Diabetes Mellitus	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Hyperuricaemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/9 (11.1%)		0/8 (0%)		2/9 (22.2%)		0/8 (0%)
Hypoventilation	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Oropharyngeal spasm	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Rhinitis allergic	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Asthma	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Chronic obstructive pulmonary disease	0/9 (0%)		0/8 (0%)		3/9 (33.3%)		1/8 (12.5%)
Productive cough	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Bronchial obstruction	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Dyspnoea	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Wheezing	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Echymosis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Vascular disorders
Hot flush	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Venous insufficiency	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)

Limitations/Caveats

- Early termination of trial leading to small numbers of subjects analyzed

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.