Safety and Efficacy of Technosphere® Insulin Inhalation Powder and Lantus® Compared to Humalog® and Lantus® Over 16-Weeks

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00700622
• Collaborator: (none)
• Enrollment: 130
• Locations: 22
• Arms: 2
• Duration (Months): 22
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The objective of this study is to demonstrate that TI® Inhalation Powder combined with Lantus® is as effective as Humalog® combined with Lantus® on HbA1c.

Condition or Disease	Intervention/Treatment	Phase
Diabetes, Type 1	Drug: Technosphere Insulin; Drug: Insulin glargine; Drug: Insulin lispro	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase3, Multi-Center, Open-Label, Randomized, Clinical Trial Evaluating the Efficacy and Safety of Technosphere® Insulin Inhalation Powder in Combination With Lantus® Versus Humalog® in Combination With Lantus® in Subjects With Type 1 Diabetes Mellitus Over a 16-Week Treatment Period
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TI + Insulin glargine Technosphere Insulin Inhalation Powder in combination with Lantus (insulin glargine)	Drug: Technosphere Insulin; Technosphere Insulin Inhalation Powder 15U or 30U
Experimental: Insulin lispro + Insulin glargine Humalog (insulin lispro) in combination with Lantus (insulin glargine)	Drug: Insulin glargine; Lantus-injectible supplied as 3mL (300 units) pens; Drug: Insulin lispro; Humalog autopen cartridges pre-filled with 3mL (300 units)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c to Week 16 [Baseline to Week 16]

   Change from Baseline in glycosylated hemoglobin at Week 16

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men or women ≥ 18 and ≤ 80 years old

• Clinical diagnosis of type 1 diabetes mellitus for more than 12 months

• Body mass index (BMI) ≤ 30 kg/m2

• Stable antidiabetic regimen of sc insulin therapy at a total daily dose ≤ 1.5 IU/kg/day

• HbA1c > 7.0% and ≤ 9.0%

• C-peptide level ≤ 0.30 pmol/mL

• Nonsmokers (includes cigarettes, cigars, pipes, and chewing tobacco) for at least the preceding 6 months

• Negative urine cotinine defined as ≤ 100 ng/mL

• Pulmonary function tests (PFTs):

• Forced expiratory volume in 1 second (FEV1) ≥ 70% Third National Health and Nutrition Examination Survey (NHANES III) predicted

• FEV1 as a percentage of FEV1/forced vital capacity (FVC) ≥ 70% (NHANES III) predicted

• Total lung capacity (TLC) ≥ 80% predicted (Intermountain Thoracic Society [ITS])

• Single breath carbon monoxide diffusing capacity of the lung, hemoglobin-corrected (DLco-Hb) (uncorrected) ≥ 70% predicted

• For the subset of subjects having Doppler echocardiograms: right ventricular systolic pressure (RVSP) ≤ 40 mm Hg at Visit 1

• Written informed consent

Exclusion Criteria:

• Treatment with any type of antidiabetic drugs, other than sc insulin, within the preceding 12 weeks

• Two or more severe hypoglycemic episodes within 6 months of screening or episode of severe hypoglycemia between Visit 1 and Visit 5

• Any hospitalization or emergency room visit due to poor diabetic control within 6 months of Visit 1, or hospitalization or emergency room visit due to poor diabetic control between Visit 1 and Visit 5

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

• Previous exposure to an inhaled insulin product within 3 months of Visit 1

• History of insulin pump use within 6 weeks of Visit 1

• Allergy or known hypersensitivity to insulin or to any of the drugs to be used in the trial, or a history of hypersensitivity to TI Inhalation Powder or to drugs with a similar chemical structure

• Significant improvement in pre- to postbronchodilator spirometry at Visit 1 (defined as an increase of 12% and 200 mL in either FEV1 or FVC)

• History of chronic obstructive pulmonary disease (COPD), clinically proven asthma, or any other clinically important pulmonary disease (eg, obstructive sleep apnea) confirmed by pulmonary function testing or radiologic findings

• Inability to perform spirometry maneuvers meeting recommended American Thoracic Society (ATS) standards of acceptability and repeatability criteria

• Active respiratory infection (subject could return after 30 days from resolution for rescreening); if respiratory infection manifested after Visit 1 but before Visit 1 PFTs, subject was to be scheduled for PFTs after 30 days from resolution of respiratory infection. An additional hemoglobin was to be required

• Major organ system diseases, including:

• Seizure disorder

• Significant cardiovascular dysfunction or history within 3 months of Visit 1, eg, congestive heart failure (New York Heart Association [NYHA] Class III or IV), or serious arrhythmia, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks, or cerebrovascular accident

• Uncontrolled hypertension with a systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg at Visit 1 despite pharmacologic treatment

• Nephrotic syndrome; renal dysfunction or disease; serum creatinine > 2.0 mg/dL (0.11 mmol/L) in men and > 1.8 mg/dL (0.1 mmol/L) in women; or blood urea nitrogen (BUN) > 50 mg/dL (2.8 mmol/L)

• Cancer (other than excised cutaneous basal cell carcinoma) within the past 5 years or any history of lung neoplasms

• History of active viral or cirrhotic hepatic disease or abnormal liver enzymes as evidenced by serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN)

• Active infection (eg, human immunodeficiency virus [HIV], hepatitis) or history of severe infection within 30 days of Visit 1

• Anemia (hemoglobin ≤ 10.5 g/dL for women or ≤ 11.5 g/dL for men)

• Diagnosis of systemic autoimmune or collagen vascular disease requiring previous or current treatment with systemic corticosteroids, cytotoxic drugs, or penicillamine

• Any concurrent illness, other than diabetes mellitus, not controlled by a stable therapeutic regimen

• Current or previous chemotherapy or radiation therapy that might result in pulmonary toxicity

• Use of medications prescribed for weight loss (eg, sibutramine, orlistat) within 12 weeks of Visit 1

• Any history of or current use of amiodarone

• Clinically significant abnormalities on screening laboratory evaluation (unless discussed with and approved by the medical monitor)

• Women who were pregnant, lactating, or planning to become pregnant during the trial

• Women of childbearing potential (defined as premenopausal and not surgically sterilized or postmenopausal for fewer than 2 years) not practicing adequate birth control. Adequate birth control was defined as using oral, percutaneous, or transdermal contraceptives; condoms and diaphragms (double barrier) with a spermicide; or intrauterine devices. Postmenopausal for this trial included amenorrhea for 2 or more years or surgically sterile

• Current drug or alcohol abuse or a history of drug or alcohol abuse that, in the opinion of the PI, would make the subject an unsuitable candidate for participation in the trial

• Exposure to any investigational medications or devices within 30 days before trial entry, or participation in another clinical trial while participating in this trial

• Unable or unlikely to comprehend and follow the trial protocol (including SBGM and diabetes education)

• Unable or unlikely to comprehend how to use the MedTone Inhaler or inability to use the device

• Unable or unlikely to follow a meal plan that included at least 2 meals/day (with or without a third meal or additional snacks)

• Noncompliance with medication or procedures that, in the PI's opinion, might affect the trial data or subject safety and that precluded the subject from further participation in the trial

• Any other concurrent medical or major psychiatric condition that, in the opinion of the PI, made the subject unsuitable for the clinical trial or could limit the validity of the informed consent or impair the subject's ability to participate in the trial

• For the subset of subjects having Doppler echocardiograms:

• Subjects with left ventricular ejection fraction (LVEF) ≤ 35% at Visit 1

• Subjects with known history of sickle cell disease

• Previous use of Redux® (dexfenfluramine) or Pondimin® (fenfluramine)

• History of valvular heart disease, including mild or greater aortic insufficiency or moderate or greater mitral insufficiency

• Significant cardiovascular dysfunction or history within 12 months of Visit 1 (eg, congestive heart failure [NYHA Class III or IV]) or serious arrhythmia, treatment with medications to control or treat arrhythmias, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks, or cerebrovascular accident

• History of pulmonary embolism or deep venous thrombosis in the 12 months before Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Diabetes/Lipid Management and Research Center	Huntington Beach	California	United States	92648
2	The Whittier Institute for Diabetes Clinical Trials	La Jolla	California	United States	92037
3	Dorothy L & James E Frank Diabetes Research Institute	San Mateo	California	United States	94401
4	Barbara Davis Center for Diabetes Young Adult Clinic	Aurora	Colorado	United States	80045
5	University of Miami Diabetes Research Institute	Miami	Florida	United States	33136
6	University of Miami School of Medicine	Miami	Florida	United States	33136
7	Atlanta Diabetes Associates	Atlanta	Georgia	United States	30309
8	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112-2699
9	Washington University School of Medicine	St. Louis	Missouri	United States	63110
10	Deaconess Billings Clinic Research Center	Billings	Montana	United States	59101
11	Mountain Diabetes & Endocrine Center	Asheville	North Carolina	United States	28803
12	Endocrine Research Physicians East PA	Greenville	North Carolina	United States	27834
13	Your Diabetes Endocrine Nutrition Group, Inc.	Mentor	Ohio	United States	44060
14	OHSU Diabetes Center Research Oregon Health & Science University	Portland	Oregon	United States	97239
15	AM Diabetes and Endocrinology Center	Barrtlett	Tennessee	United States	38133
16	Dallas Diabetes & Endocrine Center	Dallas	Texas	United States	75230
17	Baylor Endocrine Center	Dallas	Texas	United States	75246
18	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
19	Diabetes Research Center -Fletcher Allen Health Care	South Burlington	Vermont	United States	05403
20	Diabetes Care Center	Seattle	Washington	United States	98105
21	Centro de Pesquisas em Diabetes Ltda	Porto Alegre	RS	Brazil	-90035-170
22	CPClin-Centro de Pesquisas Clinicas	Sao Paulo		Brazil	01244-030

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: NCT00700622
• Other Study ID Numbers: MKC-TI-117
• First Posted: Jun 18, 2008
• Last Update Posted: Oct 16, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro

Study Results

Participant Flow

Recruitment Details	The FPFV was May 30, 2008. Multinational trial conducted in the US and Brazil.
Pre-assignment Detail	2 week screening period prior to randomization - 276 Screened / 138 Eligible. 130 subjects were randomized; 138 screen failures and 8 discontinued prior to randomization.

Arm/Group Title	TI + Insulin Glargine	Insulin Lispro + Insulin Glargine
Arm/Group Description	Technosphere Insulin Inhalation Powder in combination with Lantus (insulin glargine)	Humalog (insulin lispro) in combination with Lantus (insulin glargine)
Period Title: Overall Study
STARTED	65	65
COMPLETED	52	60
NOT COMPLETED	13	5

Baseline Characteristics

Arm/Group Title	TI + Insulin Glargine	Insulin Lispro + Insulin Glargine	Total
Arm/Group Description	Technosphere Insulin Inhalation Powder in combination with Lantus (insulin glargine)	Humalog (insulin lispro) in combination with Lantus (insulin glargine)	Total of all reporting groups
Overall Participants	65	65	130
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.6 (11.82)	39.4 (11.46)	39.0 (11.60)
Sex: Female, Male (Count of Participants)
Female	25 38.5%	32 49.2%	57 43.8%
Male	40 61.5%	33 50.8%	73 56.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	74.49 (13.270)	74.18 (13.894)	74.3 (13.53)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.22 (9.238)	169.61 (9.807)	170.9 (9.579)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.07 (3.744)	25.63 (3.141)	25.3 (3.454)
HbA1c (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	7.76 (0.550)	7.62 (0.602)	7.69 (0.579)
Waist Circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	86.26 (10.445)	87.31 (10.669)	86.78 (10.530)
Fasting Blood Glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	178.06 (76.916)	176.20 (67.268)	177.15 (72.084)
Race (participants) [Number]
Caucasian	56 86.2%	59 90.8%	115 88.5%
Black	3 4.6%	0 0%	3 2.3%
Hispanic	5 7.7%	5 7.7%	10 7.7%
Other	1 1.5%	1 1.5%	2 1.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c to Week 16
Description	Change from Baseline in glycosylated hemoglobin at Week 16
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Intent to Treat with Available Data at Week 16

Arm/Group Title	TI + Insulin Glargine	Insulin Lispro + Insulin Glargine
Arm/Group Description	Technosphere Insulin Inhalation Powder in combination with Lantus (insulin glargine)	Humalog (insulin lispro) in combination with Lantus (insulin glargine)
Measure Participants	52	58
Least Squares Mean (Standard Error) [percentage of total hemoglobin]	-0.10 (0.087)	-0.03 (0.082)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro + Insulin Glargine
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A sample size of 92 subjects in each group was required to complete the trial. Approximately 230 subjects were to be randomized to achieve 184 completers (assuming a 20% dropout rate). This would have provided 80% power for a noninferiority design to test the difference of a 4-month change in HbA1c levels between treatment groups, assuming the upper noninferiority margins Δ of 0.5% with a standard deviation of 1.2 and a 1-sided alpha of 0.025.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.119
	Estimation Comments

Adverse Events

Time Frame	SAEs: From first dose to 30d post last dose AEs: From first dose to 30d post last dose
Arm/Group Title	TI + Insulin Glargine		Insulin Lispro + Insulin Glargine
Arm/Group Description	Technosphere Insulin Inhalation Powder in combination with Lantus (insulin glargine)		Humalog (insulin lispro) in combination with Lantus (insulin glargine)
All Cause Mortality
	TI + Insulin Glargine		Insulin Lispro + Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TI + Insulin Glargine		Insulin Lispro + Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/65 (1.5%)		3/65 (4.6%)
Injury, poisoning and procedural complications
Delayed recovery from anesthesia	0/65 (0%)		1/65 (1.5%)
Intentional overdose	0/65 (0%)		1/65 (1.5%)
Metabolism and nutrition disorders
Hypoglycemia	1/65 (1.5%)		2/65 (3.1%)
Hypoglycemic seizure	0/65 (0%)		1/65 (1.5%)
Psychiatric disorders
Suicide attempt	0/65 (0%)		1/65 (1.5%)
Other (Not Including Serious) Adverse Events
	TI + Insulin Glargine		Insulin Lispro + Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/65 (64.6%)		34/65 (52.3%)
Endocrine disorders
Hypoglycaemia	21/65 (32.3%)		23/65 (35.4%)
General disorders
Chest discomfort	4/65 (6.2%)		0/65 (0%)
Infections and infestations
Sinusitis	5/65 (7.7%)		2/65 (3.1%)
Upper respiratory infection	5/65 (7.7%)		6/65 (9.2%)
Influenza	3/65 (4.6%)		11/65 (16.9%)
Nasopharyngitis	3/65 (4.6%)		4/65 (6.2%)
Respiratory, thoracic and mediastinal disorders
Cough	29/65 (44.6%)		0/65 (0%)
Pharyngolaryngeal pain	4/65 (6.2%)		2/65 (3.1%)

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.