An Open-label, Multi-center, International, Three-year, Safety and Tolerability 'Follow on' Trial

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00754624
• Collaborator: (none)
• Enrollment: 229
• Locations: 40
• Arm: 1
• Duration (Months): 53
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Safety Follow-Up Trial to PDC-INS-0008 and MKC-TI-005

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Technosphere® Insulin Inhalation Powder and MedTone™ Inhaler	Phase 2

Detailed Description

This is an uncontrolled study without comparator. Subjects were followed up to 4 years on Technosphere Insulin. Of 229 subjects 199 were exposed for ≥12 mo, 175 for ≥ 24 mo, 60 for ≥ 36 mo, 31 for ≥ 42 mo, & 2 for 48 mo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 229 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Four-year, Safety and Tolerability, Open-Label, "Follow on" Trial Evaluating Technosphere® Insulin in Subjects With Type 2 Diabetes Mellitus.
• Study Start Date: May 1, 2004
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TI Inhalation Powder Technosphere® Insulin Inhalation Powder	Drug: Technosphere® Insulin Inhalation Powder and MedTone™ Inhaler; Inhalation starting at 15, 30, or 60U doses and can be titrated up or down by 15U to a minimum of 15U or a maximum of 90U

Outcome Measures

Primary Outcome Measures

1. Annual Rate of Change in FEV1 From Baseline to End of Study [Baseline to 48 months]

Secondary Outcome Measures

1. Annual Rate of Change in FVC From Baseline to End of Study [Baseline to 48 months]

2. Annual Rate of Change in DLCo From Baseline to End of Study [Baseline to 48 months]

3. Change in HbA1c From Baseline to Last Measurement on Study Drug (Maximum of 48 Months) [Baseline to last measurement on study drug (maximum of 48 months]

   Change in HbA1c from Baseline to last measurement on study drug (maximum of 48 months)

4. Change in FPG From Baseline to Last Study Measurement on Treatment (Maximum of 48 Months) [Baseline to last study measurement on treatment (maximum of 48 months)]

   Change from Baseline to last study measurement on treatment (maximum of 48 months)

5. Change in Weight in kg From Baseline to End of Study [Baseline to last measurement on study drug (maximum of 48 months)]

   Baseline to last measurement on study drug (maximum of 48 months)

6. High Resolution Computerized Tomography Scans of the Chest [End of study]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Previous completion of PDC-INS-0008 or MKC-TI-005

• Subjects must be able to attend all scheduled visits and, in the opinion of the Investigator, be able to complete this safety trial

• Subjects must be able to understand English or have access to validated primary language trial documents

• Written informed consent

Exclusion Criteria:

• Drug or alcohol dependency

• Smokers (subjects are expected to remain non-smokers throughout their participation in this trial)

• Known hypersensitivity to the trial drug or to drugs of similar chemical structures

• Anemia (hemoglobin level < 11 g/dL for females or < 12 g/dL for males)

• Evidence of moderate or greater ketones in urine

• Women of childbearing potential practicing inadequate birth control. (Adequate birth control is defined as using oral contraceptives, condoms or diaphragms with spermicide, intrauterine devices, Depo-Provera, contraceptive patches or surgical sterilization)

• Women who are pregnant

• Clinically significant adverse events that remain unresolved from the previous trial and/or clinically significant abnormal laboratory values which are determined by the Investigator or the MKC Medical Monitor to be unsafe or confounding to continued participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dorothy L & James E Frank Diabetes Research Institute	San Mateo	California	United States	94401
2	Sansum Medical Research Institute	Santa Barbara	California	United States	93105
3	Alliance Medical Group of Greater Waterbury	Middlebury	Connecticut	United States	06762
4	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
5	Soundview Research Associates	Norwalk	Connecticut	United States	06851
6	University of Miami School of Medicine	Miami	Florida	United States	33136
7	Oschner Clinic Foundation	New Orleans	Louisiana	United States	70121
8	International Diabetes Center	Minneapolis	Minnesota	United States	55416
9	Diabetes Care & Information Center of New York	Flushing	New York	United States	11365
10	Diabetes Team Associated	New York	New York	United States	10016
11	Endocrine Research - Physician's East PA	Greenville	North Carolina	United States	27834
12	Your Diabetes Endocrine Nutrition Group	Mentor	Ohio	United States	44060
13	Dallas Diabetes & Endocrine Center	Dallas	Texas	United States	75230
14	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
15	Texas Diabetes Institute	San Antonio	Texas	United States	78207
16	Diabetes & Glandular Disease Research Assoc PA	San Antonio	Texas	United States	78229
17	Diabetes Care Center	Seattle	Washington	United States	98105
18	MBAL "Pleven"	Pleven	BGR	Bulgaria	5800
19	SBALENG-Sofia Institute of Endocrinology	Sofia	BGR	Bulgaria	1303
20	MBAL Alexandrovska Hospital	Sofia	BGR	Bulgaria	1431
21	Military Medical Academy	Sofia	BGR	Bulgaria	1431
22	Central Clinical Base	Sofia	BGR	Bulgaria	1606
23	MBAL "Sweta Marina" - Varna	Varna	BGR	Bulgaria	5000
24	II-nd MBAL	Sofia		Bulgaria	1202
25	Military Medical Academy	Sofia		Bulgaria	1431
26	University Hospital in Brno	Brno-Bohunice	CZE	Czech Republic	625 00
27	Military Hospital in Brno	Brno	CZE	Czech Republic	636 00
28	Hospital of "Milosrdnych brain"	Brno	CZE	Czech Republic	639 00
29	Surgery of Diabetology	Melnik	CZE	Czech Republic	276 01
30	University Hospital of 3rd Faculty	Prague 10	CZE	Czech Republic	100 34
31	Diabetologicka oridnace	Prague 2	CZE	Czech Republic	120 00
32	General Hospital in Prague and 1st Faculty of Medicine of	Prague 2	CZE	Czech Republic	120 00
33	Institute for Clinical and Exp Medicine	Prague 4	CZE	Czech Republic	140 21
34	University Hospital Na Bulovce	Prague 8	CZE	Czech Republic	180 81
35	Surgery of Diabetology Petrovice	Prague	CZE	Czech Republic	109 00
36	Surgery of Diabetology Stodulky	Prague	CZE	Czech Republic	155 00
37	Surgery of Diabetology Slany	Slany	CZE	Czech Republic	274 01
38	Surgery of Diabetology Zastavka	Zastavka, Brno	CZE	Czech Republic	664 84
39	Surgery of Diabetology (Brno)	Brno		Czech Republic	612 00
40	ikfe Berlin	Berlin	DEU	Germany	D 10115

Sponsors and Collaborators

• Mannkind Corporation

Investigators

• Study Director: Anders Boss, MD, Mannkind Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT00754624
• Other Study ID Numbers: MKC-TI-010
• First Posted: Sep 18, 2008
• Last Update Posted: Oct 16, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin

Study Results

Participant Flow

Recruitment Details	First patient enrolled May 31, 2004 Multi-center international trial conducted in USA, Bulgaria, Czech Republic, and Germany. Conducted in medical offices, hospital clinics, and universities.
Pre-assignment Detail	This was a follow-on trial for subjects who completed one of the two parent trials (PDC-IND-0008 or MKC-TI-005). Inclusion/Exclusion was participation in these parent trials.

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Period Title: Overall Study
STARTED	229
COMPLETED	160
NOT COMPLETED	69

Baseline Characteristics

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Overall Participants	229
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	56.4
Sex: Female, Male (Count of Participants)
Female	93 40.6%
Male	136 59.4%
DLCo (mL/min/mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/mmHg]	26.16 (6.21)
FEV1 (Liters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Liters]	2.99 (0.70)
FPG (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	167.7 (42.1)
FVC (Liters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Liters]	3.85 (0.89)
HbA1c (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	7.97 (1.20)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	87.2 (15.2)

Outcome Measures

1. Primary Outcome

Title	Annual Rate of Change in FEV1 From Baseline to End of Study
Time Frame	Baseline to 48 months

Outcome Measure Data

Analysis Population Description

Safety Population defined as all subjects who received at least one dose of study drug

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	229
Mean (Standard Error) [Liters per year]	-0.048 (0.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder
	Comments	A random coefficient model with a random intercept and slope associated with each subject, was fitted (using the PROC MIXED procedure in SAS) to the observed FEV1 data to estimate the annual rate of decline. The model included terms for baseline FEV1 and time (in years) of FEV1 measurements. Missing pulmonary functions were not imputed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.048
	Confidence Interval	(2-Sided) 95%; -0.059 to -0.037
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Annual Rate of Change in FVC From Baseline to End of Study
Time Frame	Baseline to 48 months

Outcome Measure Data

Analysis Population Description

Safety

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	229
Mean (Standard Error) [Liters per year]	-0.058 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder
	Comments	A random coefficient model with a random intercept and slope associated with each subject, was fitted (using the PROC MIXED procedure in SAS) to the observed FVC data to estimate the annual rate of decline. The model included terms for baseline FVC and time (in years) of FVC measurements. Missing pulmonary functions were not imputed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.058
	Confidence Interval	(2-Sided) 95%; -0.072 to -0.043
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Annual Rate of Change in DLCo From Baseline to End of Study
Time Frame	Baseline to 48 months

Outcome Measure Data

Analysis Population Description

Safety

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	229
Mean (Standard Error) [mL/min/mmHg per year]	-0.311 (0.073)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder
	Comments	A random coefficient model with a random intercept and slope associated with each subject, was fitted (using the PROC MIXED procedure in SAS) to the observed DLco data to estimate the annual rate of decline. The model included terms for baseline DLco and time (in years) of DLco measurements. Missing pulmonary functions were not imputed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.311
	Confidence Interval	(2-Sided) 95%; -0.454 to -0.168
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in HbA1c From Baseline to Last Measurement on Study Drug (Maximum of 48 Months)
Description	Change in HbA1c from Baseline to last measurement on study drug (maximum of 48 months)
Time Frame	Baseline to last measurement on study drug (maximum of 48 months

Outcome Measure Data

Analysis Population Description

Safety

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	225
Mean (Standard Deviation) [percentage]	0.20 (1.20)

5. Secondary Outcome

Title	Change in FPG From Baseline to Last Study Measurement on Treatment (Maximum of 48 Months)
Description	Change from Baseline to last study measurement on treatment (maximum of 48 months)
Time Frame	Baseline to last study measurement on treatment (maximum of 48 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	225
Mean (Standard Deviation) [milligrams per deciliter]	-5.34 (51.43)

6. Secondary Outcome

Title	Change in Weight in kg From Baseline to End of Study
Description	Baseline to last measurement on study drug (maximum of 48 months)
Time Frame	Baseline to last measurement on study drug (maximum of 48 months)

Outcome Measure Data

Analysis Population Description

Safety

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	229
Mean (Standard Deviation) [kilograms]	1.42 (4.41)

7. Secondary Outcome

Title	High Resolution Computerized Tomography Scans of the Chest
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

participants in Safety population with available post-baseline data

Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
Measure Participants	206
"Normal" HRCT subjects	47 20.5%
"Abnormal, clinically not significant" subjects	147 64.2%
"Abnormal, Clinically Significant" HRCT subjects	12 5.2%

Adverse Events

Time Frame	May 31, 2004 to June 5, 2008
Arm/Group Title	TI Inhalation Powder
Arm/Group Description	Technosphere® Insulin Inhalation Powder
All Cause Mortality
	TI Inhalation Powder
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TI Inhalation Powder
	Affected / at Risk (%)	# Events
Total	30/229 (13.1%)
Blood and lymphatic system disorders
Anaemia	1/229 (0.4%)
Microcytic anaemia	1/229 (0.4%)
Cardiac disorders
Coronary artery disease	3/229 (1.3%)
Myocardial ischaemia	2/229 (0.9%)
Acute myocardial infarction	1/229 (0.4%)
Angina pectoris	1/229 (0.4%)
Atrioventricular block complete	1/229 (0.4%)
Cardiac failure	1/229 (0.4%)
Cardio-respiratory arrest	1/229 (0.4%)
Cardiovascular disorder	1/229 (0.4%)
Myocardial infarction	1/229 (0.4%)
Eye disorders
Cataract	1/229 (0.4%)
Infections and infestations
Appendicitis	1/229 (0.4%)
Gastroenteritis	1/229 (0.4%)
Sinusitis	1/229 (0.4%)
Injury, poisoning and procedural complications
Ankle fracture	1/229 (0.4%)
Device failure	1/229 (0.4%)
Thermal burn	1/229 (0.4%)
Metabolism and nutrition disorders
Diabetes mellitus	1/229 (0.4%)
Hypoglycaemic seizure	1/229 (0.4%)
Musculoskeletal and connective tissue disorders
Localised osteoarthritis	2/229 (0.9%)
Back pain	1/229 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bronchial carcinoma	1/229 (0.4%)
Colon adenoma	1/229 (0.4%)
Meningioma	1/229 (0.4%)
Pancreatic carcinoma metastatic	1/229 (0.4%)
Prostate cancer metastatic	1/229 (0.4%)
Prostatic adenoma	1/229 (0.4%)
Renal cell carcinoma stage unspecified	1/229 (0.4%)
Nervous system disorders
Ataxia	1/229 (0.4%)
Diabetic neuropathy	1/229 (0.4%)
Dizziness	1/229 (0.4%)
Syncope	1/229 (0.4%)
Vertebrobasilar insufficiency	1/229 (0.4%)
Renal and urinary disorders
Calculus ureteric	1/229 (0.4%)
Renal failure acute	1/229 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	1/229 (0.4%)
Pneumothorax	1/229 (0.4%)
Pulmonary oedema	1/229 (0.4%)
Vascular disorders
Aortic aneurysm	1/229 (0.4%)
Arterial stenosis	1/229 (0.4%)
Deep vein thrombosis	1/229 (0.4%)
Hypertension	1/229 (0.4%)
Other (Not Including Serious) Adverse Events
	TI Inhalation Powder
	Affected / at Risk (%)	# Events
Total	156/229 (68.1%)
Eye disorders
Cataract	12/229 (5.2%)
Diabetic retinopathy	13/229 (5.7%)
Infections and infestations
Upper respiratory tract infection	40/229 (17.5%)
Nasopharyngitis	32/229 (14%)
Sinusitis	13/229 (5.7%)
Bronchitis	12/229 (5.2%)
Metabolism and nutrition disorders
Hypoglycaemia	94/229 (41%)
Hypercholesterolaemia	17/229 (7.4%)
Hypertriglyceridaemia	13/229 (5.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	19/229 (8.3%)
Back pain	18/229 (7.9%)
Nervous system disorders
Headache	14/229 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	40/229 (17.5%)
Productive cough	25/229 (10.9%)
Vascular disorders
Hypertension	15/229 (6.6%)

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.