Efficacy and Safety in Subjects With Type 2 Diabetes Receiving Subcutaneous Basal Insulin and Prandial Inhalation of Technosphere/Insulin Versus Subcutaneous Premixed Insulin Therapy Over a 52-Week Treatment Period and a 4-Week Follow-up

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00309244
• Collaborator: (none)
• Enrollment: 677
• Locations: 151
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this 13 month study (12 month treatment period and 1 month follow-up period) is to determine whether inhaled insulin is safe and effective in the treatment of type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Type 2	Drug: Technosphere® Insulin Inhalation Powder; Drug: 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 677 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Prospective, Multi-Center, Open-Label, Randomized, Controlled Clinical Trial Comparing the Efficacy and Safety in Subjects With Type 2 Diabetes Receiving Subcutaneous Basal Insulin and Prandial Inhalation of Technosphere /Insulin Versus Subcutaneous Premixed Insulin Therapy Over a 52-Week Treatment Period and a 4-Week Follow-up
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TI + Insulin glargine Technosphere® Insulin Inhalation Powder + insulin glargine	Drug: Technosphere® Insulin Inhalation Powder; Inhalation, 15U/30U
Active Comparator: BPR 70/30 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)	Drug: 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin); BPR 70/30, which is a premix of intermediate acting and rapid acting insulin given sc

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c to Week 52 [Baseline to Week 52]

Secondary Outcome Measures

1. Change From Baseline in Weight to Week 52 [Baseline to Week 52]

2. Change From Baseline in Fasting Plasma Glucose to Week 52 [Baseline to Week 52]

3. Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% [Week 52]

4. Incidence of Total Hypoglycemia [52 Weeks]

   Defined as hypoglycemic symptoms that are relieved with carbohydrate intake or blood glucose measurement <= 63 mg/dL, regardless of symptoms.

5. Incidence of Severe Hypoglycemia [52 Weeks]

   Severe hypoglycemia occurs when all 3 of the following occur simultaneously: Subject requires the assistance of another person; Subject exhibits at least 1 cognitive neurological symptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, seizure, loss of consciousness); Measured BG is ≤ 49 mg/dL (2.7 mmol/L), or, in the absence of a BG measurement, clinical symptoms are reversed by oral carbohydrates, sc glucagon or intravenous glucose administration; OR, Measured BG is ≤ 36 mg/dL (2.0 mmol/L) with or without symptoms.

6. Total Hypoglycemia Event Rate [52 Weeks]

   Number of Hypoglycemic Events/Total Subject Exposure Time (in months)

7. Severe Hypoglycemia Event Rate [52 Weeks]

   Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)

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 2 diabetes mellitus

• HbA1c > 7.0% and ≤ 11.0%

• BMI ≤ 40 kg/m2

• Negative smoking status and urine cotinine test

• Written informed consent

• Receiving sc insulin 2-3 times daily administered as any of the following 3 regimens: self-mix regimen, pre-mix regimen, or long-acting analogue and regular or rapid-acting insulin analogue not to exceed 3 daily injections. Subjects may also have received oral antidiabetic agents including metformin or thiazolidinediones.

• No dose adjustments for insulin and oral antidiabetic agents within the preceding 6 weeks.

• FEV1 ≥ 70% of NHANES III predicted; TLC) ≥ 80% of predicted (Intermountain Thoracic Society); DLCO uncorrected ≥ 70% of predicted

Exclusion Criteria:

• Total daily dose of insulin ≥1.4 IU/kg body weight

• Treatment with any sulfonylureas and/or meglitinides and/or alpha-glucosidase inhibitors within the preceding 8 weeks

• Treatment with pramlintide acetate (Symlin®), and/or any incretins (e.g., exenatide [Byetta®]) within the preceding 8 weeks

• Unstable diabetes mellitus control, defined as 2 or more episodes of severe hypoglycemia (requiring third party intervention) and/or any hospitalization or emergency room visit due to poor diabetic control or hyperglycemia requiring hospitalization within the preceding 6 months

• Exposure to an inhaled insulin at any time, treatment with an investigational drug within the preceding 3 months, and/or current participation in another clinical trial

• Allergy to insulin or to any drugs to be used as part of the clinical trial, or history of hypersensitivity to the investigational drug or to drugs of similar chemical structures

• History of active viral and/or cirrhotic hepatic disease and/or abnormal liver enzymes as evidenced by serum aspartate aminotransferase (AST)and/or alanine aminotransferase (ALT) ≥ 3 x Upper Limit of Normal (ULN)(Includes active hepatitis A, positive hepatitis B and/or hepatitis C serology)

• Serum creatinine > 1.8 mg/dL in women and > 2.0 mg/dL in men History of chronic obstructive pulmonary disease (COPD), asthma (any history of bronchospasm or asthma after the age of 14), and/or any other clinically important pulmonary disease confirmed by documented history, pulmonary function testing, or radiologic findings

• Congestive heart disease graded as class III or class IV according to New York Heart Association criteria and subjects currently being treated pharmacologically for ventricular dysrhythmias using amiodarone

• History of myocardial infarction, cardiac surgery, coronary angioplasty, and/or stroke within the preceding 3 months

• Symptomatic coronary artery disease, including crescendo angina, unstable angina, and/or unstable or symptomatic cardiac arrhythmias

• Poorly controlled arterial hypertension despite pharmacologic treatment, defined as systolic blood pressure (BP) > 180 mm Hg and/or diastolic BP > 110 mm Hg at screening

• History of malignancy within the preceding 5 years (other than excised basal cell carcinoma of the skin), any history of lung neoplasm, and/or subjects with current or previous chemotherapy or radiation therapy that may result in pulmonary toxicity

• History of acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), or positive human immunodeficiency virus (HIV) serology

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

• Visit 1/Screening (Week -3), but prior to Visit 1 PFTs and before Visit 3/Baseline (Week 0), subject will be scheduled for PFTs after 30 days from resolution of respiratory infection. An additional hemoglobin and urine β-HCG (for women of childbearing potential age only) will be required

• Women who are pregnant, lactating or planning to become pregnant

• Women of childbearing potential (defined as pre-menopausal and not surgically sterilized or postmenopausal for less than 2 years) not practicing adequate birth control. Adequate birth control is defined as using oral, percutaneous and/or transdermal contraceptives; condoms and diaphragms with a spermicide, or intrauterine devices

• Current drug and/or alcohol abuse

• Subjects who in the opinion of the Investigator will be unable to comply with the requirements of the protocol

• Severe complications of diabetes mellitus, in the opinion of the 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

• Any other concurrent medical or major psychiatric condition which, in the opinion of the Investigator, makes the subject unsuitable for the clinical trial, or could limit the validity of the ICF and/or impair the subject's ability to participate in the trial

• Inability to perform PFT maneuvers meeting recommended American Thoracic Society (ATS) acceptability and repeatability criteria.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Coastal Clinical Research Inc	Mobile	Alabama	United States	36608
2	Quality of Life Medical & Research Center	Tucson	Arizona	United States	85712
3	Southern Arizona VA Healthcare System	Tucson	Arizona	United States	85723
4	Tucson Clinical Research	Tucson	Arizona	United States	85741
5	International Clinical Research Network	Chula Vista	California	United States	91911
6	Saad Hijazi MD Inc	Fresno	California	United States	93710
7	Valley Research	Fresno	California	United States	93720
8	Diabetes/Lipid Management and Research Center	Huntington Beach	California	United States	92648
9	South Bay Clinical Research	Inglewood	California	United States	90301
10	Southern California Endocrine Center	Pasadena	California	United States	91105
11	Coastal Biomedical Research Inc	Santa Monica	California	United States	90404
12	Diabetes Research Center	Tustin	California	United States	92780
13	University of Miami Diabetes Research Institute	Miami	Florida	United States	33136
14	International Research Associates LLC	Miami	Florida	United States	33156
15	Laureate Clinical Research Group	Atlanta	Georgia	United States	30308
16	Atlanta Pharmaceutical Research Center	Dunwoody	Georgia	United States	30338
17	North Atlanta Endocrinology & Diabetes PC	Lawrenceville	Georgia	United States	30045
18	Atlanta Center for Clinical Research	Roswell	Georgia	United States	30075
19	John H Stoger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
20	Clintell Inc	Skokie	Illinois	United States	60076
21	Clintell Inc (Ellyin)	Skokie	Illinois	United States	60077
22	Medical Research of Louisiana	Metairie	Louisiana	United States	70002
23	Joslin Diabetes Center University of Maryland Medicine	Baltimore	Maryland	United States	21201
24	James A Dicke MDPA	Towson	Maryland	United States	21204
25	Wayne State University	Detroit	Michigan	United States	48201
26	Michigan Institute of Medicine	Livonia	Michigan	United States	48152
27	KMED Research	St Clair Shores	Michigan	United States	48081
28	Radiant Research Inc (Minneapolis)	Edina	Minnesota	United States	55435
29	International Diabetes Center	Minneapolis	Minnesota	United States	55416
30	Center for Urologic Clinical Trials University of Minnesota	Minneapolis	Minnesota	United States	55455
31	MedEx Healthcare Research Inc	St Louis	Missouri	United States	63117
32	Amin Radparvar's Private Practice	St Peters	Missouri	United States	63376
33	Billings Clinic Research Division	Billings	Montana	United States	59101
34	Montana Health Research Institute	Billings	Montana	United States	59102
35	Creighton Diabetes Center	Omaha	Nebraska	United States	68131
36	New Mexico Clinical Research & Osteoporosis Center	Albuquerque	New Mexico	United States	87106
37	University of New Mexico HCS	Albuquerque	New Mexico	United States	87131
38	Winthrop University Hospital	Mineola	New York	United States	11501
39	North Shore Diabetes and Endocrine Associates	New Hyde Park	New York	United States	11042
40	Univeristy of Physicians Group Endocrine Division	Staten Island	New York	United States	10301
41	Sensenbrenner Primary Care	Charlotte	North Carolina	United States	28277
42	East Carolina University (Tanenberg)	Greenville	North Carolina	United States	27834
43	Physician's East PA	Greenville	North Carolina	United States	27834
44	Valley Medical Primary Care	Centerville	Ohio	United States	45459
45	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
46	Providence Health Partners - Center of Clinical Research	Dayton	Ohio	United States	45439
47	Cleveland Clinic Health System	East Cleveland	Ohio	United States	44112
48	Wells Institute for Health Awareness	Kettering	Ohio	United States	45429
49	Oregon Medical Group Clinical Resesarch	Eugene	Oregon	United States	97401
50	Lane Medical Research Group	Eugene	Oregon	United States	97404
51	Portland Diabetes & Endocrinology Center	Portland	Oregon	United States	97210
52	New Hope Research of Oregon	Portland	Oregon	United States	97219
53	Covance CRU Inc.	Portland	Oregon	United States	97239
54	Pennsylvania Research Institute	Bensalem	Pennsylvania	United States	19020
55	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
56	Upstate Pharmaceutical Research	Greenville	South Carolina	United States	29615
57	Southeastern Research Associates Inc	Taylors	South Carolina	United States	29687
58	AM Diabetes and Endocrinology Center	Bartlett	Tennessee	United States	38133
59	Memphis Internal Medicine PLLC	Memphis	Tennessee	United States	38119
60	The Endocrine Clinic	Memphis	Tennessee	United States	38119
61	Israel Hartman MD	Arlington	Texas	United States	76014
62	South Arlington Primary Care Assoc PA	Arlington	Texas	United States	76017
63	Dallas Diabetes & Endocrine Center	Dallas	Texas	United States	75230
64	North Texas Endocrine Center	Dallas	Texas	United States	75231
65	Radiant Research Dallas-North	Dallas	Texas	United States	75231
66	Baylor Endocrine Center	Dallas	Texas	United States	75246
67	Galenos Research	Dallas	Texas	United States	75251
68	Spuhler Medical Associates	Friendswood	Texas	United States	77546
69	Clinical Trial Network	Houston	Texas	United States	77074
70	Quality Assurance Research Center Inc	San Antonio	Texas	United States	78205
71	Covenant Clinic Research	San Antonio	Texas	United States	78229
72	Diabetes & Glandular Disease Research Assoc PA	San Antonio	Texas	United States	78229
73	SAM Clinical Research Center	San Antonio	Texas	United States	78229
74	Salt Lake Research	Salt Lake City	Utah	United States	84107
75	Sentara Medical Group	Norfolk	Virginia	United States	23502
76	Clinical Research Associates of Tidewater	Norfolk	Virginia	United States	23507
77	Larry D Stonesifer MD Inc PS	Federal Way	Washington	United States	98003
78	Rainier Clinical Research Center Inc	Renton	Washington	United States	98055
79	Cedar Research	Tacoma	Washington	United States	98405
80	Liberty Research Center	Tacoma	Washington	United States	98405
81	Hospital Interzonal de Agudos Pedro Fiorito	Avellaneda	Buenos Aires	Argentina	B1870ARG
82	CITDEEM - Centro de Investigacion y Tratamiento En Diabetes y Enfermedades Endocrino-Metabolicas	San Miguel de Tucuman	Tucuman	Argentina	4000
83	FUNDAPRES/CIMel	Buenos Aires		Argentina	B1824KAJ
84	Centro Endocrinologic Tiempo	Buenos Aires		Argentina	C1117ABH
85	Hospital Italiano de Buenos Aires	Buenos Aires		Argentina	C1181ACH
86	Cons Asoc de Endocrinologia	Buenos Aires		Argentina	C1425AGC
87	Centro Medico Dra De Salvo	Buenos Aires		Argentina	C1426ABP
88	Hospital de Clinicas de Porto Alegre	Porto Alegre	Rio Grande do Sul	Brazil	90035-903
89	Hospital Sao Lucas da PUCRS	Porto Alegre	Rio Grande do Sul	Brazil	90610-000
90	Universidade Estabual de Maringa	Maringa Parana		Brazil	87020-900
91	Nucleo de Medicina Integrada	Mogi das Cruzes		Brazil	08780-090
92	Instituto Estadual De Diabetes e Endocrinologia Luis Capriglione	Rio de Janeiro		Brazil	20211-340
93	Ccbr Brasil Centro de Analises e Pesquisas Clinicas Ltda	Rio de Janeiro		Brazil	22271-100
94	Hospital Guilherme Alvaro	Santos		Brazil	11045-904
95	CPClin-Centro de Pesquisas Clinicas	Sao Paulo		Brazil	01244-030
96	Hospital do Rim e Hipertensao	Sao Paulo		Brazil	04025-011
97	Instituto da Saude e Bem Estar da Mulher	Sao Paulo		Brazil	04062-003
98	Blumenau Servicos Medicos S/C Ltda	Sao Paulo		Brazil	05302-001
99	Centro de Pesquisa Clinica e Medicina Avancada	Sao Paulo		Brazil	05437-010
100	Keele Medical Place	Downsview	Ontario	Canada	M3M 3E5
101	Quest Clinical Trials	Markham	Ontario	Canada	L6B 1A1
102	Lifestyle Metabolism Center	Oakville	Ontario	Canada	L6H 3P1
103	Sarnia Institute of Clinical Research	Sarnia	Ontario	Canada	N7T 4X3
104	Lifestyle Metabolism Center	Thornhill	Ontario	Canada	L4J 8L7
105	Lifestyle Metabolism Center	Toronto	Ontario	Canada	M4R 2G4
106	Hospital del Salvador	Santiago	Region Metropolitana	Chile
107	Hospital Padre Alberto Hurtado	Santiago	Region Metropolitana	Chile
108	Hospital Clinico Pontificia Universidad Catolica de Chile	Santiago		Chile
109	Hospital San Borja ArriaranUniversidad de Chile	Santiago		Chile
110	Instituto Mexicano de Investigacion	Mexico City	Durango	Mexico	06700
111	Hospital OCA	Monterrey, Nuevo Leon	MX	Mexico	64000
112	Hospital Universitario Dr Jose E Gonzalez	Monterrey	Nuevo Leon	Mexico	64460
113	Hospital Santa Engracia-CIMA	Garza Garcia		Mexico	66260
114	Centro de Estudios en Diabetes	Mexico City		Mexico	01120
115	Cifbiotec	Mexico City		Mexico	CP14050
116	Oddzial Chorob Wewnetrznych	Bialystock	POL	Poland	15-950
117	NZOZ Specjalistyczny Osrodek Internistyczno - Diabetologiczny	Bialystok	POL	Poland	15-435
118	Katedra I Klinika Chorob Metabolicznych Collegium Medicum Uniwersytety Jagiellonskiego	Krakow	POL	Poland	31 501
119	Klliniczny nr 1 im Norberta Barlickiego Uniwersytetu Medycznego w Lodzi	Lodz	POL	Poland	90 153
120	Instytut Centrum Zdrowia (009) Matki Polki	Lodz	POL	Poland	93-338
121	Szpital Kolejowy im Dr w Roeflera(009) Oddzial Gastorenterologii	Pruszkow	POL	Poland	05 800
122	NZOZ Diabetologiczna Poradnia Specjalistyczna	Warszawa		Poland	01-911
123	NHI Kemerovo Regional Clinical Hospital	Kemerovo	RUS	Russian Federation	650061
124	NI Principal Military Clinical Hospital n a academician N.N. Burdenko of the Ministry of Defense	Moscow	RUS	Russian Federation	105229
125	NEI HPE Moscow State University of Medicine and Dentistry of FAHSD City Clinical Hospital #70	Moscow	RUS	Russian Federation	111399
126	Moscow City Clinical Hospital # 13	Moscow	RUS	Russian Federation	115280
127	SEI HPE Moscow Medical Academy IM Sechenov of Roszdrav Clinic of Endocrinology	Moscow	RUS	Russian Federation	119435
128	SI Internal Affairs of Moscow- Clinical Hospital	Moscow	RUS	Russian Federation	125299
129	RAAMS Endocrinology and Diabetology Department	Moscow	RUS	Russian Federation	125315
130	NEI HPE Smolensk State Medical Academy of FAHSD RNHI Smolensk Regional Clinical Hospital	Smolensk	RUS	Russian Federation	214018
131	St Petersburg NHI City Polytclinic #77 City Diabetological Center #4	St Petersburg	RUS	Russian Federation	193012
132	Central Medical Sanitary Unit #122	St Petersburg	RUS	Russian Federation	194291
133	Pavlov State Medical Univ of St Petersburg	St Petersburg	RUS	Russian Federation	197022
134	MHI Clinical Hospital for Emergency Care na NV Soloviev	Yaroslavl	RUS	Russian Federation	150003
135	MCHI Medical Sanitary Unit of Novo-Yaroslavsky Oil Refining Plant	Yaroslavl	RUS	Russian Federation	150023
136	NHI Yaroslavl Regional Clinical Hospital	Yaroslavl	RUS	Russian Federation	150062
137	NI Central Clinical Hospital of RAS	Moscow		Russian Federation	117 593
138	City Clinical Hospital # 61	Moscow		Russian Federation	119 048
139	Complejo Hospitalario Nuestra Senora de Valme	Sevilla	Andalucia	Spain	41014
140	Hospital de Mataro	Mataro	Barcelona	Spain	08304
141	Hospital del Mar (Cano)	Barcelona		Spain	08003
142	Centro Médico Teknon	Barcelona		Spain	08022
143	Hospital Universitario de la Princessa	Madrid		Spain	28006
144	Hospital Ramon y Cajal	Madrid		Spain	28034
145	Corporacion Sanitaria Parc Tauli Unidad de Endocrinologia	Sabadell		Spain	08208
146	Complejo Hospitalario Virgen del Rocio	Sevilla		Spain	41013
147	Hospital Virgen Macarena (policlinico) 2ª planta Servicio de Endocrinologia y Nutricion	Sevilla		Spain	41071
148	Birchwood Surgery	Letchworth	Herts	United Kingdom	SG6 4UB
149	Lister Hospital	Stevenage	Herts	United Kingdom	SG1 4AB
150	Guy's & St Thomas Hospital	London		United Kingdom	SE1 9RT
151	Yaxley Group Practice	Peterborough		United Kingdom	PE7 3JL

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: NCT00309244
• Other Study ID Numbers: MKC-TI-102
• First Posted: Mar 31, 2006
• Last Update Posted: Oct 16, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Aspart; Protamines

Study Results

Participant Flow

Recruitment Details	First subject enrolled Feb. 23, 2006 Multi-national trial conducted in US, Canada, Mexico, Brazil, Argentina, Chile, Spain, UK, Poland, Russia
Pre-assignment Detail	3 week Screening period prior to randomization - 2064 Screened / 673 Eligible . 677 subjects were randomized. ( 4 ineligible subjects were randomized in error) 1391 screen failures. 23 Subjects randomized but never dosed.

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder (administered at each meal) + subcutaneous insulin glargine (administered once daily at bedtime). Doses are individualized for each patient.	70% insulin aspart protamine suspension and 30% insulin aspart subcutaneous injection (rDNA origin), administered twice daily (before breakfast and before main evening meal). Doses are individualized for each patient.
Period Title: Overall Study
STARTED	334	343
COMPLETED	216	246
NOT COMPLETED	118	97

Baseline Characteristics

Arm/Group Title	TI + Insulin Glargine	BPR 70/30	Total
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)	Total of all reporting groups
Overall Participants	323	331	654
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (10.68)	55.9 (9.91)	55.9 (10.29)
Sex: Female, Male (Count of Participants)
Female	160 49.5%	185 55.9%	345 52.8%
Male	163 50.5%	146 44.1%	309 47.2%
Fasting Plasma Glucose (FPG) (milligrams per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter]	171.8 (68.53)	176.2 (67.15)	174 (67.82)
HbA1c (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	8.7 (1.14)	8.7 (1.10)	8.7 (1.12)
Weight (kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram]	88.1 (17.33)	85.7 (18.07)	86.9 (17.74)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c to Week 52
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT) with Last Observation Carried Forward (LOCF); participants with available data at baseline and post-baseline.

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	302	316
Least Squares Mean (Standard Error) [percent]	-0.59 (0.063)	-0.71 (0.061)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Sample size was set to meet regulatory requirement of 250 subjects per arm with 52-week data, resulting in > 90% power for a non-inferiority test of the difference in 12-month change of HbA1c scores between treatment groups with non-inferiority margin of 0.4%, standard deviation of 1.2 and 1-sided alpha of 0.025. Allowing for a 25% drop-out rate, 677 subjects were randomized.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Weight to Week 52
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT) population; participants with available data at baseline and Week 52.

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	194	227
Least Squares Mean (Standard Error) [kilogram]	0.9 (0.32)	2.5 (0.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments	ANCOVA model with terms of pooled site and treatment as fixed effects and baseline weight as covariate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -2.4 to -0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.41
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose to Week 52
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT) population; participants with available data at baseline and Week 52.

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	197	218
Least Squares Mean (Standard Error) [milligrams per deciliter]	-35.7 (4.61)	-17.9 (4.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments	ANCOVA model with terms of pooled site and treatment as fixed effects and baseline fasting plasma glucose as covariate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-17.7
	Confidence Interval	(2-Sided) 95%; -29.3 to -6.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.90
	Estimation Comments

4. Secondary Outcome

Title	Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0%
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT); participants with available data at baseline and Week 52.

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	213	243
Number [participants]	47 14.6%	65 19.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments	logistic regression analysis with the terms of treatment and baseline HbA1c in the model
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2793
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.774
	Confidence Interval	(2-Sided) 95%; 0.486 to 1.231
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Incidence of Total Hypoglycemia
Description	Defined as hypoglycemic symptoms that are relieved with carbohydrate intake or blood glucose measurement <= 63 mg/dL, regardless of symptoms.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	323	331
Number [percentage of participants]	47.99 14.9%	68.58 20.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.423
	Confidence Interval	(2-Sided) 95%; 0.307 to 0.581
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Treatment + Site

6. Secondary Outcome

Title	Incidence of Severe Hypoglycemia
Description	Severe hypoglycemia occurs when all 3 of the following occur simultaneously: Subject requires the assistance of another person; Subject exhibits at least 1 cognitive neurological symptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, seizure, loss of consciousness); Measured BG is ≤ 49 mg/dL (2.7 mmol/L), or, in the absence of a BG measurement, clinical symptoms are reversed by oral carbohydrates, sc glucagon or intravenous glucose administration; OR, Measured BG is ≤ 36 mg/dL (2.0 mmol/L) with or without symptoms.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	323	331
Number [percentage of participants]	4.33 1.3%	9.97 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.409
	Confidence Interval	(2-Sided) 95%; 0.215 to 0.780
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Treatment + Site

7. Secondary Outcome

Title	Total Hypoglycemia Event Rate
Description	Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	323	331
Number [Number of events/subject-month]	0.41	0.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	Generalized Estimation Equation
	Comments	Based on Poisson distribution

8. Secondary Outcome

Title	Severe Hypoglycemia Event Rate
Description	Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TI + Insulin Glargine	BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Measure Participants	323	331
Number [Number of events/100 subject-months]	0.73	2.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI + Insulin Glargine, BPR 70/30
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0591
	Comments
	Method	Generalized Estimating Equation
	Comments	Based on Poission distribution

Adverse Events

Time Frame	From first dose to 30 days after last dose
Arm/Group Title	TI + Insulin Glargine		BPR 70/30
Arm/Group Description	Technosphere® Insulin Inhalation Powder + Insulin glargine		70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
All Cause Mortality
	TI + Insulin Glargine		BPR 70/30
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TI + Insulin Glargine		BPR 70/30
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/323 (11.5%)		31/331 (9.4%)
Blood and lymphatic system disorders
Anaemia	0/323 (0%)		1/331 (0.3%)
Cardiac disorders
Acute myocardial infarction	1/323 (0.3%)		0/331 (0%)
Angina pectoris	0/323 (0%)		2/331 (0.6%)
Atrial fibrillation	2/323 (0.6%)		1/331 (0.3%)
Cardiac arrest	0/323 (0%)		1/331 (0.3%)
Cardiac failure acute	1/323 (0.3%)		0/331 (0%)
Coronary artery atherosclerosis	1/323 (0.3%)		0/331 (0%)
Coronary artery disease	2/323 (0.6%)		0/331 (0%)
Coronary artery insufficiency	0/323 (0%)		2/331 (0.6%)
Coronary artery occlusion	1/323 (0.3%)		0/331 (0%)
Hypertensive heart disease	0/323 (0%)		1/331 (0.3%)
Ischaemic cardiomyopathy	1/323 (0.3%)		0/331 (0%)
Myocardial infarction	1/323 (0.3%)		0/331 (0%)
Ventricular tachycardia	1/323 (0.3%)		0/331 (0%)
Eye disorders
Diabetic retinopathy	0/323 (0%)		1/331 (0.3%)
Optic atrophy	0/323 (0%)		1/331 (0.3%)
Optic neuropathy	0/323 (0%)		1/331 (0.3%)
Retinal detachment	1/323 (0.3%)		0/331 (0%)
Vitreous haemorrhage	1/323 (0.3%)		0/331 (0%)
Gastrointestinal disorders
Abdominal hernia	1/323 (0.3%)		0/331 (0%)
Constipation	1/323 (0.3%)		0/331 (0%)
Duodenal ulcer haemorrhage	1/323 (0.3%)		0/331 (0%)
Gastric ulcer	0/323 (0%)		1/331 (0.3%)
Gastritis	0/323 (0%)		1/331 (0.3%)
Umbilical hernia	0/323 (0%)		1/331 (0.3%)
General disorders
Chest pain	0/323 (0%)		1/331 (0.3%)
Oedema peripheral	1/323 (0.3%)		0/331 (0%)
Pyrexia	0/323 (0%)		1/331 (0.3%)
Hepatobiliary disorders
Cholecystitis	0/323 (0%)		2/331 (0.6%)
Cholelithiasis	0/323 (0%)		2/331 (0.6%)
Immune system disorders
Autoimmune disorder	1/323 (0.3%)		0/331 (0%)
Infections and infestations
Appendicitis	0/323 (0%)		2/331 (0.6%)
Diabetic foot infection	1/323 (0.3%)		0/331 (0%)
Endocarditis	1/323 (0.3%)		0/331 (0%)
Gangrene	1/323 (0.3%)		0/331 (0%)
Gastroenteritis viral	1/323 (0.3%)		0/331 (0%)
Hepatitis viral	1/323 (0.3%)		0/331 (0%)
Localised infection	1/323 (0.3%)		0/331 (0%)
Pneumonia	0/323 (0%)		1/331 (0.3%)
Staphylococcal sepsis	1/323 (0.3%)		0/331 (0%)
Urinary tract infection	1/323 (0.3%)		0/331 (0%)
Wound infection	1/323 (0.3%)		0/331 (0%)
Injury, poisoning and procedural complications
Electric shock	1/323 (0.3%)		0/331 (0%)
Facial bones fracture	1/323 (0.3%)		0/331 (0%)
Fall	0/323 (0%)		2/331 (0.6%)
Injury	1/323 (0.3%)		0/331 (0%)
Limb injury	1/323 (0.3%)		0/331 (0%)
Procedural complication	0/323 (0%)		1/331 (0.3%)
Rib fracture	0/323 (0%)		1/331 (0.3%)
Road traffic accident	0/323 (0%)		1/331 (0.3%)
Investigations
International normalised ratio increased	1/323 (0.3%)		0/331 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	1/323 (0.3%)		0/331 (0%)
Hyperglycaemia	1/323 (0.3%)		0/331 (0%)
Hypoglycaemia	3/323 (0.9%)		6/331 (1.8%)
Hypoglycaemic seizure	1/323 (0.3%)		0/331 (0%)
Obesity	0/323 (0%)		1/331 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/323 (0.3%)		0/331 (0%)
Back pain	0/323 (0%)		1/331 (0.3%)
Bone pain	0/323 (0%)		1/331 (0.3%)
Intervertebral disc degeneration	1/323 (0.3%)		0/331 (0%)
Intervertebral disc disorder	1/323 (0.3%)		0/331 (0%)
Intervertebral disc protrusion	1/323 (0.3%)		0/331 (0%)
Musculoskeletal chest pain	1/323 (0.3%)		0/331 (0%)
Osteoarthritis	1/323 (0.3%)		0/331 (0%)
Tenosynovitis	1/323 (0.3%)		0/331 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal adenoma	0/323 (0%)		1/331 (0.3%)
Benign pancreatic neoplasm	0/323 (0%)		1/331 (0.3%)
Breast cancer	0/323 (0%)		1/331 (0.3%)
Breast cancer stage iii	1/323 (0.3%)		0/331 (0%)
Colon cancer	0/323 (0%)		1/331 (0.3%)
Gastrointestinal cancer metastatic	1/323 (0.3%)		0/331 (0%)
Pancreatic carcinoma	0/323 (0%)		1/331 (0.3%)
Prostate cancer metastatic	1/323 (0.3%)		0/331 (0%)
Uterine leiomyoma	0/323 (0%)		1/331 (0.3%)
Nervous system disorders
Ataxia	1/323 (0.3%)		0/331 (0%)
Cerebrovascular accident	0/323 (0%)		1/331 (0.3%)
Dizziness	2/323 (0.6%)		0/331 (0%)
Encephalitis	1/323 (0.3%)		0/331 (0%)
Haemorrhagic stroke	1/323 (0.3%)		0/331 (0%)
Loss of consciousness	1/323 (0.3%)		3/331 (0.9%)
Syncope	0/323 (0%)		1/331 (0.3%)
Psychiatric disorders
Psychotic disorder	1/323 (0.3%)		0/331 (0%)
Renal and urinary disorders
Renal failure acute	1/323 (0.3%)		1/331 (0.3%)
Reproductive system and breast disorders
Adenomyosis	0/323 (0%)		1/331 (0.3%)
Uterine prolapse	0/323 (0%)		1/331 (0.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/323 (0.3%)		0/331 (0%)
Hydrothorax	0/323 (0%)		1/331 (0.3%)
Pulmonary oedema	1/323 (0.3%)		0/331 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/323 (0.3%)		0/331 (0%)
Vascular disorders
Essential hypertension	0/323 (0%)		1/331 (0.3%)
Thrombosis	0/323 (0%)		1/331 (0.3%)
Other (Not Including Serious) Adverse Events
	TI + Insulin Glargine		BPR 70/30
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	225/323 (69.7%)		251/331 (75.8%)
Infections and infestations
Upper respiratory tract infection	39/323 (12.1%)		24/331 (7.3%)
Nasopharyngitis	30/323 (9.3%)		28/331 (8.5%)
Influenza	18/323 (5.6%)		18/331 (5.4%)
Urinary tract infection	10/323 (3.1%)		21/331 (6.3%)
Metabolism and nutrition disorders
Hypoglycaemia	155/323 (48%)		228/331 (68.9%)
Nervous system disorders
Headache	18/323 (5.6%)		12/331 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	106/323 (32.8%)		20/331 (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 multi-center Study publication, PI may publish the Study results subject to MNKD rights herein.