Efficacy and Safety of Prandial Inhalation of Technosphere/Insulin in Combination With Metformin or Technosphere/Insulin Alone Versus 2 Oral Anti-Diabetic Agents in Subjects With Type 2 Diabetes

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00332488
• Collaborator: (none)
• Enrollment: 547
• Locations: 120
• Arms: 3
• Patients Per Site: 4.6

Study Details

Study Description

Brief Summary

to demonstrate the efficacy of inhaled Technosphere/Insulin in combination with metformin versus combination metformin and a secretagogue

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Technosphere Insulin; Drug: Metformin & Secretagogues; Drug: Technosphere Insulin & Metformin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 547 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, 24-Week, Multi-Center, Open-Label, Randomized, Controlled Trial Comparing the Efficacy and Safety of Prandial Inhalation of Technosphere/Insulin in Combination With Metformin or Technosphere/Insulin Alone Versus 2 Oral Anti-Diabetic Agents (Metformin and a Secretagogue) in Subjects With Type 2 Diabetes Mellitus Sub-optimally Controlled on Combination Metformin and a Secretagogue.
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Technosphere Insulin	Drug: Technosphere Insulin; Inhalation, 15U/30U, prandial
Active Comparator: 2 Metformin & Secretagogues	Drug: Metformin & Secretagogues; Metformin tablets,Secretagogues supplied as any of the currently marketed brands and formulations.
Experimental: 3 Technosphere & Metformin	Drug: Technosphere Insulin & Metformin; Technosphere Insulin Inhalation Powder 15U/30U, Metformin tablets

Outcome Measures

Primary Outcome Measures

1. Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue [Baseline to Week 12]

Secondary Outcome Measures

1. Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue [Baseline to Week 12]

   (Change from baseline within TI Alone) minus (change from baseline within metformin + secretagogue)

2. Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment) [Week 24]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Non-smokers with clinical diagnosis of Type 2 diabetes mellitus for >or= to 6 months

• Stable regimen of metformin for > or = to 1000mg/day or maximum tolerated dose) and a secretagogue < or = 1/2 the maximum manufacturer-recommended daily dose without any dose adjustments within the preceding 6 wks.

• Fixed dose combination products of metformin and sulfonylurea are acceptable as long as each individual dose meets inclusion criteria

• HbA1c >or= to 7.5% and < or= to 11.0%

• BMI < or = to 40kg/m2.

• FEV1> or = to 70%, Total Lung capacity and > or =80% DLco > or= to 70%

Exclusion Criteria:

• Treatment with any type of anti-diabetic therapy, other than metformin & secretagogues within the preceding 12 weeks

• Serum creatinine > 1.4mg/dL in female subjects and >1.5mg/dL in male subjects

• History of chronic obstructive pulmonary disease, clinically proven asthma and/or any other clinically important pulmonary function testing and/or radiologic findings

• Evidence of serious complications of diabetes (e.g. autonomic neuropathy)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Radiant Research-Birmingham	Birmingham	Alabama	United States	35209
2	Parkway Medical Center	Birmingham	Alabama	United States	35215
3	Redpoint Research	Phoenix	Arizona	United States	85029
4	Arizona Center for Clinical Research	Phoenix	Arizona	United States	85032
5	International Clinical Research Network	Chula Vista	California	United States	91911
6	National Jewish Medical & Research Center	Denver	Colorado	United States	80206
7	Creekside Endocrine Associates	Denver	Colorado	United States	80209
8	Jennifer Hone MD	Denver	Colorado	United States	80220
9	Chase Medical Research, LLC	Waterbury	Connecticut	United States	06708
10	Center for Diabetes & Endocrine Care	Hollywood	Florida	United States	33021
11	International Research Associates LLC	Miami	Florida	United States	33156
12	Cedar-Crosse Research Center	Chicago	Illinois	United States	60607
13	John H Stoger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
14	Clintell Inc	Skokie	Illinois	United States	60076
15	James A Dicke MDPA	Towson	Maryland	United States	21204
16	East Coast Clinical Research Inc	Haverhill	Massachusetts	United States	01830
17	Wayne State University	Detroit	Michigan	United States	48201
18	Michigan Institute of Medicine	Livonia	Michigan	United States	48152
19	Clayton Medical Research	St Louis	Missouri	United States	63117
20	Raidant Research-St Louis	St Louis	Missouri	United States	63141
21	Washington University School of Medicine	St. Louis	Missouri	United States	63110
22	Creighton Diabetes Center	Omaha	Nebraska	United States	68131
23	Lovelace Scientific Resources (Albuquerque)	Albuquerque	New Mexico	United States	87108
24	Winthrop University Hospital	Mineola	New York	United States	11501
25	North Shore Diabetes and Endocrine Associates	New Hyde Park	New York	United States	11042
26	Metrolina Internal Medicine	Charlotte	North Carolina	United States	28204
27	Charlotte Clinical Research Inc	Charlotte	North Carolina	United States	28211
28	Sensenbrenner Primary Care	Charlotte	North Carolina	United States	28277
29	Duke Medical Center	Durham	North Carolina	United States	27710
30	Dayton Clinical Research	Dayton	Ohio	United States	45406
31	Providence Health Partners - Center of Clinical Research	Dayton	Ohio	United States	45439
32	Radiant Research	Portland	Oregon	United States	97239
33	Upstate Pharmaceutical Research	Greenville	South Carolina	United States	29615
34	Collierville Medical Specialists	Collierville	Tennessee	United States	38017
35	Memphis Internal Medicine (Kathawala)	Memphis	Tennessee	United States	38119
36	GoodLife Medical Center PLLC	Memphis	Tennessee	United States	38120
37	Baylor Endocrine Center	Dallas	Texas	United States	75246
38	Quality Assurance Research Center Inc	San Antonio	Texas	United States	78205
39	Clinical Trials of Texas Inc	San Antonio	Texas	United States	78229
40	Covenant Clinic Research	San Antonio	Texas	United States	78229
41	Diabetes & Glandular Disease Research Assoc PA	San Antonio	Texas	United States	78229
42	SAM Clinical Research Center	San Antonio	Texas	United States	78229
43	Cedar Research	Tacoma	Washington	United States	98405
44	Hospital Interzonal de Agudos Pedro Fiorito	Avellaneda	Buenos Aires	Argentina	B1870ARG
45	Centro Endocrinologic Tiempo	Buenos Aires		Argentina	C1117ABH
46	Hospital Italiano de Buenos Aires	Buenos Aires		Argentina	C1181ACH
47	Cons Asoc de Endocrinologia	Buenos Aires		Argentina	C1425AGC
48	CIMeL	Buenos Aires		Argentina
49	Hospital de Clinicas de Porto Alegre	Porto Alegre	Rio Grande do Sul	Brazil	90035-903
50	Hospital Sao Lucas da PUCRS	Porto Alegre	Rio Grande do Sul	Brazil	90610-000
51	Ccbr Brasil Centro de Analises e Pesquisas Clinicas Ltda	Rio de Janeiro		Brazil	22271-100
52	Hospital Guilherme Alvaro	Santos		Brazil	11045-904
53	CPClin-Centro de Pesquisas Clinicas	Sao Paulo		Brazil	01244-030
54	UNIFRSP	Sao Paulo		Brazil	04020-050
55	Hospital do Rim e Hipertensao	Sao Paulo		Brazil	04025-011
56	Instituto de Pesquisa Clinica e Medicina Avancada	Sao Paulo		Brazil	05437-010
57	Quest Clinical Trials	Markham	Ontario	Canada	L6B 1A1
58	Lifestyle Metabolism Center	Oakville	Ontario	Canada	L6H 3P1
59	Lifestyle Metabolism Center	Thornhill	Ontario	Canada	L4J 8L7
60	Lifestyle Metabolism Center	Toronto	Ontario	Canada	M4R 2G4
61	Trial Management Group Inc (Henein	Toronto	Ontario	Canada	M4T 1N5
62	Unimedico Management	Richmond Hill		Canada	L4C 9M7
63	Hospital Padre Alberto Hurtado	Santiago	Region Metropolitana	Chile
64	Hospital Clinico Pontificia Universidad Catolica de Chile	Santiago		Chile
65	Hospital del Salvador	Santiago		Chile
66	Instituto de Informacion de Tramiento y Educacion en Salud	Santiago		Chile
67	Diabetologicka a interni ambulance	Ostrava-Kuncice	CZE	Czech Republic	70702
68	Institute for Clinical and Exp Medicine	Prague 4	CZE	Czech Republic	140 21
69	University Hospital Na Bulovce	Prague 8	CZE	Czech Republic	180 81
70	Diabetologicka ambulance (Chmura)	Ostrava		Czech Republic	70200
71	Interní a diabetologická Outpatient	Ostrava		Czech Republic	70900
72	II interni klinika FN Kralovske Vinohrady	Praha 10		Czech Republic	10034
73	Endokrinologicky ustav	Praha 1		Czech Republic	11694
74	3rd Medical Department General Faculty Hospital	Praha 2		Czech Republic	12801
75	Instituto Mexicano de Investigacion	Mexico City	Durango	Mexico	06700
76	Hospital Universitario Dr Jose E Gonzalez	Monterrey	Nuevo Leon	Mexico	64460
77	Hospital Santa Engracia-CIMA	Garza Garcia		Mexico	66260
78	Centro de Estudios en Diabetes	Mexico City		Mexico	01120
79	Hospital General de Mexico Servicio EndocrinologiaJefe Del Servicio	Mexico City		Mexico	06726
80	OCA-MIRC	Monterrey		Mexico	64020
81	Klinika Endocrinologii Diabetologii I	Bialystock	POL	Poland	15-276
82	NZOZ Specjalistyczny Osrodek Internistyczno - Diabetologiczny	Bialystok	POL	Poland	15-435
83	Katedra I Klinika Chorob Metabolicznych Collegium Medicum Uniwersytety Jagiellonskiego	Krakow	POL	Poland	31 501
84	Instytut Centrum Zdrowia (009) Matki Polki	Lodz	POL	Poland	93-338
85	Spzital Kolejowy imm Wlodzimierza Roeflera	Pruszkow	POL	Poland	05-800
86	Oddzial Kliniczny Diabetologii (009) Kliniczny nr 1 im Norberta Barlickiego Uniwersytety Meycznego	Lodz		Poland	90-153
87	Niepubliczny Zaklad Opieki Zdrowotnej VIVAMED	Warsaw		Poland	03 580
88	Centrum Leczenia Chorob cywilizacyjnych	Warszawa		Poland	02 777
89	NHI Kemerovo Regional Clinical Hospital	Kemerovo	RUS	Russian Federation	650061
90	NI Principal Military Clinical Hospital n a academician N.N. Burdenko of the Ministry of Defense	Moscow	RUS	Russian Federation	105229
91	NEI HPE Moscow State University of Medicine and Dentistry of FAHSD City Clinical Hospital #70	Moscow	RUS	Russian Federation	111399
92	NI Endrocrinological Research Centre of RAMS In patient replacing technologies department	Moscow	RUS	Russian Federation	115478
93	NI Moscow Regional Scientific Research Clinical Institute na MF Vladimirsky	Moscow	RUS	Russian Federation	129110
94	NEI HPE Smolensk State Medical Academy of FAHSD RNHI Smolensk Regional Clinical Hospital	Smolensk	RUS	Russian Federation	214018
95	St Petersburg NHI City Polytclinic #77 City Diabetological Center #4	St Petersburg	RUS	Russian Federation	193012
96	Central Medical Sanitary Unit #122	St Petersburg	RUS	Russian Federation	194291
97	TUV Medico-Military Academy	St Petersburg	RUS	Russian Federation	198013
98	St Petersburg NHI Municipal Multi-Speciality Hospital # 2	St. Petersburg	RUS	Russian Federation	194354
99	MHI Clinical Hospital for Emergency Care na NV Soloviev	Yaroslavl	RUS	Russian Federation	150003
100	NHI Yaroslavl Regional Clinical Hospital	Yaroslavl	RUS	Russian Federation	150062
101	NI Central Clinical Hospital of RAS	Moscow		Russian Federation	117 593
102	Complejo Hospitalario Nuestra Senora de Valme	Sevilla	Andalucia	Spain	41014
103	Hospital Clinic I Provincial	Barcelona		Spain	08036
104	Hospital Universitario de la Princessa	Madrid		Spain	28006
105	Hospital Ramon y Cajal	Madrid		Spain	28034
106	Corporacion Sanitaria Parc Tauli Unidad de Endocrinologia	Sabadell		Spain	08208
107	Bukovinian State Medical University Dept of Clinical Immun	Chernivtsy	UKR	Ukraine	58022
108	Dniepropetrovsh State Medical Academy	Dniepropetrovsk	UKR	Ukraine	49023
109	Donetsk State Medical University	Donetsk	UKR	Ukraine	83003
110	Donetsk State Medical University (Chair of Immun Allergogoly & Endocrin)	Donetsk	UKR	Ukraine	83099
111	Railway Clinical Hospital on Donetsk Station	Donetsk	UKR	Ukraine	83114
112	Chair Family Med of National Med University	Kiev	UKR	Ukraine	04050
113	Institute of Endocrinology and Metabolism	Kiev	UKR	Ukraine	04114
114	Ukr Scientifically Practical Centre of Endocrine Surgery	Kiev	UKR	Ukraine	2175
115	Odessa State Medical University Dept of Gen Practice and Med Rehab	Odessa	UKR	Ukraine	65009
116	Odessa Reg. Clinical Hosp Outpatient Department	Odessa	UKR	Ukraine	65025
117	Odessa State Med Dept of Family Med and Gen Practice	Odessa	UKR	Ukraine	65039
118	Vinnitsa State Medical University	Vinnitsa	UKR	Ukraine	21010
119	Outpatient Clinic of Family Physician "Rusanovka"	Kiev		Ukraine	02147
120	Public Institution City Policlinic #20 Odessa	Odessa		Ukraine	65114

Sponsors and Collaborators

• Mannkind Corporation

Investigators

• Study Director: For MannKind sponsored trials, the Overall Study Official is the Chief Scientific Officer, Mannkind Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT00332488
• Other Study ID Numbers: MKC-TI-103
• First Posted: Jun 1, 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; Metformin; Secretagogues

Study Results

Participant Flow

Recruitment Details	31 May 2006 (first subject enrolled) to 03 Mar 2008 (last subject completed. Multi-national trial conducted in Argentina, Brazil, Canada, Chile, Czech Republic, Mexico, Poland, Russian Federation, Spain, Ukraine, and USA.
Pre-assignment Detail	2 week screening period prior to randomization. 1512 patients screened with 528 patients randomized. 977 patients failed screening criteria, 9 subjects passed screening but were not randomized, 2 subjects failed screening but were randomized.

Arm/Group Title	TI Inhalation Powder Alone	Metformin & Secretagogues	TI Inhalation Powder + Metformin
Arm/Group Description	Technosphere® Insulin Inhalation Powder administered prior to each meal without any other anti-diabetic treatment; dose individualized for each subject	Metformin (>= 1,000 mg/day or maximum tolerate dose) & Secretagogue (Sulfonylurea or meglitinide at >= half maximum manufacturer recommended dose or maximum tolerated dose)	Technosphere® Insulin Inhalation Powder administered prior to each meal (dose individualized for each subject) & Metformin (>= 1,000 mg/day or maximum tolerate dose)
Period Title: Initial Treatment Phase (Weeks 0 - 12)
STARTED	183	170	175
COMPLETED	133	152	119
NOT COMPLETED	50	18	56
Period Title: Initial Treatment Phase (Weeks 0 - 12)
STARTED	29	72	254
COMPLETED	27	70	233
NOT COMPLETED	2	2	21

Baseline Characteristics

Arm/Group Title	TI Inhalation Powder Alone	Metformin & Secretagogues	TI Inhalation Powder + Metformin	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	177	162	169	508
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	57.3	57.6	56.8	57.2
Sex: Female, Male (Count of Participants)
Female	93 52.5%	88 54.3%	101 59.8%	282 55.5%
Male	84 47.5%	74 45.7%	68 40.2%	226 44.5%
Body Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	86.1 (15.6)	84.2 (16.2)	83.9 (13.9)	84.8 (15.27)
Fasting Plasma Glucose (milligrams per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter]	193.5 (52.4)	194.6 (48.5)	188.6 (49.7)	192.2 (50.23)
HbA1c (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	8.9 (0.95)	8.9 (0.94)	9.0 (0.97)	8.9 (0.95)

Outcome Measures

1. Primary Outcome

Title	Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) Population with Last Observation Carried Forward

Arm/Group Title	Metformin & Secretagogues	TI Inhalation Powder + Metformin
Arm/Group Description	Metformin & Secretagogues	Technosphere® Insulin Inhalation Powder & Metformin
Measure Participants	162	169
Least Squares Mean (95% Confidence Interval) [Percentage of total hemoglobin]	-0.78 (-0.78)	-0.70 (-0.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin & Secretagogues, TI Inhalation Powder + Metformin
	Comments	ANCOVA fitting model change from baseline in A1c with fixed effects for treatment and pooled site and baseline A1c as a covariate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.420
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue
Description	(Change from baseline within TI Alone) minus (change from baseline within metformin + secretagogue)
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT) Population for patients with available data

Arm/Group Title	TI Inhalation Powder Alone	Metformin & Secretagogues
Arm/Group Description	Technosphere® Insulin Inhalation Powder	Metformin & Secretagogues
Measure Participants	133	153
Mean (Standard Deviation) [Percentage of total hemoglobin]	0.12 (1.3)	-0.76 (0.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin & Secretagogues, TI Inhalation Powder + Metformin
	Comments	ANCOVA fitting model change from baseline in A1c with fixed effects for treatment and pooled site and baseline A1c as a covariate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments	Type III
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment)
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent to Treat: Subjects who stayed on original treatment

Arm/Group Title	TI Inhalation Powder Alone	Metformin & Secretagogues	TI Inhalation Powder + Metformin
Arm/Group Description	Technosphere® Insulin Inhalation Powder	Metformin & Secretagogues	Technosphere® Insulin Inhalation Powder & Metformin
Measure Participants	29	72	77
Mean (Standard Deviation) [percentage of total hemoglobin]	-1.82 (1.114)	-1.23 (1.080)	-1.68 (1.014)

Adverse Events

Time Frame	From first dose until 30 days after last dose of study medication
Adverse Event Reporting Description	Subjects in the TI Alone and Metformin + Secretagogue arms may have transferred to the TI + Metformin Arm for study period 2. There are 181, 166 and 351 subjects in the TI Alone, Metformin + Secretagogue and TI + Metformin treatment arms, respectively, across all 24 weeks of the study.
Arm/Group Title	TI Inhalation Powder Alone		Metformin & Secretagogues		TI Inhalation Powder + Metformin
Arm/Group Description	Technosphere® Insulin Inhalation Powder		Metformin & Secretagogues		Technosphere® Insulin Inhalation Powder & Metformin
All Cause Mortality
	TI Inhalation Powder Alone		Metformin & Secretagogues		TI Inhalation Powder + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	TI Inhalation Powder Alone		Metformin & Secretagogues		TI Inhalation Powder + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/181 (2.8%)		5/166 (3%)		11/351 (3.1%)
Cardiac disorders
ACUTE CORONARY SYNDROME	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
ANGINA UNSTABLE	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
ATRIAL FIBRILLATION	0/181 (0%)		2/166 (1.2%)		0/351 (0%)
ISCHAEMIC CARDIOMYOPATHY	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
SUPRAVENTRICULAR TACHYCARDIA	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
ANGINA PECTORIS	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
Gastrointestinal disorders
RETROPERITONEAL HAEMORRHAGE	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
INTESTINAL OBSTRUCTION	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
PANCREATITIS ACUTE	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
Hepatobiliary disorders
CHOLECYSTITIS	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
CHOLECYCTITIS ACUTE	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
Infections and infestations
SEPSIS	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
CELLULITIS	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
Injury, poisoning and procedural complications
ROAD TRAFFIC ACCIDENT	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
ANKLE FRACTURE	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
FALL	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
LOWER LIMB FRACTURE	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
Metabolism and nutrition disorders
HYPERGLYCAEMIA	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
HYPOGLYCAEMIA	1/181 (0.6%)		0/166 (0%)		2/351 (0.6%)
Musculoskeletal and connective tissue disorders
DUPUYTREN'S CONTRACTURE	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
Nervous system disorders
LOSS OF CONSCIOUSNESS	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
TRANSIENT ISCHAEMIC ATTACK	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
IIIRD NERVE PARALYSIS	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
Renal and urinary disorders
BLADDER NECK OBSTRUCTION	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
CALCULUS BLADDER	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
URETHRAL STRICTURE	0/181 (0%)		1/166 (0.6%)		0/351 (0%)
Vascular disorders
HYPOTENSION	1/181 (0.6%)		0/166 (0%)		0/351 (0%)
DEEP VEIN THROMBOSIS	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
HYPERTENSIVE CRISIS	0/181 (0%)		0/166 (0%)		1/351 (0.3%)
Other (Not Including Serious) Adverse Events
	TI Inhalation Powder Alone		Metformin & Secretagogues		TI Inhalation Powder + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/181 (39.8%)		42/166 (25.3%)		138/351 (39.3%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION	7/181 (3.9%)		12/166 (7.2%)		8/351 (2.3%)
NASOPHARYNGITIS	4/181 (2.2%)		13/166 (7.8%)		18/351 (5.1%)
Metabolism and nutrition disorders
HYPOGLYCAEMIA	24/181 (13.3%)		21/166 (12.7%)		84/351 (23.9%)
Respiratory, thoracic and mediastinal disorders
COUGH	49/181 (27.1%)		6/166 (3.6%)		62/351 (17.7%)

Limitations/Caveats

Wks 12-24 was a non-randomized treatment period of the trial; outcomes were not analyzed for Wks 12-24. Safety results include entire trial; patients counted in multiple treatments for safety.

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.