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

Phase 3

Completed

Conditions: Diabetes Type 2

Interventions: Drug: 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
Drug: Technosphere® Insulin Inhalation Powder

Registration Number: NCT00309244

Lead Sponsor: Mannkind Corporation

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 677

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BPR 70/30	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)	70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
TI + Insulin glargine	Technosphere® Insulin Inhalation Powder	Technosphere® Insulin Inhalation Powder + insulin glargine

Primary Outcome Measures

Name	Time	Method
Change From Baseline in HbA1c to Week 52	Baseline to Week 52

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Weight to Week 52	Baseline to Week 52
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.
Change From Baseline in Fasting Plasma Glucose to Week 52	Baseline to Week 52
Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0%	Week 52
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.
Total Hypoglycemia Event Rate	52 Weeks	Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Severe Hypoglycemia Event Rate	52 Weeks	Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)

Trial Locations

Locations (149): Valley Research
🇺🇸
Fresno, California, United States
Physician's East PA
🇺🇸
Greenville, North Carolina, United States
Clintell Inc
🇺🇸
Skokie, Illinois, United States
Clintell Inc (Ellyin)
🇺🇸
Skokie, Illinois, United States
Dallas Diabetes & Endocrine Center
🇺🇸
Dallas, Texas, United States
North Texas Endocrine Center
🇺🇸
Dallas, Texas, United States
International Research Associates LLC
🇺🇸
Miami, Florida, United States
Tucson Clinical Research
🇺🇸
Tucson, Arizona, United States
Coastal Clinical Research Inc
🇺🇸
Mobile, Alabama, United States
Southern Arizona VA Healthcare System
🇺🇸
Tucson, Arizona, United States
Saad Hijazi MD Inc
🇺🇸
Fresno, California, United States
International Clinical Research Network
🇺🇸
Chula Vista, California, United States
Diabetes/Lipid Management and Research Center
🇺🇸
Huntington Beach, California, United States
Coastal Biomedical Research Inc
🇺🇸
Santa Monica, California, United States
South Bay Clinical Research
🇺🇸
Inglewood, California, United States
Southern California Endocrine Center
🇺🇸
Pasadena, California, United States
Diabetes Research Center
🇺🇸
Tustin, California, United States
University of Miami Diabetes Research Institute
🇺🇸
Miami, Florida, United States
Atlanta Pharmaceutical Research Center
🇺🇸
Dunwoody, Georgia, United States
Laureate Clinical Research Group
🇺🇸
Atlanta, Georgia, United States
North Atlanta Endocrinology & Diabetes PC
🇺🇸
Lawrenceville, Georgia, United States
Atlanta Center for Clinical Research
🇺🇸
Roswell, Georgia, United States
John H Stoger Jr Hospital of Cook County
🇺🇸
Chicago, Illinois, United States
Medical Research of Louisiana
🇺🇸
Metairie, Louisiana, United States
Joslin Diabetes Center University of Maryland Medicine
🇺🇸
Baltimore, Maryland, United States
James A Dicke MDPA
🇺🇸
Towson, Maryland, United States
Wayne State University
🇺🇸
Detroit, Michigan, United States
Michigan Institute of Medicine
🇺🇸
Livonia, Michigan, United States
KMED Research
🇺🇸
St Clair Shores, Michigan, United States
Radiant Research Inc (Minneapolis)
🇺🇸
Edina, Minnesota, United States
Amin Radparvar's Private Practice
🇺🇸
St Peters, Missouri, United States
MedEx Healthcare Research Inc
🇺🇸
St Louis, Missouri, United States
Montana Health Research Institute
🇺🇸
Billings, Montana, United States
Creighton Diabetes Center
🇺🇸
Omaha, Nebraska, United States
New Mexico Clinical Research & Osteoporosis Center
🇺🇸
Albuquerque, New Mexico, United States
University of New Mexico HCS
🇺🇸
Albuquerque, New Mexico, United States
Winthrop University Hospital
🇺🇸
Mineola, New York, United States
North Shore Diabetes and Endocrine Associates
🇺🇸
New Hyde Park, New York, United States
Univeristy of Physicians Group Endocrine Division
🇺🇸
Staten Island, New York, United States
Sensenbrenner Primary Care
🇺🇸
Charlotte, North Carolina, United States
East Carolina University (Tanenberg)
🇺🇸
Greenville, North Carolina, United States
Valley Medical Primary Care
🇺🇸
Centerville, Ohio, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Cleveland Clinic Health System
🇺🇸
East Cleveland, Ohio, United States
Providence Health Partners - Center of Clinical Research
🇺🇸
Dayton, Ohio, United States
Wells Institute for Health Awareness
🇺🇸
Kettering, Ohio, United States
Oregon Medical Group Clinical Resesarch
🇺🇸
Eugene, Oregon, United States
New Hope Research of Oregon
🇺🇸
Portland, Oregon, United States
Lane Medical Research Group
🇺🇸
Eugene, Oregon, United States
Covance CRU Inc.
🇺🇸
Portland, Oregon, United States
Pennsylvania Research Institute
🇺🇸
Bensalem, Pennsylvania, United States
Upstate Pharmaceutical Research
🇺🇸
Greenville, South Carolina, United States
Southeastern Research Associates Inc
🇺🇸
Taylors, South Carolina, United States
AM Diabetes and Endocrinology Center
🇺🇸
Bartlett, Tennessee, United States
Memphis Internal Medicine PLLC
🇺🇸
Memphis, Tennessee, United States
Israel Hartman MD
🇺🇸
Arlington, Texas, United States
South Arlington Primary Care Assoc PA
🇺🇸
Arlington, Texas, United States
Radiant Research Dallas-North
🇺🇸
Dallas, Texas, United States
Galenos Research
🇺🇸
Dallas, Texas, United States
Baylor Endocrine Center
🇺🇸
Dallas, Texas, United States
Spuhler Medical Associates
🇺🇸
Friendswood, Texas, United States
Clinical Trial Network
🇺🇸
Houston, Texas, United States
Clinical Research Associates of Tidewater
🇺🇸
Norfolk, Virginia, United States
Sentara Medical Group
🇺🇸
Norfolk, Virginia, United States
Rainier Clinical Research Center Inc
🇺🇸
Renton, Washington, United States
Larry D Stonesifer MD Inc PS
🇺🇸
Federal Way, Washington, United States
Cedar Research
🇺🇸
Tacoma, Washington, United States
Liberty Research Center
🇺🇸
Tacoma, Washington, United States
Hospital Interzonal de Agudos Pedro Fiorito
🇦🇷
Avellaneda, Buenos Aires, Argentina
CITDEEM - Centro de Investigacion y Tratamiento En Diabetes y Enfermedades Endocrino-Metabolicas
🇦🇷
San Miguel de Tucuman, Tucuman, Argentina
Centro Endocrinologic Tiempo
🇦🇷
Buenos Aires, Argentina
Hospital Italiano de Buenos Aires
🇦🇷
Buenos Aires, Argentina
FUNDAPRES/CIMel
🇦🇷
Buenos Aires, Argentina
Cons Asoc de Endocrinologia
🇦🇷
Buenos Aires, Argentina
Centro Medico Dra De Salvo
🇦🇷
Buenos Aires, Argentina
Universidade Estabual de Maringa
🇧🇷
Maringa Parana, Brazil
Nucleo de Medicina Integrada
🇧🇷
Mogi das Cruzes, Brazil
Ccbr Brasil Centro de Analises e Pesquisas Clinicas Ltda
🇧🇷
Rio de Janeiro, Brazil
Hospital Guilherme Alvaro
🇧🇷
Santos, Brazil
Instituto Estadual De Diabetes e Endocrinologia Luis Capriglione
🇧🇷
Rio de Janeiro, Brazil
CPClin-Centro de Pesquisas Clinicas
🇧🇷
Sao Paulo, Brazil
Blumenau Servicos Medicos S/C Ltda
🇧🇷
Sao Paulo, Brazil
Centro de Pesquisa Clinica e Medicina Avancada
🇧🇷
Sao Paulo, Brazil
Hospital do Rim e Hipertensao
🇧🇷
Sao Paulo, Brazil
Instituto da Saude e Bem Estar da Mulher
🇧🇷
Sao Paulo, Brazil
Keele Medical Place
🇨🇦
Downsview, Ontario, Canada
Quest Clinical Trials
🇨🇦
Markham, Ontario, Canada
Lifestyle Metabolism Center
🇨🇦
Toronto, Ontario, Canada
Sarnia Institute of Clinical Research
🇨🇦
Sarnia, Ontario, Canada
Hospital del Salvador
🇨🇱
Santiago, Region Metropolitana, Chile
Hospital Padre Alberto Hurtado
🇨🇱
Santiago, Region Metropolitana, Chile
Hospital Clinico Pontificia Universidad Catolica de Chile
🇨🇱
Santiago, Chile
Hospital San Borja ArriaranUniversidad de Chile
🇨🇱
Santiago, Chile
Instituto Mexicano de Investigacion
🇲🇽
Mexico City, Durango, Mexico
Hospital OCA
🇲🇽
Monterrey, Nuevo Leon, MX, Mexico
Hospital Universitario Dr Jose E Gonzalez
🇲🇽
Monterrey, Nuevo Leon, Mexico
Hospital Santa Engracia-CIMA
🇲🇽
Garza Garcia, Mexico
Centro de Estudios en Diabetes
🇲🇽
Mexico City, Mexico
Oddzial Chorob Wewnetrznych
🇵🇱
Bialystock, POL, Poland
NZOZ Specjalistyczny Osrodek Internistyczno - Diabetologiczny
🇵🇱
Bialystok, POL, Poland
Katedra I Klinika Chorob Metabolicznych Collegium Medicum Uniwersytety Jagiellonskiego
🇵🇱
Krakow, POL, Poland
NZOZ Diabetologiczna Poradnia Specjalistyczna
🇵🇱
Warszawa, Poland
Klliniczny nr 1 im Norberta Barlickiego Uniwersytetu Medycznego w Lodzi
🇵🇱
Lodz, POL, Poland
Szpital Kolejowy im Dr w Roeflera(009) Oddzial Gastorenterologii
🇵🇱
Pruszkow, POL, Poland
Instytut Centrum Zdrowia (009) Matki Polki
🇵🇱
Lodz, POL, Poland
Moscow City Clinical Hospital # 13
🇷🇺
Moscow, RUS, Russian Federation
NHI Kemerovo Regional Clinical Hospital
🇷🇺
Kemerovo, RUS, Russian Federation
NI Principal Military Clinical Hospital n a academician N.N. Burdenko of the Ministry of Defense
🇷🇺
Moscow, RUS, Russian Federation
NEI HPE Moscow State University of Medicine and Dentistry of FAHSD City Clinical Hospital #70
🇷🇺
Moscow, RUS, Russian Federation
RAAMS Endocrinology and Diabetology Department
🇷🇺
Moscow, RUS, Russian Federation
SI Internal Affairs of Moscow- Clinical Hospital
🇷🇺
Moscow, RUS, Russian Federation
NEI HPE Smolensk State Medical Academy of FAHSD RNHI Smolensk Regional Clinical Hospital
🇷🇺
Smolensk, RUS, Russian Federation
SEI HPE Moscow Medical Academy IM Sechenov of Roszdrav Clinic of Endocrinology
🇷🇺
Moscow, RUS, Russian Federation
Central Medical Sanitary Unit #122
🇷🇺
St Petersburg, RUS, Russian Federation
St Petersburg NHI City Polytclinic #77 City Diabetological Center #4
🇷🇺
St Petersburg, RUS, Russian Federation
Pavlov State Medical Univ of St Petersburg
🇷🇺
St Petersburg, RUS, Russian Federation
MCHI Medical Sanitary Unit of Novo-Yaroslavsky Oil Refining Plant
🇷🇺
Yaroslavl, RUS, Russian Federation
MHI Clinical Hospital for Emergency Care na NV Soloviev
🇷🇺
Yaroslavl, RUS, Russian Federation
NHI Yaroslavl Regional Clinical Hospital
🇷🇺
Yaroslavl, RUS, Russian Federation
Complejo Hospitalario Nuestra Senora de Valme
🇪🇸
Sevilla, Andalucia, Spain
NI Central Clinical Hospital of RAS
🇷🇺
Moscow, Russian Federation
City Clinical Hospital # 61
🇷🇺
Moscow, Russian Federation
Hospital de Mataro
🇪🇸
Mataro, Barcelona, Spain
Hospital del Mar (Cano)
🇪🇸
Barcelona, Spain
Centro Médico Teknon
🇪🇸
Barcelona, Spain
Hospital Ramon y Cajal
🇪🇸
Madrid, Spain
Hospital Universitario de la Princessa
🇪🇸
Madrid, Spain
Corporacion Sanitaria Parc Tauli Unidad de Endocrinologia
🇪🇸
Sabadell, Spain
Complejo Hospitalario Virgen del Rocio
🇪🇸
Sevilla, Spain
Hospital Virgen Macarena (policlinico) 2ª planta Servicio de Endocrinologia y Nutricion
🇪🇸
Sevilla, Spain
Birchwood Surgery
🇬🇧
Letchworth, Herts, United Kingdom
Lister Hospital
🇬🇧
Stevenage, Herts, United Kingdom
Guy's & St Thomas Hospital
🇬🇧
London, United Kingdom
Yaxley Group Practice
🇬🇧
Peterborough, United Kingdom
International Diabetes Center
🇺🇸
Minneapolis, Minnesota, United States
Center for Urologic Clinical Trials University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Quality Assurance Research Center Inc
🇺🇸
San Antonio, Texas, United States
Covenant Clinic Research
🇺🇸
San Antonio, Texas, United States
Diabetes & Glandular Disease Research Assoc PA
🇺🇸
San Antonio, Texas, United States
SAM Clinical Research Center
🇺🇸
San Antonio, Texas, United States
Salt Lake Research
🇺🇸
Salt Lake City, Utah, United States
Hospital de Clinicas de Porto Alegre
🇧🇷
Porto Alegre, Rio Grande do Sul, Brazil
Hospital Sao Lucas da PUCRS
🇧🇷
Porto Alegre, Rio Grande do Sul, Brazil
Portland Diabetes & Endocrinology Center
🇺🇸
Portland, Oregon, United States
The Endocrine Clinic
🇺🇸
Memphis, Tennessee, United States
Billings Clinic Research Division
🇺🇸
Billings, Montana, United States
Cifbiotec
🇲🇽
Mexico City, Mexico
Quality of Life Medical & Research Center
🇺🇸
Tucson, Arizona, United States
Thomas Jefferson University
🇺🇸
Philadelphia, Pennsylvania, United States