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

Diabetes Type 2 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00309244
• Other study ID #: MKC-TI-102
• Status: Completed
• Phase: Phase 3
• First received: March 27, 2006
• Last updated: October 9, 2014
• Start date: February 2006
• Est. completion date: September 2008

Study information

• Verified date: October 2014
• Source: Mannkind Corporation
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 677
• Est. completion date: September 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 ß-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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Diabetes Type 2

Intervention

Drug:
• Technosphere® Insulin Inhalation Powder
Inhalation, 15U/30U
• 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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Mannkind Corporation

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Chile,  Mexico,  Poland,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in HbA1c to Week 52		Baseline to Week 52	No
Secondary	Change From Baseline in Weight to Week 52		Baseline to Week 52	No
Secondary	Change From Baseline in Fasting Plasma Glucose to Week 52		Baseline to Week 52	No
Secondary	Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0%		Week 52	No
Secondary	Incidence of Total Hypoglycemia	Defined as hypoglycemic symptoms that are relieved with carbohydrate intake or blood glucose measurement <= 63 mg/dL, regardless of symptoms.	52 Weeks	Yes
Secondary	Incidence of Severe Hypoglycemia	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.	52 Weeks	Yes
Secondary	Total Hypoglycemia Event Rate	Number of Hypoglycemic Events/Total Subject Exposure Time (in months)	52 Weeks	Yes
Secondary	Severe Hypoglycemia Event Rate	Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)	52 Weeks	Yes