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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

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ClinicalTrials.gov Identifier: NCT00332488
Recruitment Status : Completed
First Posted : June 1, 2006
Results First Posted : October 16, 2014
Last Update Posted : October 16, 2014
Sponsor:
Information provided by (Responsible Party):
Mannkind Corporation

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 2
Interventions Drug: Technosphere Insulin
Drug: Metformin & Secretagogues
Drug: Technosphere Insulin & Metformin
Enrollment 547
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 Details 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
Hide 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
Reason Not Completed
Adverse Event             8             2             6
Physician Decision             13             2             10
Withdrawal by Subject             21             10             20
Various             4             0             20
Lost to Follow-up             1             3             0
Protocol Violation             3             1             0
Period Title: Transfer Treatment Phase (Weeks 12 – 24)
Started 29 [1] 72 [2] 254 [3]
Completed 27 70 233
Not Completed 2 2 21
Reason Not Completed
Adverse Event             0             0             3
Lost to Follow-up             0             0             1
Physician Decision             0             0             3
Protocol Violation             0             0             1
Withdrawal by Subject             2             2             8
Various             0             0             5
[1]
Subjects on TI who achieved an HbA1c < 7.5% or had an HbA1c decrease from baseline >= 1.0%
[2]
Subjects on treatment who achieved an HbA1c < 7.5% or had an HbA1c decrease from baseline >= 1.0%
[3]
Subjects in this arm who met HbA1c criteria + subjects from other arms who did not
Arm/Group Title TI Inhalation Powder Alone Metformin & Secretagogues TI Inhalation Powder + Metformin Total
Hide Arm/Group Description [Not Specified] [Not Specified] [Not Specified] Total of all reporting groups
Overall Number of Baseline Participants 177 162 169 508
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 177 participants 162 participants 169 participants 508 participants
57.3
(26 to 75)
57.6
(18 to 75)
56.8
(37 to 77)
57.2
(18 to 77)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 177 participants 162 participants 169 participants 508 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  
Mean (Standard Deviation)
Unit of measure:  Kilograms
Number Analyzed 177 participants 162 participants 169 participants 508 participants
86.1  (15.6) 84.2  (16.2) 83.9  (13.9) 84.8  (15.27)
Fasting Plasma Glucose   [1] 
Mean (Standard Deviation)
Unit of measure:  Milligrams per deciliter
Number Analyzed 177 participants 162 participants 169 participants 508 participants
193.5  (52.4) 194.6  (48.5) 188.6  (49.7) 192.2  (50.23)
[1]
Measure Description: Fasting Plasma Glucose
HbA1c   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage
Number Analyzed 177 participants 162 participants 169 participants 508 participants
8.9  (0.95) 8.9  (0.94) 9.0  (0.97) 8.9  (0.95)
[1]
Measure Description: Glycated hemoglobin measurement
1.Primary Outcome
Title Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue
Hide Description [Not Specified]
Time Frame Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to Treat (ITT) Population with Last Observation Carried Forward
Arm/Group Title Metformin & Secretagogues TI Inhalation Powder + Metformin
Hide Arm/Group Description:
Metformin & Secretagogues
Technosphere® Insulin Inhalation Powder & Metformin
Overall Number of Participants Analyzed 162 169
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage of total hemoglobin
-0.78
(-0.92 to -0.64)
-0.70
(-0.84 to -0.56)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.420
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.08
Confidence Interval (2-Sided) 95%
-0.11 to 0.27
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue
Hide Description (Change from baseline within TI Alone) minus (change from baseline within metformin + secretagogue)
Time Frame Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to Treat (ITT) Population for patients with available data
Arm/Group Title TI Inhalation Powder Alone Metformin & Secretagogues
Hide Arm/Group Description:
Technosphere® Insulin Inhalation Powder
Metformin & Secretagogues
Overall Number of Participants Analyzed 133 153
Mean (Standard Deviation)
Unit of Measure: Percentage of total hemoglobin
0.12  (1.3) -0.76  (0.92)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TI Inhalation Powder Alone, Metformin & Secretagogues
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 [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
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
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment)
Hide Description [Not Specified]
Time Frame Week 24
Hide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Technosphere® Insulin Inhalation Powder
Metformin & Secretagogues
Technosphere® Insulin Inhalation Powder & Metformin
Overall Number of Participants Analyzed 29 72 77
Mean (Standard Deviation)
Unit of Measure: percentage of total hemoglobin
-1.82  (1.114) -1.23  (1.080) -1.68  (1.014)
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
TI Inhalation Powder Alone Metformin & Secretagogues TI Inhalation Powder + Metformin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/181 (2.76%)   5/166 (3.01%)   11/351 (3.13%) 
Cardiac disorders       
ACUTE CORONARY SYNDROME  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
ANGINA UNSTABLE  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
ATRIAL FIBRILLATION  1  0/181 (0.00%)  2/166 (1.20%)  0/351 (0.00%) 
ISCHAEMIC CARDIOMYOPATHY  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
SUPRAVENTRICULAR TACHYCARDIA  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
ANGINA PECTORIS  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
Gastrointestinal disorders       
RETROPERITONEAL HAEMORRHAGE  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
INTESTINAL OBSTRUCTION  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
PANCREATITIS ACUTE  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
Hepatobiliary disorders       
CHOLECYSTITIS  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
CHOLECYCTITIS ACUTE  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
Infections and infestations       
SEPSIS  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
CELLULITIS  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
Injury, poisoning and procedural complications       
ROAD TRAFFIC ACCIDENT  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
ANKLE FRACTURE  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
FALL  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
LOWER LIMB FRACTURE  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
Metabolism and nutrition disorders       
HYPERGLYCAEMIA  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
HYPOGLYCAEMIA  1  1/181 (0.55%)  0/166 (0.00%)  2/351 (0.57%) 
Musculoskeletal and connective tissue disorders       
DUPUYTREN’S CONTRACTURE  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
Nervous system disorders       
LOSS OF CONSCIOUSNESS  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
TRANSIENT ISCHAEMIC ATTACK  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
IIIRD NERVE PARALYSIS  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
Renal and urinary disorders       
BLADDER NECK OBSTRUCTION  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
CALCULUS BLADDER  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
URETHRAL STRICTURE  1  0/181 (0.00%)  1/166 (0.60%)  0/351 (0.00%) 
Vascular disorders       
HYPOTENSION  1  1/181 (0.55%)  0/166 (0.00%)  0/351 (0.00%) 
DEEP VEIN THROMBOSIS  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
HYPERTENSIVE CRISIS  1  0/181 (0.00%)  0/166 (0.00%)  1/351 (0.28%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 7.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
TI Inhalation Powder Alone Metformin & Secretagogues TI Inhalation Powder + Metformin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   72/181 (39.78%)   42/166 (25.30%)   138/351 (39.32%) 
Infections and infestations       
UPPER RESPIRATORY TRACT INFECTION  1  7/181 (3.87%)  12/166 (7.23%)  8/351 (2.28%) 
NASOPHARYNGITIS  1  4/181 (2.21%)  13/166 (7.83%)  18/351 (5.13%) 
Metabolism and nutrition disorders       
HYPOGLYCAEMIA  1  24/181 (13.26%)  21/166 (12.65%)  84/351 (23.93%) 
Respiratory, thoracic and mediastinal disorders       
COUGH  1  49/181 (27.07%)  6/166 (3.61%)  62/351 (17.66%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 7.1
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: MannKind Corporation
Phone: 201-983-5000
EMail: aboss@mannkindcorp.com
Layout table for additonal information
Responsible Party: Mannkind Corporation
ClinicalTrials.gov Identifier: NCT00332488    
Other Study ID Numbers: MKC-TI-103
First Submitted: May 31, 2006
First Posted: June 1, 2006
Results First Submitted: July 22, 2014
Results First Posted: October 16, 2014
Last Update Posted: October 16, 2014