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Safety Study of Subcutaneously-Injected Prandial INSULIN-PH20 NP Compared to Insulin Lispro Injection in Participants With Type 1 Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT00883558
Recruitment Status : Completed
First Posted : April 17, 2009
Results First Posted : September 8, 2014
Last Update Posted : September 8, 2014
Sponsor:
Information provided by (Responsible Party):
Halozyme Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label)
Condition Diabetes Mellitus, Type 1
Interventions Drug: Insulin Lispro
Drug: regular human insulin
Drug: recombinant human hyaluronidase PH20
Drug: Insulin glargine
Enrollment 48

Recruitment Details  
Pre-assignment Details  
Arm/Group Title All Enrolled Participants INSULIN-PH20 NP First, Then Insulin Lispro Insulin Lispro First, Then INSULIN-PH20 NP
Hide Arm/Group Description

Prior to randomization, all enrolled participants underwent a 1-month dose titration period.

Insulin Lispro (Titration Period): 100 units per milliliter (U/mL), injected subcutaneously before meals, with doses titrated to each individual participant's glycemic control needs, for 1 month.

Participants requiring basal insulin used twice daily, subcutaneous injections of 100 U/mL insulin glargine or maintained their usual regimen through an infusion pump.

Following a 1-month dose titration period, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle.

INSULIN-PH20 NP (Treatment A): 100 units per milliliter (U/mL) non-preserved (NP) formulation of recombinant human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.

Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.

Participants requiring basal insulin used twice daily, subcutaneous injections of 100 U/mL insulin glargine or maintained their usual regimen through an infusion pump.

Following a 1-month dose titration period, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle.

Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.

INSULIN-PH20 NP (Treatment A): 100 U/mL non-preserved (NP) formulation of recombinant human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.

Participants requiring basal insulin used twice daily, subcutaneous injections of 100 U/mL insulin glargine or maintained their usual regimen through an infusion pump.

Period Title: Titration Period (Weeks 0 to 4)
Started 48 0 0
Completed 46 0 0
Not Completed 2 0 0
Reason Not Completed
Withdrawal by Subject             2             0             0
Period Title: First Treatment Cycle (Weeks 4 to 16)
Started 0 22 24
Received at Least 1 Dose of Study Drug 0 22 24
Completed 0 19 23
Not Completed 0 3 1
Reason Not Completed
Adverse Event             0             1             0
Withdrawal by Subject             0             1             1
Protocol Violation             0             1             0
Period Title: Second Treatment Cycle (Weeks 16 to 28)
Started 0 19 23
Received at Least 1 Dose of Study Drug 0 19 23
Completed 0 19 22
Not Completed 0 0 1
Reason Not Completed
Withdrawal by Subject             0             0             1
Arm/Group Title All Randomized Participants
Hide Arm/Group Description

Following a 1-month titration period, participants were randomly assigned to 1 of 2 study treatments (Treatment A or B) for the first of two, 3-month treatment cycles. Each participant then received the second treatment for the second cycle.

INSULIN-PH20 NP (Treatment A): 100 U/mL non-preserved (NP) formulation of regular human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, doses titrated to each participant individually.

Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, doses titrated to each participant individually.

Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine or maintained their usual regimen through an insulin pump.

Overall Number of Baseline Participants 46
Hide Baseline Analysis Population Description
Participants who were randomized and received at least 1 dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 46 participants
41.6  (13.28)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 46 participants
Female
22
  47.8%
Male
24
  52.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 46 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
2
   4.3%
White
44
  95.7%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 46 participants
Hispanic or Latino
2
   4.3%
Not Hispanic or Latino
44
  95.7%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 46 participants
46
1.Primary Outcome
Title Postprandial Glucose Excursion
Hide Description A 2-hour postprandial glucose excursion was measured for 3 meals over 3 days during each treatment cycle (3 days during Week 14 of the first treatment cycle and 3 days during Week 26 of the second treatment cycle). For each of the 3 days, the mealtime (breakfast, lunch, and dinner) excursions were calculated as the post-meal glucose value minus the pre-meal value as determined by 8-point glucose monitoring. The average of all excursions over the 3 days for the corresponding treatment cycle is presented.
Time Frame Week 14 and Week 26
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who completed both treatment cycles with evaluable postprandial glucose data.
Arm/Group Title INSULIN-PH20 NP Insulin Lispro
Hide Arm/Group Description:
100 units per milliliter (U/mL) non-preserved formulation of recombinant human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase (INSULIN-PH20 NP), injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
100 units per milliliter (U/mL) insulin lispro, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
Overall Number of Participants Analyzed 37 37
Mean (Standard Deviation)
Unit of Measure: milligrams per deciliter (mg/dL)
17.23  (36.040) 14.47  (35.113)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection INSULIN-PH20 NP, Insulin Lispro
Comments A total of at least 40 participants were to be enrolled in the study, and 30 participants were expected to complete both treatment cycles. Assuming a standard deviation for blood glucose of 45 milligrams per deciliter (mg/dL) and a true difference between the treatments of 0 mg/dL, the study had approximately 80% power to show that INSULIN-PH20 NP was non-inferior to insulin lispro with respect to the overall two-hour postprandial blood glucose excursion.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority of INSULIN-PH20 NP to insulin lispro was supported if the upper limit of the one-sided 95% confidence interval for the difference in blood glucose between the treatments did not exceed 21.6 mg/dL.
Statistical Test of Hypothesis P-Value 0.3217
Comments [Not Specified]
Method Mixed Models Analysis
Comments Adjustments included treatment, phase, and treatment sequence as fixed effects and participant within treatment sequence as a random effect.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.06
Confidence Interval (1-Sided) 95%
14.11
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time Spent With Blood Glucose Value Outside a 71-139 Milligrams Per Deciliter (mg/dL) Range During Continuous Glucose Monitoring
Hide Description Participants were provided a continuous glucose monitoring (CGM) device, consisting of a sensor, transmitter, and receiver. Total time the participant's blood glucose was outside the 71-139 mg/dL range during 3 days of CGM during each treatment cycle (3 days during Week 14 of the first treatment cycle and 3 days during Week 26 of the second treatment cycle) is presented.
Time Frame Week 14 and Week 26
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants that completed both treatment cycles with evaluable CGM data.
Arm/Group Title INSULIN-PH20 NP Insulin Lispro
Hide Arm/Group Description:
100 units per milliliter (U/mL) non-preserved formulation of recombinant human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase (INSULIN-PH20 NP), injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
100 units per milliliter (U/mL) insulin lispro, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
Overall Number of Participants Analyzed 40 40
Mean (Standard Deviation)
Unit of Measure: hours
14.58  (3.155) 13.37  (3.933)
3.Secondary Outcome
Title Number of Participants With Hypoglycemic Events
Hide Description The number of participants with at least one hypoglycemic event (HE) reported during the entire study is presented. Additionally, the number of participants with severe HEs (those that necessitated administration of carbohydrate or glucagon, or resuscitation, by another person) is also presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time Frame Baseline through Week 29
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 dose of study drug.
Arm/Group Title INSULIN-PH20 NP Insulin Lispro
Hide Arm/Group Description:
100 units per milliliter (U/mL) non-preserved formulation of recombinant human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase (INSULIN-PH20 NP), injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
100 units per milliliter (U/mL) insulin lispro, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
Overall Number of Participants Analyzed 45 43
Measure Type: Number
Unit of Measure: participants
Overall 45 43
Severe HE 2 0
Time Frame An adverse event was considered treatment-emergent if the start date of the event was on or after the date of randomization.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title INSULIN-PH20 NP Treatment Period Insulin Lispro Treatment Period
Hide Arm/Group Description 100 units per milliliter (U/mL) non-preserved formulation of recombinant human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase (INSULIN-PH20 NP), injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months. 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously before meals, with doses titrated to each individual participant’s glycemic control needs, for 3 months.
All-Cause Mortality
INSULIN-PH20 NP Treatment Period Insulin Lispro Treatment Period
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
INSULIN-PH20 NP Treatment Period Insulin Lispro Treatment Period
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/45 (4.44%)      1/43 (2.33%)    
Injury, poisoning and procedural complications     
Haemothorax  1  0/45 (0.00%)  0 1/43 (2.33%)  1
Rib fracture  1  0/45 (0.00%)  0 1/43 (2.33%)  1
Musculoskeletal and connective tissue disorders     
Intervertebral disc degeneration  1  1/45 (2.22%)  1 0/43 (0.00%)  0
Reproductive system and breast disorders     
Uterine haemorrhage  1  1/22 (4.55%)  1 0/20 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (12.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
INSULIN-PH20 NP Treatment Period Insulin Lispro Treatment Period
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   17/45 (37.78%)      11/43 (25.58%)    
Gastrointestinal disorders     
Food poisoning  1  0/45 (0.00%)  0 2/43 (4.65%)  2
General disorders     
Injection site haematoma  1  2/45 (4.44%)  3 1/43 (2.33%)  1
Infections and infestations     
Nasopharyngitis  1  7/45 (15.56%)  7 7/43 (16.28%)  8
Upper respiratory tract infection  1  1/45 (2.22%)  1 3/43 (6.98%)  3
Sinusitis  1  2/45 (4.44%)  2 1/43 (2.33%)  1
Bronchitis  1  2/45 (4.44%)  2 0/43 (0.00%)  0
Fungal infection  1  2/45 (4.44%)  2 1/43 (2.33%)  1
Metabolism and nutrition disorders     
Hypoglycaemia  1  2/45 (4.44%)  2 0/43 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  0/45 (0.00%)  0 2/43 (4.65%)  2
Respiratory, thoracic and mediastinal disorders     
Cough  1  3/45 (6.67%)  3 0/43 (0.00%)  0
Vascular disorders     
Hypertension  1  2/45 (4.44%)  2 0/43 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (12.0)
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.
All information obtained as a result of this study or during the conduct of this study will be regarded as confidential. The investigator agrees to use the information for the purpose of carrying out this study and for no other purpose, unless written permission from the sponsor (Halozyme) is obtained.
Results Point of Contact
Name/Title: Vice President, Endocrinology Clinical Development
Organization: Halozyme Therapeutics, Inc.
Phone: 858-794-8889
Responsible Party: Halozyme Therapeutics
ClinicalTrials.gov Identifier: NCT00883558     History of Changes
Other Study ID Numbers: HALO-117-203
First Submitted: April 15, 2009
First Posted: April 17, 2009
Results First Submitted: August 28, 2014
Results First Posted: September 8, 2014
Last Update Posted: September 8, 2014