Randomized, Double Blind, 2 Way Crossover Study of CSII W... | NCT01526733

Status Module

Oversight Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Insulin (Aspart or Lispro)-Sham	Sham Comparator	In Phase I or Phase II of the study, participants received 0.15 units per kilogram (U/kg) insulin (either insulin aspart or insulin lispro) as a continuous subcutaneous insulin infusion (CSII) for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.	Drug: Sham Injection Drug: Insulin aspart Drug: Insulin lispro
Insulin (Aspart or Lispro)-rHuPH20	Experimental	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of recombinant human hyaluronidase (rHuPH20). Each Phase was separated by a washout period of 5 to 21 days.	Drug: Recombinant human hyaluronidase PH20 Drug: Insulin aspart Drug: Insulin lispro

Name	Type	Description	Arm Group Labels	Other Names
Sham Injection	Drug		Insulin (Aspart or Lispro)-Sham
Recombinant human hyaluronidase PH20

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Early Insulin Exposure (%AUC[0-60])	Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve [AUC{0 360}]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose during a euglycemic clamp.	10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4

Secondary Outcomes

Measure	Description	Time Frame
Maximum Glucose Infusion Rate (GIRmax)	Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.	0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Males or females of age 18 to 65 years, inclusive. Females of child-bearing potential must use a standard and effective means of birth control for the duration of the study.
Non-smoking participants with Type 1 diabetes mellitus (T1DM) treated with insulin for ≥12 months. Nonsmoking means abstinence from cigarettes and cigars for 3 months and negative cotinine screening tests at screening.
Body mass index (BMI) 18.0 to 35.0 kilograms per meter squared (kg/m²), inclusive.
Glycosylated hemoglobin A1c (HbA1c) ≤10% based on local laboratory results.
Fasting connecting peptide of insulin (C-peptide) <0.6 nanograms per milliliter (ng/mL).
Current treatment with insulin <90 units per day (U/d).
Current use of rapid acting insulin analog.
Routine use of CSII as the primary route of insulin administration for at least 3 months prior to screening
Participants should be in good general health based on medical history and physical examination without medical conditions that might prevent the completion of study drug infusions and assessments required in the study protocol.

Exclusion Criteria:

Known or suspected allergy to any component of any of the study drugs in this study.
Previous enrollment in this study.
Use of drugs that may interfere with the interpretation of study results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia. Participants taking maintenance doses of blood thinners (for example, coumadin or heparin) will be excluded.
Use of any long-acting insulin injection within 72 hours of Study Day 1; participants will continue to refrain from use throughout the duration of the study (Phases I and II).
Recurrent major hypoglycemia or hypoglycemic unawareness, as judged by the Investigator.
Current addiction to alcohol or substances of abuse as determined by the Investigator.
Blood donation or phlebotomy (>500 milliliters [mL]) within the previous 8 weeks of the Screening Visit(s) in this study.
Pregnancy, breastfeeding, the intention of becoming pregnant, or not using adequate contraceptive measures (adequate contraceptive measures consist of sterilization, intra-uterine device [IUD], oral or injectable contraceptives, or barrier methods).
Symptomatic gastroparesis.
Receipt of any investigational drug within 4 weeks of Study Day 1.

Name	Affiliation	Role
Linda Morrow, MD	Profil Institute for Clinical Research, Inc.	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Profil Institute for Clinical Research		Chula Vista	California	91911	United States

Label	URL
Sponsor's Website	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Insulin-rHuPH20, Then Insulin-sham	In Phase I, participants received 0.15 units per kilogram (U/kg) insulin (either insulin aspart or insulin lispro) as a continuous subcutaneous insulin infusion (CSII) for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 milliliter (mL) (150 U) injection of recombinant human hyaluronidase PH20 (rHuPH20). In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Phase I and II were separated by a washout period of 5 to 21 days.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

ID	Title	Description
BG000	All Enrolled Participants	All participants enrolled in the study.

Units	Counts
Participants	BG00025

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00031.6± 9.13

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00014
Male	BG00011

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000
Asian	BG0000

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0002
Not Hispanic or Latino	BG00023

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG00025

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Early Insulin Exposure (%AUC[0-60])

Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve [AUC{0 360}]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable %AUC(0-60) data.

Posted

Mean

Standard Deviation

percentage of AUC(0-60)

10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Units	Counts
Participants	OG00021 OG00121

Title

Denominators

Categories

Day 1

Title	Measurements
	OG00033.53± 11.81 OG00117.85± 8.24

Day 4

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Mixed Models Analysis	A mixed model with fixed effects for treatment, day, and interaction of treatment with day was performed using a compound symmetric covariance matrix.	<0.0001	Comparison of Day 1 Insulin (Aspart or Lispro)-rHuPH20 versus Day 1 Insulin-sham.	Geometric Least Squares Mean Ratio	2.15			2-Sided	90	1.71	2.71					Superiority or Other

Secondary

Maximum Glucose Infusion Rate (GIRmax)

Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable GIRmax data.

Posted

Mean

Standard Deviation

milligrams/kilogram/minute

0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Secondary

Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax)

Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable tGIRmax data.

Posted

Mean

Standard Deviation

minutes

0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Secondary

Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max)

Early and late tGIR50%max are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable early and late tGIR50%max data.

Posted

Mean

Standard Deviation

minutes

0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Secondary

Time to 50% Total Glucose Infused (50%Gtot)

Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable 50%Gtot data.

Posted

Mean

Standard Deviation

minutes

0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Secondary

Area Under the Glucose Concentration Curve (AUC[0-360])

Area under the glucose concentration curve from 0 to 360 minutes (AUC[0-360]) is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable AUC(0-360) data.

Posted

Mean

Standard Deviation

picomoles*minutes/liter

30 minutes and 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Secondary

Duration of Insulin Action (AUMC[0-360]/AUC[0-360])

Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC[0-360]) by the area under the concentration versus time curve (AUC[0-360]). AUCM is the total area under the first moment curve. First moment curve is obtained by plotting concentration-time versus time. It can be used to measure how long a drug stays in the body. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Participants who completed both phases of the study and with evaluable AUMC(0-360)/AUC(0-360) data.

Posted

Mean

Standard Deviation

ratio

10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

ID	Title	Description
OG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.
OG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Insulin (Aspart or Lispro)-rHuPH20	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.			0	24	13	24
EG001	Insulin (Aspart or Lispro)-Sham	In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.			0	23	9	23

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (12.0)	Systematic Assessment	EG0002 affected24 at risk EG0014 affected23 at risk
Nausea	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0002 affected24 at risk EG0011 affected23 at risk
Vomiting	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0002 affected24 at risk EG0010 affected23 at risk
Constipation	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Injection site pain	General disorders	MedDRA (12.0)	Systematic Assessment	EG0003 affected24 at risk EG0011 affected23 at risk
Injection site pruritus	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0012 affected23 at risk
Injection site haemorrhage	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Injection site haematoma	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Injection site induration	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Injection site inflammation	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 affected24 at risk EG0011 affected23 at risk
Tenderness	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 affected24 at risk EG0011 affected23 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0011 affected23 at risk
Clavicle fracture	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 affected24 at risk EG0011 affected23 at risk
Sunburn	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Headache	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0002 affected24 at risk EG0013 affected23 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 affected24 at risk EG0011 affected23 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk
Ecchymosis	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0001 affected24 at risk EG0010 affected23 at risk

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
C005703	salicylhydroxamic acid
D061267	Insulin Aspart
D061268	Insulin Lispro

ID	Term
D061266	Insulin, Short-Acting
D061385	Insulins
D010187	Pancreatic Hormones
D036361	Peptide Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D010455	Peptides
D000602	Amino Acids, Peptides, and Proteins