Liquid Meal Study With Insulin Lispro With/Without Recombinant Human Hyaluronidase PH20 (rHuPH20) and Regular Human Insulin With rHuPH20 to Compare Pharmacokinetics, Postprandial Glycemic Response, and Optimal Insulin Dose in Participants With Type 2 Diabetes Mellitus (T2DM)

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00916357
• Collaborator: (none)
• Enrollment: 23
• Location: 1
• Arms: 6
• Duration (Months): 4
• Patients Per Site Per Month: 5.7

Study Details

Study Description

Brief Summary

This is a single-center, Phase 2, randomized, double-blind, 3-way crossover meal study in participants with Type 2 Diabetes Mellitus (T2DM) to determine the optimum dose and compare the pharmacokinetics (PK) and postprandial glycemic response of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), and Humulin-R + rHuPH20 administered subcutaneously.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Humalog; Drug: Humulin-R; Drug: Recombinant human hyaluronidase PH20 (rHuPH20)	Phase 2

Detailed Description

This study design was chosen to assess the differences between pharmacokinetic (PK) and pharmacodynamic (PD) parameters, including postprandial glycemic response, of Humalog + recombinant human hyaluronidase PH20 (rHuPH20), Humalog alone, and Humulin-R + rHuPH20 at optimal doses following a liquid meal.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Official Title: Phase 2, Double-Blind Randomized, 3-way Cross-Over Liquid Meal Study With Optimal Doses of SC Administered Insulin Lispro With and Without rHuPH20 and Regular Human Insulin With rHuPH20 to Compare Pharmacokinetics, Postprandial Glycemic Response, and Optimal Insulin Dose in Patients With T2DM
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Humalog, Then Humalog + rHuPH20, Then Humulin-R + rHuPH20 A subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3 to 14 day washout period.	Drug: Humalog; Other Names: Insulin lispro ; Drug: Humulin-R; Other Names: Humulin Regular human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humalog, Then Humulin-R + rHuPH20, Then Humalog + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Drug: Humalog; Other Names: Insulin lispro ; Drug: Humulin-R; Other Names: Humulin Regular human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humalog + rHuPH20, Then Humalog, Then Humulin-R + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20(rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Drug: Humalog; Other Names: Insulin lispro ; Drug: Humulin-R; Other Names: Humulin Regular human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humalog + rHuPH20, Then Humulin-R + rHuPH20, Then Humalog A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog following a 3- to 14-day washout period.	Drug: Humalog; Other Names: Insulin lispro ; Drug: Humulin-R; Other Names: Humulin Regular human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humulin-R + rHuPH20, Then Humalog, Then Humalog + rHuPH20 A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	Drug: Humalog; Other Names: Insulin lispro ; Drug: Humulin-R; Other Names: Humulin Regular human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX
Active Comparator: Humulin-R + rHuPH20, Then Humalog + rHuPH20, Then Humalog A subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog alone following a 3- to 14-day washout period.	Drug: Humalog; Other Names: Insulin lispro ; Drug: Humulin-R; Other Names: Humulin Regular human insulin ; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20 HYLENEX

Outcome Measures

Primary Outcome Measures

1. Postprandial Glucose (PPG) Excursion Following a Liquid Meal [Predose up to 480 minutes after study drug injection]

   Postprandial glucose (PPG) values in participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal are reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least square mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.

Secondary Outcome Measures

1. Maximum Serum Insulin Concentration (Cmax) [Predose up to 480 minutes after study drug injection]

   Maximum serum insulin concentration (Cmax) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

2. Time To Maximum Serum Insulin Concentration (Tmax) [Predose up to 480 minutes after study drug injection]

   Time to maximum serum insulin concentration (Tmax) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

3. Time to Early 50% Maximum Serum Insulin Concentration (Early[t50%]) [Predose up to 120 minutes after study drug injection]

   Time to early 50% maximum serum insulin concentration (early[t50%]) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, and 120 minutes after injection of each study drug.

4. Time to Late 50% Maximum Serum Insulin Concentration (Late[t50%]) [Predose up to 480 minutes after study drug injection]

   Time to late 50% maximum serum insulin concentration (late[t50%]) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

5. Mean Residence Time From Time 0 to the End of Blood Sampling (MRT[Last]) [Predose up to 480 minutes after study drug injection]

   Mean residence time from time 0 to the end of blood sampling (MRT[last]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

6. Area Under the Concentration Time-Curve for Serum Insulin From Time 0 to the End of Blood Sampling (AUC[Last]) [Predose up to 480 minutes after study drug injection]

   Area under the concentration time-curve for serum insulin from time 0 to the end of blood sampling (AUC[last]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 during a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least squares mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.

7. Area Under the Time-Concentration Curve for Blood Glucose (AUC[BG]) [Predose up to 480 minutes after study drug injection]

   Area under the time-concentration curve for blood glucose (AUC[BG]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), and Humulin-R + rHuPH20 following a liquid meal is reported. AUC(BG) values are reported for participants whose blood glucose (BG) was elevated higher than 160 milligrams per deciliter (mg/dL) or 140 mg/dL, or lower than 70 mg/dL within 4 hours of consuming a liquid meal. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least squares mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.

8. Minimum Postprandial Glucose (PPG) [Predose up to 480 minutes after study drug injection]

   Minimum postprandial glucose (PPG) in participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

9. Percentage of Participants Without Hypoglycemia [Predose up to 480 minutes after study drug injection]

   Percentage of participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 who did not experience hypoglycemia following a liquid meal is reported. Hypoglycemia was defined as any blood glucose values lower than 70 milligrams per deciliter (mg/dL) or symptoms of hypoglycemia responding to treatment with glucose. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

10. Time to Percentage of Insulin Exposure (as Measured by Area Under the Curve [AUC]) [Predose up to 480 minutes following after injection of study drug]

    Time to percentage of exposure to insulin, as measured by area under the curve (AUC), following a liquid meal for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female of age 18 to 70 years, inclusive

• Participants with Type 2 diabetes mellitus (T2DM) per World Health Organization criteria treated with basal and/or bolus insulin for ≥12 months.

• Body mass index (BMI) between 18 to 45 kilograms per square meter (kg/m^2), inclusive

• Glycosylated hemoglobin A1c (HbA1c) ≤10%

• Current treatment with insulin ≥60 Units/day (U/d)

• A participant taking oral hypoglycemic agents must be on a stable dose for >8 weeks with the exception of thiazolidinediones (TZD), which should be >12 weeks.

• Total body weight >65 kilograms (kg) (143 pounds [lb]) for men and >46 kg (101 lb) for women

• Vital signs (blood pressure [BP], pulse rate, and body temperature) within normal range or, if out of range, assessed by the Investigator as not clinically significant (NCS)

• 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 injections and assessments in this protocol

• Decision making capacity and willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures including adequate venous access.

• Signed and written Internal Review Board-approved informed consent

Exclusion Criteria:

• Known or suspected allergy to any components of any of the study drugs in this study

• Previous enrollment in this study

• A participant who has proliferative retinopathy, proliferative maculopathy, and/or severe neuropathy (in particular, autonomic neuropathy) as judged by the Investigator

• As judged by the Investigator, clinically significant active disease of the gastrointestinal, cardiovascular (including a history of arrhythmia or conduction delays on electrocardiogram [ECG] and New York Heart Association [NYHA] Class III/IV heart disease), hepatic, neurological, renal, genitourinary, or hematological systems

• As judged by the Investigator, uncontrolled hypertension (diastolic BP ≥100 millimeters of mercury [mmHg] and/or systolic BP ≥160 mmHg after 5 minutes in the supine position).

• As judged by the Investigator, clinically significant findings in routine laboratory data (anemia with hematocrit less than 33% at screening is specifically exclusionary)

• Positive human immunodeficiency virus (HIV) antibody test, hepatitis B (anti-HBsAg), or hepatitis C (anti-HCV) antibody test

• Current addiction to alcohol or substances of abuse as determined by the Investigator

• Known use of drugs (other than oral hypoglycemic agents) 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

• Recurrent major hypoglycemia or hypoglycemic unawareness as determined by the Investigator

• Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation in this study

• Symptomatic gastroparesis

• Donation of blood in excess of 500 milliliters (mL) within 56 days before dosing

• Use of any investigational drug or device 30 days before enrollment in this study

• Pregnancy, breast-feeding, 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, barrier methods, or remaining abstinent)

• Any condition (intrinsic or extrinsic) that, in the judgment of the Investigator, will interfere with study participation or evaluation of data

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Profil Institute for Clinical Research, Inc.	Chula Vista	California	United States	91911

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

• Principal Investigator: Marcus Hompesch, M.D., Profil Institute for Clinical Research, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT00916357
• Other Study ID Numbers: HALO-117-204
• First Posted: Jun 9, 2009
• Last Update Posted: Aug 18, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Halozyme Therapeutics: recombinant human hyaluronidase PH20 (rHuPH20); Insulin lispro; Regular human insulin
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Lispro

Study Results

Participant Flow

Arm/Group Title	Humalog, Then Humalog + rHuPH20, Then Humulin-R + rHuPH20	Humalog, Then Humulin-R + rHuPH20, Then Humalog + rHuPH20	Humalog + rHuPH20, Then Humalog, Then Humulin-R + rHuPH20	Humalog + rHuPH20, Then Humulin-R + rHuPH20, Then Humalog	Humulin-R + rHuPH20, Then Humalog, Then Humalog + rHuPH20	Humulin-R + rHuPH20, Then Humalog + rHuPH20, Then Humalog
Arm/Group Description	A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with up to 0.3- to 0.5-U/kg Humalog + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 nanograms/kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20). The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humulin-R + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period	A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humulin-R + rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog following a 3- to 14-day washout period.	A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog alone. The DF process and injection of appropriate dose was then repeated with 0.3-to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20 following a 3- to 14-day washout period.	A subcutaneous (SC) injection of up to 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20. After a 3- to 14-day washout period, the DF process and injection of appropriate dose was repeated with 0.3- to 0.5-U/kg Humalog + 3.75 ng/kg rHuPH20. The DF process and injection of appropriate dose was then repeated with 0.3- to 0.5-U/kg Humalog alone following a 3- to 14-day washout period.
Period Title: Period 1
STARTED	4	4	4	4	3	4
Received at Least 1 Dose of Study Drug	4	4	4	4	3	4
COMPLETED	3	4	4	4	3	4
NOT COMPLETED	1	0	0	0	0	0
Period Title: Period 1
STARTED	3	4	4	4	3	4
COMPLETED	3	4	4	4	3	4
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1
STARTED	3	4	4	4	3	4
COMPLETED	3	4	4	3	3	4
NOT COMPLETED	0	0	0	1	0	0
Period Title: Period 1
STARTED	3	4	4	3	3	4
COMPLETED	3	4	4	3	3	4
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1
STARTED	3	4	4	3	3	4
COMPLETED	3	4	4	3	3	4
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Participants who received at least 1 dose of Humalog, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 during dose-finding (DV) visits or experimental (data gathering) visits.
Overall Participants	23
Age (Years (yr)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years (yr)]	52.2 (8.07)
Sex: Female, Male (Count of Participants)
Female	9 39.1%
Male	14 60.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 39.1%
Not Hispanic or Latino	14 60.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 4.3%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	1 4.3%
Black or African American	4 17.4%
White	17 73.9%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Number) [Number]
United States	23 100%

Outcome Measures

1. Primary Outcome

Title	Postprandial Glucose (PPG) Excursion Following a Liquid Meal
Description	Postprandial glucose (PPG) values in participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal are reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least square mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable postprandial glucose (PPG) excursion data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
60-minute PPG	162.71 (32.28)	144.67 (28.08)	169.38 (28.64)
90-minute PPG	166.05 (34.53)	143.62 (30.75)	166.71 (33.83)
120-minute PPG	159.10 (30.73)	138.24 (32.34)	159.90 (39.56)
CBGMax(0-4hr)	177.81 (33.46)	165.38 (21.39)	181.62 (31.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	60 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	60 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2600
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	60 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated measures Analysis of Variance
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	90 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0039
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	90 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9300
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	90 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	120 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0190
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	120 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9200
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	120 minutes after study drug injection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0150
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	Peak postprandial glucose (PPG) values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0950
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	Peak postprandial glucose (PPG) values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6000
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	Peak postprandial glucose (PPG) values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0310
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

2. Secondary Outcome

Title	Maximum Serum Insulin Concentration (Cmax)
Description	Maximum serum insulin concentration (Cmax) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable maximum serum insulin concentration (Cmax) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Mean (Standard Deviation) [Picomoles per liter (pm/L)]	3329.49 (1090.02)	5661.92 (1307.75)	3011.56 (962.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1800
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

3. Secondary Outcome

Title	Time To Maximum Serum Insulin Concentration (Tmax)
Description	Time to maximum serum insulin concentration (Tmax) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable time to maximum serum insulin concentration (Tmax) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Mean (Standard Deviation) [Minutes (min)]	74.29 (36.27)	43.10 (16.01)	81.67 (40.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4800
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

4. Secondary Outcome

Title	Time to Early 50% Maximum Serum Insulin Concentration (Early[t50%])
Description	Time to early 50% maximum serum insulin concentration (early[t50%]) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, and 120 minutes after injection of each study drug.
Time Frame	Predose up to 120 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable time to early 50% maximum serum insulin concentration (early[t50%]) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Mean (Standard Deviation) [Minutes (min)]	27.02 (8.67)	18.71 (5.80)	21.46 (8.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1000
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

5. Secondary Outcome

Title	Time to Late 50% Maximum Serum Insulin Concentration (Late[t50%])
Description	Time to late 50% maximum serum insulin concentration (late[t50%]) for participants receiving Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable time to late 50% maximum serum insulin concentration (late[t50%]) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Mean (Standard Deviation) [Minutes (min)]	206.86 (41.66)	123.93 (44.59)	220.33 (51.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog alone + Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3000
	Comments	Treatment comparison for Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

6. Secondary Outcome

Title	Mean Residence Time From Time 0 to the End of Blood Sampling (MRT[Last])
Description	Mean residence time from time 0 to the end of blood sampling (MRT[last]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable mean residence time from time 0 to the end of blood sampling (MRT[last]) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Mean (Standard Deviation) [Minutes (min)]	148.79 (22.46)	108.23 (20.56)	150.24 (27.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7700
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

7. Secondary Outcome

Title	Area Under the Concentration Time-Curve for Serum Insulin From Time 0 to the End of Blood Sampling (AUC[Last])
Description	Area under the concentration time-curve for serum insulin from time 0 to the end of blood sampling (AUC[last]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 during a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least squares mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable area under the concentration time-curve for serum insulin from time 0 to the end of blood sampling (AUC[last]) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Least Squares Mean (Standard Deviation) [Minutes * picomoles /1000 (min*pm/1000)]	578.67 (144.66)	668.33 (146.52)	571.42 (132.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0100
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8200
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0056
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

8. Secondary Outcome

Title	Area Under the Time-Concentration Curve for Blood Glucose (AUC[BG])
Description	Area under the time-concentration curve for blood glucose (AUC[BG]) for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), and Humulin-R + rHuPH20 following a liquid meal is reported. AUC(BG) values are reported for participants whose blood glucose (BG) was elevated higher than 160 milligrams per deciliter (mg/dL) or 140 mg/dL, or lower than 70 mg/dL within 4 hours of consuming a liquid meal. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug. Least squares mean difference was calculated and tested using repeated measures analysis of variance with fixed effect for treatment.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable area under the time-concentration curve for blood glucose (AUC[BG]) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
AUC(BG) >160 mg/dL	2017.46 (2811.82)	722.82 (1030.52)	2509.65 (3332.36)
AUC(BG) >140 mg/dL	4233.71 (4383.35)	2696.54 (2548.03)	4905.92 (4829.71)
AUC(BG) <70 mg/dL	571.20 (850.07)	197.00 (480.75)	408.50 (602.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	Participants with blood glucose (BG) >160 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	Participants with blood glucose (BG) >160 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	Participants with blood glucose (BG) >160 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	Participants with blood glucose (BG) >140 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.099
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	Participants with blood glucose (BG) >140 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	Participants with blood glucose (BG) >140 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	Participants with blood glucose (BG) <70 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	Participants with blood glucose (BG) <70 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	Participants with blood glucose (BG) <70 milligrams per deciliter (mg/dL)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

9. Secondary Outcome

Title	Minimum Postprandial Glucose (PPG)
Description	Minimum postprandial glucose (PPG) in participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 following a liquid meal is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable minimum postprandial glucose (PPG) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Mean (Standard Deviation) [Milligrams per deciliter (mg/dL)]	76.38 (22.58)	88.52 (27.37)	75.62 (20.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8800
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

10. Secondary Outcome

Title	Percentage of Participants Without Hypoglycemia
Description	Percentage of participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 who did not experience hypoglycemia following a liquid meal is reported. Hypoglycemia was defined as any blood glucose values lower than 70 milligrams per deciliter (mg/dL) or symptoms of hypoglycemia responding to treatment with glucose. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes after study drug injection

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humulin-R + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humulin-R + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Number [Percentage of participants]	81.0 352.2%	71.4 NaN	71.4 NaN

11. Secondary Outcome

Title	Time to Percentage of Insulin Exposure (as Measured by Area Under the Curve [AUC])
Description	Time to percentage of exposure to insulin, as measured by area under the curve (AUC), following a liquid meal for participants who received Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 is reported. Blood samples were collected at 30, 20, 10, and within 5 minutes before and at 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of each study drug.
Time Frame	Predose up to 480 minutes following after injection of study drug

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of Humalog alone, Humalog + recombinant human hyaluronidase PH20 (rHuPH20), or Humulin-R + rHuPH20 with evaluable time to percentage of insulin exposure as measured by area under the curve (AUC) data.

Arm/Group Title	Humalog Alone	Humalog + rHuPH20	Humulin-R + rHuPH20
Arm/Group Description	Humalog alone: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)	Humalog + rHuPH20: A single, subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20)
Measure Participants	21	21	21
Time to 10% Insulin Exposure	46.05 (8.98)	30.49 (7.13)	43.41 (10.21)
Time to 50% Insulin Exposure	135.73 (21.18)	94.49 (20.06)	137.52 (27.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	Analysis for 10% of exposure (area under the curve [AUC])
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	Analysis for 10% of exposure (area under the curve [AUC])
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1800
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	Analysis for 10% of exposure (area under the curve [AUC])
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humalog + rHuPH20
	Comments	Analysis for 50% of exposure (area under the curve [AUC])
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison for Humalog alone and Humalog + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Humalog Alone, Humulin-R + rHuPH20
	Comments	Analysis for 50% of exposure (area under the curve [AUC])
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7200
	Comments	Treatment comparison of Humalog alone and Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20).
	Method	Repeated Measures Analysis of Variance
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Humalog + rHuPH20, Humulin-R + rHuPH20
	Comments	Analysis for 50% of exposure (area under the curve [AUC])
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Treatment comparison of Humalog + recombinant human hyaluronidase PH20 (rHuPH20) and Humulin-R + rHuPH20.
	Method	Repeated Measures Analysis of Variance
	Comments

Adverse Events

Adverse Event Reporting Description	Adverse events were classified by the body system affected.
Arm/Group Title	Humalog Alone		Humalog + rHuPH20		Humulin-R + rHuPH20
Arm/Group Description	Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog alone for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout period), followed by a SC injection of the appropriate dose of Humalog during Periods 1, 2, or 3 of the study.		Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humalog + 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humalog + rHuPH20 during Periods 1, 2, or 3 of the study.		Participants who received a subcutaneous (SC) injection of 0.3- to 0.5-units per kilogram (U/kg) of Humulin-R + 3.75 nanograms per kilogram (ng/kg) of recombinant human hyaluronidase PH20 (rHuPH20) for up to 3 dose-finding (DF) visits (each visit separated by a 3- to 14-day washout), followed by a single SC injection of the appropriate dose of Humulin-R + rHuPH20 during Periods 1, 2, or 3 of the Study
All Cause Mortality
	Humalog Alone		Humalog + rHuPH20		Humulin-R + rHuPH20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Humalog Alone		Humalog + rHuPH20		Humulin-R + rHuPH20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		1/22 (4.5%)		0/22 (0%)
Infections and infestations
Urosepsis	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Pyelonephritis acute	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Renal colic	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Ureteric obstruction	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Other (Not Including Serious) Adverse Events
	Humalog Alone		Humalog + rHuPH20		Humulin-R + rHuPH20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/22 (50%)		5/22 (22.7%)		10/22 (45.5%)
Gastrointestinal disorders
Nausea	2/22 (9.1%)	2	1/22 (4.5%)	1	1/22 (4.5%)	1
Diarrhoea	1/22 (4.5%)	1	1/22 (4.5%)	1	0/22 (0%)	0
Abdominal pain	1/22 (4.5%)	1	1/22 (4.5%)	1	0/22 (0%)	0
Abdominal pain upper	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Vomiting	1/22 (4.5%)	1	0/22 (0%)	0	1/22 (4.5%)	1
General disorders
Injection site pain	0/22 (0%)	0	1/22 (4.5%)	1	1/22 (4.5%)	1
Injection site erythema	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Induration	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Asthenia	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Pyrexia	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Infections and infestations
Influenza	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Rhinitis	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Nasopharyngitis	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Oral herpes	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Upper respiratory tract infection	0/22 (0%)	0	0/22 (0%)	0	2/22 (9.1%)	2
Injury, poisoning and procedural complications
Limb injury	0/22 (0%)	0	1/22 (4.5%)	2	0/22 (0%)	0
Skin laceration	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Nodule on extremity	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Coccydynia	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Pain in extremity	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Nervous system disorders
Headache	3/22 (13.6%)	4	0/22 (0%)	0	2/22 (9.1%)	4
Dizziness	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Skin and subcutaneous tissue disorders
Erythema	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Surgical and medical procedures
Tooth extraction	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.