Evaluation of the Allergenicity of AMPHADASE INJECTION (Hyaluronidase Injection USP) (H001-A2)

A Randomized, Double-Blinded, Negative- and Positive-Controlled Study for Evaluation of the Allergenicity of Amphadase® in Healthy Volunteers Using Intradermal Skin Test

This study is designed to evaluate the allergenicity of Amphadase® in healthy volunteers using an intradermal skin test.

Study Overview

• Status: Completed
• Conditions: Allergic Skin Reaction
• Intervention / Treatment: Drug: Hyaluronidase; Drug: Histamine; Drug: Saline

• Study Type: Interventional
• Enrollment (Actual): 253
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Amphastar Site 0022
    • Lake Oswego, Oregon, United States, 97035
      • Amphastar Site 0023
    • Portland, Oregon, United States, 97202
      • Amphastar Site 0026
  • Washington
    • Renton, Washington, United States, 98057
      • Amphastar Site 0038
    • Seattle, Washington, United States, 98115
      • Amphastar Site 0034

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Healthy volunteers of either gender; Those without clinically significant cardiovascular gastrointestinal, hepatic, neurological, psychiatric, endocrine, or other major systemic disease that would unduly risk the subject's safety or interfere with the interpretation of results, assessed according to the judgment of the Principal Investigator. A non-inclusive list which would not be exclusionary and define healthy individual for the purposes of this study are:

• hypothyroidism,
• stable hypertension except those subjects on beta blockers including ocular preparations,
• seasonal/perennial allergic rhinitis if able to wash out of antihistamines,
• stable, mild intermittent asthma (subjects using beta agonists as a monotherapy on an as-needed basis, excluding daily usage),
• migraine if not taking excluded medications,
• mild anxiety/depression if not taking excluded medications, and

• mild arthritic conditions if not taking excluded medications.

  • Willingness and ability to sign an informed consent document;
  • 18 - 80 years of age;
  • Intact skin at the forearm ;
  • Female participants are currently practicing effective birth control methods or abstinence.

Exclusion Criteria:

• Known allergy, hypersensitivity or contraindications to hyaluronidase, thimerosal, edetate disodium (EDTA);
• Use of medications within a duration considered to interfere with skin testing.
• Known dermographism which may interfere with skin testing.
• Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm H; Intradermal injection of Amphadase (hyaluronidase 150 USP units/mL)	Drug: Hyaluronidase; Subjects received intradermal injections of 0.02 mL Amphadase® (hyaluronidase 150 USP units/mL) at two random sites on their forearms.; Other Names: Amphadase®
Active Comparator: Arm P; Intradermal injection of Histatrol (histamine base 0.1 mg/mL)	Drug: Histamine; Subjects received one intradermal injection of 0.02 mL Histatrol® (histamine base 0.1 mg/mL) at one random sites on their forearms.; Other Names: Histatrol®
Placebo Comparator: Arm N; Intradermal injection of saline (0.02 mL)	Drug: Saline; Subjects received one intradermal injection of 0.02 mL saline at one random site on their forearm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive Allergic Reaction to Amphadase® in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. A positive reaction consisted of: a) reaction appearing within 30 minutes of drug placement; b) wheal (>8 mm) with or without pseudopods; c) reaction accompanying erythema; and d) reaction accompanying localized itching.	Up to 30 minutes after the final study drug injection
Positive Allergic Reaction to Amphadase® in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. A positive reaction consisted of: a) reaction appearing within 30 minutes of drug placement; b) wheal (>8 mm) with or without pseudopods; c) reaction accompanying erythema; and d) reaction accompanying localized itching.	Up to 30 minutes after the final study drug injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Observed Wheal Size in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The observed wheal size is the greatest wheal diameter measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Observed Erythema Size in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The observed erythema size is the greatest erythema diameter measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Allergic Wheal Size in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The allergic wheal size is the greatest wheal diameter with accompanying erythema and localized itching measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Allergic Erythema Size in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The allergic erythema size is the greatest erythema diameter with accompanying localized itching measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Local Itchiness Rate in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The local itchiness rate is the percentage of subjects that reported localized itching at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Erythema Responder Rate in the Per-Protocol Population (PPP)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The erythema responder rate is the percentage of subjects that showed an erythema reaction at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Observed Wheal Size in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The observed wheal size is the greatest wheal diameter measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Observed Erythema Size in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The observed erythema size is the greatest erythema diameter measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Allergic Erythema Size in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The allergic erythema size is the greatest erythema diameter with accompanying localized itching measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Local Itchiness Rate in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The local itchiness rate is the percentage of subjects that reported localized itching at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Erythema Responder Rate in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The erythema responder rate is the percentage of subjects that showed an erythema reaction at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection
Allergic Wheal Size in the Intent-to-Treat Population (ITT)	Subjects received intradermal injections at 4 injection sites following a randomized configuration of study medications. Injection sites were monitored for any characteristic immediate reactions after the study drug injections. The allergic wheal size is the greatest wheal diameter with accompanying erythema and localized itching measured at the injection site(s) for a specific study drug injection.	Up to 30 minutes after the final study drug injection

Collaborators and Investigators

• Sponsor: Amphastar Pharmaceuticals, Inc.
• Investigators: Study Chair: Selina Su, MPH, A:mphastar Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Barr J, Kirkpatrick N, Dick A, Leonard L, Hawksworth G, Noble DW. Effects of adrenaline and hyaluronidase on plasma concentrations of lignocaine and bupivacaine after peribulbar anaesthesia. Br J Anaesth. 1995 Dec;75(6):692-7. doi: 10.1093/bja/75.6.692.
• Brydon CW, Basler M, Kerr WJ. An evaluation of two concentrations of hyaluronidase for supplementation of peribulbar anaesthesia. Anaesthesia. 1995 Nov;50(11):998-1000. doi: 10.1111/j.1365-2044.1995.tb05940.x.
• Ahluwalia HS, Lukaris A, Lane CM. Delayed allergic reaction to hyaluronidase: a rare sequel to cataract surgery. Eye (Lond). 2003 Mar;17(2):263-6. doi: 10.1038/sj.eye.6700243. No abstract available.
• Agrawal A, McLure HA, Dabbs TR. Allergic reaction to hyaluronidase after a peribulbar injection. Anaesthesia. 2003 May;58(5):493-4. doi: 10.1046/j.1365-2044.2003.03154_17.x. No abstract available.
• Kempeneers A, Dralands L, Ceuppens J. Hyaluronidase induced orbital pseudotumor as complication of retrobulbar anesthesia. Bull Soc Belge Ophtalmol. 1992;243:159-66.
• Minning CA Jr. Hyaluronidase allergy simulating expulsive choroidal hemorrhage. Arch Ophthalmol. 1994 May;112(5):585-6. doi: 10.1001/archopht.1994.01090170029012. No abstract available.
• Szepfalusi Z, Nentwich I, Dobner M, Pillwein K, Urbanek R. IgE-mediated allergic reaction to hyaluronidase in paediatric oncological patients. Eur J Pediatr. 1997 Mar;156(3):199-203. doi: 10.1007/s004310050582.
• Allergy testing. American College of Physicians. Ann Intern Med. 1989 Feb 15;110(4):317-20. No abstract available.
• Poulsen LK. In vivo and in vitro techniques to determine the biological activity of food allergens. J Chromatogr B Biomed Sci Appl. 2001 May 25;756(1-2):41-55. doi: 10.1016/s0378-4347(01)00070-6.
• Howard A, Mercer P, Nataraj HC, Kang BC. Bevel-down superior to bevel-up in intradermal skin testing. Ann Allergy Asthma Immunol. 1997 Jun;78(6):594-6. doi: 10.1016/s1081-1206(10)63222-x.
• Barbaud A, Reichert-Penetrat S, Trechot P, Jacquin-Petit MA, Ehlinger A, Noirez V, Faure GC, Schmutz JL, Bene MC. The use of skin testing in the investigation of cutaneous adverse drug reactions. Br J Dermatol. 1998 Jul;139(1):49-58. doi: 10.1046/j.1365-2133.1998.02313.x.
• Fisher MM, Bowey CJ. Intradermal compared with prick testing in the diagnosis of anaesthetic allergy. Br J Anaesth. 1997 Jul;79(1):59-63. doi: 10.1093/bja/79.1.59.
• Ruzicka T, Gerstmeier M, Przybilla B, Ring J. Allergy to local anesthetics: comparison of patch test with prick and intradermal test results. J Am Acad Dermatol. 1987 Jun;16(6):1202-8. doi: 10.1016/s0190-9622(87)70158-3.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: September 13, 2012
• First Submitted That Met QC Criteria: September 17, 2012
• First Posted (Estimate): September 21, 2012

Study Record Updates

• Last Update Posted (Estimate): January 20, 2017
• Last Update Submitted That Met QC Criteria: January 18, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: hyaluronidase; enzymes with tissue spreading activity; allergic reaction; intradermal skin testing
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Histamine Agents; Histamine Agonists; Histamine
• Other Study ID Numbers: API-H001-CLN-A2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No