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Efficacy, Safety and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma (IH) (TIM01)

Primary Purpose

Infantile Hemangioma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
0.25% Timolol Maleate Gel Forming Solution
0.5% Timolol Maleate Gel Forming Solution
Sponsored by
Kanecia Obie Zimmerman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infantile Hemangioma focused on measuring Hemangioma, Infantile Hemangioma, Pharmacokinetics

Eligibility Criteria

undefined - 84 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  1. Documented informed consent from legal guardian
  2. 0-84 days postnatal age at time of first study dose or when enrolled into the non-intervention cohort.

  3. Clinical diagnosis of superficial cutaneous or mucosal infantile hemangioma (must include all of the following):

    1. Superficial lesion in the dermis
    2. Thin <2 mm in thickness
    3. Small >=5 cm at its longest dimension and <=10cm2
    4. Involves skin or keratinized mucosa

Exclusion Criteria

  1. History of previous treatment with any pharmacologic or laser therapy for IH
  2. Ongoing therapy with an oral beta blocker or oral corticosteroid (e.g., cardiac arrhythmia, adrenal insufficiency, upper airway obstruction, tetralogy of fallot (TOF), hypertension, reactive airways disease)
  3. IH that requires systemic therapy (defined by dynamic complication scale >3)
  4. IH of the non-keratinized mucosa
  5. Infants with more than one hemangioma that requires therapy
  6. Hemodynamically significant cardiovascular disease, as determined by the investigator
  7. Known allergy to beta blockers or vehicle
  8. Heart rate <100 beats per minute at screening visit
  9. Known prenatal or postnatal diagnosis of 2nd/3rd degree atrioventricular block
  10. History of Reactive Airways Disease (RAD)
  11. Any condition which would make the participant, in the opinion of the investigator unsuitable for the study.

Sites / Locations

  • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Indiana University Health
  • Johns Hopkins Medical Center
  • Boston Children's Hospital
  • Mayo Clinic
  • Dartmouth-Hitchcock Medical Center
  • Columbia University Medical Center
  • Cincinnati Children's Hospital Medical Center
  • Children's Hospital of Philadephia
  • The University of Texas Medical School at Houston
  • DCOL Center for Clinical Research
  • Medical College of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

No Intervention

Arm Label

0.25% Timolol Treatment

0.5% Timolol Treatment

Non-Intervention Group

Arm Description

Subjects assigned to this arm will be randomized to 0.25% timolol for 180 days. If during the 180 days the subject is considered a treatment failure, the subject will be unblinded. If the subject is on 0.25% timolol they will be changed to 0.5% timolol.

Subjects assigned to this arm will be randomized to 0.5% timolol for 180 days. If during the 180 days the subject is considered a treatment failure, the subject will be unblinded. If the subject is on 0.5% timolol the treating physician will decide to either continue 0.5% timolol or withdraw the subject and begin an alternative treatment.

Subjects assigned to this group will not receive treatment. The subject will only be photographed on the same schedule as the intervention group.

Outcomes

Primary Outcome Measures

Number of Participants With Partial Response of Hemangioma Volume as Measured by VAS (Visual Analog Scale) Within Each Treatment Arm and Compared With Untreated Controls
The VAS-volume is a 100 mm scale used to independently grade hemangioma volume. -100 indicates hemangioma has doubled in size, 0 indicates no change, and +100 indicates complete shrinkage. Partial response is defined as >20% and up to 80% reduction in volumetric size of hemangioma.

Secondary Outcome Measures

Number of Participants With Partial Response in Hemangioma Color as Measured by VAS (Visual Analog Scale) Within Each Treatment Arm and Compared With Untreated Controls
The VAS-color is a 100 mm scale used to independently grade hemangioma color. -100 indicates hemangioma is twice as intense, 0 indicates no change, and +100 indicates complete resolution. Partial response is defined as >30% and up to 80% reduction in color of hemangioma.
Number of Participants With Partial Response of Hemangioma Volume as Measured by VAS (Visual Analog Scale) Within Each Treatment Arm
The VAS-volume is a 100 mm scale used to independently grade hemangioma volume. -100 indicates hemangioma has doubled in size, 0 indicates no change, and +100 indicates complete shrinkage. Partial response is defined as >20% and up to 80% reduction in volumetric size of hemangioma.
Comparison of Partial Response of Hemangioma Color From Baseline to 180 Days, Within Each Treatment Arm
Comparison of partial response of hemangioma color (partial response or greater as assessed by VAS-color) between the two treatment arms. Partial response: >30% and up to 80% reduction in color of hemangioma.
Change in Hemangioma Dynamic Complication Scale (HDCS)
Absolute change in hemangioma dynamic complication scale from Day 0 to end of study within each treatment arm. The HDCS provides a 6-point severity grading system for 12 individual hemangioma-related complications (grade 0 represents absent to minimal; grade 5 = most severe). The total score ranges from 0-60.
Number of Participants Who Reach Partial Response, Assessed by Volume
Assess time to partial response or greater by VAS-volume, comparing baseline to day 30, day 60, day 120 and day 180. Partial response: >20% and up to 80% reduction in volumetric size of hemangioma
Number of Participants Who Reach Partial Response, Assessed by Hemangioma Color
Assess time to partial response or greater by VAS-color, comparing baseline to day 30, day 60, day 120 and day 180. Partial response: >30% and up to 80% reduction in color of hemangioma
Change in Hemangioma Quality of Life (IH-QoL) Assessment for Infants
Absolute change in IH-QoL score scale from Day 0 to end of study within each treatment arm. The IH-QoL score scale consists of 4 domains (physical symptom of patient, social functioning of patient, social and psychological functioning of caregiver, and emotional functioning of caregiver) and 29 items, with each item scored on a Likert scale : 0 = never a problem, 1 = almost never a problem, 2 = sometimes a problem, 3 = often a problem and 4 = almost always a problem). The total range is 0-116; the higher the total number indicates a worse outcome.
Number of Serious Adverse Events and Adverse Events of Special Interest in Infants Treated With Topical Timolol Maleate
Serious adverse events and adverse events of special interest from randomization to Day 180 in infants treated with topical timolol maleate (0.25% and 0.5%) GFS for the treatment of infantile hemangioma.

Full Information

First Posted
August 12, 2016
Last Updated
December 16, 2022
Sponsor
Kanecia Obie Zimmerman
Collaborators
The Emmes Company, LLC, National Institutes of Health (NIH)
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1. Study Identification

Unique Protocol Identification Number
NCT02913612
Brief Title
Efficacy, Safety and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma (IH)
Acronym
TIM01
Official Title
Efficacy, Safety, and Pharmacokinetics of Timolol in Infants With Infantile Hemangioma (IH)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
May 5, 2017 (Actual)
Primary Completion Date
October 20, 2020 (Actual)
Study Completion Date
October 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Kanecia Obie Zimmerman
Collaborators
The Emmes Company, LLC, National Institutes of Health (NIH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess the safety and efficacy of Timolol 0.25% and 0.5% doses.
Detailed Description
Primary: Describe the efficacy of 0.25% and 0.5% topical timolol maleate Gel-forming solution (GFS) as assessed through Infantile Hemangioma (IH) changes in volume. Secondary: Describe the safety of topical timolol maleate GFS for treatment of IH.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infantile Hemangioma
Keywords
Hemangioma, Infantile Hemangioma, Pharmacokinetics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
105 (Actual)

8. Arms, Groups, and Interventions

Arm Title
0.25% Timolol Treatment
Arm Type
Experimental
Arm Description
Subjects assigned to this arm will be randomized to 0.25% timolol for 180 days. If during the 180 days the subject is considered a treatment failure, the subject will be unblinded. If the subject is on 0.25% timolol they will be changed to 0.5% timolol.
Arm Title
0.5% Timolol Treatment
Arm Type
Experimental
Arm Description
Subjects assigned to this arm will be randomized to 0.5% timolol for 180 days. If during the 180 days the subject is considered a treatment failure, the subject will be unblinded. If the subject is on 0.5% timolol the treating physician will decide to either continue 0.5% timolol or withdraw the subject and begin an alternative treatment.
Arm Title
Non-Intervention Group
Arm Type
No Intervention
Arm Description
Subjects assigned to this group will not receive treatment. The subject will only be photographed on the same schedule as the intervention group.
Intervention Type
Drug
Intervention Name(s)
0.25% Timolol Maleate Gel Forming Solution
Intervention Description
50:50 Randomized 0.25% Timolol Maleate Gel Forming Solution
Intervention Type
Drug
Intervention Name(s)
0.5% Timolol Maleate Gel Forming Solution
Intervention Description
50:50 Randomized 0.5% Timolol Maleate Gel Forming Solution
Primary Outcome Measure Information:
Title
Number of Participants With Partial Response of Hemangioma Volume as Measured by VAS (Visual Analog Scale) Within Each Treatment Arm and Compared With Untreated Controls
Description
The VAS-volume is a 100 mm scale used to independently grade hemangioma volume. -100 indicates hemangioma has doubled in size, 0 indicates no change, and +100 indicates complete shrinkage. Partial response is defined as >20% and up to 80% reduction in volumetric size of hemangioma.
Time Frame
180 days
Secondary Outcome Measure Information:
Title
Number of Participants With Partial Response in Hemangioma Color as Measured by VAS (Visual Analog Scale) Within Each Treatment Arm and Compared With Untreated Controls
Description
The VAS-color is a 100 mm scale used to independently grade hemangioma color. -100 indicates hemangioma is twice as intense, 0 indicates no change, and +100 indicates complete resolution. Partial response is defined as >30% and up to 80% reduction in color of hemangioma.
Time Frame
180 days
Title
Number of Participants With Partial Response of Hemangioma Volume as Measured by VAS (Visual Analog Scale) Within Each Treatment Arm
Description
The VAS-volume is a 100 mm scale used to independently grade hemangioma volume. -100 indicates hemangioma has doubled in size, 0 indicates no change, and +100 indicates complete shrinkage. Partial response is defined as >20% and up to 80% reduction in volumetric size of hemangioma.
Time Frame
180 days
Title
Comparison of Partial Response of Hemangioma Color From Baseline to 180 Days, Within Each Treatment Arm
Description
Comparison of partial response of hemangioma color (partial response or greater as assessed by VAS-color) between the two treatment arms. Partial response: >30% and up to 80% reduction in color of hemangioma.
Time Frame
180 days
Title
Change in Hemangioma Dynamic Complication Scale (HDCS)
Description
Absolute change in hemangioma dynamic complication scale from Day 0 to end of study within each treatment arm. The HDCS provides a 6-point severity grading system for 12 individual hemangioma-related complications (grade 0 represents absent to minimal; grade 5 = most severe). The total score ranges from 0-60.
Time Frame
baseline, day 180
Title
Number of Participants Who Reach Partial Response, Assessed by Volume
Description
Assess time to partial response or greater by VAS-volume, comparing baseline to day 30, day 60, day 120 and day 180. Partial response: >20% and up to 80% reduction in volumetric size of hemangioma
Time Frame
30 days, 60 days, 120 days, 180 days
Title
Number of Participants Who Reach Partial Response, Assessed by Hemangioma Color
Description
Assess time to partial response or greater by VAS-color, comparing baseline to day 30, day 60, day 120 and day 180. Partial response: >30% and up to 80% reduction in color of hemangioma
Time Frame
180 days
Title
Change in Hemangioma Quality of Life (IH-QoL) Assessment for Infants
Description
Absolute change in IH-QoL score scale from Day 0 to end of study within each treatment arm. The IH-QoL score scale consists of 4 domains (physical symptom of patient, social functioning of patient, social and psychological functioning of caregiver, and emotional functioning of caregiver) and 29 items, with each item scored on a Likert scale : 0 = never a problem, 1 = almost never a problem, 2 = sometimes a problem, 3 = often a problem and 4 = almost always a problem). The total range is 0-116; the higher the total number indicates a worse outcome.
Time Frame
baseline, day 180
Title
Number of Serious Adverse Events and Adverse Events of Special Interest in Infants Treated With Topical Timolol Maleate
Description
Serious adverse events and adverse events of special interest from randomization to Day 180 in infants treated with topical timolol maleate (0.25% and 0.5%) GFS for the treatment of infantile hemangioma.
Time Frame
up to 270 days
Other Pre-specified Outcome Measures:
Title
Pharmacokinetics (PK) Analysis Measuring Maximum Concentration of Timolol in Plasma Specimen
Description
The PK blood samples will be 1.0 ml each and collected between the following timeframes after application of Timolol: within 2 hours, 2-4 hours, 5-7 hours, 8-10 hours or 11-12 hours.
Time Frame
Up to 12 hours
Title
Pharmacokinetics (PK) Analysis Measuring Area Under the Curve of Timolol in Plasma Specimen
Description
The PK blood samples will be 1.0 ml each and collected between the following timeframes after application of Timolol: within 2 hours, 2-4 hours, 5-7 hours, 8-10 hours or 11-12 hours.
Time Frame
Up to 12 hours
Title
Pharmacokinetics (PK) Analysis Measuring Volume of Distribution of Timolol in Plasma Specimen
Description
The PK blood samples will be 1.0 ml each and collected between the following timeframes after application of Timolol: within 2 hours, 2-4 hours, 5-7 hours, 8-10 hours or 11-12 hours.
Time Frame
Up to 12 hours
Title
Pharmacokinetics (PK) Analysis Measuring Clearance of Timolol in Plasma Specimen
Description
The PK blood samples will be 1.0 ml each and collected between the following timeframes after application of Timolol: within 2 hours, 2-4 hours, 5-7 hours, 8-10 hours or 11-12 hours.
Time Frame
Up to 12 hours

10. Eligibility

Sex
All
Maximum Age & Unit of Time
84 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Documented informed consent from legal guardian 0-84 days postnatal age at time of first study dose or when enrolled into the non-intervention cohort. Clinical diagnosis of superficial cutaneous or mucosal infantile hemangioma (must include all of the following): Superficial lesion in the dermis Thin <2 mm in thickness Small >=5 cm at its longest dimension and <=10cm2 Involves skin or keratinized mucosa Exclusion Criteria History of previous treatment with any pharmacologic or laser therapy for IH Ongoing therapy with an oral beta blocker or oral corticosteroid (e.g., cardiac arrhythmia, adrenal insufficiency, upper airway obstruction, tetralogy of fallot (TOF), hypertension, reactive airways disease) IH that requires systemic therapy (defined by dynamic complication scale >3) IH of the non-keratinized mucosa Infants with more than one hemangioma that requires therapy Hemodynamically significant cardiovascular disease, as determined by the investigator Known allergy to beta blockers or vehicle Heart rate <100 beats per minute at screening visit Known prenatal or postnatal diagnosis of 2nd/3rd degree atrioventricular block History of Reactive Airways Disease (RAD) Any condition which would make the participant, in the opinion of the investigator unsuitable for the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kanecia Zimmerman, MD, MHS
Organizational Affiliation
Duke Clinical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kristin Holland, MD
Organizational Affiliation
Medical College of Wisconsin
Official's Role
Study Chair
Facility Information:
Facility Name
Ann and Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana University Health
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Johns Hopkins Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Dartmouth-Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadephia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
The University of Texas Medical School at Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
DCOL Center for Clinical Research
City
Longview
State/Province
Texas
ZIP/Postal Code
75605
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Efficacy, Safety and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma (IH)

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