Propranolol Dose Escalation in Lymphedema in Patients

• Sponsor: Columbia University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02595996
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Actual Duration (Months): 40
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a study to investigate the safety and efficacy of propranolol in the treatment of patients with primary lymphedema. The primary goal is to assess patient tolerability of increasing doses of propranolol. The secondary goal is to assess lymphedema symptoms and signs in response to propranolol treatment.

Condition or Disease	Intervention/Treatment	Phase
Primary Lymphedema	Drug: Propranolol	Phase 2

Detailed Description

Lymphatic malformations (LMs) arise from abnormal development of lymphatic vasculature. Primary lymphedema is considered a form of LM. Recently, results in the investigators' laboratory demonstrated that propranolol, a pan beta-adrenergic receptor (βAR) antagonist, had cytotoxic and anti-proliferative effects against cells isolated from LM tissues. Preliminary results from treating symptomatic LM patients with propranolol at a dose range from 0.7-1mg/kg/day demonstrated a 70% positive response rate, with patients reporting improvement in their symptoms.

Propranolol has been used for different indications for many years. Propranolol is accepted for use in infants with hemangiomas and supraventricular tachycardia. Hemangeol was approved by the FDA for use in infants with hemangiomas. However, βAR antagonists are not without potential adverse effects, including hypotension, bradycardia, hypoglycemia, bronchospasms, and sleep disturbances. FDA-approved dose range for treating hemangiomas in infants (>5 weeks old, >2kg) ranged from 1-3mg/kg/day in divided doses. Propranolol doses of up to 4mg/kg/day has been used for pediatric supraventricular tachycardia. Therefore, the investigator's experience with propranolol use in LM patients have been at the low end of most accepted clinical indications. The investigators propose to escalate propranolol dosages up to 3mg/kg/day in this study, well below the dose ranges currently used in clinical settings.

This dose range of 0.7-1mg/kg/day was chosen for LM patients as it was the low end of dose range for infants treated with propranolol for problematic hemangiomas, a related vascular anomaly. At this dose, no significant hemodynamic adverse effects were noted in LM patients. However, when patients stopped propranolol or their dose fell below 0.7mg/kg/day, they suffered rebound worsening of their symptoms. Moreover, inflammatory events such as infections temporarily overcame the effects of 0.7-1mg/kg/day of propranolol. Thus, it is unknown whether maximum propranolol efficacy was achieved at the current dose range. The investigators propose to examine whether optimized propranolol usage for treatment of LM patients has been achieved. The primary endpoint for this study is to ascertain whether LM patients can tolerate higher doses of propranolol, as measured by known propranolol adverse effects and patient-reported symptoms. A secondary endpoint will address whether patient-reported LM symptoms and quality of life are improved with higher doses of propranolol; objective findings such as LM size on physical examination and imaging studies will be analyzed as well. In addition, LM tissue biopsies will acquired from patients before and after propranolol treatment for further analyses of disease progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Intra-patient Dose Escalation Study of Propranolol in Patients With Lymphedema
• Actual Study Start Date: Jun 7, 2017
• Actual Primary Completion Date: Oct 8, 2020
• Actual Study Completion Date: Oct 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Patients will be given propranolol in escalating doses	Drug: Propranolol; escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day; Other Names: Inderal

Outcome Measures

Primary Outcome Measures

1. Number of Patients That Tolerated Propranolol [8 weeks]

   To assess whether patients tolerated propranolol

Secondary Outcome Measures

1. Number of Patients With Improved Quality of Life Based on Self-reported Questionnaires [8 weeks]

   To assess subjective lymphedema symptoms improvements only - whether patients' general quality of life symptoms improved on propranolol treatment by self-reported questionnaires (SF 36)

2. Number of Patients With Decreased Fluid Retention by Weight [8 weeks]

   To assess whether patients' lymphedema signs are improved on propranolol by weight (BMI kg/m^2) - objective signs of improvement of their lymphedema

3. Number of Patients With Lower Limb Discrepancy [8 weeks]

   To assess whether patients' lymphedema signs are improved on propranolol by limb girth discrepancy measurement (%) - objective signs of improvement of their lymphedema

4. Number of Patients With Decreased Fluid Retention on MRI [baseline to 8 weeks]

   To assess whether patients' lymphedema signs are improved on propranolol - the decrease in fluid retention will be calculated by the measurement of fat (a number) divide by the measurement of fluid (a number) to yield a ratio - if a patient has a lower ratio at 8 weeks than at baseline, they will be reported in this category.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Primary lymphedema

• Measurable disease

• Adequate functional status: Karnofsky >50% (>age 16), Lanky >50 (<age 16),

• No prior therapy within 4 weeks of enrollment

• Adequate bone marrow, renal function, cardiac, and pulmonary function, negative pregnancy test (for women).

Exclusion Criteria:

• Secondary lymphedema

• Patients already receiving other investigational drugs

• Patients with known contraindications to receiving propranolol

• Other medical comorbidities including but not limited to: pheochromocytoma, bradycardia, bronchospasm/reactive airway disease, decompensated heart failure, heart block, ongoing active infections.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Columbia University	New York	New York	United States	10032

Sponsors and Collaborators

• Columbia University

Investigators

• Principal Investigator: June K. Wu, MD, Columbia University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 22, 2018

More Information

Publications

None provided.

• Responsible Party: June Wu, Assistant Professor of Surgery, Columbia University
• ClinicalTrials.gov Identifier: NCT02595996
• Other Study ID Numbers: AAAP9262
• First Posted: Nov 4, 2015
• Last Update Posted: Oct 22, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Lymphedema; Propranolol

Study Results

Participant Flow

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Overall Participants	1
Age (Count of Participants)
<=18 years	1 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients That Tolerated Propranolol
Description	To assess whether patients tolerated propranolol
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Study terminated due to lack of funding. Data was not analyzed or disclosed due to subject confidentiality being an issue (n=1).

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Measure Participants	0

2. Secondary Outcome

Title	Number of Patients With Improved Quality of Life Based on Self-reported Questionnaires
Description	To assess subjective lymphedema symptoms improvements only - whether patients' general quality of life symptoms improved on propranolol treatment by self-reported questionnaires (SF 36)
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Study terminated due to lack of funding. Data was not analyzed or disclosed due to subject confidentiality being an issue (n=1).

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Measure Participants	0

3. Secondary Outcome

Title	Number of Patients With Decreased Fluid Retention by Weight
Description	To assess whether patients' lymphedema signs are improved on propranolol by weight (BMI kg/m^2) - objective signs of improvement of their lymphedema
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Study terminated due to lack of funding. Data was not analyzed or disclosed due to subject confidentiality being an issue (n=1).

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Measure Participants	0

4. Secondary Outcome

Title	Number of Patients With Lower Limb Discrepancy
Description	To assess whether patients' lymphedema signs are improved on propranolol by limb girth discrepancy measurement (%) - objective signs of improvement of their lymphedema
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Study terminated due to lack of funding. Data was not analyzed or disclosed due to subject confidentiality being an issue (n=1).

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Measure Participants	0

5. Secondary Outcome

Title	Number of Patients With Decreased Fluid Retention on MRI
Description	To assess whether patients' lymphedema signs are improved on propranolol - the decrease in fluid retention will be calculated by the measurement of fat (a number) divide by the measurement of fluid (a number) to yield a ratio - if a patient has a lower ratio at 8 weeks than at baseline, they will be reported in this category.
Time Frame	baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

Study terminated due to lack of funding. Data was not analyzed or disclosed due to subject confidentiality being an issue (n=1).

Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Measure Participants	0

Adverse Events

Time Frame	Up to 8 weeks
Arm/Group Title	Treatment
Arm/Group Description	Patients will be given propranolol in escalating doses Propranolol: escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
All Cause Mortality
	Treatment
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	0/1 (0%)

Limitations/Caveats

Study terminated due to lack of funding. Data was not analyzed or disclosed due to subject confidentiality being an issue (n=1).

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.