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Propranolol Dose Escalation in Lymphedema in Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02595996
Recruitment Status : Terminated (Lack of funding)
First Posted : November 4, 2015
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
June Wu, Columbia University

Tracking Information
First Submitted Date  ICMJE September 18, 2015
First Posted Date  ICMJE November 4, 2015
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE June 7, 2017
Actual Primary Completion Date October 8, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2015)
Number of patients that tolerated propranolol [ Time Frame: 8 weeks ]
To assess whether patients tolerated propranolol
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2015)
  • Number of patients with improved quality of life based on self-reported questionnaires [ Time Frame: 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)
  • Number of patients with decreased fluid retention by weight [ Time Frame: 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
  • Number of patients with lower limb discrepancy [ Time Frame: 8 weeks ]
    To assess whether patients' lymphedema signs are improved on propranolol by limb girth discrepancy measurement (%) - objective signs of improvement of their lymphedema
  • Number of patients with decreased fluid retention on MRI [ Time Frame: 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 catergory.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Propranolol Dose Escalation in Lymphedema in Patients
Official Title  ICMJE An Intra-patient Dose Escalation Study of Propranolol in Patients With Lymphedema
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Primary Lymphedema
Intervention  ICMJE Drug: Propranolol
escalating doses of propranolol from 1mg/kg/day to 2mg/kg/day to 3mg/kg/day
Other Name: Inderal
Study Arms  ICMJE Experimental: Treatment
Patients will be given propranolol in escalating doses
Intervention: Drug: Propranolol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 14, 2020)
1
Original Estimated Enrollment  ICMJE
 (submitted: November 2, 2015)
20
Actual Study Completion Date  ICMJE October 8, 2020
Actual Primary Completion Date October 8, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02595996
Other Study ID Numbers  ICMJE AAAP9262
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party June Wu, Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: June K. Wu, MD Columbia University
PRS Account Columbia University
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP