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Propranolol Dose Escalation in Lymphedema in Patients

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ClinicalTrials.gov Identifier: NCT02595996
Recruitment Status : Recruiting
First Posted : November 4, 2015
Last Update Posted : July 21, 2017
Sponsor:
Information provided by (Responsible Party):
June Wu, Columbia University

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
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 : June 7, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


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 Name: Inderal




Primary Outcome Measures :
  1. Number of patients that tolerated propranolol [ Time Frame: 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 [ 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)

  2. 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

  3. 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

  4. 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.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02595996


Contacts
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Contact: June K. Wu, MD 212-342-3704 jw92@cumc.columbia.edu
Contact: Roman Nowygrod, MD 212-305-5374 rn5@cumc.columbia.edu

Locations
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United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: June Wu, MD       jw92@cumc.columbia.edu   
Principal Investigator: June Wu, MD         
Sponsors and Collaborators
Columbia University
Investigators
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Principal Investigator: June K. Wu, MD Columbia University

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Responsible Party: June Wu, Assistant Professor of Surgery, Columbia University
ClinicalTrials.gov Identifier: NCT02595996     History of Changes
Other Study ID Numbers: AAAP9262
First Posted: November 4, 2015    Key Record Dates
Last Update Posted: July 21, 2017
Last Verified: July 2017

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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:
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Propranolol
Lymphedema
Lymphatic Diseases
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents