Clinical trial NCT02595996: Propranolol Dose Escalation in Lymphedema in Patients
Official title: An Intra-patient Dose Escalation Study of Propranolol in Patients With Lymphedema
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Primary Lymphedema
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2015-11-04
Enrollment: 1
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Number of Patients That Tolerated Propranolol
timeFrame: 8 weeks
Secondary outcomes:
measure: Number of Patients With Improved Quality of Life Based on Self-reported Questionnaires
timeFrame: 8 weeks
measure: Number of Patients With Decreased Fluid Retention by Weight
timeFrame: 8 weeks
measure: Number of Patients With Lower Limb Discrepancy
timeFrame: 8 weeks
measure: Number of Patients With Decreased Fluid Retention on MRI
timeFrame: baseline to 8 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University
state: New York
Study officials:
affiliation: Columbia University
name: June K. Wu, MD
role: PRINCIPAL_INVESTIGATOR
References: