Futility and underpowering of endpoint data

The treatment of lymphedema has been a major focus of attention for physicians and scientists for several decades. At this time, no successful techniques have been developed to prevent lymphedema, and therefore, a great deal of emphasis is placed on treatment modalities that can lessen the severity and impede the progression of this debilitating condition.

The treatment on offer usually consists of a maintenance phase using compression garments and an intensive treatment phase, which includes the use of skin care, compression bandaging, exercise and manual lymphatic drainage (MLD). The intensive phase is usually described as complex decongestive therapy (CDT). This is time consuming and requires high resource usage. Pneumatic compression devices (PCD) offer and alternative to MLD and can be used by the patient. There are a number of devices on the market that are categorized into 1. without calibrated gradient compression 2. With calibrated gradient compression.

This trial will compare two PCDs, a simple device without calibrated compression, and an advanced device with calibrated compression, in the reduction of swelling and maintenance of reduced limb volume in 262 patients with lower limb lymphoedema. The primary end point will be limb volume reduction over 12 weeks of treatment, with secondary outcome after 24 weeks.

This is a Multicentre, prospective, single (assessor) blind randomised study. The primary objective of the study is to assess volume reduction in the treatment of lymphoedematous legs with an advanced PCD compared to a simple PCD in patients with lower limb lymphoedema. The main outcome is the percentage volume reduction of the affected limb at end of treatment compared to baseline.

Secondary objectives of the study are Assessment of safety Quality of life Health economic parameters

In total 262 patients with leg lymphoedema will be enrolled into the study. Patients eligible for the study are those who suffer from late stage II and stage III according to the International Society of Lymphology lymphoedema staging. Lymphoedematous legs can be of primary or secondary origin and uni or bilaterally affected. Medical history will be taken at baseline.

Patients will be taught how to use the device they have been randomised to. Visits will then take place at weeks 1,4,8,12 and 24 weeks. The device will be used for up to 60 minutes each day on the trial limb. At each visit sequential circumferences of the affected and unaffected limbs will be measured with a tape measure.

All adverse events will be documented. At beginning and end of study quality of life questionnaires and health economic information will be completed by the patients.

At the Derby site assessment of tissue quality will be made using ultrasound and moisture meter to assess tissue fluid.

Inclusion Criteria:

• Subjects must be ≥ 18 years old or legal age in host country.
• Subjects must have a diagnosis of primary or secondary late Stage 2 or 3 unilateral or bilateral lower extremity lymphoedema.
• At time of initial evaluation, individuals must be at least 3 months post-surgery, chemotherapy and/or radiation treatment for cancer if applicable.
• If subjects were treated in a clinic setting for lymphoedema (Phase 1 treatment) they must be at least 3 months post completion of their acute care.

Exclusion Criteria:

• Diagnosis of active or recurrent cancer, or less than 3 months at the time of initial evaluation from the completion of chemotherapy, radiation therapy or primary surgery for the treatment of cancer.
• Diagnosis of acute infection. The source of the infection must be treated for 2 weeks prior to admittance into the study.
• Diagnosis of acute thrombophlebitis (in last 2 months)
• Diagnosis of peripheral arterial disease (PAD): PAD is defined as an Ankle Brachial Index (ABI), of 0.7 or lower.
• Diagnosis of pulmonary embolism or deep vein thrombosis within the previous 6 months
• Diagnosis of pulmonary edema
• Diagnosis of congestive heart failure (uncontrolled)
• Diagnosis of chronic kidney disease with a Glomerular Filtration Rate (GFR) of less than 30 mls per minute.
• Patients with poorly controlled asthma (i.e. those with severe persistent symptoms throughout the day, night time awakenings several times per week, use of a beta2 agonist inhaler several times per day and those whose normal activity is extremely limited).
• Pregnancy
• Any condition where increased venous and lymphatic return is undesirable
• Inability or unwillingness to participate in all aspects of study protocol and/or inability to provide informed consent
• Currently participating in another clinical trial