Design This study will follow the Standard Protocol Items: Recommendations for
Interventional Trials (SPIRIT) reporting guidelines.
Study design and participants We will conduct a crossover randomized controlled trial
(RCT) involving 58 women diagnosed with lipedema. To be eligible for participation, women
must be between 18 and 65 years old and have a confirmed diagnosis of lipedema. Exclusion
criteria include ongoing eating disorders and orthopedic limitations that prevent
exercise training. Eligible participants will be randomized (1:1) using block
randomization in eForsk to either the exercise intervention group or the control group.
The exercise intervention group will undergo 12 weeks of high-intensity interval training
(HIIT), tailored to each participant's fitness level and the severity of their lipedema.
The control group will continue their usual lifestyle during this period. Following the
12-week intervention, there will be a 12-week wash-out period during which all
participants will resume their normal activities. After the wash-out period, participants
will switch groups, allowing all included participants to receive the exercise
intervention and potentially experience the benefits of HIIT. In total, the study
duration for each participant will be 9 months.
Recruitment Patients will be recruited in Trøndelag, Norway, primarily through The Clinic
of Rehabilitation at St. Olavs Hospital and the social media channels of the Norwegian
Lymphedema and Lipedema Foundation (NLLF). Additionally, posters will be displayed at
general practitioner offices and various physiotherapy clinics in the Trondheim area.
Eligible patients will receive comprehensive information about the study and will be
given at least one week to consider their participation.
Exercise intervention Exercise testing and training will be conducted at state-of-the-art
exercise training facility at the Norwegian University of Science and Technology (NTNU),
the NextMove Core facility, supported by highly experienced staff. The exercise
intervention group perform three sessions of HIIT per week for 12 weeks. HIIT involves 4
times 4-minutes intervals at 85-95% of maximal heart rate (HRmax) with 3-minutes active
breaks (~60% HRmax) between the intervals. Two HIIT sessions are supervised at the
NextMove core facility, and performed on treadmills or spinning bikes, while the last
session of HIIT is unsupervised. In this unsupervised session, HIIT in a pool will be
recommended based on the potential benefits gained from compression. The criteria for
adequate compliance to the exercise intervention program will be set to ≥80%. With
standardized templated from the NextMove core facility, the participants are required to
write a diary of their physical activity during the entire study period, including the
exercise intervention period, the wash-out period, and the control period.
Data collection During the first study visit, participants will be randomized into groups
and receive comprehensive information about the study and all included procedures. Data
collection will occur primarily on four separate test days: before and after both the
exercise intervention period and the control period. On these test days, anthropometric
and physiological measurements will be taken, questionnaires will be completed, and
fasting blood samples and tissue biopsies will be collected.
General information, including details on lipedema (type and stage, and time of
diagnosis), comorbidities, sleep patterns, and the use of medications, supplements, and
clinical aids (e.g., compression aids and their frequency of use), will also be gathered.
Each test day will last approximately three hours. During this time, fasting blood
samples and anthropometric measurements will be taken first, followed by a light meal,
completion of questionnaires, and performance of physiological measurements.
Additionally, participants who consent to adipose tissue biopsies will have two samples
collected: one within five days before the first exercise session and one within five
days after the final exercise session.
Pain registration Pain will be registered before and after both the intervention period
and the control period using the RAND-36 health survey (Pain Dimension) (primary
endpoint). RAND-36 (also known as SF-36) includes two questions designed to measure the
intensity of pain and the extent to which pain interferes with normal work (both outside
the home and housework). One of the questions assess the intensity of pain experienced
over the past four weeks with six response options from "none" to "very severe". The
second question evaluates the degree to which pain has interfered with daily activities
and work with five response options from "not at all" to "extremely". In addition, pain
will be registered before and after both the intervention period and the control period
using the questionnaire Brief Pain Inventory (BPI). This questionnaire includes four
questions that assess the severity of pain right now and at its worst, least, and
average. Each question gives a possible answer of 0 to 10, were 0 means no pain and 10 is
the worst pain you can imagine. The four BPI questions contribute with the same weight,
and they are combined to a final pain severity score with a range from 0 to 40. The
results from RAND-36 and BPI will be evaluated separately. While both tools assess pain,
the BPI provides a deeper and more detailed assessment of pain characteristics and
functional impact compared to the broader, more generalized assessment provided by the
RAND-36 pain dimension. However, the questionnaires focus on different timeframes, as
RAND-36 assesses pain over a retrospective period of the past 4 weeks whereas BPI assess
pain over the past 24 hours or at the present moment (current pain intensity).
Potentially, RAND-36 can be more useful for assessing chronic pain, and BPI for assessing
more chronic pain, however, the best tool for assessing pain in lipedema is currently
unknown.
Anthropometric measurements Body composition, including weight (kg), body mass index
(kg/m2), muscle mass (kg), adipose tissue mass (%), basal metabolic rate (kcal), and
mineral status (kg), will be measured non-invasively using the bioimpedance instrument
InBody 770 (Biospace CO, Ltd, Seul, Korea). The instrument provides both total adipocyte
mass and adipose tissue mass in the lower limbs (secondary endpoints). The heigh (m) will
be measured without shoes. The circumference (cm) of the waist, hip, right calf, and
right thigh will be measured with standard procedures at NextMove, and the waist-to-hip
ratio (cm/cm) will be calculated. A measuring board will be used to ensure similar site
for pre- and post-measurement of the right calf and thigh.
Quality of life The RAND-36 questionnaire will be used to detect potential changes in
health-related quality of life during the study period (secondary endpoint). This
questionnaire includes 36 questions covering eight health domains, including vitality,
physical functioning, bodily pain, general health perceptions, physical role functioning,
emotional role functioning, social role functioning, and mental health. Each domain is
scored on a scale from 0 to 100, where the scaled scores are weighted sums of all
questions within each of the eight domains. A higher score indicates better health and
well-being.
Physiological measurements Blood pressure will be measured in a sitting position after
minimum five minutes rest in a quiet room with a handheld sphygmomanometer (Tycos,
5098-02CB, USA) by trained personnel. At the pre- and post-tests, the blood pressure will
be measured at the same time-point of the day for each participant. The first reading
will be discarded and the mean of the next three consecutive readings will be used.
Additional readings will be required if the coefficient of variation is above 15%.
Maximal oxygen uptake (VO2max) will be measured using ergospirometry (Metalyzer ll,
Cortex Biophysik GmBH, Leipzig, German) supervised by qualified personnel. To demonstrate
cardiometabolic effects from the HIIT intervention, VO2max will be measured during uphill
treadmill walking or running. A 10-minute warm-up (~60% of HRmax) will be performed
before increasing the workload (speed or incline) every minute until exhaustion. The
criteria for reaching VO2max is a levelling off oxygen uptake (VO2) despite increased
workload, and a respiratory exchange ratio of ≥1.05. HR will be measured continuously
during the test with Polar belt and watch (Polar, Polar Electro, Kempele, Finland), and
the data will be used to determine HRmax.
Blood samples and adipose tissue biopsies Four fasting venous blood samples will be drawn
by qualified personnel and by standard in-hospital procedures at St.Olavs Hospital.
Directly after collection, one 3mL EDTA-tube and one 3mL Li-heparin-tube will be sent to
routine biochemical analyses at St. Olavs hospital for such as glucose, HbA1C,
triglycerides, HDL-cholesterol, total cholesterol, serum ferritin and hs-CRP. The two
remaining tubes (serum and EDTA) will be centrifuged, aliquoted, and stored in the
LipidEx biobank at -80°C for explorative analyses.
Two adipose tissue biopsies will be collected by experienced personnel from the Research
outpatient clinic at St.Olavs Hospital before and after the exercise intervention. The
collected adipose biopsies will be used to advance our physiological understanding of
exercise-induced effects on adipose tissue in lipedema patients. To ensure patient
comfort during the procedure, local anesthesia will be administered at the site of biopsy
to minimize pain and discomfort associated with the needle insertion. The proposed
methodology will adhere to rigorous sterilization protocols, including the use of sterile
equipment, gloves, and disinfection procedures. A fine needle is used to avoid the need
for extensive incisions and to reduce patient discomfort and recovery time. One biopsy
will be snap-frozen in liquid nitrogen and stored at -80°C for later explorative
analyses. Another biopsy will be placed in histology cassettes and fixed in 4%
formaldehyde in 0.1 M phosphate buffer for 24 hours. The samples will be dehydrated,
embedded in paraffin, sectioned, and stained at the general lab at the Institute for
Circulation and Medical Imaging, NTNU in later explorative analyses.
