Explanation for the choice of comparators {6b}
The intervention group: Participants are treated with a 10ml intra articular injection of autologous, micro fragmented adipose tissue.
The control group: Participants receive a 10ml intra articular injection with isotonic saline (placebo).
The aim of the study is to find out if the active treatment is better than no treatment. A saline injection was chosen as the comparator as it was considered the best alternative to mimick 'no treatment' in a blinded setup.
Intervention description {11a}
Description of the active treatment:
The active treatment is an intra articular injection with autologous, micro fragmented adipose tissue prepared using the Lipogems® system.
Harvest of adipose tissue is performed in local anesthesia under sterile conditions in the operating theatre. The patient is positioned supine, and the lower abdomen is used as donor site, and this is marked on the skin with a surgical marker. The area is approximately 8 cm (crania-caudal) x 20 cm (lateral) and situated just below the umbilicus. In patients, where tissue harvest from the abdominal area is not possible due to low fat mass or scarring from earlier procedures, harvest is performed from the lateral thigh area. Surgical cleaning is performed twice and a sterile draping is applied. The adipose tissue is prepared for harvesting by injection of tumescence using a disposable 17G blunt cannula connected to a suspension of 40 ml Carbocain 1%, 250 ml isotonic saline, 0.5 mg adrenaline and 10mmol Bicarbonate. Fifteen minutes after installation of the local anesthesia, approximately 100 ml fat is harvested manually using a 13G blunt suction cannula connected to a Vaclock® 20 ml syringe via two stab punctures. At the end of the procedure, the skin is closed with a band aid, and the patient is given an elastic compression bandage to be used for 3-4 weeks or as long as the area of liposuction is sore and swollen.
The harvested fat is immediately processed in the Lipogems® processing kit, a disposable closed device that progressively and mechanically reduces the size of the adipose tissue clusters while eliminating blood residues with pro-inflammatory properties during constant irrigation. The entire process, carried out in one surgical step, is performed in complete immersion in physiological saline solution minimizing traumatic action on the important cell products. The resulting micro-fragmented tissue is collected in two 5 ml syringes to be re-injected in the patient´s knee joint.
Implantation of the graft is performed with the patient supine using two injections sites in order to reduce the risk of extra-articular injection. Local anesthesia with lidocaine 1% is given in the skin at the two injection areas. The first injection is in the intercondylar notch. On a 90 degrees bend knee the lateral soft spot is located just lateral to the patella tendon and approximately 1 cm proximal to the tibial plateau. The syringe is introduced 2-4 cm perpendicular to the tibial axis aiming in the direction of the cruciate ligaments. To make sure the needle is positioned intra-articular, 1 ml of saline is injected; if there is any resistance to the injection the needle is repositioned and the procedure done over again. Injection is performed using a 21-gauge syringe. The second injection is done with the knee in full extension. The syringe is introduced from lateral into the suprapatellar pouch posterior to the patella. Injection of 1 ml saline is repeated to ensure intraarticular position. At the end of the procedure the skin is closed with two band aids.
Criteria for discontinuing or modifying allocated interventions {11b}
The trial is a one-time intervention. The intervention cannot be discontinued or modified.
Strategies to improve adherence to interventions {11c}
Not applicable since it’s a onetime intervention.
Relevant concomitant care permitted or prohibited during the trial {11d}
Participants is allowed standard pain medication and physiotherapy. Any type of intraarticular injection or operation is not permitted, and will lead to exclusion from the trial.
Provisions for post-trial care {30}
There are no provisions for the participants in the trial.
Patients are covered by the patient insurance of Copenhagen University Hospital Køge and Hvidovre Hospital respectively.
Outcomes {12}
Primary outcome
The primary outcome, the Knee injury and Osteoarthritis Outcome Score (KOOS4), is evaluated at 6 months after the intervention. See Figure 2 for study timeline.
The KOOS questionnaire was developed in the 1990s as an instrument to assess the opinion of patient’s with knee osteoarthritis about their knee and associated problems. Since the first publication in 1998, the psychometric properties of the KOOS have been assessed in more than twenty individual studies from all over the world. Furthermore, KOOS one year post surgery has been evaluated and compared to other instruments in several reviews [20, 21, 22, 23]
KOOS4 constructs an average score for 4 out of the 5 KOOS subscale scores. It was first used by Frobell et al. in 2010 [24]. The fifth subscale concerning activities of daily living (ADL) is excluded in the KOOS 4 as the subscale is thought to add unwanted ‘noise’ to the constructed outcome in active patients with few to none difficulties within ADL [23]. As the population of the trial is active patients, KOOS4 was chosen as the primary outcome.
Secondary outcomes (recorded at 3, 6, 12 and 24 months)
- The Knee injury and Osteoarthritis Outcome Score (including all 5 subscales).
The KOOS holds 42 items in 5 separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL) [23, 25].
The 5 patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have 5 possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the 5 scores is calculated as the sum of the items included. Scores are transformed to a 0–100 scale, with 0 representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved [23].
The Knee injury and Osteoarthritis Outcome Score is recorded at each follow up.
The Tegner activity scale was described in 1985 [26], and was designed for ACL and meniscal injuries. The Tegner activity scale has been frequently used as a patient-administered activity rating for patients with different knee disorders. The Tegner score is a patient-administered score of activity level with 11 defined grades. From 0, representing disability because of knee injury to 10 (professional level soccer) [26].
Tegner activity score is recorded at each follow up.
Changes in work status. Is the patient working full- or part time or not working. Our study groups are primarily patients who are eligible to work, and not patients already retired
The patients are asked if they work full time, part time or not working. The patient answers if the work is hard physical work, moderate physical or light physical work.
Work status is recorded at each follow up.
- Participation in sport and physical activity:
Does the patient participate in sports or other forms of physical activity? Does the level of physical activity rise or fall after treatment? This is recorded at each follow up. The patients are asked what type of physical activity they participate in, and how many hours a week.
At three months it is recorded if an infection in the knee or at the donor site has occurred.
Recall VAS pain scale for the donor site first week after surgery, after 2 weeks, after one month and at present (3 months).
At six months donor site morbidity is recorded as VAS pain scale for the donor site.
If the patient does not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure, and this is registered at follow-up. A clinically relevant difference is estimated to be 10 points [27]. The number of patients experiencing failure of the treatment is recorded.
Participant timeline {13}
Participant timeline
Sample size {14}
120 patients will be included; 60 patients in each group. The sample size calculation is based on a clinical relevant difference of 10 point in KOOS4, a standard deviation (SD) of 15 and power of 0.90 (two sided). 98 patients are required; due to the risk of drop out 120 patients will be included; 60 in each group. The used SD and clinically relevant difference are recommended at KOOS.nu.
Recruitment {15}
Participants are recruited from the arthroplasty and sports surgery departments of each hospital. Both departments have many patient contacts, which will give a continuous enrolment of possible participants.
Assignment of interventions: allocation
Sequence generation {16a}
Randomization is computer based, performed in blocks of twelve and following the random allocation rule to ensure balanced group sizes. Patients are allocated 1:1 to either the control or the intervention group.
Concealment mechanism {16b}
Two researchers with no other connection to the trial is responsible for packing of continuously numbered, sealed, opaque envelopes. The allocation key is stored by and only accessible by the researcher who generated the allocation key. If a participant need to know the allocated treatment ahead of trial termination the study nurse will arrange this. Patients are still followed up according to the intention to treat principle.
Implementation {16c}
An experienced senior researcher with no other connection to the trial is responsible for generation of the allocation key.
Assignment of interventions: Blinding
Who will be blinded {17a}
Blinding of the patient is secured as follows: The liposuction and micro fragmentation of the fatty tissue is performed in the operating theatre. When the graft is ready for use, two 5 ml syringes containing active treatment and two 5 ml syringes containing saline are prepared.
The randomization envelope is opened by the treating surgeon, who is not blinded to the intervention.
The patient as well as the scrub nurse is blinded to the treatment. Both are visually shielded by the surgical drapes. Before opening the randomization envelope, the patient is informed that after opening of the envelope there is no further communication with the treating surgeon. The surgeon is silent once the randomization has taken place to limit subliminal bias. After the intraarticular injection of either micro fragmented fat or saline, the surgeon empties the remaining syringes in order to conceal the given treatment.
Injection is performed with a 21G cannula. Due to the difference in viscosity of the graft and saline, the treating surgeon cannot be blinded.
In order to investigate if the blinding is working, the patients will be asked at 6 months follow up which group he/she believes he/she was assigned to.
The data assessment is blinded as the data analysts are blinded.
Procedure for unblinding if needed {17b}
The participants can ask to be unblinded upon request. The project manager will ask the person responsible for generation of the allocation key. The person has no other connection to the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
The Redcap database makes it easy to assess the correctness and completeness of the assembled data.
Plans to promote participant retention and complete follow-up {18b}
The study nurse will be responsible for follow-up. The database will show if the participants have completed the questionnaires. If the questionnaire is not completed, the study nurse will make a phone call to the participant.