Genicular Artery Embolisation for Knee Osteoarthritis II (GENESISII)

Genicular artEry embolisatioN in patiEnts With oSteoarthrItiS of the Knee II

This clinical study is designed as a double-blind sham controlled randomised trial with the option of sham group crossover to receive the GAE treatment at 6 months after unblinding. This study will determine if embolisation of abnormal neovasculature arising from branches of the genicular arteries reduces pain in patients with knee osteoarthritis. The study patient population will consist of up to 110 subjects with knee pain for at least 3 months that is resistant to conservative treatment measures. Subjects will be treated with knee embolisation or 2 mL of saline in the sham arm. At 6 months, all subjects in the sham arm will be allowed to cross-over and receive the embolisation procedure with a follow-up duration of 18 months. The total planned study duration is 3.5 years.

Study Overview

• Status: Recruiting
• Conditions: Knee Osteoarthritis
• Intervention / Treatment: Procedure: Genicular Artery Embolisation; Procedure: Genicular Artery Injection

Detailed Description

This is a single-center, randomised trial to compare patients who receive genicular artery embolisation of the knee with patients who receive a sham procedure with saline injection.

The study population will consist of up to 110 subjects with knee pain that is resistant to conservative treatment measures for at least 3 months. Subjects will be followed for 24 months. At 6 months patients will be unblinded and offered an optional crossover to receive the GAE procedure with 18 months follow-up.

Alongside a sham surgery placebo arm, a high-quality systematic review of surgical RCTs was used as a suitable benchmark to inform the sample size and power calculation.

With a 0-100 scale for the primary endpoint of KOOS4, assuming a 1:1 randomization, a mean difference of 6.4 (i.e., effect size) between GAE and Sham treatments, a common standard deviation of 10 (i.e., a Cohen's D of 0.64), an alpha error of 2-sided 0.05 and a power of 0.85, the 2-arm total sample size the requirement is 88 subjects (44 each arm) by Normal approximation. Allowing for a participant dropout rate of 20%, the enrolment goal is 110 participants, approximately 55 in each study arm.

All study subjects will undergo a physical exam and history, a contrast-enhanced knee MRI, blood serum and neuropschological assessment with a functional head MRI to identify potential predictors of treatment success.

In the GAE treatment arm subject will undergo a genicular artery embolization with Embozene microspheres (100 micron) (Varian Medical Systems) and the Sham group will receive saline through the transarterial catheter through groin access.

Participants will be randomly assigned to have particulate embolisation with 100-micron Embozene particles, or to injection with 2 ml heparinized normal saline (sham arm) At 6 months participants will be unblinded and there will be an open extension period for 6 months, in which participants in the sham arm will be offered GAE.

Follow-up visits will be at 1 month, 3 months, 6 months, 12 months and 24 months post randomisation. At these visits subjects will complete the KOOS score, the visual analog scale (VAS) pain score, an analgesia diary, and at specific time points the EQ-5D-3L, and report any new adverse events (AEs).All subjects will undergo a contrast-enhanced knee MRI at baseline and at 6 and 12 months.

At 6 months after unblinding the sham group subjects have the option to cross over and receive the GAE treatment with follow-up at 1 month, 3 months, 6 months, 12 months and 18 months.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Heike S Hausen, MD; Phone Number: 2068903102; Email: Heike.Hausen@varian.com
• Study Contact Backup: Name: Kate Pietrovito; Phone Number: +19782908408; Email: Kathleen.Pietrovito@varian.com

Study Locations

• United Kingdom
  • Reading, United Kingdom, RG1 5AN
    • Recruiting
    • Royal Berkshire NHS Foundation Trust
    • Contact: Mark W Little, MD; Phone Number: 01183225111; Email: Mark.Little@royalberkshire.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

ALL inclusion criteria below need to be fulfilled for the patient to participate in the study.

• Participant is willing and able to give informed consent for participation in the study.
• Participants aged 45 years or above.
• Grade 1-3 knee OA on X-ray as per Kellgren-Lawrence Grading Scale
• Knee pain for at least 3 months resistant to conservative non-surgical treatment (e.g., physiotherapy, steroid injections, weight loss programs, PRP (platelet-rich plasma) injections)
• Be able to lie flat for at least 6 hours-this will be assessed by asking how participants sleep (bed, chair recumbent, semi-recumbent) and assessing what prevents them from lying flat overnight (breathlessness, back pain, etc)
• Minimum score of 50 on baseline 0 - 100 VAS

Exclusion Criteria:

The patient may not enter the study if ANY of the following apply:

• Rheumatoid arthritis or infectious arthritis
• Severe knee OA (grade 4 on x-ray as per Kellgren-Lawrence Grade)
• Renal impairment: eGFR <45. Assessed from medical records or a blood test if required as is part of standard clinical practice when considering a patient for a therapeutic intervention.
• Patients with a bleeding diathesis, or other bleeding risk such as patients on warfarin which cannot be stopped easily (e.g., patients with metallic heart valves) assessed by asking the patient and from medical records. Uncorrectable bleeding diathesis: INR>1.6, Platelets <50,000
• Requires oxygen on ambulation. Assessed by asking the patient and from medical records.
• Low life expectancy (<1 year)
• Communication difficulty due to language barriers
• Contraindication to MRI
• Known allergies to barium sulfate, 3-aminopropyltrialkoxysilane, polyphosphazene or IV radiopaque contrast agent
• History of Peripheral Arterial Disease (PAD) with intermittent claudication and/or rest pain
• Pregnancy or positive pregnancy test (the participant will be exposed to ionising radiation during the fluoroscopy procedure)
• Any other significant disease or disorder which, in the opinion of the recruiting physician, may put the participants at risk because of participation in the study, or may influence the result of the study or the participant's ability to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GAE Treatment; The genicular artery embolisation procedure identifies abnormal blood vessels in the knee via angiogram imaging. Through groin access and puncture of the femoral artery through a small sheath tiny microspheres (Embozene(TM)) will be injected into this area and reduce blood flow in order to reduce pain.	Procedure: Genicular Artery Embolisation; Transarterial catheter directed embolisation of hypervascularity in patients with mild to moderate knee osteoarthritis; Other Names: Embozene Microspheres; Embozene
Sham Comparator: Sham Procedure; In the control (sham) arm patients will not undergo the embolisation procedure with microspheres, instead they will have 2ml of saline injected into their knee artery supplying the abnormal area of the knee. The remainder of the procedure is otherwise identical between the two groups.	Procedure: Genicular Artery Injection; Transarterial catheter directed injection of normal (0.9%) saline in patients with mild to moderate knee osteoarthritis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine if embolisation of abnormal neovasculature arising from branches of the genicular arteries reduces pain in patients with knee OA compared to Sham treatment	Change from baseline to 6 months post randomisation in the mean score on four Knee Injury and Osteoarthritis Outcome Score subscales, covering pain, symptoms, activities of daily living, and quality of life (KOOS4); scores range from 0 (worst) to 100 (best)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of pain relief	Pain relief at 6 months post randomisation, using the patient-reported 0 - 100 visual analogue scale (VAS) pain score	6 months
Determine if embolisation improves pain, function, and quality of life in patients with knee OA compared to Sham treatment	All 5 subscales of the KOOS questionnaire will be analysed at 6 months post randomisation.	6 months
Determine clinical success	The proportion of subjects reporting at least a 10- point improvement in KOOS scores at 6-months (where a 10-point change from baseline is defined as the minimum clinically important difference (MCID)	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine safety and toxicity	Proportion of subjects experiencing relevant adverse events (as per SIR Adverse Event Classification System) at 6 months post randomisation	6 months follow-up
Determine if improvement of knee osteoarthritis can be described by imaging analysis following GAE vs Sham	Whole Organ Magnetic Resonance Imaging Score (WORMS) for non-invasive assessment of synovial hypertrophy and neo-vascularization for osteoarthritis at 6 months post randomisation.	6 months
Quantification of a personalised psychometric pain profile to determine whether treatment response can be predicted using behavioural indicators of predisposition to central facilitation of pain	Pain Catastrophizing Scale (PCS) patient questionnaire: Score reflects on painful experiences of the patient. Score from 0 (minimum) to 52 (maximum). A higher score means worse outcome	6 months
Determine quality of life changes	Changes in quality of life measured by Euro-Quality of Life-5D-3L (EQ-5D-3L) assessing five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each having three levels (3L): no problems, some problems, extreme problems (labelled 1-3) in a descriptive fashion.	6 months
Assess patient reported acceptability of study treatment	The PROM questionnaire (Patient reported outcome measures) (10 question patient questionnaire) reports scores between 9 (minimum) to 90 (maximum) where a high score is considered worse acceptance (worse outcome)	1 week after treatment
Determine if patient's need for analgesia will be reduced	Change of analgesia intake at 6 months post randomisation.	6 months
Assess durability of GAE	Time to failure, i.e., time to next invasive intervention for those receiving GAE treatment following (a) randomisation, or (b) crossing over to GAE from Sham arm.	24 months
Perform a health economic cost effectiveness analysis of GAE versus other treatment modalities in the moderate knee OA space	Changes in quality of life measured by EuroQoL-5D (EQ-5D-3L) combined with the time assessment to failure (durability of GAE), i.e., time to next invasive intervention for those receiving GAE treatment following (a) randomization, or (b) crossing over to GAE from Sham arm will be assessed together to describe the cost effectiveness.	6 months
Determine if embolisation improves pain, function, and quality of life in patients with knee OA in the treatment group	All 5 subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire will be analysed at 12 and 24 months post randomisation. Scores range from 0 (minimum, worst) to 100 (maximum, best).	24 months follow-up
Determine quality of life changes in the GAE group at 12 and 24 months	Changes in quality of life measured by Euro-Quality of Life-5D-3L (EQ-5D-3L) assessing five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression, each having three levels (3L): no problems, some problems, extreme problems (labelled 1-3) at 12 and 24 months post randomisation in a descriptive fashion.	24 months follow-up
Describe imaging outcomes of knee at 12 months in GAE	Whole Organ Magnetic Resonance Imaging Score (WORMS) for non-invasive assessment of synovial hypertrophy and neo-vascularization for osteoarthritis will be evaluated in the GAE group at 12 months post randomisation.	12 months
Determine if patient's need for analgesia will be reduced in the GAE group	Change of analgesia intake at 12 and 24 months post randomisation.	24 months
Assessment of pain relief in the GAE group	Pain relief at 12 and 24 months post randomisation, using the patient-reported 0 - 100 visual analogue scale (VAS) pain score	24 months
Determine if embolisation improves pain, function, and quality of life in patients with knee OA in the treatment group and compare with the Sham group in subjects who do not cross over at 12 and 24 months	All 5 subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS) will be analysed at 12 and 24 months post randomisation in the GAE and Sham group. Scores range from 0 (worst) to 100 (best).	24 Months
Determine quality of life changes in the GAE and sham group	The second part of the Euro-Quality of Life-5D-3L questionnaire consists of a visual analytic scale (VAS) on which the patient rates his / her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health) at 12 and 24 months post randomisation in the GAE group and compare with the Sham group in subjects who do not cross over.	24 months
Determine if patient's need for analgesia will be reduced	Compare changes of analgesia intake at 12 and 24 months post randomisation in the GAE group with the Sham group in subjects who do not cross over.	24 months
Assessment of pain relief	Compare pain relief in the GAE group at 12 and 24 months post randomisation, using the patient-reported 0 - 100 visual analogue scale (VAS) pain score, and compare to the Sham group in subjects who do not cross over.	24 months
Determine if embolisation improves pain, function, and quality of life in patients with knee OA in the Sham crossover group at 1, 3, 6, 12 and 18 months	All 5 subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS) will be analysed at 1,3,6, 12 and 18 months post treatment in the Sham crossover group. Scores range from 0 (worst) to 100 (best).	18 months
Assessment of pain relief in the Sham crossover group	Pain relief at 1,3,6,12 and 18 months post treatment in the Sham crossover group, using the patient-reported 0 - 100 visual analogue scale (VAS) pain score	18 months
Determine if patient's need for analgesia will be reduced in the Sham crossover group	Change of analgesia intake at 1,3,6,12 and 18 months post treatment in the Sham crossover group.	18 months
Determine quality of life changes in the Sham crossover group	Changes in quality of life measured by Euro-Quality of Life-5D-3L (EQ-5D-3L) assessing five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression, each having three levels (3L): no problems, some problems, extreme problems (labelled 1-3) at 6, 12 and 18 months post treatment in a descriptive fashion.	18 months
Determine if improvement of knee osteoarthritis can be described by imaging analysis in the Sham crossover group following GAE	Whole Organ Magnetic Resonance Imaging Score (WORMS) for non-invasive assessment of synovial hypertrophy and neo-vascularization for osteoarthritis at 6 and 12 months post treatment in the Sham crossover group	12 months
Quantification of mindfulness as part of a personalised psychometric pain profile to determine whether treatment response can be predicted using behavioural indicators of predisposition to central facilitation of pain	Five-Facet Mindfulness Patient Questionnaire (FFMQ): Reporting a score between 15 (minimum) and 75 (maximum). Higher scores are better and indicative of high trait mindfulness.	6 months
Assessment of depressive symptoms as part of a personalised psychometric profile	Patient Health Questionnaire (PHQ-9): Reports a score between 0 (minimum) and 27 (maximum) with higher scores being worse representing high depressive symptoms	6 months
Assessment of patient's psychological flexibility as part of personalised psychometric profile	Pain Interference - Short Form 6b (PROMIS) patient questionnaire: Reports a score between 6 (minimum) and 30 (maximum), with higher scores being worse representing high pain interference	6 months
Assessment of a patient's anxiety as part of a personalised psychometric profile	Generalized Anxiety Disorder (GAD-7) patient questionnaire: reports a score between 0 (minimum) and 21 (maximum). Higher scores are worse representing more severe levels of anxiety.	6 months
Quantification of patient's psychological flexibility as part of a personalised psychometric profile	Committed Action Questionnaire (CAQ-8): Reports a score between 0 (minimum) and 48 (maximum). Higher scores mean better outcome representing high commitment to goals.	6 months
Quantification of a patient's intolerance of uncertainty	Intolerance of Uncertainty Scale - Short Form patient questionnaire: Reports a score between 0 (minimum) and 60 (maximum). Higher scores are worse representing high intolerance of uncertainty.	6 months
Quantification of a patient's sleep quality as part of personalised psychometric profile	Pittsburgh Sleep Quality Index (PSQI) patient questionnaire: Reports a score between 0 (minimum) to 21 (maximum). Higher scores are worse indicating worse sleep quality.	6 months
Assessment of psychological inflexibility in pain as part of a personalised psychometric pain profile to determine whether treatment response can be predicted using behavioural indicators of predisposition to central facilitation of pain	Psychological Inflexibility in Pain Scale (PIPS) patient questionnaire: reports scores between 16 (minimum) to 112 (maximum). Higher scores (worse results) indicate low flexibility in regard to dealing with pain.	6 months
Quantification of the perspective of a participant's viewpoint on pain as part of a personalised psychometric pain profile	Pain Priors Questionnaire	6 months
Behavioural quantification of psychological flexibility to stratify patients who achieve optimal clinical outcomes from the treatment procedure.	Wisconsin Card Sorting Task: reports reaction time measured in milliseconds (lower value is better outcome as better cognitive function)	6 months
Assess functional connectivity between brain regions and investigate the influence of metabolite levels within pain modulatory regions as a neurochemical marker for vulnerability to further chronic pain states.	Functional head MRI	6 months
Assess patient's capacity of central pain modulation	Quantitative sensory testing: Central pain modulation (CPM) measures the degree to which pain at one site inhibits pain at a distal site. The difference between the initial and final rating is taken as a score of the participant's CPM capacity with a range of -10 to 10 with -10 representing a better result with high pain inhibition/modulation.	6 months
Assess patient's intrinsic attention to pain	Intrinsic Attention to Pain (IAP) test measures whether a participant's attention is intrinsically gravitated towards, or away from pain during thermal stimulation with a score range of +2 to -2, with + 2 representing worse results indicating an inability to attentionally disengage from pain.	6 months
Assess patient's capacity of central facilitation of pain	Temporal Summation (TS) test: describes the degree to which pain responses are centrally enhanced by rapid repeated presentation. A score between -10 to 10 is reported with 10 representing high pain summation as a worse result and -10 no pain summation.	6 months
Perception of health by patient in the GAE and sham group	The second part of the Euro-Quality of Life-5D-3L questionnaire consists of a visual analytic scale (VAS) on which the patient rates his / her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health).	6 months
Perception of health by patient in the GAE group	The second part of the Euro-Quality of Life-5D-3L questionnaire consists of a visual analytic scale (VAS) on which the patient rates his / her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health).	24 months follow-up
Perception of health by patient in GAE and sham group at 12 and 24 months	The second part of the Euro-Quality of Life-5D-3L questionnaire consists of a visual analytic scale (VAS) on which the patient rates his / her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health) at 12 and 24 months post randomisation in the GAE group and compare with the Sham group in subjects who do not cross over.	24 months
Perception of health by patient in sham crossover group at 6, 12 and 18 months	The second part of the Euro-Quality of Life-5D-3L questionnaire consists of a visual analytic scale (VAS) on which the patient rates his / her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health) at 6, 12 and 18 months post treatment.	18 months

Collaborators and Investigators

• Sponsor: Varian, a Siemens Healthineers Company
• Investigators: Principal Investigator: Mark W Little, MD, Royal Berkshire NHS Foundation Trust, Reading, UK

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2022
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: April 11, 2022
• First Submitted That Met QC Criteria: June 13, 2022
• First Posted (Actual): June 21, 2022

Study Record Updates

• Last Update Posted (Actual): December 3, 2024
• Last Update Submitted That Met QC Criteria: November 28, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Microspheres; Osteoarthritis, Knee; Artery Embolization; Embozene; Joint diseases
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: VAR-2021-11; 286849 (Other Identifier: IRAS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No