NCT02034409: PLUS+OA

A Pilot Trial to Assess Low-Intensity Ultrasound in Osteoarthritis

Completed Phase 1, PHASE2 Results posted Last updated 18 October 2021

What this trial tests

Phase 1, PHASE2 trial testing Pulsed Low Intensity Ultrasound in Osteoarthritis, Degenerative in 140 participants. Completed in 30 September 2020.

Timeline

22 May 2015

Primary endpoint
1 June 2020

30 September 2020

Quick facts

Lead sponsor	VA Office of Research and Development
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	140
Start date	22 May 2015
Primary completion	1 June 2020
Estimated completion	30 September 2020
Sites	3 locations across United States

Drugs / interventions tested

• Pulsed Low Intensity Ultrasound
• Sham Comparator

Conditions studied

• Osteoarthritis, Degenerative — all drugs for Osteoarthritis, Degenerative →

Sponsor

VA Office of Research and Development — full company profile →

Who can join

40 and older, any sex, with Osteoarthritis, Degenerative. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness Primary · 48 weeks

Outcome Measures in Rheumatology Clinical Trials- Osteoarthritis Research Society International (OMERACT-OARSI) Response incorporates changes in pain and global assessment to define response in OA clinical trials. A response is classified as: 1) An improvement in either pain or function of at least 50 percent accompanied by an absolute decrease of at least 20 mm on the visual-analogue scale for pain or function, OR 2) The occurrence of at least two of the following: a) a decrease in pain of at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale; b) an impr

Group	Value	95% CI
Sham	37
PLIUS	38
Sham	18
PLIUS	16

Co-Primary Measure: b) Disease Modification as Measured by Change From Baseline in Cartilage Thickness of the Central Medial Femoral Condyle Disease Primary · Baseline, 48 weeks

The study has been designed to determine if PLIUS potentially diminishes articular cartilage thinning by measuring cartilage thickness in the tibial femoral joint. The measure selected to best evaluate this is cartilage thickness of the central medial femoral condyle because studies of the OAI (Osteoarthritis Initiative) data have shown this region to be among those most sensitive to change and, due to the anatomical positioning of the device, the most likely to be affected by treatment.

Group	Value	95% CI
Sham	-42.2	± 297.0
PLIUS	-73.8	± 168.1

Change From Baseline in WOMAC Stiffness Subscale Score Secondary · Baseline, week 24, week 48

The WOMAC® Index questionnaire is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 200. The higher the score, the worse the symptoms.

Change from Baseline to week 24

Group	Value	95% CI
Sham	-33.6	-47.6 – -19.7
PLIUS	-27.7	-40.2 – -15.1

Change from Baseline to week 48

Group	Value	95% CI
Sham	-49.8	-64.6 – -35.1
PLIUS	-37.1	-51.6 – -22.6

Change From Baseline in WOMAC Pain Subscale Score Secondary · Baseline, week 24, week 48

The WOMAC® Index questionnaire \[33\] is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. WOMAC pain scores from 0-500 mm. The higher the score, the worse the symptoms.

Change from Baseline to week 24

Group	Value	95% CI
Sham	-84.2	-109.4 – -58.9
PLIUS	-91.4	-111.1 – -71.7

Change from Baseline to week 48

Group	Value	95% CI
Sham	-117.1	-146.2 – -87.9
PLIUS	-93.4	-124.4 – -62.3

Change From Baseline in WOMAC Functional Limits Subscale Score Secondary · Baseline, week 24, week 48

The WOMAC® Index questionnaire \[33\] is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 1700. The higher the score, the worse the symptoms.

Change from Baseline to week 24

Group	Value	95% CI
Sham	-285.2	-377.1 – -193.2
PLIUS	-241.1	-316.9 – -165.4

Change from Baseline to week 48

Group	Value	95% CI
Sham	-407.3	-510.8 – -303.7
PLIUS	-283.1	-399.7 – -166.5

Change From Baseline in Total WOMAC Score Secondary · Baseline, week 24, week 48

The WOMAC® Index questionnaire is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with osteoarthritis of the hip and/or knee. The WOMAC has been linguistically validated and is a reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. Range is from 0 - 2400. The higher the score, the worse the symptoms.

Change from Baseline to week 24

Group	Value	95% CI
Sham	-403.0	-527.3 – -278.6
PLIUS	-360.2	-460.8 – -259.5

Change from Baseline to week 48

Group	Value	95% CI
Sham	-574.1	-713.8 – -434.4
PLIUS	-413.6	-571.4 – -255.7

Change From Baseline in Patient Global Assessment of Disease Status Secondary · Baseline, week 24, week 48

A patient global assessment of disease status on a Visual Analog Scale (VAS) will be measured at each clinic visit. Patients will be asked to quantify their disease status on a 100 mm VAS as follows: "Considering all the ways your arthritis of the knee affects you, mark 'X' on the scale for how well you are doing." The scale shows the left hand marker "Very Well", and the right hand marker "Very Poor." Range 0 to 100 mm. The higher the score, the worse the symptoms.

Change from Baseline to Week 24

Group	Value	95% CI
Sham	-16.6	-23.3 – -9.9
PLIUS	-15.0	-21.4 – -8.7

Change from Baseline to Week 48

Group	Value	95% CI
Sham	-23.7	-30.8 – -16.5
PLIUS	-17.6	-26.3 – -9.0

Change From Baseline in Investigator Global Assessment of Disease Status Secondary · Baseline, week 24, week 48

An investigator global assessment of disease status on a 100 mm VAS was measured at each clinic visit as follows: "Make a global assessment of the patient's disease status, with regard to the index knee, by marking an 'X' on the scale below.", with left hand marker "Very Well" and right hand marker "Very Poor." Range 0 to 100 mm. The higher the score, the worse the symptoms.

Change from Baseline to Week 24

Group	Value	95% CI
Sham	-18.4	-25.0 – -11.9
PLIUS	-15.8	-22.5 – -9.0

Change from Baseline to Week 48

Group	Value	95% CI
Sham	-28.6	-36.6 – -20.6
PLIUS	-18.9	-27.9 – -9.9

Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Constant Pain Subscale Secondary · Baseline, week 24, week 48

This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered. Study participants are asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants responded to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the symptoms.

Change from Baseline to Week 24

Group	Value	95% CI
Sham	-14.6	-20.1 – 9.1
PLIUS	-12.4	-18.0 – -6.8

Change from Baseline to Week 48

Group	Value	95% CI
Sham	-18.4	-24.0 – -12.8
PLIUS	-13.7	-20.7 – -6.7

Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Intermittent Pain Subscale Secondary · Baseline, week 24, week 48

This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered and takes less than 10 minutes to complete. Study participants will be asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants will respond to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the s

Baseline to Week 24

Group	Value	95% CI
Sham	-17.7	-23.2 – -12.3
PLIUS	-13.4	-18.2 – -8.5

Baseline to Week 48

Group	Value	95% CI
Sham	-20.2	-26.8 – -13.6
PLIUS	-15.0	-21.5 – -8.5

Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Total Pain Score Secondary · Baseline, week 24, week 48

This 11-item tool is designed to assess pain in individuals with knee osteoarthritis taking into account both constant and intermittent pain experiences. This tool is designed to be interviewer-administered and takes less than 10 minutes to complete. Study participants will be asked to respond to the questionnaire items based on index knee in the past week (i.e., past 7-day period). Study participants will respond to all questions for the same joint. This tool is intended to be responsive to change in OA pain over time or with treatment. Range 0 to 100 mm. The higher the score, the worse the s

Change from Baseline to Week 24

Group	Value	95% CI
Sham	-16.3	-21.3 – -11.3
PLIUS	-12.9	-17.9 – -8.0

Change from Baseline to Week 48

Group	Value	95% CI
Sham	-19.4	-25.2 – 13.6
PLIUS	-14.4	-20.8 – -7.9

Number of Participants Discontinuing the Study Device Due to an Adverse Device Event Secondary · Baseline, 4, 8, 12, 24, 36, and 48-week visits

Difference between study groups in number of participants who discontinued usage of the study device due to adverse device events at 4, 8, 12, 24, 36, and 48-week visits.

Group	Value	95% CI
Sham	0
PLIUS	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Through study completion, an average of 48 weeks.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Sham

Serious: 13/65 (20%)

Deaths: 1/65

PLIUS

Serious: 19/67 (28%)

Deaths: 0/67

Serious adverse events (29 terms)

Reaction	System	Sham	PLIUS
Ascitis	Gastrointestinal disorders	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Abdominal Pain	Gastrointestinal disorders	—	—
Alcohol Poisoning	Injury, poisoning and procedural complications	—	—
Angina, Unstable	Cardiac disorders	—	—
Appendicitis	Gastrointestinal disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Atrioventricular block, complete	Cardiac disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Coronary artery stenosis	Cardiac disorders	—	—
Dural arteriovenous fistula	Vascular disorders	—	—
Dysphagia	Gastrointestinal disorders	—	—
Hypertension	Cardiac disorders	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—
Intestinal obstruction	Gastrointestinal disorders	—	—
Lipoma	Skin and subcutaneous tissue disorders	—	—
Lumbar radiculopathy	Musculoskeletal and connective tissue disorders	—	—
Oropharyngeal cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Pharyngo-oesophageal diverticulum	Gastrointestinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Prostatectomy	Renal and urinary disorders	—	—
Prostatitis	Infections and infestations	—	—

Most-reported serious reactions: Ascitis, Chronic obstructive pulmonary disease, Myocardial infarction, Osteoarthritis, Abdominal Pain, Alcohol Poisoning, Angina, Unstable, Appendicitis.

Data from ClinicalTrials.gov NCT02034409 adverse events section.

Sponsor's own description

The purpose of this exploratory trial is to investigate whether PLIUS is potentially effective as a disease and symptom modifying intervention in patients with early knee OA.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine.
   de Lucas B, Pérez LM, Bernal A, Gálvez BG. · · 2020 · cited 38× · PMID 32957737 · DOI 10.3390/genes11091086
2. Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.
   Sawitzke AD, Jackson CG, Carlson K, Bizien MD, et al · · 2022 · cited 4× · PMID 35258579 · DOI 10.1001/jamanetworkopen.2022.0632