A Pilot Trial to Assess Low-Intensity Ultrasound in Osteoarthritis

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02034409

Acronym

PLUS+OA

Enrollment

140

Registered

2014-01-13

Start date

2015-05-22

Completion date

2020-09-30

Last updated

2021-10-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Osteoarthritis, Degenerative

Keywords

Knee Osteoarthritis, Pulsed Low Intensity Ultrasound

Brief summary

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.

Detailed description

Osteoarthritis (OA), the most common form of arthritis, is a prevalent and debilitating disease without therapies that alter disease progress and is currently managed with symptom-modifying therapies that are only modestly effective. In spite of substantial progress in understanding the pathogenesis of OA, no effective disease modifying interventions have been established. Degenerative joint cartilage is a central feature of OA, yet joint cartilage has a limited capacity for repair. Results from animal research demonstrate that pulsed low intensity ultrasound (PLIUS) mechanically stimulates, and may promote, cartilage repair. This exploratory trial will investigate whether PLIUS is potentially effective as a disease and symptom modifying intervention in patients with early knee OA.

Interventions

DEVICEPulsed Low Intensity Ultrasound

20 minutes daily for 48 weeks

DEVICESham Comparator

20 minutes daily for 48 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Intervention model description

Participants in this double-blind, randomized, sham-controlled trial will be randomly assigned to receive either sham or PLIUS device for 48 weeks.

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

Inclusion criteria

* 40 years of age or older, and a US Military Veteran * Clinical symptoms of osteoarthritis for at least 6 months * Pain in the index knee on motion or weight bearing for the majority of days during the month before screening * Clinical diagnosis of primary osteoarthritis of the knee based on clinical and radiographic criteria * American Rheumatism Association Functional Class I, II, or III * Females of childbearing potential must be willing to use a reliable form of medically acceptable contraception

Exclusion criteria

* Concurrent medical/arthritis condition(s), or any other illness per the opinion of the investigator, that could interfere with the evaluation of pain or efficacy * Spine or hip pain of significant magnitude * History of significant ligament or meniscal injury of the index joint requiring surgical repair * Arthroscopy of the index knee within 6 months of study entry * Unable to undergo MRI of the knee * Pregnancy or lactation * Corticosteroid treatment within 1 to 3 months prior to study entry * Intra-articular injection of hyaluronic acid or congeners to the index knee within 6 months of study entry * Use of excluded therapy(ies) prior to study entry * Use of disease modifying anti-rheumatic medications and chronic tetracycline or its derivatives * Exposure to glucosamine, chondroitin sulfate, or any other investigational treatment, within 1 month of study entry * Use of any medical therapy, complementary or alternative regimens for the treatment of osteoarthritis within 7 days prior to study entry * Initiation of physical therapy or muscle conditioning program to the lower extremities within 2 months within 2 months prior to study entry * Unlikely to comply with study requirements

Design outcomes

Primary

Measure	Time frame	Description
Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness	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 improvement in function of at least 20 percent and a decrease of at least 10 mm on the visual-analogue scale; c) an increase in the patient's global assessment score by at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale
Co-Primary Measure: b) Disease Modification as Measured by Change From Baseline in Cartilage Thickness of the Central Medial Femoral Condyle Disease	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.

Secondary

Measure	Time frame	Description
Change From Baseline in WOMAC Stiffness Subscale Score	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 in WOMAC Pain Subscale Score	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 in WOMAC Functional Limits Subscale Score	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 in Total WOMAC Score	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 in Patient Global Assessment of Disease Status	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 in Investigator Global Assessment of Disease Status	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 in Intermittent and Constant Osteoarthritis Pain (ICOAP) Constant Pain Subscale	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 in Intermittent and Constant Osteoarthritis Pain (ICOAP) Intermittent Pain Subscale	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 symptoms.
Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Total Pain Score	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 symptoms.
Number of Participants Discontinuing the Study Device Due to an Adverse Device Event	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.

Countries

United States

Participant flow

Recruitment details

Participants were recruited at 2 medical centers between May 2015 and January 2019. The first participant was enrolled May 2017 and the last participant was enrolled in January 2019.

Pre-assignment details

140 participants began, and 136 completed, the 4-Week Sham Run-in Period. 4 of the 140 Sham Run-in participants were withdrawn due to being less than 80% treatment compliance.

Participants by arm

Arm	Count
Sham Treatment to index knee with sham device for 48 weeks Sham Comparator: 20 minutes daily for 48 weeks	65
PLIUS Treatment to index knee with PLIUS device for 48 weeks Pulsed Low Intensity Ultrasound: 20 minutes daily for 48 weeks	67
Total	132

Withdrawals & dropouts

Period	Reason	FG000	FG001
Sham-Controlled Treatment Period	Adverse Event	1	1
Sham-Controlled Treatment Period	Lost to Follow-up	0	1
Sham-Controlled Treatment Period	misrandomized	2	2
Sham-Controlled Treatment Period	Physician Decision	1	3
Sham-Controlled Treatment Period	Withdrawal by Subject	8	8
Sham Run-in Period	Participants withdrawn per protocol because less than 80% treatment compliance	4	0

Baseline characteristics

Characteristic	Sham	Total	PLIUS
Age, Continuous	64.4 years STANDARD_DEVIATION 10.9	63.6 years STANDARD_DEVIATION 10.7	62.9 years STANDARD_DEVIATION 10.5
ARA Functional Class Class I	0 Participants	2 Participants	2 Participants
ARA Functional Class Class II	48 Participants	100 Participants	52 Participants
ARA Functional Class Class III	17 Participants	30 Participants	13 Participants
ARA Functional Class Class IV	0 Participants	0 Participants	0 Participants
BMI	31.6 kg/m^2 STANDARD_DEVIATION 5.5	31.7 kg/m^2 STANDARD_DEVIATION 5.5	31.8 kg/m^2 STANDARD_DEVIATION 5.4
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants	23 Participants	13 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	55 Participants	109 Participants	54 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	6 Participants	3 Participants
Race (NIH/OMB) Black or African American	5 Participants	10 Participants	5 Participants
Race (NIH/OMB) More than one race	3 Participants	12 Participants	9 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	3 Participants	2 Participants
Race (NIH/OMB) White	52 Participants	100 Participants	48 Participants
Region of Enrollment United States	65 Participants	132 Participants	67 Participants
Sex: Female, Male Female	7 Participants	13 Participants	6 Participants
Sex: Female, Male Male	58 Participants	119 Participants	61 Participants
Years with Osteoarthritis	11.7 years STANDARD_DEVIATION 11.2	13.4 years STANDARD_DEVIATION 12.3	15.0 years STANDARD_DEVIATION 13.2

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 65	0 / 67
other Total, other adverse events	0 / 65	0 / 67
serious Total, serious adverse events	13 / 65	19 / 67

Outcome results

Primary

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

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 improvement in function of at least 20 percent and a decrease of at least 10 mm on the visual-analogue scale; c) an increase in the patient's global assessment score by at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale

Time frame: 48 weeks

Population: Participants with baseline and 48 week values.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Sham	Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness	OMERACT-OARSI responders	37 Participants
Sham	Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness	OMERACT-OARSI non-responders	18 Participants
PLIUS	Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness	OMERACT-OARSI responders	38 Participants
PLIUS	Co-Primary Measure: a) Symptom Reduction: OMERACT-OARSI Treatment Responsiveness	OMERACT-OARSI non-responders	16 Participants

Comparison: Sample size has been calculated with ranking and selection methodology, a procedure used for Phase II trials. The purpose of the procedure as applied to this study is to identify whether PLIUS has a high probability of being more effective than sham. This is accomplished by obtaining sample estimates of the outcome for the PLIUS and sham groups and determining whether the PLIUS group outcome is better by the pre-specified margin of difference.

Primary

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

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.

Time frame: Baseline, 48 weeks

Population: Participants with baseline and 48 week value

Arm	Measure	Value (MEAN)	Dispersion
Sham	Co-Primary Measure: b) Disease Modification as Measured by Change From Baseline in Cartilage Thickness of the Central Medial Femoral Condyle Disease	-42.2 μm	Standard Deviation 297
PLIUS	Co-Primary Measure: b) Disease Modification as Measured by Change From Baseline in Cartilage Thickness of the Central Medial Femoral Condyle Disease	-73.8 μm	Standard Deviation 168.1

Secondary

Change From Baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) Constant Pain Subscale

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.