PB125, Osteoarthritis, Pain, Mobility, and Energetics

Study Overview
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Brief Summary
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Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator in the body. It controls how well cells protect themselves against stress. PB125 (Pathways Bioscience) is a plant based activator of this important regulator Nrf2. PB125 is made up of three plant extracts (rosemary, ashwagandha, and Sophora japonica) so that it contains these things; 1. Carnosol, 2. Withaferin A, and 3. Luteolin. Carnosol comes from rosemary leaves. Rosemary is a spice often used in Italian foods and grown in many herb gardens all around Fort Collins. Withaferin A comes from the medicinal plant Withania somnifera, also called ashwagandha. Ashwaganda is commonly known as Indian Winter cherry or Indian Ginseng and it is one of the most important herbs of Ayurveda (the traditional system of medicine in India) used for millennia. Finally, luteolin is found widely in plants including those present in the diet (peppers, onions, celery, herbs/spices). Some people purchase these herbs commercially, and take them on their own for a variety of purposes. Typically, when you buy them, they will be in much higher doses than they are in PB125. What makes PB125 different is that very low doses of each of the 3 components work together-synergistically-to activate Nrf2 and increase the ability of cells to respond to stress. It is unknown if there are any benefits to taking PB125 and the risks are currently unknown. The purpose of this study is to examine changes in muscle, in joint pain, in mobility (standing and walking) and in leg strength that occur after consuming PB125 every day for 3 months. We want to make these measurements in people who have been diagnosed with mild to moderate osteoarthritis-a degenerative joint disease-in their knees.

Detailed Description
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Preventing or slowing age-related decline in musculoskeletal function is important for maintaining mobility and independence. In the US, osteoarthritis (OA) is the primary cause of disability in adults, with no medical or surgical therapeutic intervention known to restore the degenerated cartilage. The loss of skeletal muscle mass and function with age, is also linked to increased risk of other diseases, risk of falls, and decreased quality of life. Therefore, OA and muscle loss together are primary contributors to age-related decreases in mobility and independence. Evidence suggests a decrease in muscle quality is associated with or precedes primary knee OA, suggesting that these two conditions may share a common cause. We will treat 50-65 year old people with mild or moderate OA in both knees, and reported loss of muscle strength, with a supplement already available for use in humans to reduce oxidative stress and inflammation. The supplement is called PB125. In this pilot clinical trial, we will measure the ability of muscle to make energy, measure mobility (walking and standing) and strength, and assess pain following PB125 or placebo treatment.

Official Title
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Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activation, Mobility, and Energetics: A Pilot and Feasibility Clinical Trial of PB125 Treatment for Improving Musculoskeletal and Pain Outcomes in Osteoarthritis

Conditions
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Osteoarthritis, Knee, Muscle Weakness, Pain, Joint

Intervention / Treatment
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* Dietary Supplement: PB125
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: bilateral knee osteoarthritis Exclusion Criteria: smoking pregnant/breastfeeding BMI >30 known liver, renal, heart disease, diabetes, autoimmune disease, cancer use of methotrexate, etanercept, infliximab, leflunomide, plaquenil recent serious illness intraarticular stem cell injection intraarticular steroid or hyaluronic acid injection within 4 months current enrollment in another trial of investigational drugs known hypersensitivity to ashwagandha, luteolin, rosemary, or rice flour use of anticoagulants or known bleeding disorder unwillingness to comply with protocol plans for knee replacement in the next 3 years unable to complete mobility testing without ambulatory aid unable to climb 1-2 flights or stairs without stopping/shortness of breath/discomfort blood product transfusion within 30 days unable to provide legal consent

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Primary comparisons will be between pre-test and post-test measures. We had initially planned control group comparisons as well, but the pandemic has cut this pilot study short of budget and time. Therefore, the primary comparisons will now be pre-test to post-test to maximize the number of participants enrolled to receive the experimental treatment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PB125<br>Twice daily oral administration of 1 capsule of PB125 (Pathways Bioscience). Treatment will last 12 weeks. | Dietary Supplement: PB125<br>* Nrf2 activator containing active ingredients carnosol, withaferin A, and luteolin.<br>|
| Placebo Comparator: Placebo<br>Twice daily oral administration of 1 capsule of rice flour placebo (Pathways Bioscience). Treatment will last 12 weeks. Because of pandemic restricting study time frame, enrollment will favor the experimental arm in this pilot study | Dietary Supplement: Placebo<br>* Placebo comparator to P125<br>* Other names: Flour;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mobility-6 min self-paced walk | Change in Distance walked | Change from baseline at 12 weeks | 
| Mobility-sit to stand | Change in Time for 5 sit to stand repetitions | Change from baseline at 12 weeks | 
| Mobility-static balance | Yes/No ability to complete 30 sec trials with eyes open or closed on firm and foam surfaces | Change from baseline at 12 weeks | 
| Mobility-6 min fast-paced walk | Change in Distance walked | Change from baseline at 12 weeks | 
| Intermittent and Constant Knee Pain | Weekly change in Intermittent and Constant Pain Score (ICOAP) 11 question survey of pain on a 0-4 scale | Change weekly for 12 weeks | 
| Energetics-Submaximal Oxygen Consumption | Change in oxygen (O2) flux in permeabilized muscle fibers at submaximal adenosine diphosphate (ADP) concentrations | Change from baseline at 12 weeks | 
| Energetics-Maximal Oxygen Consumption | Change in O2 flux in permeabilized muscle fibers at maximal ADP concentrations | Change from baseline at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Energetics-hydrogen peroxide emission | Change in Hydrogen peroxide emission in permeabilized muscle fibers | Change from baseline at 12 weeks | 
| Bone Mineral Density | Bone mineral density via dual x-ray absorptiometry (DEXA) | Change from baseline at 12 weeks | 
| Knee Range of Motion | Change in active and passive bilateral knee range of motion | Change from baseline at 12 weeks | 
| Leg extensor strength | Change in maximal force generated during knee extension | Change from baseline at 12 weeks |