Trial of Oral Hyaluronic Acid for the Prevention of Aromatase Inhibitor-Associated Arthralgias

Study Overview
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Brief Summary
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This is a single center, double-blinded, placebo-controlled, randomized Phase II trial to determine whether oral hyaluronic acid will prevent aromatase inhibitor (AI)-associated arthralgias. Subjects must have ER/PR-positive breast cancer tumor with history of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) which resolved after cessation of their AI (anastrazole or letrozole) within 90 days of enrollment. Subjects will be stratified by initial AI, thus within each initial AI, subjects will be randomized to receive either the experimental treatment (hyaluronic acid) or placebo. Subjects will begin the assigned treatment for 2 weeks prior to transitioning to the second AI. Evaluations will be taken at baseline, 6 weeks (1 month on study drug and AI), 14 weeks (3 months on study drug and AI), and at 26 weeks (6 months on study drug and AI). Treatment with hyaluronic acid and placebo will last for 26 weeks total.

Detailed Description
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Primary Objective To determine whether oral HA will prevent AI-induced arthralgias and preserve physical function. Secondary Objectives To explore whether oral HA will have an acceptable safety and tolerability profile. To determine whether oral HA will prevent other AI associated symptoms as assessed by patient reported outcomes (PRO's). To assess how many of the subjects are 90% compliant with taking the HA as directed. Exploratory Objective To determine if mi486, (a microRNA enriched in skeletal muscle) and other biomarkers associated with AIMSS (TNF, IL-6, IL-17) vary with the administration of HA.

Official Title
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Single Center, Placebo-Controlled Trial of Oral High-Molecular Weight Hyaluronic Acid for the Prevention of Aromatase Inhibitor-Associated Arthralgias

Conditions
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Breast Neoplasm Female, Arthralgia

Intervention / Treatment
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* Drug: Hyaluronic Acid (HA)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Study Population ER/PR-Positive Breast Cancer Subjects whose AIMSS resolved with cessation of their AI and are candidates for switching to a different AI and who meet the inclusion and exclusion criteria will be eligible for participation in this study. Inclusion Criteria Age ≥ 18 years old. Had been taking anastrazole or letrozole, and discontinued it within the past 90 days due to pain and/or stiffness. The AI-related pain/stiffness must have resolved. Prior tamoxifen use is allowed. A prior switch from exemestane is allowed. Women who have undergone a total mastectomy or breast conserving surgery for Stage 0-3 breast cancer +/- chemotherapy, +/- antiHer2Neu therapy, +/- radiotherapy. Must have ER and/or PR positive tumors. Women who are postmenopausal by the presence of natural amenorrhea ≥ 12 months or by ovarian ablation (bilateral oophorectomy, radiation, or administration of a gonadotropin-releasing hormone agonist). Eastern Cooperative Oncology Group Performance Score (ECOG PS) 0-3 (Appendix II). Patients may or may not be taking non-opioid analgesics. Adequate renal and hepatic function: i) Include only subjects with AST and ALT < 2.0 × ULN; AP < 1.5 × ULN; total bilirubin < 1.2 × ULN ii) Include only subjects with as calculated creatinine clearance (CrCl) > 60 mL/min determined by the central laboratory using the modified Cockcroft-Gault equation; blood urea nitrogen (BUN) < 1.5 × upper limit of normal (ULN) Written informed consent from subject and ability for subject to comply with the requirements of the study. Exclusion Criteria Presence of residual or recurrent cancer. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Consumption of HA-containing supplements in the four weeks prior to study. Known allergy to microcrystalline cellulose or HA. Any questionable reaction to injected HA will be thoroughly investigated. Prolonged systemic corticosteroid treatment, except for topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airway diseases), eye drops or local insertion (i.e., intra-articular). A short duration of systemic corticosteroids is allowed but not within 30 days prior to registration. Self-reported compliance issues and lack of regular prescription filling. Previous diagnosis of fibromyalgia and/or rheumatoid arthritis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hyaluronic Acid<br>Subjects in this arm will be given 100 mg of hyaluronic acid in capsule form. Subject in this arm will be asked to 1 capsule take twice daily for 26 weeks. | Drug: Hyaluronic Acid (HA)<br>* Dosage form: hyaluronic capsules; Dose: 100 mg; Frequency: twice daily; Duration: 26 weeks<br>|
| Placebo Comparator: Placebo<br>Subjects in this arm will be given a placebo comparator capsule that is identical to the hyaluronic capsule containing microcrystalline cellulose as the sole ingredient. Subjects in this arm will be asked to take 1 capsule twice daily for 26 weeks. | Other: Placebo<br>* Dosage form: microcrystalline cellulose (MCC) capsules; Dose: approx. 100 mg (determined by weight of HA counterpart); Frequency: twice daily; Duration: 26 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in mean change in joint pain between HA and placebo groups | As measured by the Brief Pain Inventory - Short Form (BPI-SF) questions #3-#6, #9A-G. This 14-item questionnaire was developed for use in patients with cancer that uses a scale from 0 to 10 to assess worst pain, pain severity, and pain interference over the past week. The first 8 items have to do with the severity of the pain, and the remaining 7 items ask about how the pain has affected function. | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (i.e. safety and tolerability of HA) | Summary of adverse events as measured by CTCAE v4.0 | 30 weeks | 
| Difference in mean joint symptoms between HA and placebo groups | As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) scores. This questionnaire assesses the three domains of pain, stiffness, and physical function in the lower extremities over the past 7 days. It is scored from 0 to 100, with higher scores indicating worse symptoms. | 6, 14, and 26 weeks | 
| Difference in mean joint function between HA and placebo groups | As measured by Disabilities of the Arm, Shoulder, and Hand questionnaire (QuickDASH) scores. This 11-item instrument assesses physical function and symptoms in patients with musculoskeletal disorders of the upper limbs. It is a questionnaire scored from 1 to 5, with the higher score indicating worse symptoms, and there is a validated method to calculate a single Disability/Symptom Score. | 6, 14, and 26 weeks | 
| Difference in mean quality of sleep between HA and placebo groups | As measured by Pittsburgh Sleep Quality Index (PSQI) scores. This an 18-item instrument produces a global sleep-quality score and the following component scores: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medications, and daytime dysfunction. | 6, 14, and 26 weeks | 
| Difference in global change between HA and placebo groups | As measured by Patient's Global Impression of Change scale (PGIC) scores | 6, 14, and 26 weeks | 
| Difference in mean change in WOMAC subscale 1 scores between HA and placebo groups | As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) subscale 1 scores. As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) scores. This questionnaire assesses the three domains of pain, stiffness, and physical function in the lower extremities over the past 7 days. It is scored from 0 to 100, with higher scores indicating worse symptoms. | 6, 14, and 26 weeks | 
| Difference in mean change in WOMAC subscale 2 scores between HA and placebo groups | As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) subscale 2 scores. As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) scores. This questionnaire assesses the three domains of pain, stiffness, and physical function in the lower extremities over the past 7 days. It is scored from 0 to 100, with higher scores indicating worse symptoms. | 6, 14, and 26 weeks | 
| Difference in mean change in WOMAC subscale 3 scores between HA and placebo groups | As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) subscale 3 scores. As measured by Western Ontario and McMaster osteoarthritis index (WOMAC) scores. This questionnaire assesses the three domains of pain, stiffness, and physical function in the lower extremities over the past 7 days. It is scored from 0 to 100, with higher scores indicating worse symptoms. | 6, 14, and 26 weeks | 
| Time to discontinuation of second aromatase inhibitor due to AIMSS between HA and placebo groups | As measured by patient self-report of mediation compliance (medication diary) and chart review | 26 weeks | 
| Proportion of patients that remain on second aromatase inhibitor between HA and placebo groups | As measured by patient self-report of mediation compliance (medication diary) and chart review | 26 weeks | 
| Rate of 90% compliance between HA and placebo groups | As measured by patient self-report of mediation compliance (medication diary) | 26 weeks | 
| Mean frequency of as needed analgesia between HA and placebo groups | As measured by patient self-report of mediation compliance (medication diary) | 6, 14, and 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aromatase Inhibitors