Testosterone in Treating Postmenopausal Patients With Arthralgia Caused by Adjuvant Aromatase Inhibitor Treatment

Study Overview
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Brief Summary
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This randomized phase III trial studies testosterone to see how well it works compared to placebo in treating postmenopausal patients with arthralgia (joint pain) caused by anastrozole or letrozole. Testosterone may help relieve moderate or severe arthralgia associated with the use of aromatase inhibitors, such as anastrozole or letrozole.

Detailed Description
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This is a randomized, placebo-controlled, phase III trial evaluating subcutaneous testosterone for the alleviation of aromatase inhibitor induced arthralgia. A parallel group design will be utilized for this two-arm study: subcutaneous testosterone vs. placebo. Patients are stratified according to baseline pain score (5-6 vs. 7-10) and age (< 50 vs. 50-60 vs. > 60). The primary objective is to determine whether testosterone will reduce AI-induced arthralgia and associated joint symptoms. The secondary objective is to explore whether testosterone will have an acceptable safety and tolerability profile, with particular reference to androgenic adverse events including acne, hirsutism, and alopecia. Patients are followed up to six months as defined in the protocol.

Official Title
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Randomized Double-Blind Placebo Controlled Study of Testosterone in the Adjuvant Treatment of Postmenopausal Women With Aromatase Inhibitor Induced Arthralgias

Conditions
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Arthralgia, Breast Cancer, Hot Flashes, Musculoskeletal Complications, Sexual Dysfunction

Intervention / Treatment
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* Drug: testosterone
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Receiving anastrozole (1mg) or letrozole (2.5 mg) orally once a day, for ≥ 21 days prior to registration and plan to continue it throughout the duration of study Body Mass Index (BMI) between 18 and 35 kg/m^2 Women who have undergone a total mastectomy or breast conserving surgery for primary breast cancer +/-chemo, +/-radiotherapy. Must have BOTH ER and PR receptor-positive tumors and BOTH must be ≥26% positive. Alternatively, if ER and PR are determined by Allred score, the score needs to be 5 or higher Women who are postmenopausal by surgery, radiotherapy or presence of natural amenorrhea ≥ 12 months ≥ 5/10 arthralgia (in hands, wrist, knees, or hips) while being treated with anastrozole or letrozole which is felt by the patient to be caused by their aromatase inhibitor as defined in the protocol. Note: Patients may, or may not, be taking non-opioid analgesics Ability to complete questionnaire(s) by themselves or with assistance ECOG Performance Status (PS) 0, 1 or 2 Willing to provide informed written consent Willing to return to an Alliance enrolling institution for follow-up Willing to provide blood samples for correlative research purposes Laboratory values prior to registration as defined in the protocol: Creatinine ≤1.5 x ULN Hemoglobin > 11 g/dL WBC > 3.0 Platelet Count > 100,000 SGOT (AST) ≤ 1.5 x ULN Exclusion Criteria: Presence of residual or recurrent cancer (locally or metastatic) Diabetes mellitus or glucose intolerance, defined as a fasting glucose >125 mg/dL History of coronary artery disease (angina or myocardial infarction) Patients on hormone replacement therapy (HRT) ≤ 4 weeks prior to registration. This includes the use of vaginal estrogen therapy. Known hypersensitivity to any component of testosterone. 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 (e.g. intra-articular). Note: Short duration (< 2 weeks) of systemic corticosteroids is allowed (e.g. for chronic obstructive pulmonary disease) but not within 30 days prior to registration. Receiving any other investigational agent History of a deep venous thrombosis or a thromboembolism Concurrent use of the aromatase inhibitor exemestane, as it is structurally similar to an androgen Concurrent radiation therapy or chemotherapy Current or planned use of cyclosporine, anticoagulants, oxphenbutazone, insulin, oral or injectable vitamin D doses over 4,000IU/day, or tamoxifen

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive testosterone (0.264mL) topical application daily for six months. | Drug: testosterone<br>* 10.4 mg<br>|
| Placebo Comparator: Arm II<br>Patients receive placebo (0.264mL) topical application daily for six months. | Other: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Item #3 (Average) of the Brief Pain Inventory (BPI) Average Pain From Baseline to Month 3 | The average change in Brief Pain Inventory (BPI) Average Pain scores between baseline and month 3 using Wilcoxon test are reported for each arm below. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | From baseline to 3 months | 
| Improvement in BPI Average Pain From Baseline to Month 3 | 2. Was there an improvement in BPI Average Pain from baseline to month 3? | Up to 3 months | 
| Change in BPI Average Change From Baseline Pain Score to Month Six Average Pain Score | Change in BPI Average Change from Baseline Pain Score to Month Six Average Pain Score. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | Baseline and 6 months | 
| Change in BPI Average Pain From Baseline to Month 1-6 | Change in BPI Average Pain from baseline to month 1-6. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | Baseline and months 1-6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 Or Higher Adverse Events Considered At Least Possibly Related to Treatment | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below. | Up to 6 months | 
| Number of Patients Who Reported Alopecia Using CTCAE 4.0 | The number of patients who reported alopecia using CTCAE 4.0 is reported below for each arm. | Up to 6 months | 
| Number of Patients Who Reported Acne Using CTCAE 4.0 | The number of patients who reported acne using CTCAE 4.0 is reported below for each arm. | Up to 6 months | 
| Number of Patients Who Reported Hirsutism Using CTCAE 4.0 | The number of patients who reported hirsutism using CTCAE 4.0 is reported below for each arm by grade. | Up to 6 months | 
| Change in Hot Flash Frequency From Baseline to Week 8 | Change in hot flash frequency from baseline to week 8. Hot flash frequency is a count of the number of hot flashes per day and is a number from 0 to infinity. Higher values are worse. | baseline and week 8 | 
| The Change of Libido From Baseline to Month 3 as Measured by the MENQOL | Change in how bothered are you by decreased sex drive from baseline to month 3. This is assessed using one question off of the MENQOL (Menopause-Specific Quality of Life) questionnaire. The question asks How bothered are you by a decrease in your sexual drive. This is collected on a scale ranging from 0=Not at all bothered to 6=Extremely bothered, with higher values being worse. | baseline and month 3 | 
| The Change of Menopause Specific Quality of Life From Baseline to Month 3 as Measured by MENQOL How Bothered Are You by Hot Flashes | The change of menopause specific quality of life from baseline to month 3 as measured by MENQOL how bothered are you by Hot Flashes. This is one question from the MENQOL (Menopause-Specific Quality of Life) questionnaire. The question asks How bothered are you by hot flashes or flushes. This is collected on a scale ranging from 0=Not at all bothered t 6=Extremely bothered, with higher values being worse. | baseline and month 3 | 
| Change in BPI Worst Pain From Baseline to Month 3 | Change in BPI Worst Pain from baseline to month 3. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | baseline and month 3 | 
| Change in BPI Least Pain From Baseline to Month 3 | Change in BPI Least Pain from baseline to month 3. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | baseline and month 3 | 
| Change in BPI Pain Right Now From Baseline to Month 3 | Change in BPI Pain right now from baseline to month 3. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | baseline and month 3 | 
| Change in Average Joint Stiffness From Baseline to Month 3 as Measured by BPI Item #5 (Joint Stiffness) | Change in average joint stiffness from baseline to month 3. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | baseline and month 3 | 
| The Intrapatient Change in Activity Level (Interference of Activity) for Each Month From Baseline as Measured by Item#6 (Interference) of the BPI-AIA. | The intrapatient change in activity level (interference of activity) for each month from baseline as measured by item#6 (interference) of the BPI-AIA. Change in general activity from baseline to month 3. The BPI scales range from 0 to 10 with 0 meaning no pain and 10 meaning pain as bad as you can imagine. | baseline and month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hot flashes, musculoskeletal complications, sexual dysfunction, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, arthralgia, stage IA breast cancer, stage IB breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer