Can we Use Estrogen-containing Therapy to Improve Pain in Women After Menopause With Hand Osteoarthritis?

Study Overview
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Brief Summary
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Post-menopausal women aged 40-65 with symptomatic hand osteoarthritis are invited to take part in this feasibility study. The study's aim is to investigate whether it is acceptable to women with painful hand OA to take an estrogen-containing therapy, and what is the best way of collecting some of the information in order to facilitate planning a full size trial. The investigator's long-term aim is to find out whether giving estrogen-containing therapy to women after the menopause improves hand OA symptoms.

Official Title
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Hand Osteoarthritis: Investigating Pain Effects in a Randomised Placebo-controlled Feasibility Study of an Estrogen-containing Therapy

Conditions
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Hand Osteoarthritis

Intervention / Treatment
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* Drug: Estrogen-bazedoxifene
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to give informed written consent Female, aged 40-65 years old In those with an intact uterus: At least 12 months of spontaneous amenorrhea (without any menstrual bleeding in last 12 months) and last menstrual period not more than 10 years ago In those who have undergone hysterectomy or are/were using an intrauterine contraceptive device with progesterone local therapy (such as Mirena): Follicle stimulating hormone (FSH) ≥30 milli-International Units per millilitre (mIU/ml) on screening blood test AND a history of menopausal symptoms in the last 1 to 10 years, in keeping with appropriate timing of menopausal status Hand pain, aching or stiffness on most days in the last 3 months At least 2, painful hand joints of any type (interphalangeal joints (IPJ) or base of thumbs) Fulfils American College of Rheumatology clinical diagnostic criteria for hand OA (3 or more of following): Hard tissue enlargement of 2 or more of the following joints: 2nd or 3rd distal interphalangeal joints (DIPJ), 2nd or 3rd proximal interphalangeal joints (PIPJ), first carpometacarpal joints (CMCJ) Hard tissue enlargement of 2 or more of the DIPJs Less than 3 swollen metacarpophalangeal joints (MCPJ) Deformity of at least one of the joints listed in first point OR, for those with base of thumb osteoarthritis only not fulfilling these criteria, has clinical symptoms and examination findings consistent with base of thumb osteoarthritis. Hand pain has not responded adequately to National Institute for Health and Care Excellence core guidance for management of OA, including the use of paracetamol or non-steroidal anti-inflammatory drug (NSAID) gel, except where there is contraindication or intolerance Average hand pain is reported as typically more than 4 out of 10 in severity, or average hand pain in the last 7 days of 4/10 or more on a visual analogue scale In the Investigator's opinion, is able and willing to comply with all study requirements Exclusion criteria Other cause of hand pain, including inflammatory arthritis, connective tissue disorder, chronic pain or alternative clinical diagnosis such as tenosynovitis or carpal tunnel syndrome Pregnancy or breast feeding, or risk of this during study Use of one or more prohibited treatments within specified timeframe, or not willing to avoid treatment for the duration of the study: Oral contraceptive pill, or systemic HRT within the last 6 months (Use of an intrauterine contraceptive device with progesterone local therapy (Mirena) or vaginal topical estrogen use (known low systemic absorption) are not exclusions to participation) Anti-estrogen medication within the last 6 months Oral, intramuscular or intraarticular steroid within the last 3 months Intraarticular hyaluronan to a hand joint within the last 6 months Initiation of new oral analgesia within the last 4 weeks Initiation of glucosamine, chondroitin, hand exercises or other relevant non- pharmacological therapy within the last 6 weeks Hand surgery within the last 6 months, or planned within the next 6 months Medications likely to increase hepatic metabolism of study medication, including: St. John's Wort Anti-convulsants (phenobarbital, phenytoin, carbamazepine, lamotrigine) Some anti-infectives (rifampicin, rifabutin, nevirapine, efavirenz, ritonavir and nelfinavir) Presence of one or more medical contraindications to the use of systemic hormonal replacement therapy: In those aged 40-45 years, FSH <30 mIU/ml on screening blood test, i.e. non- confirmatory of menopausal status Any history of breast, endometrial, ovarian or skin cancer Any other history of other cancer within 5 years (except treated Basal Cell Carcinoma, BCC) Relevant breast issue on routine national breast screening in prior 3 years Undiagnosed genital bleeding, or untreated endometrial hyperplasia, active uterine fibroids or endometriosis Active or past history of venous thromboembolism (VTE) (including deep venous thrombosis, pulmonary embolism and retinal vein thrombosis), or at high risk of VTE (such as known thrombophilic disorders (such as Protein C, S or anti-thrombin deficiency) or presence of a strong family history of VTE). Women with a first degree relative with a history of VTE, or other strong family history of VTE at the Investigators' discretion. Active or past history of arterial thrombo-embolic disease (such as myocardial infarction, angina or stroke) or strong family history of stroke) Clinically significant immobility Migraine or active epilepsy Uncontrolled hypertension (or diastolic pressure greater than 90 mmHg or systolic pressure greater than 145 mmHg at screening visit) Uncontrolled diabetes mellitus or uncontrolled hypertriglyceridaemia Body Mass Index (BMI) greater than 30 Active malabsorption syndrome or clinically significant small bowel disease Acute liver disease, clinically significant abnormal liver function, active gallbladder disease or porphyria Clinically significant renal impairment Intolerance to lactose, fructose or glucose (including galactose intolerance, lactase deficiency, fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency) Known sensitivity to either conjugated equine estrogens, bazedoxifene or the combination Any other significant or uncontrolled disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study Participants who have participated in another research trial involving an investigational product in the past 8 weeks

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estrogen-bazedoxifene<br>Tablet, once daily for 6 months. | Drug: Estrogen-bazedoxifene<br>* Conjugated estrogens 0.45 mg-bazedoxifene acetate 20 mg.<br>* Other names: Duavive;|
| Placebo Comparator: Placebo<br>Closely matched tablet, once daily for 6 months. | Drug: Placebo oral tablet<br>* Placebo oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility: Rates of eligible participant identification, rates of recruitment/randomisation from different sources, retention rates |  | From the date of recruitment opening until the date of recruitment closing, 1 year | 
| Feasibility: Frequency of adverse events related to the active study medication |  | Through study completion, 7 months | 
| Feasibility: Bang's Blinding Index (likelihood of unblinding) | Self-complete questionnaire which assesses likelihood that participant or Investigator have become unblinded | Week 24 | 
| Feasibility: Monitoring study medication compliance (via diaries) | Participants will be asked to record any missed doses of study medication on a paper diary which will be provided at each visit. We will ask participants to bring the diary to each study visit and any missed doses will be recorded in the Case Report Form. | From randomisation to end of treatment at Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain and function: Average hand pain over last 14 days (NRS 0-10) | Numerical Rating Scale 0-to-10, where 0 is no pain and 10 is pain as bad as you can imagine | Collected at: Baseline, Week 4, Week 12, Week 24 | 
| Pain and function: Remote pain-rating prior to a visit (NRS 0-10) | Numerical Rating Scale 0-to-10, where 0 is no pain and 10 is pain as bad as you can imagine | Collected at: Baseline, Week 4, Week 12, Week 24 | 
| Pain and function: Prevalence of joint pain elsewhere (pain manikin) | Prevalence of joint pain elsewhere in the 4 weeks preceding the study visit | Collected at: Baseline, Week 12, Week 24 | 
| Pain and function: Functional Index for Hand OA (FIHOA) | Validated measurement of hand OA-related functional impairment. It includes 10 questions scored according to a 4-grade scale. The score ranges from 0 (no functional impairment) to 30 points (maximal impairment). | Collected at: Baseline, Week 12, Week 24 | 
| Pain and function: EQ-5D-5L | Validated measurement of quality of life across five dimensions and their associated levels of severity on a 1 (no problems) to 5 (extreme problems) scale. | Collected at: Baseline, Week 12, Week 24 | 
| Menopause symptoms: The Menopause Specific Quality of Life Questionnaire (MENQOL) | Validated measurement of menopausal symptoms and their associated degree of severity; 30 items in a Likert-scale format. Items are rated as present or not present and if present how bothersome, on a 0 (not bothersome) to 6 (extremely bothersome) scale. The interventional version is being used here, which includes an additional 3 questions relevant to Hormonal Replacement Therapy (HRT) use which has been used in a trials setting. | Collected at: Baseline, Week 12, Week 24 | 
| Menopause symptoms: Greene Climacteric Scale | A 21-item validated questionnaire that measures a variety of menopausal symptoms on a 4-point Likert scale (0 = not at all to 3 = extremely), plus one sexual function probe. | Collected at: Baseline, Week 12, Week 24 | 
| Joint appearance: Cosmesis score of Michigan Hand Questionnaire (4 questions, questions 28-31) | Subdomain of hand-specific outcomes instrument that measures outcomes of patients with conditions of, or injury to, the hand or wrist. | Collected at: Baseline, Week 12, Week 24 | 
| Joint appearance: Investigator-recorded tender and swollen joint counts | Investigator examination of tender and swollen hand joints, binary recording (1 swollen, 0 not swollen). | Collected at: Baseline, Week 12, Week 24 | 
| Joint appearance: Photographic recording of swollen hand joints | Standardised digital photography of hands | Collected at: Baseline, Week 12, Week 24 | 
| Joint function: Jamar grip strength - average of 3 measurements | Handgrip strength will be measured in kilograms to the nearest hundred grams in both hands using a Jamar dynamometer. Both hands will be alternately assessed three times and the average score recorded. | Collected at: Baseline, Week 12, Week 24 | 
| End of Treatment questionnaire (study-specific) | A study specific end of treatment questionnaire will be designed to include items on acceptability. | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis, Hand, Hormone, Pain, Estrogen