Plain English Summary
Background and study aims
As people age, their bones naturally become less dense in minerals, but for some people this can lead to osteoporosis, an advanced stage of a condition that leads to brittle bones that break (fracture) easily. It is often seen in women who have been through the menopause, or people who are at risk of osteoporosis due to various health or lifestyle factors. In older people, osteoporosis is often diagnosed following a minor fall which has led to a bone fracture. The bones most often fractured are those of the hips and spine, and these injuries cause problems for millions of people around the world (9 million every year) as a result of pain, hospital admissions, lack of independence at home or the need to move into sheltered/nursing home care. There are some similarities between the bones of older people and the bones of people taking steroid medications. This is because steroids reduce bone mineral density. A new drug called AZD4017 has been developed to reduce the level of steroids that are naturally produced by the body in local tissues; it may help to reduce the loss of bone mineral density that occurs as people age. The aim of this study is to look at the effect of AZD4017 on bones in women diagnosed with osteopaenia, a condition where some bone density has been lost but it has not yet progressed to the stage of osteoporosis.
Who can participate?
Women aged 50 and over diagnosed with osteopaenia
What does the study involve?
Participants are randomly allocated into one of two groups. Those in group 1 (intervention group) are given the drug AZD4017 to take for 90 days. Those in group 2 (control group) are given a placebo (dummy tablet with no drug in it) to take for 90 days. Participants have 5 visits to the clinic while taking the drug, and another 3 months later. Participants have blood tests and scans to check the effect of AZD4017 on bones, and urine tests to make sure that steroid production in the tissues is reduced in response to the drug. Participants also have muscle tests (walk, stand and grip tests) to see if blocking steroid production improves muscle strength.
What are the possible benefits and risks of participating?
AZD4017 has the potential to be developed into an effective treatment for patients with osteoporosis and high fracture risk. The participants involved in this study are not at high risk of fracture, and as such, are unlikely to gain any direct benefits.
Where is the study run from?
1. Northern General Hospital (UK)
2. Chapel Allerton Hospital (UK)
When is the study starting and how long is it expected to run for?
May 2015 to December 2017
Who is funding the study?
Medical Research Council (MRC) (UK)
Who is the main contact?
Dr L Flanagan
Trial website
Additional identifiers
EudraCT number
2013-003387-32
ClinicalTrials.gov number
Protocol/serial number
15665
Study information
Scientific title
Phase II study of the impact of AZD4017, a selective 11bHSD1 inhibitor, on biochemical markers of bone turnover in post-menopausal osteopaenia
Acronym
Study hypothesis
The drug AZD4017, which reduces steroid production in tissue, may reverse some of the bone changes that are seen with aging and improve muscle strength.
Ethics approval
Multicentre Research Ethics Committee (MREC), 11/11/2013, ref: 13/SC/0523
Study design
Randomised interventional treatment study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Osteoporosis
Intervention
Participants will take AZD4017, a selective 11ß-HSD1 inhibitor, for 90 days. Control group participants will take a placebo (dummy tablet with no drug in it) for 90 days.
Intervention type
Drug
Phase
Phase II
Drug names
AZD4017
Primary outcome measure
Change from baseline in serum osteocalcin after 90 days.
Secondary outcome measures
1. Change from baseline in serum ßCTx after 90 days
2. Change in bone density, microstructure and strength after 180 days
3. Change in bone remodelling after 90 days
4. Change in muscle strength after 90 days
Overall trial start date
29/05/2015
Overall trial end date
30/04/2016
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current inclusion criteria as of 21/06/2017:
1. Provision of informed consent prior to any study specific procedures
2. Aged >50 and post-menopausal based on amenorrhoea for >12 months
3. Documented presence of osteopenia (BMD T-score at lumbar spine and/or total hip of less than or equal to -1 and greater than -2.5) as measured by DXA
4. Placebo treatment for the duration of the study must not be considered detrimental to the study participant
5. Must be able to understand the patient information sheet and consent form and comply with study requirements
Previous inclusion criteria:
1. Provision of informed consent prior to any study specific procedures
2. Aged >50 and postmenopausal based on amenorrhoea for >12 months
3. Documented presence of osteopaenia (bone density T-score at lumbar spine or hip of less than -1 and greater than -2.5 by Dual-energy X-ray Absorptiometry (DXA) criteria)
4. Placebo treatment for the duration of the study must not be considered detrimental to the study subject
5. Must be able to understand the patient information sheet and consent form and comply with study requirements
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
Planned Sample Size: 100; UK Sample Size: 100
Participant exclusion criteria
Current exclusion criteria as of 21/06/2017:
Bone-related exclusion criteria:
1. Clinical or biochemical evidence of secondary causes of bone loss (screening tests to include but are not restricted to: normal serum sodium, potassium, urea, creatinine (eGFR at >60 mls/min), LFTs, ALP, TFTs; free T4 and TSH), FBC and ESR (<40mm/hr))
2. Vitamin D deficiency (defined as a 25-OH vitamin D level of <20nmol/L)
3. The current or recent use (within the last 2 years) of medication likely to have an impact on bone (oestrogens, aromatase inhibitors, bisphosphonates, fluoride, denosumab, strontium ranelate, anti-convulsants; and oral, inhaled or nasal glucocorticoids). Participants already on calcium/vitamin D supplementation will be asked to continue this for the duration of the study. Those with a 25-OH vitamin D level of 20-50nmol/L at screening will be supplemented prior to inclusion. Medications will be reviewed at the screening visit
4. Bilateral fractures of the radius and/or tibia
General exclusion criteria:
1. Women of child-bearing potential (WOCBP). Note: WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea≥ 12 consecutive months or women on hormone replacement therapy with documented serum follicle stimulating hormone level >35 mIU/mL)
2. Have an estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease (GFR calculation) using theMDRD equation of <60ml/min/1.73m2
3. Have any endocrine disorder that would merit therapy according to national guidelines. The only exception to this is patients with hypothyroidism on treatment with thyroid function tests within normal parameters for a minimum of 3 months
4. Suspicion of, or known Gilbert's disease
5. CK >2 x ULN on 2 consecutive measurements
6. ALT and/or AST > 1.5*ULN
7. ALP > ULN
8. Bilirubin (total) > 1.5*ULN
9. Participant is, at the time of signing the informed consent, a user of recreational or illicit drugs (including marijuana) or has had a recent history (within the last year) of drug or alcohol abuse or dependence, on questioning or clinical history
10. Have uncontrolled systemic hypertension (BP >150/90) on 3 successive measurements on the morning of the screening visit. Note: Participants with controlled hypertension (BP of 150/90 or better on same treatment for 3 months) may be included, and should continue on the same anti hypertensive medication for the duration of the study. Thus, if hypertension is identified at screening and the hypertension is then treated and remains controlled for 3 months, then the patient may enter screening again
11. Are receiving systemic (including vaginal/rectal) or inhaled glucocorticoid treatment at the time of the screening visit. Note: Topical (skin) application of mild, over-the-counter topical steroid containing medication to small localised areas of the skin is permitted
12. Are taking probenecid at the time of the screening visit
13. Have any screening laboratory abnormality which is outside the local reference ranges specified in the Investigator Site File that, in the investigator’s judgement, is considered to be clinically significant
14. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results of the participant’s ability to participate in the study. Specifically, a diagnosis of any inflammatory disorder that might reasonably need treatment with glucocorticoids during the course of the study, should be considered for exclusion
15. History or presence of any significant gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
16. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP as judged by the investigator
17. Have known hypersensitivity or intolerance to 11β-HSD1 antagonists or to AZD4017
18. Have been involved in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
19. Have participated in any other clinical study within 1 month prior to the screening visit
20. Previous randomisation for treatment in the present study
Previous exclusion criteria:
Bone-related exclusion criteria:
1. Clinical or biochemical evidence of secondary causes of bone loss
2. 25-OH vitamin D level <20nmol/L
3. The current or recent use (within 2 years) of medication likely to have an impact on bone (oestrogens, aromatase inhibitors, bisphosphonates, fluoride, denosumab, strontium ranelate, anti-convulsants, teriparatide; and oral, inhaled or nasal glucocorticoids). Patients already on calcium/vitamin D supplementation will continue this for the study. Those with a 25-OH vitamin D level of 2050nmol/L at screening will be supplemented prior to inclusion
General exclusion criteria:
1. Women of child-bearing potential
2. eGFR calculated by MDRD equation <60ml/min/1.73m2
3. Any endocrine disorder, e.g. thyroid dysfunction
4. Suspicion of or known Gilbert's disease
5. CK > twice upper limit normal on 2 consecutive measurements
6. Liver transaminases > upper limit normal
7. Alkaline phosphatase > upper limit normal
8. Bilirubin (total) > upper limit normal
9. User of recreational or illicit drugs (including marijuana) or has had a recent history (within the last year) of drug or alcohol abuse or dependence
10. Uncontrolled systemic hypertension (BP >150/90); on 3 successive measurements on the morning of the screening visit
11. Systemic (including vaginal/rectal) or inhaled glucocorticoid treatment at the time of the screening visit
12. Probenicid therapy at the time of the screening visit
13. Any screening laboratory abnormality that, in the investigator’s judgement, is considered to be clinically significant
14. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results of the subject’s ability to participate in the study. Specifically, a diagnosis of any inflammatory disorder that might reasonably need treatment with glucocorticoids during the course of the study
15. History of any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
16. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of
IP as judged by the investigator
17. Hypersensitivity or intolerance to 11ß-HSD1 antagonists or to AZD4017
18. Involvement in the planning and/or conduct of the study
19. Participation in any other clinical study within 1 month prior to the screening visit
20. Previous randomisation for treatment in the present study
Recruitment start date
29/05/2015
Recruitment end date
01/12/2017
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom
Trial participating centre
Chapel Allerton Hospital
Chapeltown Road
Leeds
LS7 4SA
United Kingdom
Funders
Funder type
Research council
Funder name
Medical Research Council
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list