TICSI: Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition

Sponsor

University of Oxford (Other)

Overall Status

Completed

CT.gov ID

NCT03111810

Collaborator

AstraZeneca (Industry)

Enrollment

Location

Arms

38.2

Actual Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Currently, 2-3% of the population of the United Kingdom and United States of America receive glucocorticoid therapy. Significant adverse effects are not confined to chronic use; recurrent short-course administration is associated with increased morbidity and mortality. The adverse metabolic features associated with glucocorticoid use include obesity, skeletal muscle myopathy, hypertension, insulin resistance and diabetes and are collectively termed 'iatrogenic Cushing's syndrome'. The efficacy of glucocorticoid therapy is not in doubt, but there are no interventions to reduce their metabolic consequences. Within metabolic tissues (liver, skeletal muscle, adipose), 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid and therefore is able to tightly control the availability of glucocorticoids to activate the glucocorticoid receptor. In preclinical studies, the investigators have shown that 11β-HSD1 is critical in regulating the development of the adverse features associated with circulating glucocorticoid excess, endorsing our observations in a patient with Cushing's disease, who was protected from a classical phenotype due to a functional deficit in 11β-HSD1.

This study is the first clinical evaluation of the impact of the selective 11β-HSD1 inhibitor, AZD4017, in healthy volunteers taking exogenous glucocorticoids (prednisolone). The investigators propose that in tissues expressing high levels of 11β-HSD1, prednisolone action will be amplified, driving adverse effects within these tissues and have hypothesized that AZD4017 in humans will reduce the adverse metabolic consequences of Prednisolone administration without compromise to its anti-inflammatory action.

Our specific research objectives are:

To demonstrate the beneficial effect of the selective 11β-HSD1 inhibitor, AZD4017, upon the prednisolone-induced deterioration in metabolic phenotype, including glucose disposal and endogenous glucose production rates.
To determine the impact of AZD4017 on the anti-inflammatory actions of Prednisolone.
To identify the tissue-specific (skeletal muscle, adipose) mechanisms underpinning the response to Prednisolone therapy administered in conjunction with AZD4017.

The investigators will perform a randomized, double-blind placebo controlled study to determine if co-administration of the selective 11β-HSD1 inhibitor, AZD4017, limits the adverse effects of short-course exogenous glucocorticoid administration. 32 healthy male volunteers will have detailed metabolic investigations including 2-step hyperinsulinaemic euglycaemic clamps (with stable isotope measurements of lipid and carbohydrate metabolism), as well as assessment of skeletal muscle forearm glucose uptake. All volunteers will then be treated with Prednisolone (20mg daily) and randomized to the co-administration of placebo or AZD4017. After 1 week of therapy, all investigations will be repeated. Our hypothesis is that the adverse metabolic effects of Prednisolone will be reduced by co-administration of AZD4017.

Condition or Disease	Intervention/Treatment	Phase
Iatrogenic Cushing's Disease	Drug: AZD4017 and prednisolone Drug: Placebo Oral Tablet and prednisolone	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition (TICSI)

Actual Study Start Date :

May 25, 2017

Actual Primary Completion Date :

Aug 1, 2020

Actual Study Completion Date :

Aug 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active Prednisolone 20mg once daily and AZD4017 400mg twice daily for 7 days.	Drug: AZD4017 and prednisolone The drug AZD4017 will be given together with prednisolone 20mg daily for 7 days to compare its effects on metabolic tissues against the placebo arm where the participants will take placebo and prednisolone 20mg daily for 7 days. Other Names: 11 beta-Hydroxysteroid dehydrogenase inhibitor
Placebo Comparator: Placebo Oral Tablet Prednisolone 20mg once daily and placebo twice daily for 7 days.	Drug: Placebo Oral Tablet and prednisolone Placebo Oral tablet will be given together with prednisolone 20mg daily for 7 days to compare the effects on metabolic tissues of AZD4017 and prednisolone 20mg daily against the placebo arm. Other Names: Placebo

Arm

Intervention/Treatment

Active Comparator: Active

Prednisolone 20mg once daily and AZD4017 400mg twice daily for 7 days.

Drug: AZD4017 and prednisolone

The drug AZD4017 will be given together with prednisolone 20mg daily for 7 days to compare its effects on metabolic tissues against the placebo arm where the participants will take placebo and prednisolone 20mg daily for 7 days.

Other Names:

11 beta-Hydroxysteroid dehydrogenase inhibitor

Placebo Comparator: Placebo Oral Tablet

Prednisolone 20mg once daily and placebo twice daily for 7 days.

Drug: Placebo Oral Tablet and prednisolone

Placebo Oral tablet will be given together with prednisolone 20mg daily for 7 days to compare the effects on metabolic tissues of AZD4017 and prednisolone 20mg daily against the placebo arm.

Other Names:

Placebo

Outcome Measures

Primary Outcome Measures

Changes in the detrimental side effects of prednisolone by AZD4017. [2 years]
To evaluate whether AZD4017 can limit the detrimental effect of prednisolone (20mg) on glucose disposal. This will be achieved by measuring glucose disposal during a hyperinsulinaemic euglycaemic clamp.

Secondary Outcome Measures

Changes in hepatic insulin sensitivity by AZD4017 when given with prednisolone (20mg) compared to prednisolone (20mg) given alone. [2 years]
Measurement of endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp.
Changes in blood pressure associated with prednisolone and AZD4017 administration [2 years]
The participants will have 24h ambulatory blood pressure measurements taken.
Changes in adipose tissue gene expression profile associated with prednisolone and AZD4017 administration. [2 years]
Gene expression changes will be measured from adipose tissue biopsies.
Change in whole body oxidation associated with prednisolone and AZD4017 administration [2 years]
Measurement of incorporation of carbon-13 into breath carbon dioxide using Gas chromatography combustion isotope ratio mass spectrometry.
Changes in skeletal muscle gene expression profile associated with prednisolone and AZD4017 administration. [2 years]
Gene expression changes measured in skeletal muscle biopsies.
Changes in circulating inflammatory cytokines and inflammatory response in circulating inflammatory cells associated with prednisolone and AZD4017 administration. [2 years]
Measurement of inflammatory cytokines, isolation of peripheral blood mononuclear cells and defining their response to inflammatory stress.
Changes in bone turnover associated with prednisolone and AZD4017 administration. [2 years]
Measurement of serum and urine markers of bone turnover including type I collagen cross-linked N-telopeptide and osteocalcin
Changes in body composition (total and regional lean and fat mass) associated with prednisolone and AZD4017 administration. [2 years]
Measurement of total and regional lean and fat mass on dual energy x-ray absorptiometry scan.
Changes in urinary steroid metabolite profile associated with prednisolone and AZD4017 administration. [2 years]
Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

The following criteria apply to both arms and each volunteer who has a successful screening visit will be randomized to one of the arms defined above (see section 6): We estimate that we will need to screen 40-50 patients in order to achieve our recruitment target.

Male volunteers without diabetes (HbA1C < 48mmol/mol at screening)
BMI 20-30kg/m2
Age 18-60years
For individuals identified from Oxford Biobank - fasting insulin and / or glucose and / or insulin resistance as measured by Homeostatic model assessment (HOMA) - insulin resistance in the 40th-60th percentile
BP<160/100 mmHg with stable antihypertensive therapy for >3 months
Stable lipid lowering therapy for >3 months
No contraindications to AZD4017 or prednisolone treatment Study participants who are sexually active with a female partner of childbearing potential must be surgically sterilized, practicing true abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, e.g. calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception) or agree, along with their partners, to use two forms of highly effective methods of birth control (i.e. condom plus another highly effective method defined below), and not rely on barrier methods and spermicide alone, from the time of screening and for the duration of the study. For the proposed clinical study, all study subjects will be male.

For male study subjects whose partner is pregnant, or whose partner is a woman of child-bearing potential (WOCBP) who is established on and continuing to use a highly effective method of contraception, in addition to the stipulations above, males should continue to use a condom (in addition to the highly effective method) for 1 week following the last dose of study drug (5 drug elimination half-lives rounded up to 1 week).

For male study subjects whose partner is not pregnant but is a WOCBP who is not established on and continuing to use a highly effective method of contraception, males should continue to use a condom (in addition to the highly effective method) for 3 weeks following the last dose of study drug (5 drug elimination half-lives plus 2 weeks).

Male study participants must also not donate sperm from the time of screening until 3 weeks after final dose of study drug (5 drug elimination half-lives plus 2 weeks).

Highly effective methods of contraception are defined as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (either oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (either oral [specifically Cerazette™], injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence.

We would advise that competitive elite athletes do not take part in the study as there is the possibility that the prednisolone could impact upon their athletic performance

Exclusion Criteria:

The participant may not enter the study if any of the following apply:

Age <18 or >60years
Body mass index <20 or >30kg/m2
A diagnosis of diabetes (type 1 or type 2)
A blood haemoglobin <120mg/dL
Haemorrhagic disorders
Anticoagulant treatment
Renal impairment with estimated Glomerular Filtration Rate <60ml/min
Abnormal liver chemistry with aspartate aminotransferase, alanine transaminase and/or Gamma-glutamyltransferase and/or bilirubin more than the upper limit of normal
Glucocorticoid therapy (including inhaled, topical or oral) within the last 6 months
Concomitant anti-inflammatory medication including NSAIDs, disease modifying anti-rheumatic drugs (DMARDs) / steroid-sparing medications (e.g. methotrexate, sulphasalazine, hydroxychloroquine, azathioprine, leflunomide, biologics [anti-Tumor necrosis factor alpha, interleukin-1ra]).
Any medical condition in the opinion of the investigator that might impact upon safety or validity of the results - recent (within 2 weeks) or active infection, known liver disease, known thyroid disease, active malignancy, existing inflammatory condition (e.g. inflammatory arthropathy, inflammatory bowel disease, autoimmune disease, connective tissue disease)
Current evidence of alcohol abuse or a significant history of alcohol abuse, as judged by the investigator.
Contraindication to any of the study treatments or known or suspected hypersensitivity to the investigational product, compounds of the same class, other study treatments or any excipients.
Unwilling, or unable, to give informed consent.
Participation in another investigational medicinal product trial / study within the past 6 months