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

Primary Purpose

Iatrogenic Cushing's Disease

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
AZD4017 and prednisolone
Placebo Oral Tablet and prednisolone
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Iatrogenic Cushing's Disease focused on measuring Corticosteroids, Prednisolone, 11 beta-Hydroxysteroid dehydrogenase1 inhibitor, Iatrogenic Cushing's disease, AZD4017

Eligibility Criteria

18 Years - 60 Years (Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • University of Oxford

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active

Placebo Oral Tablet

Arm Description

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

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

Outcomes

Primary Outcome Measures

Changes in the detrimental side effects of prednisolone by AZD4017.
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.
Measurement of endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp.
Changes in blood pressure associated with prednisolone and AZD4017 administration
The participants will have 24h ambulatory blood pressure measurements taken.
Changes in adipose tissue gene expression profile associated with prednisolone and AZD4017 administration.
Gene expression changes will be measured from adipose tissue biopsies.
Change in whole body oxidation associated with prednisolone and AZD4017 administration
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.
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.
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.
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.
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.
Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample.

Full Information

First Posted
March 17, 2017
Last Updated
May 12, 2021
Sponsor
University of Oxford
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03111810
Brief Title
Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition
Acronym
TICSI
Official Title
Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition (TICSI)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
May 25, 2017 (Actual)
Primary Completion Date
August 1, 2020 (Actual)
Study Completion Date
August 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Iatrogenic Cushing's Disease
Keywords
Corticosteroids, Prednisolone, 11 beta-Hydroxysteroid dehydrogenase1 inhibitor, Iatrogenic Cushing's disease, AZD4017

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active
Arm Type
Active Comparator
Arm Description
Prednisolone 20mg once daily and AZD4017 400mg twice daily for 7 days.
Arm Title
Placebo Oral Tablet
Arm Type
Placebo Comparator
Arm Description
Prednisolone 20mg once daily and placebo twice daily for 7 days.
Intervention Type
Drug
Intervention Name(s)
AZD4017 and prednisolone
Other Intervention Name(s)
11 beta-Hydroxysteroid dehydrogenase inhibitor
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet and prednisolone
Other Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Changes in the detrimental side effects of prednisolone by AZD4017.
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Changes in hepatic insulin sensitivity by AZD4017 when given with prednisolone (20mg) compared to prednisolone (20mg) given alone.
Description
Measurement of endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp.
Time Frame
2 years
Title
Changes in blood pressure associated with prednisolone and AZD4017 administration
Description
The participants will have 24h ambulatory blood pressure measurements taken.
Time Frame
2 years
Title
Changes in adipose tissue gene expression profile associated with prednisolone and AZD4017 administration.
Description
Gene expression changes will be measured from adipose tissue biopsies.
Time Frame
2 years
Title
Change in whole body oxidation associated with prednisolone and AZD4017 administration
Description
Measurement of incorporation of carbon-13 into breath carbon dioxide using Gas chromatography combustion isotope ratio mass spectrometry.
Time Frame
2 years
Title
Changes in skeletal muscle gene expression profile associated with prednisolone and AZD4017 administration.
Description
Gene expression changes measured in skeletal muscle biopsies.
Time Frame
2 years
Title
Changes in circulating inflammatory cytokines and inflammatory response in circulating inflammatory cells associated with prednisolone and AZD4017 administration.
Description
Measurement of inflammatory cytokines, isolation of peripheral blood mononuclear cells and defining their response to inflammatory stress.
Time Frame
2 years
Title
Changes in bone turnover associated with prednisolone and AZD4017 administration.
Description
Measurement of serum and urine markers of bone turnover including type I collagen cross-linked N-telopeptide and osteocalcin
Time Frame
2 years
Title
Changes in body composition (total and regional lean and fat mass) associated with prednisolone and AZD4017 administration.
Description
Measurement of total and regional lean and fat mass on dual energy x-ray absorptiometry scan.
Time Frame
2 years
Title
Changes in urinary steroid metabolite profile associated with prednisolone and AZD4017 administration.
Description
Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample.
Time Frame
2 years

10. Eligibility

Sex
Male
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Facility Information:
Facility Name
University of Oxford
City
Oxford
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
10700481
Citation
van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM. 2000 Feb;93(2):105-11. doi: 10.1093/qjmed/93.2.105.
Results Reference
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PubMed Identifier
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Citation
Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken). 2013 Feb;65(2):294-8. doi: 10.1002/acr.21796.
Results Reference
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PubMed Identifier
23612224
Citation
Gathercole LL, Lavery GG, Morgan SA, Cooper MS, Sinclair AJ, Tomlinson JW, Stewart PM. 11beta-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev. 2013 Aug;34(4):525-55. doi: 10.1210/er.2012-1050. Epub 2013 Apr 23.
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Citation
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PubMed Identifier
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Tomlinson JW, Draper N, Mackie J, Johnson AP, Holder G, Wood P, Stewart PM. Absence of Cushingoid phenotype in a patient with Cushing's disease due to defective cortisone to cortisol conversion. J Clin Endocrinol Metab. 2002 Jan;87(1):57-62. doi: 10.1210/jcem.87.1.8189.
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Scott JS, Bowker SS, Deschoolmeester J, Gerhardt S, Hargreaves D, Kilgour E, Lloyd A, Mayers RM, McCoull W, Newcombe NJ, Ogg D, Packer MJ, Rees A, Revill J, Schofield P, Selmi N, Swales JG, Whittamore PR. Discovery of a potent, selective, and orally bioavailable acidic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017). J Med Chem. 2012 Jun 28;55(12):5951-64. doi: 10.1021/jm300592r. Epub 2012 Jun 19.
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Hazlehurst JM, Gathercole LL, Nasiri M, Armstrong MJ, Borrows S, Yu J, Wagenmakers AJ, Stewart PM, Tomlinson JW. Glucocorticoids fail to cause insulin resistance in human subcutaneous adipose tissue in vivo. J Clin Endocrinol Metab. 2013 Apr;98(4):1631-40. doi: 10.1210/jc.2012-3523. Epub 2013 Feb 20.
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Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition

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