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

This study is currently recruiting participants.
Verified October 2017 by University of Oxford
Sponsor:
ClinicalTrials.gov Identifier:
NCT03111810
First Posted: April 13, 2017
Last Update Posted: October 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
University of Oxford
  Purpose

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:

  1. 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.
  2. To determine the impact of AZD4017 on the anti-inflammatory actions of Prednisolone.
  3. 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 Intervention Phase
Iatrogenic Cushing's Disease Drug: AZD4017 and prednisolone Drug: Placebo Oral Tablet and prednisolone Phase 2

Study Type: Interventional
Study Design: 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)

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • Changes in the detrimental side effects of prednisolone by AZD4017. [ Time Frame: 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. [ Time Frame: 2 years ]
    Measurement of endogenous glucose production rate during a hyperinsulinaemic euglycaemic clamp.

  • Changes in blood pressure associated with prednisolone and AZD4017 administration [ Time Frame: 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. [ Time Frame: 2 years ]
    Gene expression changes will be measured from adipose tissue biopsies.

  • Change in whole body oxidation associated with prednisolone and AZD4017 administration [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 2 years ]
    Steroid metabolites measured by gas chromatography, mass spectrometry in a timed overnight urine sample.


Estimated Enrollment: 32
Actual Study Start Date: May 25, 2017
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Placebo

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03111810


Contacts
Contact: Jeremy W Tomlinson, MD PhD 44(0)1865 857359 jeremy.tomlinson@ocdem.ox.ac.uk
Contact: Nadia Othonos, MB ChB 44(0)1865 857359 nantia.othonos@ocdem.ox.ac.uk

Locations
United Kingdom
University of Oxford Recruiting
Oxford, United Kingdom
Contact: Jeremy W Tomlinson, MD PhD    44(0)1865 857359    jeremy.tomlinson@ocdem.ox.ac.uk   
Contact: Nadia Othonos, MD       Nantia.Othonos@ocdem.ox.ac.uk   
Sponsors and Collaborators
University of Oxford
AstraZeneca
  More Information

Publications:

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03111810     History of Changes
Other Study ID Numbers: 212634
First Submitted: March 17, 2017
First Posted: April 13, 2017
Last Update Posted: October 6, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by University of Oxford:
Corticosteroids
Prednisolone
11 beta-Hydroxysteroid dehydrogenase1 inhibitor
Iatrogenic Cushing's disease
AZD4017

Additional relevant MeSH terms:
Cushing Syndrome
Pituitary ACTH Hypersecretion
ACTH-Secreting Pituitary Adenoma
Adrenocortical Hyperfunction
Adrenal Gland Diseases
Endocrine System Diseases
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pituitary Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Prednisolone acetate
Methylprednisolone acetate
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone hemisuccinate
Prednisolone phosphate
Niacinamide
Anti-Inflammatory Agents
Glucocorticoids
Hormones