Targeting Iatrogenic Cushing's Syndrome With 11ß-hydroxysteroid Dehydrogenase Type 1 Inhibition

• Register: ClinicalTrials.gov
• Last refreshed on: 24 May 2021
• Main ID: NCT03111810
• Date of registration: 17/03/2017
• Prospective Registration: Yes
• Primary sponsor: University of Oxford
• Public title: Targeting Iatrogenic Cushing's Syndrome With 11ß-hydroxysteroid Dehydrogenase Type 1 Inhibition TICSI
• Scientific title: Targeting Iatrogenic Cushing's Syndrome With 11ß-hydroxysteroid Dehydrogenase Type 1 Inhibition (TICSI)
• Date of first enrolment: May 25, 2017
• Target sample size: 32
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03111810
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 2

Countries of recruitment

United Kingdom

Key inclusion & exclusion 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



Age minimum: 18 Years
Age maximum: 60 Years
Gender: Male

Health Condition(s) or Problem(s) studied

Iatrogenic Cushing's Disease

Intervention(s)

Drug: AZD4017 and prednisolone

Drug: Placebo Oral Tablet and prednisolone

Primary Outcome(s)

Changes in the detrimental side effects of prednisolone by AZD4017. [Time Frame: 2 years]

Secondary Outcome(s)

Changes in body composition (total and regional lean and fat mass) associated with prednisolone and AZD4017 administration. [Time Frame: 2 years]

Changes in urinary steroid metabolite profile associated with prednisolone and AZD4017 administration. [Time Frame: 2 years]

Change in whole body oxidation associated with prednisolone and AZD4017 administration [Time Frame: 2 years]

Changes in adipose tissue gene expression profile associated with prednisolone and AZD4017 administration. [Time Frame: 2 years]

Changes in hepatic insulin sensitivity by AZD4017 when given with prednisolone (20mg) compared to prednisolone (20mg) given alone. [Time Frame: 2 years]

Changes in skeletal muscle gene expression profile associated with prednisolone and AZD4017 administration. [Time Frame: 2 years]

Changes in circulating inflammatory cytokines and inflammatory response in circulating inflammatory cells associated with prednisolone and AZD4017 administration. [Time Frame: 2 years]

Changes in blood pressure associated with prednisolone and AZD4017 administration [Time Frame: 2 years]

Changes in bone turnover associated with prednisolone and AZD4017 administration. [Time Frame: 2 years]

Secondary ID(s)

212634

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

AstraZeneca