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Trial record 1 of 1 for:    NCT04659915
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Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin (Gluco-Met)

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ClinicalTrials.gov Identifier: NCT04659915
Recruitment Status : Completed
First Posted : December 9, 2020
Last Update Posted : September 23, 2021
Sponsor:
Information provided by (Responsible Party):
Eleonora Seelig, University Hospital, Basel, Switzerland

Brief Summary:

Supraphysiological doses of glucocorticoids (GCs) are widely prescribed as immunosuppressants and metabolic side effects such as obesity and diabetes are extremely common. Efforts to investigate and prevent these side effects are lacking. The antidiabetic drug metformin was shown in previous studies to prevent deterioration of glucose homeostasis during GC therapy in patients. However, mechanisms of metformin counteracting GC-induced side effects remain poorly understood.

In a randomized, placebo-controlled, cross-over study, 18 healthy volunteers will receive a 7-day course of prednisone with metformin or placebo. Established methods will be used to assess systemic changes in energy homeostasis and novel techniques such as metabolomics will identify underlying pathways. This will advance the understanding of energy homeostasis during GC excess, may prevent thousands of patients from GC-induced side effects and also offers a model for targeting disrupted endogenous GCs secretion.


Condition or disease Intervention/treatment Phase
Glucocorticoid Effect Drug: Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets Drug: Placebo 500 mg Tablets + Prednisone 20mg Tablets Phase 4

Detailed Description:

Obesity is one of the most serious health problems in the 21st century (1). Currently, more than 700 million people world-wide are obese and face an increased risk of morbidity and a reduced life-expectancy of up to 10 years (1, 2). High energy food and a sedentary lifestyle are driving the current obesity pandemic (3). Sleep deprivation and psychological stress also have been identified as contributing factors (4). Many of these factors activate the hypothalamic-pituitary-adrenal (HPA) axis, the key regulatory pathway of energy homeostasis. Activation of the HPA-axis leads to secretion of glucocorticoids (GCs) from the adrenal glands. GCs control energy homeostasis by mobilizing and redistributing energy substrates (5). In an evolutionary context, GCs are particularly important during periods of stress, especially when food is scarce. In today's environment, where food is abundantly available, GCs potentially can become deleterious by severely disrupting energy homeostasis. Therefore, the GC pathway has gained interest as a potential treatment target for the metabolic syndrome.

Next to their essential role in energy homeostasis, glucocorticoids are the most commonly prescribed immunosuppressant drugs. GCs are used for acute as well as chronic conditions in virtually all medical disciplines (6). It is well known that patients on GC treatment are at high risk for developing numerous side effects. Next to dyslipidaemia, arterial hypertension and cardiovascular disease, up to 80% of patients experience weight gain, while around 40% develop diabetes (7). Currently, no therapies exist to prevent any of these side effects. The only available strategy to prevent GC-induced side effects is to restrain GC use.

The objective of this project is to test in a clinical study in humans whether metformin can counteract the deleterious metabolic effects developed after a short-term glucocorticoid treatment. The primary objective is to test how metformin counteracts metabolic side effects of GCs compared to placebo. Secondary objectives are to detect underlying pathways in blood (metabolomics), adipose tissue (gene expression analysis) and mitochondria (Cytosensor) with metformin in combination with prednisone compared to placebo and prednisone.

This is a double-blind, randomized, placebo-controlled cross-over study. After screening, subjects will be randomized to two crossover 7-day study periods with a washout period of 28 days:

A) Participants will receive prednisone 30 mg/d p.o. and metformin (starting with a dose of 500 mg/d and increasing the dose by 500 mg every other day until 2000 mg/d are achieved).

B) Participants will receive prednisone 30 mg/d p.o. and placebo p.o. (starting with a dose of 500 mg/d and increasing the dose by 500 mg every other day until 2000 mg/d are achieved).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Double-blind, randomized, placebo-controlled cross-over study
Masking: Double (Participant, Investigator)
Masking Description: Placebo-controlled
Primary Purpose: Prevention
Official Title: Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin - A Double-blind, Randomized, Placebo-controlled, Cross-over Study
Actual Study Start Date : February 25, 2021
Actual Primary Completion Date : August 18, 2021
Actual Study Completion Date : August 18, 2021


Arm Intervention/treatment
Experimental: Metformin + Prednison

During one of the study periods, subjects receive Metformin 500 mg tablets p.o. for seven days (starting with a dose of 500 mg /d, then the dose will be increased by 500 mg the next days until 2000 mg /d is achieved).

Subjects also receive Prednisone 20 mg 1.5x/d tablets p.o. for seven days.

Drug: Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets

During one phase of the study: Metformin 500mg Day 1 1-0-0 Day 2 1-0-0 Day 3 1-0-1 Day 4 1-0-1 Day 5 2-0-1 Day 6 2-0-1 Day 7 4-0-0

In combination with prednisone 20mg: day 1 to day 7 1.5-0-0.


Placebo Comparator: Placebo + Prednison
During the other study period, subjects receive the same dose of placebo tablets p.o instead of metformin. Subjects also receive Prednisone 20 mg 1.5x/d tablets p.o. for seven days.
Drug: Placebo 500 mg Tablets + Prednisone 20mg Tablets
During another phase of the study: identical looking placebo pills starting day 1 500mg 1-0-0, day 2 500mg 1-0-0, day 3 500mg 1-0-1, day 4 500mg 1-0-1, day 5 500mg 2-0-1. day 6 2-0-1, day 7 4-0-0. In combination with prednisone 20mg: day 1 to day 7 1.5-0-0.




Primary Outcome Measures :
  1. Insulin sensitivity [ Time Frame: Two 1-week intervention periods ]
    Change in insulin sensitivity (HOMA-Index) assessed with a mixed meal tolerance test.


Secondary Outcome Measures :
  1. Lipids (mmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  2. Cortisol (nmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  3. GLP-1 (nmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  4. GIP (nmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  5. PYY (pg/ml) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  6. C-peptide (pmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  7. T3 (nmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  8. T4 (nmol/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  9. TSH (mIU/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  10. HGH (mIU/l) [ Time Frame: Two 1-week intervention periods ]
    Blood sample

  11. Sympathetic nervous system activity [ Time Frame: Two 1-week intervention periods ]
    Heart rate variability analysis

  12. Blood pressure [ Time Frame: Two 1-week intervention periods ]
    Assessment of blood pressure with a standard blood pressure monitor.

  13. Weight [ Time Frame: Two 1-week intervention periods ]
    Measurement of weight with a standard scale

  14. Energy expenditure [ Time Frame: Two 1-week intervention periods ]
    Basal metabolic rate measured with indirect calorimetry

  15. Substrate utilisation [ Time Frame: Two 1-week intervention periods ]
    Respiratory quotient assessed with indirect calorimetry

  16. GDF-15 (pg/mL) [ Time Frame: Two 1-week intervention periods ]
    Blood sample


Other Outcome Measures:
  1. Metabolomics [ Time Frame: Two 1-week intervention periods ]
    Metabolomics will be performed in blood plasma

  2. Gene expression analysis [ Time Frame: Two 1-week intervention periods ]
    Adipose tissue biobsy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Since hormone fluctuations associated with the menstrual cycle may alter cortisol levels, women will not be included in the study. Although diversity will be reduced and the statements of the study cannot be applied to the female sex, these strict inclusion criteria allow an optimal homogeneity and increase statistical power.
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • BMI 18.5 - 25 kg/m2

Exclusion Criteria:

  • Any current significant disease,
  • Any medication
  • Glucocorticoids and/ or metformin for up to four weeks before study inclusion
  • Regular alcohol intake (>30g/d),
  • Regular physical activity (>4hrs per week),
  • Known allergy to metformin,
  • Inability or unwillingness to provide informed consent.

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): NCT04659915


Locations
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Switzerland
University Hospital Basel
Basel, Basel-Stadt, Switzerland, 4031
Sponsors and Collaborators
Eleonora Seelig
Publications of Results:
GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12.

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Responsible Party: Eleonora Seelig, Principal Investigator, University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT04659915    
Other Study ID Numbers: EKNZ 2020-01233
First Posted: December 9, 2020    Key Record Dates
Last Update Posted: September 23, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Metformin
Prednisone
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents