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Metformin in Patients Initiating ADT as Prevention and Intervention of Metabolic Syndrome (PRIME)

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ClinicalTrials.gov Identifier: NCT03031821
Recruitment Status : Not yet recruiting
First Posted : January 26, 2017
Last Update Posted : August 9, 2017
Sponsor:
Collaborators:
Prostate Cancer Canada
British Columbia Cancer Agency
Information provided by (Responsible Party):
Canadian Urologic Oncology Group

Brief Summary:
This is a multi-centre, double-blind, randomized phase III trial comparing metformin to placebo in patients with advanced prostate cancer starting intermittent androgen deprivation therapy.

Condition or disease Intervention/treatment Phase
Prostate Cancer Metabolic Syndrome Drug: Metformin Drug: Placebo Oral Tablet Phase 3

Detailed Description:

The primary objective of this study will determine if there are differences between arms with respect to the proportion of patients who meet the diagnostic criteria for metabolic syndrome after 18 months of study treatment.

It is estimated that one in seven Canadian men will be diagnosed with prostate cancer in their lifetime. In 2015, approximately 23,600 Canadian men were estimated to be diagnosed with prostate cancer and 4,000 died of this disease.

Androgen deprivation therapy (ADT) is a standard first-line treatment for men with incurable prostate cancer and has long been known to improve overall survival. It was recently shown that intermittent ADT (iADT) is non-inferior to continuous therapy, with modest improvement in quality-of-life measures being provided by the intermittent approach. Thus, iADT is considered a standard of care in patients with rising PSA after definitive local therapy.

Although the effectiveness of ADT is well established in patients with advanced prostate cancer, it is associated with important adverse effects as outlined below. The development of metabolic syndrome in particular is clinically important as it is associated with worsened quality of life and increased all-cause morbidity and mortality.

As ADT is now employed, alone or in combination with other therapies, in virtually all men with advanced prostate cancer for increasingly long periods of time (median survival of men presenting with newly diagnosed metastatic disease from recent clinical trials is at least 3 years, during which they are typically on continuous hormonal therapy), the burden of ADT toxicity among men with prostate cancer is significant and increasing.

The investigators hypothesize that the addition of metformin to a program of intermittent ADT will reduce the proportion of patients with metabolic syndrome at 18 months after initiation of ADT and will reduce the severity of individual components of metabolic syndrome in men with advanced prostate cancer. To test this hypothesis, this is a randomized, double-blinded, placebo-controlled phase 3 clinical trial of metformin in patients undergoing iADT treatment.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomized Phase 3 Trial of Metformin in Patients Initiating Androgen Deprivation Therapy as Prevention and Intervention of Metabolic Syndrome: The Prime Study
Estimated Study Start Date : October 1, 2017
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : June 1, 2023


Arm Intervention/treatment
Experimental: Metformin
Metformin 850 mg PO BID X 18 months
Drug: Metformin
Metformin Duration: 18 months 850 mg PO OD x 30 days then 850 mg PO BID for duration
Other Name: Glucophage

Placebo Comparator: Placebo

Placebo Oral Tablet

1 tablet PO BID X 18 months

Drug: Placebo Oral Tablet

Placebo Oral Tablet Duration 18 months

1 tablet (850 mg) PO OD x 30 days then 1 tablet PO BID for duration

Other Name: Placebo




Primary Outcome Measures :
  1. Proportion of patients who meet the diagnostic criteria for metabolic syndrome after 18 months of study treatment [ Time Frame: 18 months ]

    A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose.

    The prevalence of metabolic syndrome at 18 months post randomization will be calculated and compared between treatment arms using the two-sample t-test.



Secondary Outcome Measures :
  1. Proportion of patients who meet the diagnostic criteria for metabolic syndrome after 9 months of study treatment [ Time Frame: 9 months ]

    A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose.

    The prevalence of metabolic syndrome at 9 months post randomization will be calculated and compared between treatment arms using the two-sample t-test.


  2. Proportion of patients who meet the diagnostic criteria for metabolic syndrome after 12 months of study treatment [ Time Frame: 12 months ]

    A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose.

    The prevalence of metabolic syndrome at 12 months post randomization will be calculated and compared between treatment arms using the two-sample t-test.


  3. Proportion of patients who meet the diagnostic criteria for metabolic syndrome after 24 months of study treatment [ Time Frame: 24 months ]

    A diagnosis of metabolic syndrome will be made according to the harmonized definition of the metabolic syndrome as defined in the joint statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity. A patient will be classified as having metabolic syndrome if he possesses ≥3 of the aforementioned criteria: Increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting blood glucose.

    The prevalence of metabolic syndrome at 24 months post randomization will be calculated and compared between treatment arms using the two-sample t-test.


  4. Proportion of patients who meet the criteria of reduced high-density lipoprotein cholesterol assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Reduced High-Density Lipoprotein Cholesterol defined as: < 1.0 mmol/L; or drug treatment for reduced HDL cholesterol*

    *Patient taking fibrates (Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, or Fenofibrate) or nicotinic acid can be presumed to have high TG and reduced HDL-cholesterol levels; Patients taking high dose omega-3 fatty acids can be presumed to have high TG levels


  5. Proportion of patients who meet the criteria of elevated triglycerides assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Elevated Triglycerides defined as: ≥1.7 mmol/L; or drug treatment for elevated triglycerides*

    *Patient taking fibrates (Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, or Fenofibrate) or nicotinic acid can be presumed to have high TG and reduced HDL-cholesterol levels; Patients taking high dose omega-3 fatty acids can be presumed to have high TG levels


  6. Proportion of patients who meet the criteria of elevated blood pressure assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Elevated Blood Pressure defined as:

    Systolic Blood Pressure of ≥ 130 mm of Hg; or Diastolic Blood Pressure of ≥ 85 mm of Hg; or drug treatment for elevated blood pressure

    Blood pressures will be taken with patients sitting for 5 minutes in a quiet environment prior to measurement and two measurements taken (with a minimum of 5 minutes between each blood pressure measurement), with the mean recorded for this study.


  7. Proportion of patients who meet the criteria of elevated fasting blood glucose levels assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Elevated Fasting Blood Glucose defined as:

    HbA1c ≥ 6.5%; or Fasting plasma glucose ≥ 7.0 mmol/L; or drug treatment for elevated blood glucose


  8. Proportion of patients who meet the criteria of increased waist circumference assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Increased Waist Circumference defined as:

    Males (population and country specific) A) Canadians ≥102cm B) Chinese ≥ 85cm C) Japanese ≥ 85 cm D) Other Asians ≥ 90 cm E) Middle Eastern & Mediterranean ≥ 94cm F) Sub-Saharan African ≥ 94 cm G) Central & South American ≥ 90cm H) Europid ≥ 94 cm

    Measurement of waist circumference will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.


  9. Health-related Quality of Life assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Patients will undergo quality of life measurements by the EORTC QLQ-C30 core questionnaire (63) and prostate-specific module. The instruments are well validated and widely used in the population of interest. The questionnaire items are transformed for 5 functional domains, global QOL, and specific symptom scales/items relevant to the study intervention.

    The statistical analysis plan will use the standard CCTG QOL approach (Osoba et al., 1998), and will focus on change of mean scores from baseline over time by treatment allocation group. Depending on the amount of missing data, generalized linear equation modeling of mean scores may be required. The analysis will also consider the proportion of patients improved, stable or deteriorated at 18 months compared to baseline using a cut-point minimal clinical difference of 10 points on all scales. A sensitivity analysis will be executed using a cut-point of 7 points.


  10. Treatment-related toxicity [ Time Frame: 18 months ]

    Treatment related toxicity (NCI CTCAE 4.0)

    All men will be evaluated for toxicity from the time of their first oral dose of study medication. Toxicities will be graded using the current CTCAE version 4.0. The incidence of toxicities by arm will be summarized by type of adverse effect. A Fisher's Exact Test will be used to compare toxicities between the two arms.



Other Outcome Measures:
  1. Serum insulin levels assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    Fasting insulin level

    Test for significance: Two sample independent t-test.


  2. Insulin resistance assessed at 18 months of follow-up. [ Time Frame: 18 months ]

    The homoeostasis model assessment insulin resistance (HOMA-IR) (67, 68) and the Quantitative Insulin Sensitivity Check Index (QUICKI) (69), indirect measures of insulin resistance, will be the primary means of classifying insulin resistance status for this study.

    HOMA-IR = Fasting Insulin (μU/ml) * Fasting glucose (mmol/L) 22.5

    QUICKI = 1/[log fasting insulin (mU/L) + log fasting glucose (mg/dl)]


  3. Time to re-initiation of androgen deprivation therapy [ Time Frame: 18 months ]
    The median duration of time off-treatment (i.e. ADT) in days will be compared between study arms using the student t-test.

  4. Duration of time off-treatment in days [ Time Frame: 18 months ]
    The median duration of time off-treatment (i.e. ADT) in days will be compared between study arms using the student t-test.

  5. Testosterone levels assessed at 18 months of follow-up. [ Time Frame: 18 months ]
    Testosterone to be measured as per standard of care (usually every 3 months during initiation of ADT and initial off-ADT period).

  6. Body mass assessed at 18 months of follow-up. [ Time Frame: 18 months ]
    Measurement weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

  7. Abdominal girth assessed at 18 months of follow-up. [ Time Frame: 18 months ]
    Measurement of abdominal girth will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

  8. Mean BMI assessed at 12 months of follow-up. [ Time Frame: 12 months ]
    Measurement of height and weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

  9. Mean BMI assessed at 24 months of follow-up. [ Time Frame: 24 months ]
    Measurement of height and weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

  10. Mean BMI assessed at 36 months of follow-up. [ Time Frame: 36 months ]
    Measurement of height and weight will be performed by a dedicated research nurse for this study that is blinded to the patient's treatment allocation.

  11. Exercise behavior and sedentary behavior assessed at 12 months of follow-up. [ Time Frame: 12 months ]

    Exercise/sedentary questionnaire will be administered at 12 months of follow-up.

    Analyses of covariance (ANCOVA) to explore the effects of the intervention on moderate exercise minutes, vigorous exercise minutes, combined moderate and vigorous exercise minutes, and sedentary behavior hours will be conducted. Chi-square analyses to examine the effects of the intervention on meeting the exercise guidelines will be done.


  12. Exercise behavior and sedentary behavior assessed at 24 months of follow-up. [ Time Frame: 24 months ]

    Exercise/sedentary questionnaire will be administered at 24 months of follow-up.

    Analyses of covariance (ANCOVA) to explore the effects of the intervention on moderate exercise minutes, vigorous exercise minutes, combined moderate and vigorous exercise minutes, and sedentary behavior hours will be conducted. Chi-square analyses to examine the effects of the intervention on meeting the exercise guidelines will be done.


  13. Exercise behavior and sedentary behavior assessed at 36 months of follow-up. [ Time Frame: 36 months ]

    Exercise/sedentary questionnaire will be administered at 36 months of follow-up.

    Analyses of covariance (ANCOVA) to explore the effects of the intervention on moderate exercise minutes, vigorous exercise minutes, combined moderate and vigorous exercise minutes, and sedentary behavior hours will be conducted. Chi-square analyses to examine the effects of the intervention on meeting the exercise guidelines will be done.


  14. Cardiovascular mortality [ Time Frame: Through study completion, an average of 3 years ]
    For cardiovascular morality, the survival period will be defined as the date of randomization to the date of death due to cardiovascular disease or the date of censoring. All deaths that occur amongst study participants will be reviewed by the study's data safety and monitoring committee (who will be blinded to the treatment allocation of the patient in question). Deaths will be classified into 3 categories: 1) Prostate Cancer 2) Cardiovascular Disease 3) Other. Cardiovascular deaths will include cases in which cardiovascular disease, coronary artery disease, or stroke are identified as one of the causes of death, not just the underlying cause of death.

  15. Biochemical progression-free survival [ Time Frame: 36 months ]
    For bPFS, the survival period will be defined as the date of randomization to the date of biochemical progression or the date of censoring. For the purposes of this study, biochemical progression will be defined as a rise in serum PSA above their pre-randomization level (or 10ng/mL for patients who had a baseline PSA >10ng/mL) or the initiation of cancer treatment (i.e. second course of hormonal therapy, systemic therapy, etc.).

  16. Castration resistant disease-free survival [ Time Frame: 36 months ]
    For RFS-CR, the survival period will be defined as the date of randomization to the date of confirmed biochemical castration resistance or the date of censoring. For the purposes of this study, castration resistance will be defined as a continuous rise in serum PSA despite castrate levels of serum testosterone (achieved via total androgen blockade).

  17. Distant metastasis disease-free survival [ Time Frame: 36 months ]
    For RFS-DM, the survival period will be defined as the date of randomization to the date of confirmation of distant metastases or the date of censoring. Any of the following constitute a confirmation of distant metastases: imaging evidence of de novo bone metastases (X-rays, bone scan, CT, MRI, or PET scan), pathological fracture secondary to a bone metastases, imaging evidence of lymph node metastases (CT, MRI or Ultrasound Scans).

  18. Prostate cancer specific survival [ Time Frame: Through study completion, an average of 3 years ]
    For PCSS, the survival period will be defined as the date of randomization to the date of death due to prostate cancer or the date of censoring. All deaths that occur amongst study participants will be reviewed by the study's data safety and monitoring committee (who will be blinded to the study arm allocation of the patient in question). Any death that is determined to be attributable to a participant's prostate cancer will be deemed a death due to prostate cancer.

  19. Overall survival [ Time Frame: Through study completion, an average of 3 years ]
    For OS, the survival period will be defined as the date of randomization to the date of death due to any cause or the date of censoring. All deaths that occur amongst study participants will be reviewed by the study's data safety and monitoring committee (who will be blinded to the treatment allocation of the patient in question). Deaths will be classified into 3 categories: 1) Prostate Cancer 2) Cardiovascular Disease 3) Other.



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.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically confirmed adenocarcinoma of the prostate.
  • Eligible for initiating intermittent androgen deprivation therapy with either:
  • Asymptomatic metastatic disease; or
  • Biochemical recurrence of prostate cancer:
  • PSA > 3 ng/mL after prior curative intent local therapy (i.e. prostatectomy); or
  • PSA ≥ 2 ng/mL above their nadir if previously treated with definitive radiotherapy.
  • Serum testosterone > 5 nmol/L.
  • Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration/randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
  • Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate.
  • Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
  • Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre. Investigators must assure themselves the patients registered on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
  • Protocol treatment is to begin within 7 working days of patient randomization.

Exclusion Criteria:

  • Prior androgen deprivation therapy within 12 months of enrolment.
  • Prior androgen deprivation therapy associated with definitive treatment is permitted, if it has been completed at least 12 months prior to enrolment (i.e. last injection or tablet taken 12 months prior to enrolment).
  • Patients that meet ≥ 1 of the Canadian Diabetes Association criteria for the diagnosis of diabetes within 28 days of enrolment:
  • Fasting plasma glucose of ≥ 7 mmol/L; or
  • HbA1C ≥ 6.5%.
  • Patients currently taking metformin or who have taken metformin within 28 days or enrolment.
  • History of lactic acidosis or conditions that predispose to lactic acidosis:
  • Impaired Renal Function (eGFR < 45 mL/minute/1.73 m2); or
  • Liver disease, including alcoholic liver disease, as demonstrated by any of the following parameters:
  • AST >1.8 x the upper limit of normal
  • ALT > 1.8 x the upper limit of normal
  • Alkaline Phosphatase > 2x the upper limit of normal
  • Serum total bilirubin > 1.5 x the upper limit of normal (except for subjects with Gilbert's Disease who are eligible despite elevated serum bilirubin levels).
  • Alcohol abuse (habitual intake of ≥3 alcoholic beverages per day) sufficient to cause hepatic toxicity; or
  • Severe infection.
  • Congestive heart failure (defined as New York Heart Association Class III or IV functional status).
  • Patients with a history of other invasive malignancies, except adequately treated non-melanoma skin cancer or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.

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): NCT03031821


Contacts
Contact: Bernie Eigl, MD 604-877-6000 Bernie.Eigl@bccancer.bc.ca

Locations
Canada, British Columbia
BC Cancer Agency - Vancouver Cancer Centre Not yet recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Bernie Eigl, MD    604-877-6000    bernie.eigl@bccancer.bc.ca   
Principal Investigator: Bernie Eigl, MD         
Sponsors and Collaborators
Canadian Urologic Oncology Group
Prostate Cancer Canada
British Columbia Cancer Agency
Investigators
Study Chair: Bernie Eigl, MD British Columbia Cancer Agency
Study Chair: Nawaid Usmani, MD University of Alberta

Publications:
Canadian Cancer Society. Canadian Cancer Statistics 2015: Canadian Cancer Society; 2015 [Available from: http://www.cancer.ca/].
James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. doi: 10.1016/S0140-6736(15)01037-5. Epub 2015 Dec 21.
Kylin E. Studien ueber das Hypertonie-Hyperglykaemie-Hyperurikaemiesydrom. Zentralblatt fuer Innere Medizin. 1923;44:105-27.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009 Oct 20;120(16):1640-5. doi: 10.1161/CIRCULATIONAHA.109.192644. Epub 2009 Oct 5.

Responsible Party: Canadian Urologic Oncology Group
ClinicalTrials.gov Identifier: NCT03031821     History of Changes
Other Study ID Numbers: PRIME
First Posted: January 26, 2017    Key Record Dates
Last Update Posted: August 9, 2017
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Canadian Urologic Oncology Group:
Prostate Cancer
ADT
iADT
Metabolic Syndrome
Androgen Deprivation Therapy
Phase III
Phase 3
Randomized
Intermittent Androgen Deprivation Therapy

Additional relevant MeSH terms:
Syndrome
Prostatic Neoplasms
Metabolic Syndrome X
Disease
Pathologic Processes
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Metformin
Androgens
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists