A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial

A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids on Plasma Reproductive Hormones, Fertility, Withdrawal Symptoms and Myocardial Function - The LUCAS Trial

The overall objective of this randomized trial is to investigate the effects of treatment of AAS- induced male hypogonadism with combined therapy of letrozole and hCG compared with placebo on reproductive hormone levels, adherence to cessation of AAS use, fertility, cardiac function and quality of life.

Study Overview

• Status: Terminated
• Conditions: Hypogonadotropic Hypogonadism; Hypogonadism; Hypogonadism, Male
• Intervention / Treatment: Drug: Placebo; Drug: Letrozole 2.5mg, hCG

Detailed Description

A randomized, double-blinded, clinical, placebo-controlled trial enrolling 60 male illicit AAS users with documented AAS-induced hypogonadism after a period > 12 weeks of AAS cessation or a negative urine AAS doping test. Participants will be randomized to two study groups; 24 weeks of treatment with either tablet letrozole (femar®) initial dose of 2.5 mg each day versus tablet placebo. After an initial treatment period of four weeks, intramuscular injections with either hCG, initial dose 1500 IE twice weekly (letrozole group) or isotonic saline twice weekly (placebo group) will be added to therapy if plasma total testosterone level has not increased to target plasma level. Following 24 weeks of therapy, all participants will be observed for another 26 weeks without therapy. The study will have one trial center of recruitment: Department of Endocrinology, Rigshospitalet. Following participation in the study, all participants will be offered referral to an endocrine outpatient clinic if they still display clinical and biochemical signs of male hypogonadism.

A healthy group of 30 young lean eugonadal men, who have never used AAS, will be enrolled as control participants and undergo a screening visit and one visit including same procedures as the screening and randomization visits.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Male sex

  • 18 - 50 years of age
  • Hypogonadism following observational period of a minimum of 12 weeks since AAS discontinuation OR hypogonadism with a urine sample negative for AAS analyses at screening visit: plasma total testosterone ≤ 10 nmol/L AND featuring at least one symptom of male hypogonadism using IIEF in terms of erectile function (IIEF: Q1 - Q5 + Q15; total score < 26) and/or sexual desire (IIEF: Q11 + Q12; total < 7) (1) and/or ADAM questionnaire (YES to three questions other than question 1 and 7) and/or regular use of medical treatment for erectile dysfunction.
  • Motivation for permanent AAS cessation

Exclusion Criteria:

• Established cardiovascular disease

  • Established diabetes of any kind 384
  • Congenital hypogonadal conditions (cryptorchidism, Klinefelter's disease, Kallmann's disease etc.)
  • Previous established hypogonadal conditions due to other causes than illicit use of AAS
  • Current or previous treatment with testosterone on other indication than AAS-induced male hypogonadism
  • Abnormal puberty development (small testes, late or absent pubic hairing, late or absent deepening of voice, etc.)
  • Current or previous pituitary diseases including pituitary tumors
  • Current or previous tumors of the hypothalamus
  • Current or former testicular cancer
  • Current or previous prostate cancer
  • Current or previous breast cancer
  • Other cancers unless complete remission ≥ 5 year
  • Other concomitant disease or makes the patient unsuitable to participate in the study
  • Severely impaired liver function
  • Allergy or hypersensitivity to the active substance (letrozole) or excipients of Letrozol "Accord"® listed in Appendix D
  • Allergy or hypersensitivity to the active substance (hCG) or excipients of Brevactid® listed in Appendix D
  • Established Lapp lactase deficiency or glucose/galactose malabsorption
  • Severe venous phlebitis or current or previous venous thromboembolism
  • Inguinal hernia
  • treatment which according to the investigators' assessment
  • Simultaneous participation in another clinical study
  • Unable to follow treatment instructions in terms of study medication instructions
  • Ongoing criminal behavior in terms of violence or illicit distribution of drugs
  • Currently or in the foreseeable future included in anti-doping programs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Active Comparator - placebo; Intervention: Intramuscular injection - placebo Intervention: Drug: placebo	Drug: Placebo; Drug - Placebo Intramuscular injektion - placebo
Active Comparator: Active comparator - treatment; Intervention: intramuscular injection - hCG Intervention: Drug: Letrozole	Drug: Letrozole 2.5mg, hCG; Drug -Treatment Intramuscular injektion - Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in plasma total testosterone concentration after 24 weeks from baseline	24 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants who adhere to AAS cessation after 24 and 50 weeks from baseline	24 and 50 weeks
Change in total plasma testosterone concentration after 50 weeks from baseline	50 weeks
Change in plasma total testosterone secretion in response to hCG stimulation after 24 and 50 weeks from baseline	24 and 50 weeks
Change in basal plasma pituitary gonadotropins, LH and FSH, after 24 and 50 weeks from baseline	24 and 50 weeks
Change in secretion of plasma pituitary gonadotropins, LH and FSH, in response to GnRH stimulation after 24 and 50 weeks from baseline	24 and 50 weeks
Change in sperm count after 24 and 50 weeks from baseline	24 and 50 weeks
Change in sperm motility after 24 and 50 weeks from baseline	24 and 50 weeks
Change in sperm morphology after 24 and 50 weeks from baseline	24 and 50 weeks
Change in sperm acrosome reaction after 24 and 50 weeks from baseline	24 and 50 weeks
Change in sperm DNA fragmenting after 24 and 50 weeks from baseline	24 and 50 weeks
Change in testicular size assessed using ultrasound after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score IIEF (erectile function and libido) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score ADAM (hypogonadism) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of Major Depression Inventory (MDI) (depression) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of (GAD7) (anxiety) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of Buss-Perry Aggression scale (BPA) (hostility and aggression) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of COBRA (Cognitive complaints in bipolar disorder rating assessment) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of the Health Assessment Short Form-36 questionnaire from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of Body-Q 349 (Perception of own body) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in questionnaire score of the Inventory of Interpersonal Problems 32-item (IIP32) from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in myocardial function assessed by myocardial flow reserve (mL/min/gr) by Rb-82 PET from baseline and after 24 and 50 weeks	24 and 50 weeks
Change in cardiac systolic function assessed using left ventricular ejection fraction (LVEF) obtained using echocardiography and 24 and 50 weeks from baseline.	24 and 50 weeks
Change in cardiac systolic function assessed using left ventricular global longitudinal strain (GLS) obtained using echocardiography and 24 and 50 weeks from baseline.	24 and 50 weeks
Change in cardiac structure (left ventricular mass) obtained using echocardiography and 24 and 50 weeks from baseline.	24 and 50 weeks

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Caroline Michaela Kistorp, professor, MD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2021
• Primary Completion (Actual): August 15, 2023
• Study Completion (Actual): August 15, 2023

Study Registration Dates

• First Submitted: December 10, 2021
• First Submitted That Met QC Criteria: January 12, 2022
• First Posted (Actual): January 25, 2022

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; Hypogonadism; Eunuchism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: H-20036287; 2020-002612-52 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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