Mechanisms and Interventions to Address Cardiovascular Risk of Gender-affirming Hormone Therapy in Trans Men

NCT04922424 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: 2000030176
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Gender-identity differences are becoming increasingly diagnosed in the US and treatment with gender-affirming hormone therapy (GAHT) is associated with improved mental health outcomes. However, GAHT has been associated with cardiovascular risk in adult transgender patients, although mechanisms and treatments have not been explored. Understanding the cardiovascular effects and exploring the potential of a lipid sensitive statin as a potential treatment is important to optimizing safe treatment strategies for transgender men in mitigating this modifiable risk factor, and designing and implementing effective interventions.

Conditions

Hypertension; Hyperlipidemias

Outcome Measures

Primary Outcomes (11)

• flow mediated vasodilation (FMD)

  FMD measures endothelial function, measured in % change from baseline arterial diameter after release following a short period of occlusion occlusion. The % change in diameter reflects the ability of the vessel to dilate in response to sheer stress induced by the flow following the release of occlusion. This reflects the function of the endothelium, or release of nitric oxide.

  30 minutes

• Muscle Sympathetic Nerve activity (MSNA)

  measured using microneurography and expressed in bursts/min or bursts/100 heart beats

  2 hours

• Cardiovagal baroreflex sensitivity (BRS)

  This is determined as a function of change in R-R interval (from EKG) over systolic blood pressure during rest and regular breathing. Expressed in Units.

  2 hours

• Mental Stress Test

  While measuring sympathetic nervous system activity (SNS) with microneurography, we ask the subject to count backwards from 200 by 7. This increases SNS. Measured in bursts/min or burst/100 heart beats

  10 minutes

• Voluntary Breath-Hold

  While measuring sympathetic nervous system activity (SNS) with microneurography, we ask the subject to hold breath as long as possible without straining. The subject does this twice, with a break in between. This increases SNS. Measured in bursts/min or burst/100 heart beats

  10 minutes

• Systolic Blood Pressure

  SBP, measured in mmHg

  2 hours

• Diastolic Blood Pressure

  DBP, measured in mmHg

  2 hours

• serum total cholesterol

  Measured in ng/dl. Elevated total cholesterol can indicate dyslipidemia.

  5 minutes

• serum low density lipoprotein (LDL)-C

  Measured in ng/dl. Elevated LDL-C can indicate dyslipidemia

  5 minutes

• serum high density lipoprotein (HDL-C)

  Measured in ng/dl. Low HDL-C can indicate dyslipidemia

  5 minutes

• plasma endothelin-1, (S[ET-1])

  endothelial health, increased ET-1 levels in the blood indicate damage to the endothelium

  5 minutes

Secondary Outcomes (6)

• plasma Catecholamines

  5 minutes

• serum estradiol (S[E2])

  5 minutes

• serum progesterone (S[P4])

  5 minutes

• serum sex hormone binding globulin (P[SHBG])

  5 minutes

• serum testosterone

  5 minutes

Study Arms (2)

atorvastatin

EXPERIMENTAL

We are testing that the lipid sensitive statin, atorvastatin treatment will reduce low density lipoprotein cholesterone, sympathetic nerve activity, increase endothelium-dependent vasodilation and improve autonomic function in trans men, while having little impact on cis women.

Drug: Atorvastatin

Placebo

PLACEBO COMPARATOR

We are testing that the placebo will have little effect on low density lipoprotein cholesterone, sympathetic nerve activity, endothelium-dependent vasodilation, autonomic function in trans men or cis women.

Other: placebo

Interventions

Atorvastatin DRUG

Subjects will ingest placebo or ingest 20 mg atorvastatin for 30 days first. We will include 30 days of washout between treatments to minimize any potential carryover effects.

atorvastatin

placebo OTHER

Subjects will ingest placebo or ingest 20 mg atorvastatin for 30 days first. We will include 30 days of washout between treatments to minimize any potential

Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Gender Eligibility Details: trans men, cis women
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Two groups (n=10 each) of subjects will be recruited to complete this study: 1) trans men between 18 and 35 years; 2) cisgender women between 18 and 35 years (Controls). They will have a body mass index (BMI) 18-30 kg·m-2. Our subjects will be matched on BMI and IR, using hemoglobin A1c and Homeostatic Model Assessment of Insulin Resistance technique (HOMA-IR) in order to isolate testosterone effects from other co-morbidities that may impact BP, sympathetic activity or endothelial function. Subjects will have HbA1c of 4-5.9% and a HOMA-IR of 0.5-1.4 to be included in the study. Subjects who smoke, have diabetes, or BP\>140/90 will be excluded. Subjects will not be taking medications during the study, including any insulin sensitizing or CV medications.

You may not qualify if:

• Subjects with the following histories or conditions will be excluded from the study:
• Gynecologic: a. current or past estrogen-dependent neoplasia, b. unexplained vaginal bleeding, c. history of uterine fibroids, d. current pregnancy, e. known or suspected breast or uterine cancer, f. partial or complete hysterectomy.
• Cardiac: a. myocardial infarction, ventricular tachycardia or fibrillation, b. angina, c. valvular disease (mitral insufficiency or stenosis, aortic insufficiency or stenosis), d. congestive heart failure, orthopnea, paroxysmal nocturnal dyspnea, e. current arrhythmias, f. prosthetic valves.
• Pulmonary: a. current cigarette smokers, or pipe or cigar smokers, b. chronic obstructive pulmonary disease, c. adult asthma, d. dyspnea on exertion, e. current bronchitis, pneumonia, or tuberculosis, f. lung carcinoma, g. pulmonary embolus, h. deep vein thrombosis.
• Vascular: a. claudications or history of peripheral vascular disease, b. abdominal or thoracic aortic aneurysm, or repair of same, c. cerebral aneurysm, vascular malformations, d. hypertension, systolic or diastolic, or strong family history of hypertension.
• Gastrointestinal: a. GI malignancy, b. hepatitis or other liver disease, current, c. splenomegaly from any cause, d. Cholecystitis, e. current diverticulosis or diverticulitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, f. previous gastrointestinal surgery.
• Infectious Disease: any ongoing intercurrent infection. Hematologic/Oncologic: a. receiving chemotherapy or radiation therapy, b. any metastatic malignancy, c. anemia (hematocrit \< 35), d. thrombocytopenia or thrombocytosis, e. neutropenia, f. hematologic malignancy, g. bleeding dyscrasia.
• Neurologic: a. history of cerebral vascular accident with any neurologic sequels, b. uncontrolled seizures (e.g., more than 1 seizure/year), c. transient ischemic attacks, d. dementia, e. neurologic conditions producing dyscoordination, peripheral neuropathy, or myopathy.
• Endocrine: a. diabetes mellitus, b. any untreated endocrinopathy. Renal: a. chronic renal diseases, b. any history of renal disease or impairment, c. current urinary tract infection.
• Musculoskeletal: a. inflammatory arthritis history (e.g., rheumatoid, psoriatic, Reiters), b. any history of pathologic fractures, including vertebral compression fractures.
• Pharmacologic: a. any illegal drug use, b. alcohol use greater than an average of 4 oz/day over 30 days, c. coumadin or heparin use.

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale School of Medicine

New Haven, Connecticut, 06519, United States

Location

MeSH Terms

Conditions

Hypertension; Hyperlipidemias

Interventions

Atorvastatin

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Nina Stachenfeld

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participant, PI and RA will not know whether the participant is taking the atorvastatin or placebo. Supervising physician will know.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Baseline testing, then each condition (group) will receive atorvastatin or placebo, followed by washout. Then receive the other condition.

Study Record Dates

• First Submitted: June 4, 2021
• First Posted: June 10, 2021
• Study Start: September 30, 2022
• Primary Completion: August 31, 2023
• Study Completion: August 31, 2023
• Last Updated: November 3, 2022

Record last verified: 2022-10

Locations

US (1)