Impact of Medically Supervised Performance-Enhancing Substances (PES) on Elite Athletes

Impact of Medically Supervised Performance-Enhancing Substances (PES) on Elite Athletes: A Hybrid Design in a Real-World Setting

Objectives:

The primary objective is to assess the safety and tolerability of medical drugs with the potential to enhance performance (PES) in professional athletes over a 5.5 year period, encompassing a 25-week PES Exposure period and 5 year long term follow-up of period comprehensive health and safety monitoring. The secondary objective is to evaluate the impact of PES on athletic performance through validated sport specific and clinical assessments.

Methods:

This prospective hybrid design study will enrol 60 adult participants, divided into two groups. The first group will receive performance-enhancing substances (PES) directly through the study, administered as Investigational Medicinal Products (IMPs) under comprehensive medical supervision for up to 25 weeks. The second group will include natural athletes and those already using PES prescribed by their own doctors. All substances used in this study are medically approved by national regulatory agencies (e.g., FDA, MHRA, EMA, EDE, etc.), and market authorised.

Participants undergo enrollment and baseline health and performance assessments, prior to a 25 weeks of PES exposure. During the period of PES exposure, participants undergo periodic monitoring of comprehensive physiological biomarkers alongside subjective assessments. Following the PES exposure phase, participants will complete repeat baseline health and performance assessments, followed by a titration phase and, where indicated, post-cycle therapy (PCT) to support the restoration of physiological function toward baseline. The study will conclude with a five-year longitudinal follow-up period to monitor long-term health outcomes. During this phase, participants will undergo annual assessments, including cardiac electrocardiography (ECG), echocardiography, magnetic resonance imaging (MRI), blood and urine biomarkers, routine vital signs, and quality-of-life measures. Additional imaging will include brain functional MRI (fMRI) and vital organ ultrasound at years 1, 3, and 5, with cardiac CT performed as clinically indicated. Athlete safety biomarker assessments, clinical evaluations, and adverse event reporting, will be continuously evaluated by study doctors and with additional safety oversight from a Data Safety Monitoring Board, Independent Medical Commission (a multidisciplinary panel of medical experts), and a Medical Monitor.

This study employs a prospective hybrid design comprising an observational cohort alongside a non-randomised interventional cohort, allowing for individualized PES regimens, biomarker-informed adaptation, and alignment with each athlete's training cycle while providing for the first time prospective data on safety parameters and performance effects of PES. It emphasizes within-subject change over time rather than between-group comparisons, offering a more ecologically valid framework for observing enhancement in context. Participants will continue periodized training while under continuous monitoring, enabling assessment of both physiological response and performance progression under real-world conditions. Similar study designs that aim to determine optimal therapy customization to individuals with specific biomarkers are becoming increasingly popular in precision medicine.

Inclusion Criteria:

Participants are eligible to be included in the study only if all the following criteria apply:

1. Participant must be 18 years of age or older at the time of signing the informed consent.

2. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

3. For a participant that intends to and uses PES as part of the study, the participant must be retired from professional sporting organizations that prohibit the performance enhancing substances and substances studied and must not be subject to active anti-doping regulations or testing pools at the time of enrollment.

4. Participant must be under the care of a primary care provider (PCP).

5. Participant passes medical profiling assessment (measuring overall state of health and quality of life)

6. Females must meet one of the following:

   1. Postmenopausal (>45 years of age with amenorrhea for at least 12 months, without using exogenous hormonal contraception and with FSH ≥ 40 IU/L).
   2. Surgically sterile (hysterectomy, bilateral salpingectomy; oophorectomy) for at least 6 months.
   3. Using a double contraception including a barrier method (condom, diaphragm, or occlusive cap) and a highly effective method of birth control, which includes the following:

   i. Established use (i.e. at least 90 days prior to signing of ICF) of combined (estrogen and progestogen) oral, intravaginal, or transdermal hormonal contraceptive associated with inhibition of ovulation. ii. Established use (i.e. at least 90 days prior to signing of ICF) of progestogen- only oral, injectable, or implantable hormonal contraceptive associated with inhibition of ovulation.

iii. Established use (i.e. at least 90 days prior to signing of ICF) of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

iv. Bilateral tubal occlusion completed at least 90 days prior to signing of ICF.

d) Vasectomized partner with the appropriate post-vasectomy documentation of the absence of spermatozoa in the ejaculate. Participant must provide documentation before the first dose of PES.

e) Sexual abstinence, when this is in line with the preferred and usual lifestyle of the participant.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

1. A self-reported history of any significant psychological or psychiatric challenges that may affect their ability to safely engage in the study or comply with study procedures. This includes, but is not limited to:

   1. Ongoing or recently unstable conditions such as severe depression or other psychiatric disorders that have not been effectively managed, in the judgement of the clinical research team.
   2. A history of severe mental health conditions (e.g., schizophrenia, bipolar disorder) that have required intensive intervention or hospitalization within the past 5 years.

2. Prior history of malignancy (including breast cancer, lymphoma, leukemia) within the past 5 years except for cervical or prostate carcinoma in situ that has been completely resected or cured basal or squamous cell skin carcinoma.

3. Has a history of CV disease that includes any of the following:

   1. Unstable CV disease, myocardial infarction, unstable angina, cardiac bypass or coronary arteries stenting, cerebrovascular accident (stroke), or transient ischemic attack.

   2. Clinically significant cardiac arrhythmias, including congenital arrhythmia syndromes (e.g. Long QT syndrome, Brugada Syndrome) or acquired arrhythmias, including pacemaker or ICD.

      Note. Cases will be considered on a case-by-case basis following an expert sports cardiology review using the newest internationally published recommendations.

   3. Congestive heart failure (New York Heart Association class II to IV symptoms) or inherited or acquired cardiomyopathies Note. Cases will be considered on a case-by-case basis following an expert sports cardiology review using the newest internationally published recommendations.

4. Current or history of clinically significant (per Investigator's judgment) liver or biliary disease.

5. Current acute or chronic self-reported HCV and/or HBV infection.

6. Current or history of clinically significant renal disease (per Investigator's judgment) or GFR <60mL/min/1.73m2

7. Has history or presence of any results from Screening Visit laboratory tests, ECG, physical examination, or vital signs that, in the opinion of the Investigator, Medical Monitor, or Sponsor, should be exclusionary for such a candidate.

8. The use of other investigational drugs at the time of screening or within 30 days or 5 half- lives prior to signing of the ICF, whichever is longer, or longer if required by local regulations.

   Note. Upon entry into the long-term follow-up phase of the study, participation in another clinical trial may be permitted only if it does not interfere with the objectives of this study. This is at the discretion of the study Investigator.

9. Pregnant or breastfeeding.

10. Has a mental or legal incapacity.

11. Is unwilling to provide written informed consent or is unable to follow the procedures outlined in the Protocol.

Prospective approval of protocol deviations to recruitment and eligibility criteria, also known as protocol waivers or exemptions, is not permitted.