A Comparison of Side Effects in Hypogonadal Men Treated With Natesto Versus Testosterone Injections

A Comparison of Side Effects in Hypogonadal Men Treated With Natesto Versus Testosterone Injections: A Phase IV, Prospective, Randomized, Non-Blinded, Multi-Institutional Study

The purpose of this study is to evaluate changes in vascular parameters and the prevalence of side effects in subjects receiving 1 cc (200mg) every 2 weeks intramuscular (IM) of Testosterone Cypionate versus subjects receiving 11mg three times daily (TID) Natesto to participant with clinical hypogonadism.

Administration of exogenous testosterone as efficacious treatment for male hypogonadism has been part of medical practice for more than 50 years. Testosterone replacement therapy (TRT) is becoming more widely available and has seen a greater than three-fold increase in use in men 40 years and older. Current delivery systems of TRT include transdermal gels and patches, intranasal gels (currently marketed as Natesto), injection therapy, and long acting subcutaneous pellets.

Natesto is a short-acting formulation of testosterone delivered intranasally to men diagnosed with low T. This has the potential to avoid side effects related to TRT that are commonly seen with other delivery methods, namely polycythemia, acne, male-pattern hair loss, azoospermia and hyperestrogenemia.

Testosterone Cypionate injections are the most common form of TRT in the USA. Testosterone Cypionate has many reported side effects, the most common being polycythemia, gynecomastia, hair loss, acne, decreased spermatogenesis, and testicular atrophy. In a multicenter retrospective study, it has been shown that the prevalence of polycythemia in men on testosterone replacement (injections) was 11.2%. In this study, we will compare hematocrit changes caused by treatment with Testosterone Cypionate and Natesto in a parallel arm, randomized study. To date, there have been no direct head-to-haed comparisons of these formulations.

We hypothesize that the short-acting pharmacokinetics of Natesto more closely resembles the natural pulsatility of testosterone and therefore can avoid side effects traditionally seen in long-acting, exogenous testosterone formulations

Inclusion Criteria:

1. Voluntarily sign and date the study consent form(s), which have been approved by an Institutional Review Board (IRB). Written consent must be obtained prior to the initiation of any study procedures.
2. Documented diagnosis of primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired).
3. Serum total testosterone < 300 ng/dL on 2 measurements
4. Naïve to androgen replacement or has discontinued current treatment and completed a washout of 4 months following androgen treatment.
5. Men deemed to be candidates for TRT based on the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead electrocardiogram (ECG).

Exclusion Criteria:

1. History of significant sensitivity or allergy to androgens, or product excipients.

2. Clinically significant findings in the pre-study examinations including abnormal breast examination requiring follow-up, abnormal ECG.

3. Abnormal prostate digital rectal examination (DRE) with palpable nodule(s)

4. Body mass index (BMI) ≥ 40 kg/m2.

5. Clinically significant abnormal laboratory value, in the opinion of the investigator, in serum chemistry, hematology, or urinalysis including but not limited to:

   1. Baseline hemoglobin > 16 g/dL or Hematocrit (HCT) 48%
   2. Prostate Specific Antigen (PSA) > 4 ng/mL

6. History of seizures or convulsions, including febrile, alcohol or drug withdrawal seizures.

7. History of any clinically significant illness, infection, or surgical procedure within 4 weeks prior to study drug administration.

8. History of stroke or myocardial infarction within the past 5 years.

9. History of, or current or suspected, prostate or breast cancer.

10. History of diagnosed, severe, untreated, obstructive sleep apnea.

11. History of abuse of alcohol or any drug substance in the opinion of the investigator within the previous 2 years.

12. Donation or loss of 550 mL or more blood volume (including plasmapheresis) or receipt of a transfusion of any blood product within 12 weeks prior to the start of treatment.

13. Inadequate venous access for collection of serial blood samples required for pharmacokinetic profiles.

14. Receipt of any subcutaneous testosterone pellets within the last 6 months.

15. Inability to understand and provide written informed consent for the study.