DITEST is an oral formulation of native testosterone for the treatment of androgen deficiency in men. The study was a Phase 1 clinical study in hypogonadal men, defined according to FDA and Endocrine Society Guidelines, designed to evaluate the pharmacokinetic (PK) characteristics of DITEST, and to assess the safety and tolerability of DITEST in the target population.

There is an unmet need for a native oral testosterone therapy for men with androgen (testosterone) deficiency. Ideally such a treatment should have reproducible PK, does not need to be taken with fatty meals, can be taken once or twice daily, and provides physiological exposure to testosterone. This Phase 1, randomised, open-label, 2-cohort, cross-over study was therefore designed to evaluate the PK characteristics of DITEST in both the fed and fasted states according to FDA guidelines, and to assess the safety and tolerability of DITEST in the target population.

The study was conducted in male subjects from 18 to 80 years of age requiring testosterone replacement therapy for primary or secondary hypogonadism. The study was a randomised, active control, single dose, 2-way cross-over study in 2 cohorts. In each cohort subjects who meet the entry criteria at screening and baseline were randomised to one of 2 sequences:

Cohort 1: single dose of 120 mg (3 x 40 mg) DITEST followed by a single dose of 80 mg (2 x 40 mg) testosterone undecanoate (TU) or a single dose of 80 mg TU followed by single dose of 120 mg DITEST. The two treatments were separated by a minimum of a 7-day washout period, with both treatments given in the fed state.

Cohort 2: single dose of 200 mg (5 x 40 mg) DITEST (fed) followed by a single dose of 200 mg DITEST (fasted) or a single dose of 200 mg DITEST (fasted) followed by single dose of 200 mg DITEST (fed). The two treatments were separated by a minimum of a 7-day washout period.

13 subjects were recruited into cohort 1 and 12 subjects were recruited into cohort 2, resulting in a total of 25 subjects being administered study medication in this study. Subjects were not recruited into Cohort 2 until the results of subjects treated in Cohort 1 had been evaluated (this review was to determine if the intended dose for Cohort 2 needed to be adjusted). No other testosterone treatments were allowed for the duration of the study (including the washout periods).

Each subject was required to attend the study centre for a minimum of either 4 or 5 visits: a screening assessment, an evaluation of baseline testosterone levels after the washout period from the subject's current medication (only for subjects currently on testosterone replacement therapy), both dosing days, and a follow-up visit at the end of the study.

Inclusion Criteria:

• Male subjects aged 18 to 80 years.
• Diagnosis of primary testicular failure or secondary hypogonadism due to known pituitary disease or congenital deficit.
• Body mass index (BMI) >18kg/m2 and <35kg/m2
• Testosterone level <8nmol/L after washout of current testosterone treatment, if applicable.
• Normal prostate specific antigen (PSA) levels based on the age of the subject.
• Provision of written informed consent and able to participate in the study and abide by the study restrictions.

Exclusion Criteria:

• Subjects with a past history of, or current prostate cancer, male breast cancer or hepatic neoplasm.
• Subjects with a history of or current myocardial infarction (MI), unstable cardiovascular disease, or clinically relevant findings on the screening electrocardiogram (ECG) (as determined by the investigator)
• Subjects with a history of or current alcohol abuse (consumption of more than 28 units per weekweek: 1 unit equals 25mL single measure of whisky (ABV 40%), a third of a pint of beer (ABV 5-6%) or half a standard (175 mL) glass of red wine (ABV 12%).
• Subjects with other unstable or inadequately treated endocrine conditions.
• Haematocrit levels >0.5 at baseline
• Subjects with poor dental hygiene that would interfere with the collection of saliva samples or contaminate them with blood.
• Subjects with any severe co-morbidity or with any significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial.
• Participation in another clinical trial or an investigation or licensed drug or device within the 3 months prior to inclusion in this study.
• Allergic to any of the ingredients in the DITEST capsule, particularly sesame oil, or to any components of testosterone undecanoate capsules, particularly castor oil.
• Subjects with a known intolerance to alcohol (e.g. flushing) or ethnic populations at high risk of alcohol dehydrogenase (ADH) enzyme polymorphism with potential to impair metabolism of benzyl alcohol and ethanol, both of which are contained in the DITEST formulation.
• Meeting any of the contraindications for testosterone undecanoate, as detailed in the Summary of Product Characteristics (SmPC) of the comparator product.
• Subjects who are unable to consume the standard high-fat breakfast.
• Subjects who have donated blood or plasma in the previous 3 months prior to screening.
• Any subjects taking a concomitant medication known to enhance or inhibit the action of p450 CYP3A4 (rifampicin, barbiturates, carbamazepine, dichloralphenazone, phenylbutazone, phenytoin or primidone).