A Titration Trial to Determine the Effectiveness of Testosterone MD-Lotion (Cutaneous Solution) Formulations

Study Overview
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Brief Summary
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Testosterone replacement treatment is the most effective way of treating hypogonadism in men. Acrux has a propriety testosterone replacement product- Testosterone MD-Lotion (cutaneous solution), and this study will evaluate the efficacy via pharmacokinetics of various doses of this product. The study will also assess safety of the product.

Official Title
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A Phase III Open-label Titration Trial to Evaluate the Effectiveness and Safety of Different Doses of a Dermal Application of Testosterone MD-Lotion® (Cutaneous Solution) in Hypogonadal Men

Conditions
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Hypogonadism

Intervention / Treatment
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* Drug: Testosterone MD-Lotion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects with a prior documented definitive diagnosis of hypogonadism as evidenced by previously documented: Hypothalamic, pituitary or testicular disorder or age related idiopathic hypogonadism Screening serum testosterone of less than or equal to 300 ng/dL (based on the average of two morning samples taken at least 30 minutes apart) Were currently receiving treatment for hypogonadism in accordance with approved labelling, or in the Investigator's opinion are eligible to receive such treatment Body Mass Index (BMI) < 35.0 kg/m^2 Haemoglobin levels at screening greater than or equal to 11.5 g/dL Adequate venous access on left or right arm to allow collection of a number of samples by venipuncture Ability to communicate with the trial staff, understand the Trial Information Sheet and sign the Written Informed Consent Forms; willing to follow the Protocol requirements and comply with Protocol restrictions and procedures Exclusion Criteria: Current use of long acting testosterone injectables such as Nebido® Any significant history of allergy and/or sensitivity to the drug products or their excipients, including any history of sensitivity to testosterone and/or sunscreens Any clinically significant chronic illness or finding on screening physical exam and/or laboratory testing that makes it undesirable for the Investigator to enrol the trial subject in the trial and/or that in the Investigator's opinion, would interfere with the trial objectives or safety of the subject Chronic skin disorder (e.g. eczema, psoriasis) likely to interfere with transdermal drug absorption Men with suspected reversible hypogonadism Any man in whom testosterone therapy was contraindicated, which included those with: Known or suspected carcinoma (or history of carcinoma) of the prostate or clinically significant symptoms of benign prostatic hyperplasia and/or clinically significant symptoms of lower urinary obstruction and International Prostate Symptom Scores (IPSS) scores of greater than or equal to 19 Known or suspected carcinoma (or history of carcinoma) of the breast Severe liver disease (i.e. cirrhosis, hepatitis or liver tumours or liver function tests >2 times the upper limit of the normal range values) Active deep vein thrombosis, thromboembolic disorders or a documented history of these conditions Current significant cerebrovascular or coronary artery disease Untreated sleep apnoea Haematocrit of > 51 Untreated moderate to severe depression Men with clinically significant prostate exam (such as irregularities or nodules palpated) or clinically significant elevated serum Prostate Specific Antigen (PSA) levels (>4 ng/mL), or age adjusted reference range of PSA values Current or history of drug or alcohol abuse (more than 4 standard drinks per day and/or abnormal liver function tests >2 times the upper limit of the normal range values) Men taking concomitant medications (prescribed, over-the-counter or complementary) that would affect sex hormone binding globulin (SHBG) or testosterone concentrations or metabolism, warfarin, insulin, opiates, Gonadotropin-releasing hormone (GnRH), 5 alpha reductase inhibitors, propanolol, oxyphenbutazone, corticosteroids (except for physiological replacement doses), estradiol Men involved in sport in which there is screening for anabolic steroids Men with uncontrolled diabetes (haemoglobin A1c [HbA1c] greater than or equal to 10%) Men currently taking any investigational product, or have received an investigational product within 28 days prior to screening or 5 half-lives Any contraindication to blood sampling Subjects intending to have any surgical procedure during the course of the trial Subjects with a partner of child bearing potential who are not willing to use adequate contraception for the duration of the trial Subjects whose partners are pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Testosterone MD-Lotion<br>Participants received Testosterone Metered Dose (MD)-Lotion for 120 days. Participants started by receiving 3.0 mL (60 mg) of 2% Testosterone MD-Lotion, and based upon restoration to eugonadal levels, may have had their dose of testosterone adjusted upwards or downwards on Days 45 and 90. Doses could be titrated to one of the following: 1.5 mL (30 mg) of 2% Testosterone MD-Lotion applied daily by 1 dose to the axilla (1.5 mL to one axilla). 3.0 mL (60 mg) of 2% Testosterone MD-Lotion applied daily by 2 doses to the axilla (1.5 mL to each axilla). 4.5 mL (90 mg) of 2% Testosterone MD-Lotion applied daily by 3 doses to the axilla (2 x 1.5 mL to one axilla and 1 x 1.5 mL to the other axilla). 6.0 mL (120 mg) of 2% Testosterone MD-Lotion applied daily by 4 doses to the axilla (2 x 1.5 mL to each axilla). | Drug: Testosterone MD-Lotion<br>* 30 mg to 120 mg administered topically once daily for 120 days<br>* Other names: Axiron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 24-Hour Average Concentration [Cavg(0-24h)] Total Testosterone Within Normal Range at Day 120 | Cavg(0-24) is the average serum concentration calculated over the 24 hour period on Day 120. Calculated as the AUC(0-24) divided by 24 hours. Normal range for Total Testosterone was defined as 300 - 1050 nanograms per deciliter (ng/dL). | Day 120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Maximum Serum Concentration (Cmax) >1500 ng/dL | Cmax is the maximum observed serum concentration (>1500 ng/dL) during the 24 hour period on Day 120. | Day 120 | 
| Percentage of Participants With Cmax Between 1800 and 2500 ng/dL | Cmax is the maximum observed serum concentration (between 1800 and 2500 ng/dL) during the 24 hour period on Day 120. | Day 120 | 
| Percentage of Participants With Cmax >2500 ng/dL | Cmax is the maximum observed serum concentration (>2500 ng/dL) during the 24 hour period on Day 120. | Day 120 | 
| Percentage of Participants With Minimum Concentration (Cmin) <300 ng/dL | Cmin is the minimum observed serum concentration (<300 ng/dL) during the 24 hour period on Day 120. | Day 120 | 
| Change From Baseline to Endpoint in Psychosexual Daily Questionnaire | Questions included: Sexual Desire (0=none to 7=very high), Overall Sexual Activity Score (calculated as average of weekly values on scale from 0=none to 7=Frequent), Erection Maintained for Satisfactory Duration (0=not satisfactory to 7=very satisfactory), and Positive and Negative Mood (individual mood variables on scale from 0=Not at all true to 7=very true). Positive mood: sum of 4 positive mood variables-alert, full of pep/energetic, friendly, and well/good (range from 0-28). Negative mood: sum of 5 negative mood variables-angry, irritable, sad/blue, tired, and nervous (range from 0-35). | Baseline, Day 120 | 
| Change From Baseline to Endpoint in the 36-Item Short-Form Health Survey (SF-36) | The SF-36 Health Status Survey is a generic, health-related scale assessing subjects' quality of life on 8 domains: physical functioning, social functioning, bodily pain, vitality, mental health, role-physical, role-emotional and general health and 2 summary scores (mental component summary [MCS] and physical component summary [PCS]). MCS and PCS scores=0-100 (higher scores indicate better health status). | Baseline, Day 120 | 
| Change From Baseline to Endpoint in Fasting Insulin |  | Baseline, up to Day 120 | 
| Change From Baseline to Endpoint in Fasting Glucose |  | Baseline, up to Day 120 | 
| Change From Baseline to Endpoint in Prostate Specific Antigen (PSA) |  | Baseline, Day 120 | 
| Change From Baseline to Endpoint in Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) |  | Baseline, up to Day 120 | 
| Change From Baseline to Endpoint in Estradiol |  | Baseline, up to Day 120 | 
| Change From Baseline to Endpoint in Haemoglobin |  | Baseline, up to Day 120 | 
| Change From Baseline to Endpoint in Haematocrit | Haematocrit: percentage of total blood volume made up of blood cells | Baseline, up to Day 120 | 
| Change From Baseline to Endpoint in Draize Score | Draize score is a measurement of skin irritability of the application site based on erythema/eschar and oedema. Erythema/eschar scoring ranges from 0 (no erythema) to 4 (severe erythema [beet redness] to slight eschar formation [injuries in depth]). Oedema scoring ranges from 0 (no oedema) to 4 (severe oedema [raised more than 1 millimeter and extending beyond area of exposure]. The total Draize score ranges from 0 to 8. | Baseline, Day 120 |