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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00702650

Enrollment

155

Registered

2008-06-20

Start date

2008-06-30

Completion date

2009-07-31

Last updated

2011-07-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypogonadism

Brief summary

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.

Interventions

DRUGTestosterone MD-Lotion

30 mg to 120 mg administered topically once daily for 120 days

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With 24-Hour Average Concentration [Cavg(0-24h)] Total Testosterone Within Normal Range at Day 120	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).

Secondary

Measure	Time frame	Description
Percentage of Participants With Cmax Between 1800 and 2500 ng/dL	Day 120	Cmax is the maximum observed serum concentration (between 1800 and 2500 ng/dL) during the 24 hour period on Day 120.
Percentage of Participants With Cmax >2500 ng/dL	Day 120	Cmax is the maximum observed serum concentration (\>2500 ng/dL) during the 24 hour period on Day 120.
Percentage of Participants With Minimum Concentration (Cmin) <300 ng/dL	Day 120	Cmin is the minimum observed serum concentration (\<300 ng/dL) during the 24 hour period on Day 120.
Change From Baseline to Endpoint in Psychosexual Daily Questionnaire	Baseline, Day 120	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).
Change From Baseline to Endpoint in the 36-Item Short-Form Health Survey (SF-36)	Baseline, Day 120	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).
Change From Baseline to Endpoint in Fasting Insulin	Baseline, up to Day 120	—
Percentage of Participants With Maximum Serum Concentration (Cmax) >1500 ng/dL	Day 120	Cmax is the maximum observed serum concentration (\>1500 ng/dL) during the 24 hour period on 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	Baseline, up to Day 120	Haematocrit: percentage of total blood volume made up of blood cells
Change From Baseline to Endpoint in Draize Score	Baseline, Day 120	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.
Change From Baseline to Endpoint in Fasting Glucose	Baseline, up to Day 120	—

Countries

Australia, France, Germany, Sweden, United Kingdom, United States

Participant flow

Pre-assignment details

Subjects received Testosterone Metered Dose (MD)-Lotion for 120 days, at initial dose of 60 mg; may have had their dose adjusted up or down on Days 45 and 90 (3 were on 30mg; 97 on 60mg; 25 on 90mg; and 10 on 120mg). As primary outcome=subjects with normal testosterone at Day 120, results are presented for overall treatment group rather than dose.

Participants by arm

Arm	Count
Testosterone MD-Lotion 30 mg to 120 mg of 2% Testosterone MD-Lotion administered topically once daily for 120 days.	155
Total	155

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	3
Overall Study	Lost to Follow-up	2
Overall Study	Non-Compliance of Study Drug	3
Overall Study	Non-Compliance with Site Directives	1
Overall Study	Screening Testosterone Levels >300 ng/dL	1
Overall Study	Sponsor Request	1
Overall Study	Withdrawal by Subject	9

Baseline characteristics

Characteristic	Testosterone MD-Lotion
Age Continuous	51.5 years STANDARD_DEVIATION 12.7
Baseline Total Testosterone Level	196.73 nanograms per deciliter (ng/dL) STANDARD_DEVIATION 91.04
Body Mass Index (BMI)	29.53 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 3.6
Race/Ethnicity, Customized African American	6 participants
Race/Ethnicity, Customized Asian	1 participants
Race/Ethnicity, Customized Caucasian	122 participants
Race/Ethnicity, Customized Hispanic	13 participants
Race/Ethnicity, Customized Missing	11 participants
Race/Ethnicity, Customized Other - Not Specified	2 participants
Region of Enrollment Australia	10 participants
Region of Enrollment France	11 participants
Region of Enrollment Germany	9 participants
Region of Enrollment Sweden	11 participants
Region of Enrollment United Kingdom	10 participants
Region of Enrollment United States	104 participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	155 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	80 / 155
serious Total, serious adverse events	1 / 155

Outcome results

Primary

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).

Time frame: Day 120

Population: All participants who received at least one dose of study drug, had on-treatment data for at least one efficacy variable, and completed the Day 120 visit. Participants were also included if they withdrew prior to Day 120 because of adverse event or lack of efficacy (considered as treatment failures).

Arm	Measure	Value (NUMBER)
Testosterone MD-Lotion	Percentage of Participants With 24-Hour Average Concentration [Cavg(0-24h)] Total Testosterone Within Normal Range at Day 120	84.1 percentage of participants

p-value: <0.001One-Sample Binomial (Wald) test, 2-sided

Secondary

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.

Time frame: Baseline, Day 120

Population: Participants enrolled in the study who had a baseline and a measurement at endpoint: Day 120.

Arm	Measure	Value (MEAN)	Dispersion
Testosterone MD-Lotion	Change From Baseline to Endpoint in Draize Score	0 units on a scale	Standard Deviation 0.17

Secondary