Open-Label Study, Evaluating Patient Satisfaction and Symptom Improvement When Treating Male Hypogonadism With Natesto™

A 150-Day, Prospective, Phase 4, Open-Label Study, Evaluating Patient Satisfaction and Symptom Improvement When Treating Male Hypogonadism With Testosterone Nasal Gel (Natesto™)

Multicenter study consisting of two study periods as follows: a 90-day Treatment Period, with potential extension by 30 days for those patients requiring a dose increase, as determined by the treating physician. Participants receiving 122.5mg of NATESTO (5.5 mg of testosterone) per nostril twice daily may have an increased daily dose adjustment on Day 90, based on their hypogonadism symptoms.

The primary objective of the study is to measure patient satisfaction with testosterone replacement therapy before (for non-naïve patients), during and after treatment with NATESTO.

The secondary objectives of this study are to evaluate the following:

• Improvement in hypogonadism symptoms;
• Patient treatment preference versus prior testosterone replacement therapy;
• Frequency of daily dose of NATESTO;
• Safety monitoring.

The population for this study is adult men 18-65 years of age inclusive, with primary or secondary hypogonadism, with historical documented total serum testosterone concentration of ≤300 ng/dL and the ability to provide informed consent. Eligible subjects include treatment-naïve, hypogonadal patients with a documented confirmation of hypogonadism, as well as patients previously treated with an alternate topical testosterone replacement therapy (TRT) for at least three months prior to selection. Participants currently receiving topical testosterone replacement therapy will be required to discontinue their current testosterone treatment before initiating treatment with NATESTO. The approximate total duration of study participation for participants completing the study will be up to 150 days (~21 weeks).

This is a Phase 4, multicenter study consisting of two study periods as follows:

• A 90-day Treatment Period, extended to 120-days for those subjects requiring a dose increase, during which participants will receive 122.5 mg of NATESTO (5.5mg testosterone) per nostril twice daily (BID) for 90 days. At Day 90, the treating physician will assess the patient's hypogonadism symptoms, review patient's completed questionnaires and based on the Canadian Men's Health Foundation Multidisciplinary Guidelines as endorsed by both the Canadian Urological Association and the Canadian Society of Endocrinology and Metabolism1, decide if continuation at a higher dose frequency of three-times daily (TID) is required for efficacy. For TID patients, there will be a 30-day Treatment Extension during which participants whose symptoms were not adequately treated on a BID dose, will receive 122.5 mg of NATESTO TID (5.5mg testosterone) per nostril. At Day 120, the TID patient will return to the site for examination, discussion of symptoms with the physician and questionnaire completion. All patients will have their blood testosterone levels assessed at Day 90 and only TID patients at Day 120.
• Post-study follow-up: All study patients will be requested to follow up at Day 150 to confirm whether they continued therapy with NATESTO.

Patient selection will come as a result of a doctor's visit for routine controls, prescription renewal and by pre-selection by the physician from among hypogonadal patients currently receiving topical testosterone replacement therapies and willing to participate in a clinical trial with NATESTO, or as a result of an initial consultation for naïve patients.

At Visit 1, patients who agree to participate in the study will come to the site. They will provide written informed consent and undergo a complete physical examination, including a nasal examination, and medical history collection. Blood pressure, heart rate, weight, and height measurements (from which body mass index [BMI] will be determined) will also be performed. Blood will be drawn at a local lab for safety assessment. However, if these values have already been documented in their patient file from the preceding 6 months, then those values will be entered into the eCRF. Previous treatment for hypogonadism (drug and nondrug; daily dose) will be recorded, as well as other concomitant treatment with drug or nondrug therapies. Study questionnaires Treatment Satisfaction Questionnaire for Medication (TSQM) and quantitative Androgen Deficiency in the Aging Male (qADAM) will be reviewed and subjects will be given instructions for proper completion of the instruments. Patients will complete Part A of the Patient Preference and Use Questionnaire. Patients will also be provided with a prescription for a 90-day supply of the study medication, NATESTO, and a Study Drug Access Card that will be used for payment purposes at the patient's preferred pharmacy.

Non-naïve participants will be instructed to stop their current topical treatment at least one day and no more than 7 days prior to initiation of treatment with NATESTO. Patients should not take both medications simultaneously.

The open-label Treatment Period will consist of a maximum of 5 study visits: 2 visits will be done via telephone by the Study Coordinator (Visit 2, Day 30 and Visit 3, Day 60) and one clinic visit (Visit 4, Day 90), and a last clinic visit for patients who were placed on a TID dose (Visit 5, Day 120).

At Visit 2 (Day 30) and Visit 3 (Day 60), participants will be required to complete questionnaires (TSQM and qADAM) by telephone with the Study Coordinator, and will also be asked about any concurrent medications or AEs.

At Visit 4 (Day 90), the patient will return to the site. Any unreported adverse events will be recorded. Patients will undergo a basic physical examination including a nasal examination. Blood pressure, heart rate, weight, and height measurements (from which body mass index [BMI] will be determined) will be recorded. Hypogonadism symptoms will be assessed by the Investigator making reference to the qADAM questionnaire results, and the patient will complete the TSQM.

At Visit 4 (Day 90), if in the physician's judgment the patient is adequately treated with twice daily (BID) NATESTO, the physician will decide whether the patient a.) should return to their previous therapy; b.) remain on NATESTO; or c.) consider a new treatment option. The physician will provide the patient with a prescription for the treatment chosen. The BID patients will have a blood draw taken at a local laboratory for safety assessment and to assess their testosterone level. This will constitute the END OF TREATMENT for BID subjects. These adequately controlled patients will complete Part B (for Non-naïve) or Part C (for Naïve) of the Patient Preference and Use Questionnaire.

At Visit 4 (Day 90), if the physician's judgement is that the twice daily (BID) dose of NATESTO was not adequate to treat the patient's symptoms and believes that the patient will benefit from a higher dose, then a prescription will be given to the patient for three times daily (TID) NATESTO. The Study Drug Access Card will be used for payment purposes at the patient's preferred pharmacy. These patients moving to TID will have a blood draw taken at a local laboratory to assess safety as well as their testosterone level. The patient will schedule Visit 5 (Day 120) at this time.

At Visit 5 (Day 120 for TID patients only), any unreported adverse events will be recorded. Patients will undergo a basic physical examination including a nasal examination. Blood pressure, heart rate, weight, and height measurements (from which body mass index [BMI] will be determined) will be recorded. The patients will have a blood draw taken at a local laboratory for safety assessment and to assess their testosterone level. In addition to TSQM and qADAM questionnaires, subjects will also complete Part B (for Non-naïve) or Part C (for Naïve) of the Patient Preference and Use Questionnaire. The physician will decide whether the patient a.) should return to their previous therapy; b.) remain on NATESTO; or c.) consider a new treatment option. The physician will provide the patient with a prescription for the treatment chosen.

At Visit 6 (Day 150), all study patients will be asked by telephone whether they are still taking NATESTO and why (or why not).

Inclusion Criteria:

• Hypogonadal male between 18 and 65 years of age, inclusive;
• Able to understand and provide signed informed consent;
• Have documented total serum testosterone levels ≤300 ng/dL;
• Are currently being treated with any form of a topical testosterone replacement therapy for at least three months, or are treatment-naive.

Exclusion Criteria:

• In the opinion of the Investigator, significant intercurrent disease of any type, in particular liver, kidney, heart disease, stroke, or psychiatric illness;
• History of pituitary or hypothalamic tumors or history of any malignancy (including breast and prostate cancers) excluding basal cell or squamous cell carcinoma of the skin curatively treated by surgery;
• Prostatomegaly or history of abnormal PSA levels (>10.0 ng/mL). If PSA is >10 ng/mL, a recent negative biopsy must be documented (within the last 12 months);
• History of nasal disorders, nasal or sinus surgery, nasal fracture within the previous 6 months or nasal fracture that caused a deviated anterior nasal septum surgery, mucosal inflammatory disorders, specifically Sjogren's syndrome;
• Use of any form of intranasal medication delivery other than periodic short-term (less than 3 days) use of sympathomimetic decongestants;
• History of severe adverse drug reactions to testosterone therapies;
• History or current evidence of abuse of alcohol or any drug substance;
• Current treatment with other androgens (e.g., dehydroepiandrosterone [DHEA]), anabolic steroids, or other sex hormones;
• Treatment with estrogens, gonadotropin-releasing hormone (GnRH) agonists, or growth hormone within the previous 12 months;
• Treatment with drugs that interfere with the metabolism of testosterone, such as anastrozole, clomiphene, dutasteride, finasteride, flutamide, ketoconazole, spironolactone, or testolactone;
• Poor compliance history;
• Participation in any other research study during the conduct of this study or 30 days prior to the initiation of this study.