Nebido® clinical efficacy

Nebido® clinical efficacy
Module 5 Nebido® clinical efficacy Approval Number: G.MKT.GM.MH

Nebido®: clinical efficacy
The clinical efficacy of Nebido® has been evaluated in a number of studies in patients with hypogonadism, including those with: Type 2 diabetes mellitus Metabolic syndrome Obesity Hypogonadism of different etiologies ED ED, erectile dysfunction

Module 5: Nebido® clinical efficacy
Body composition

Nebido® increases lean mass and decreases fat mass in hypogonadal men
Efficacy: body composition Nebido® increases lean mass and decreases fat mass in hypogonadal men T gel 50 mg daily for 12 months Switch to Nebido® for 12 months Total lean mass (kg) Time (months) * Lean mass: arms (kg) Lean mass: trunk (kg) # Lean mass: legs (kg) † Total fat (kg) ** Total fat (%) Android fat (kg) Gynoid fat (kg) A 24-month prospective, non-randomized, open-label study in 50 hypogonadal men aged 50–65 years with hypogonadism (score >26 in the Aging Males Symptoms Scale and a calculated free testosterone <250 pmol/L). Men received an initial 12 months of treatment with testosterone gel 50 mg once daily (adjustable after 3 months up to 75–100 mg or down to 25 mg) followed by 12 months of treatment with Nebido® (administered at the end of month 12 and month 14 with successive doses every 2–3 months until the last month of the study). Lean mass increased from baseline by 2.35% and 4.5%, after 12 and 24 months respectively. Fat mass also decreased by 4.2% and 9.1%, after these respective intervals. Patients gained proportionally more muscle mass in the limbs than the trunk. *p<0.001, **p=0.003, †p=0.005, #p=0.028 versus baseline N=50 men with hypogonadism (defined as score >26 using the AMS and free T: <250 pmol/L) (mean age: 59.1 years), treated for 12 months with T gel 50 mg daily followed by 12 months of Nebido® treatment AMS, Aging Males’ Symptoms scale; T, testosterone Rodriguez-Tolrà J et al. Aging Male. 2013;16(4):184–90.

Efficacy: body composition
Nebido® shows benefits on body composition beyond caloric restriction alone in obese, hypogonadal men Placebo (n=51) Nebido® (n=49) Mean change from baseline in VAT area (cm2) p=NS * p=0.04 Mean change from baseline after 56 weeks p=0.003 p=0.002 Mean change from baseline after 10 weeks Mean change from baseline in body weight (kg) Week 0–10 (VLED) A randomized, double-blind, placebo-controlled study in 100 obese (body mass index ≥30 kg/m2) men aged 18–70 years with hypogonadism who undertook dietary restriction for 10 weeks followed by weight maintenance for 46 weeks. Men received 56 weeks of treatment with Nebido® (10-weekly) or matching placebo. Compared with placebo recipients, men who received Nebido® had greater reductions in fat mass (mean adjusted between-group difference: −2.9 kg; p=0.04) and visceral fat (−2678 mm2; p=0.04). During the period of dietary restriction, both groups lost similar amounts of lean mass (Nebido® vs placebo: −3.9 vs −4.8 kg; p=0.36), but those receiving Nebido® regained lean mass during the maintenance period, such that the lean mass lost at study end was significantly less than that lost by placebo recipients (−0.6 vs −4.0 kg; p=0.002). *p<0.05 versus baseline within group N=100 obese, hypogonadal men (body mass index: ≥30 kg/m2, total T: <12 nmol/L) aged 18–70 years who undertook dietary restriction for 10 weeks followed by weight maintenance for 46 weeks NS, not significant; T, testosterone; VAT, visceral abdominal tissue; VLED, very low energy diet Ng Tang Fui M et al. BMC Med. 2016;14(1):153.

Appendicular lean muscle mass (kg) Total body lean mass (kg)
Efficacy: body composition Nebido® increases lean mass and decreases fat mass in hypogonadal men with liver cirrhosis Placebo (n=51) Nebido® (n=50) Appendicular lean muscle mass (kg) Time (months) ** Total body lean mass (kg) † Total fat mass (kg) * A randomized, double-blind, placebo-controlled study in 101 men (median age was 55.0 years) with hypogonadism (total testosterone <12 nmol/L) and established liver cirrhosis. Men received 12 months of treatment with Nebido® or placebo. Compared with placebo recipients, those treated with Nebido® had significantly increased appendicular lean mass (+1.69kg; p=0.021) and total lean mass (+4.74kg; p=0.008), and reduced fat mass (–4.34kg; p<0.001). Bone mass, BMD and haemoglobin also increased with Nebido® treatment. *p<0.001, †p=0.008, **p<0.05 versus placebo N=101 hypogonadal men (total T: <12 nmol/L) and established liver cirrhosis (median age: 55 years) T, testosterone Sinclair M et al. J Hepatol. 2016;65(5):906–13.

Weight loss

Nebido® significantly improves weight loss in hypogonadal men
Efficacy: weight loss Nebido® significantly improves weight loss in hypogonadal men Weight (kg) Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Saad et al. 2007 -2.10 -6.08 1.88 0.30 Saad et al. 2008 -1.00 -4.35 2.35 0.56 Jo et al. 2013 -0.80 -11.64 10.04 0.88 Saad et al. 2013 -16.15 -19.68 -12.62 0.00 Tirabassi et al. 2013 -1.90 -2.99 -0.81 Zitzmann et al. 2013 -1.20 -2.54 0.14 0.08 Francomano et al. 2014a -15.30 -31.82 1.22 0.07 Francomano et al. 2014b -15.00 -21.77 -8.23 Yassin et al. 2014 -7.60 -10.36 -4.84 Overall -5.88 -9.11 -2.64 -20 -10 10 20 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 9 studies reported data for change in weight. Meta-analysis of 9 studies reporting data for change in weight CI, confidence interval Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Nebido® significantly decreases waist circumference in hypogonadal men
Efficacy: weight loss Nebido® significantly decreases waist circumference in hypogonadal men Waist circumference (cm) Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Saad et al. 2007 -7.00 -11.83 -2.17 0.00 Saad et al. 2008 -3.00 -8.87 2.87 0.32 Garcia et al. 2009 -5.60 -10.36 -0.84 0.02 Permpongkosol et al. 2010 -3.61 -5.64 -1.58 Aversa et al. 2012 -13.00 -14.81 -11.19 Saad et al. 2013 -8.78 -10.92 -6.64 Tirabassi et al. 2013 -2.00 -9.16 5.16 0.58 Zitzmann et al. 2013 -4.00 -6.01 -1.99 Francomano et al. 2014a -12.79 -22.88 -2.70 0.01 Francomano et al. 2014b -9.60 -13.93 -5.27 Yassin et al. 2014 -8.70 -10.78 -6.62 Overall -7.11 -9.59 -4.64 -10 -5 5 10 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 11 studies reported data for change in waist circumference. Meta-analysis of 11 studies reporting data for change in waist circumference; CI, confidence interval Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Physical strength

Mean right arm grip strength (kPa)
Efficacy: physical strength Long-term Nebido® treatment significantly improves muscle strength in hypogonadal men Both Nebido® and testosterone enanthate treatment improved grip strength assessed using a hand dynamometer By the end of a 114-week extension study with Nebido® alone, grip strength was significantly greater than baseline Mean right arm grip strength (kPa) * Testosterone enanthate 250 mg (n=20) Nebido® (n=20) Open-label, randomized, prospective clinical trial in hypogonadal men aged 18–65 years (baseline serum testosterone level <5 nmol/L; N=40). Men were randomized to receive Nebido® (n=20) or testosterone enanthate (n=20). Duration of treatment: 144 weeks (after completing the 30-week comparison study, all 20 men in the Nebido® arm and 16 men in the testosterone enanthate arm entered am extension study where all men received Nebido® for an additional 114 weeks. Muscle strength was determined by grip strength measurements using a hand dynamometer. This method assesses the isometric strength of the arm muscles quantitatively and with high reproducibility. *p<0.05 versus baseline N=40 men aged 18–65 years with baseline serum total testosterone level <5 nmol/L Minnemann T et al. J Endocrinol Invest. 2008;31(8):718–23.

Anemia

Nebido® can attenuate anemia in hypogonadal men
Efficacy: anemia Nebido® can attenuate anemia in hypogonadal men Prevalence of anemia (%) Time (weeks) ** * 29.6% 10.0% Hemoglobin (g/dL) Hematocrit (%) Erythropoietin (mU/mL) *p<0.001, **p<0.05 versus baseline N=58 men with symptomatic hypogonadism [mean total testosterone: <8.1 nmol/L (235 ng/dL)] (mean age: 57 years) of whom 29.6% had anemia, and 46.6% had underlying conditions including type 2 diabetes and/or hypertension, coronary artery disease and dyslipidemia; n=29 men received Nebido® therapy and completed the study (54 weeks) Zhang LT et al. J Urol. 2016;195(4 Pt 1):1057–64.

Bone mineral density

Efficacy: bone mineral density
Nebido® significantly increases bone mineral density in hypogonadal men T gel 50 mg daily for 12 months Switch to Nebido® for 12 months L1–L4 BMD Time (months) * L2–L4 BMD Total femur BMD ** Femoral neck BMD Ward’s triangle BMD Trochanter BMD † A 24-month prospective, non-randomized, open-label study in 50 hypogonadal men aged 50–65 years with hypogonadism (score >26 in the Aging Males Symptoms Scale and a calculated free testosterone <250 pmol/L). Men received an initial 12 months of treatment with testosterone gel 50 mg once daily (adjustable after 3 months up to 75–100 mg or down to 25 mg) followed by 12 months of treatment with Nebido® (administered at the end of month 12 and month 14 with successive doses every 2–3 months until the last month of the study). *p<0.001, **p=0.030, †p=0.037 versus baseline N=50 men with hypogonadism (defined as score >26 using the AMS and free T: <250 pmol/L) (mean age: 59.1 years), treated for 12 months with T gel 50 mg daily followed by 12 months of Nebido® treatment AMS, Aging Males’ Symptoms scale; BMD, bone mineral density; T, testosterone Rodriguez-Tolrà J et al. Andrology. 2013;1(4):570–5.

Efficacy: bone mineral density
Nebido® increases BMD in men with functional hypogonadism and metabolic syndrome Age-matched control group (n=20) Nebido® group (n=40) Lumbar BMD Time (months) † *** ** Femoral BMD * Change in total T Change in lumbar BMD p<0.0001 r2=0.66 Change in femoral BMD r2=0.52 A 3-year prospective study in 60 men aged 55–60 (mean age 57 ± 10) years with functional hypogonadism (testosterone level <320 ng/dL) plus metabolic syndrome and/or type 2 diabetes. 40 men received Nebido® four times/year for 36 months and 20 age-matched men with hypogonadism and metabolic syndrome in whom testosterone treatment was contraindicated were used as controls. Long-term treatment with Nebido® produced a significant increase in BMD (vertebral and femoral) that was related to increases in serum testosterone levels. *p<0.0003, **p<0.002, ***p<0.005, †p<0.05 versus baseline N=60 men with adult-onset hypogonadism [total T: <11 nmol/L (320 ng/dL) or free T: <255 pmol/L (74 pg/mL)] plus metabolic syndrome defined according to IDF criteria, with or without type 2 diabetes (mean age: 57 years) BMD, bone mineral density; IDF, International Diabetes Federation; T, testosterone Aversa A et al. Aging Male. 2012;15(2):96–102.

Months of treatment with Nebido®
Efficacy: bone mineral density Nebido® significantly improves bone mineral density in hypogonadal men with osteoporosis T-score Months of treatment with Nebido® * † # Osteopenia Osteoporosis A prospective registry study examined the effects of up to 6 years of treatment with Nebido® in 45 men (mean age: 53 ± 7 years) with hypogonadism (<12.1 nmol/L) and osteoporosis (defined by a T-score more than 2.5 standard deviations below the mean value for young adult reference data). After 1 year, 44 men were included in the registry; after 2 years, 36 men; after 3 years 32 men; after 4 years 25 men; after 5 years 10 men; and after 6 years, 4 men. The declining numbers do not reflect drop-out rates but are a result of the registry design. Testosterone levels increased significantly from baseline, and were maintained within a eugonadal range. The individual BMD variation was expressed as a T-score of measurements of the spine (L2–4) and femoral neck. Significant and progressive improvements in T-scores were observed over 6 years, with osteoporosis improving to osteopenia. *p< versus baseline; §p<0.0001, †p<0.0003, #p< versus previous year N=45 men with hypogonadism (total testosterone: <12.1 nmol/L) and osteoporosis (defined by a T-score >2.5 standard deviations below the mean value for young adult reference data) (mean age: 53 years) Haider A et al. Int J Endocrinol. 2014;2014:

Men with metabolic syndrome and/or type 2 diabetes
Module 5: Nebido® clinical efficacy Men with metabolic syndrome and/or type 2 diabetes

Efficacy: metabolic syndrome & diabetes
Nebido® improves clinical parameters in hypogonadal men with diabetes or metabolic syndrome There is a high prevalence of hypogonadism in men with type 2 diabetes and metabolic syndrome1,2 Studies show that TTh with Nebido® is effective at increasing serum testosterone levels and improving other endpoints including BMD, anthropometry, body composition, metabolic parameters, and sexual function in this patient population3–7 Furthermore, TTh with Nebido® may reduce the occurrence of, or improve, diabetic complications in men with hypogonadism and type 2 diabetes3,8 BMD, bone mineral density; TTh, testosterone therapy 1. Traish AM et al. J Androl. 2009;30(1):10– Traish AM et al. J Androl. 2009;30(1):23– Janjgava S et al. Eur J Med Res. 2014;19(1): Gianatti EJ et al. Diabetes Care. 2014;37(8):2098– Gianatti EJ et al. J Clin Endocrinol Metab. 2014;99(10):3821–8. 6. Francomano D et al. J Endocrinol Invest. 2014;37(4):401– Saad F et al. Arch Androl ;53(6):353–7. 8. Kalinchenko S et al. Cardiovasc Diabetol. 2009;8:19.

Change from baseline at 30 weeks
Efficacy: metabolic syndrome & diabetes Nebido® significantly improves clinical parameters in hypogonadal men with metabolic syndrome Nebido® significantly decreased body mass index, body weight and waist circumference, as well as levels of leptin and the HOMA-IR, as a measure of insulin resistance, versus placebo Placebo group (n=71) Nebido® group (n=113) Change from baseline at 30 weeks Body mass index (kg/m2) p<0.001 p=0.001 p=0.04 Randomized, double-blind, placebo-controlled Phase 3 trial in men (N=184) aged 35–70 years with hypogonadism (total testosterone level <12 nmol/L (i.e. 350 ng/dL) or free testosterone level <225 pmol/L (i.e. 65 pg/mL) and metabolic syndrome. Men received 30 weeks of treatment with Nebido® (n=113) or placebo (n=71) administered at baseline, and after 6 and 18 weeks. 195 (92.0%) men receiving Nebido® and 65 (91.5%) men receiving placebo completed the trial. N=184 men aged 35–70 years with metabolic syndrome and hypogonadism [total T: <12 nmol/L (350 ng/dL) or free T: <225 pmol/L (65 pg/mL)] HOMA-IR, Homeostasis Model Assessment index of Insulin Resistance; T, testosterone Kalinchenko SY et al. Clin Endocrinol (Oxf). 2010;73(5):602–12.

Glucose and LDL-C (mmol/L) Triglycerides and TC (mmol/L)
Efficacy: metabolic syndrome & diabetes Nebido® improves liver profile and metabolic parameters in hypogonadal men with metabolic syndrome After 1 year of treatment with Nebido®: Significant improvements (p<0.05) in liver function and metabolic parameters were noted The number of men with metabolic syndrome according to NCEP criteria decreased from 74 at baseline to 42 AST and ALT (mmol/L) 2 3 4 7 6 5 CRP (mg/L) Time (months) CRP ALT AST Glucose and LDL-C (mmol/L) 200 220 240 300 280 260 Triglycerides and TC (mmol/L) 54 56 62 60 58 HDL-C (mmol/L) Triglycerides Baseline Glucose HDL-C TC LDL-C Cohort of 117 men aged 34–69 years with plasma testosterone levels of 5.9–12.1 nmol/L (mean ± SD = 9.4 ± 1.7) treated with Nebido® for 1 year (administered at 0 and 6 weeks and thereafter every 12 weeks). Men were followed up for 12 months at 3-month intervals. Plasma testosterone levels were significantly increased from baseline at 1 year. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome. Hepatic inflammation secondary to liver steatosis is a potential contributor to the low-grade inflammation associated with the metabolic syndrome. Elevations of liver enzymes are associated with higher CRP concentrations. Levels of ALT, AST and CRP had decreased significantly after 1 year of testosterone treatment. Significant reductions in IPSS, prostate volume, PSA level and residual bladder volume were also observed. N=117 men aged 34–69 years with plasma total testosterone levels of 5.9–12.1 nmol/L ALT alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; TC, total cholesterol Haider A et al. Exp Clin Endocrinol Diabetes. 2010;118(3):167–71.

Efficacy: metabolic syndrome & diabetes
Nebido® has clinical benefit in obese men with adult-onset hypogonadism Waist circumference (cm) Time (months) Weight (kg) ** Hemoglobin (g/dL) * Hematocrit (%) Triglycerides (mg/dL) # HDL-C (mg/dL) Total cholesterol (mg/dL) HbA1c (%) *p<0.0001, **p=0.001, §p=0.002, #p=0.016 versus baseline N=88 obese men with symptomatic adult-onset hypogonadism (mean body mass index: 34.6 kg/m2, mean total testosterone: 7.62 nmol/L, mean age: 51.1 years) HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol Canguven O et al. Andrologia. 2017;49(10):e12768.

Nebido® significantly decreases total cholesterol in hypogonadal men
Efficacy: dyslipidemia Nebido® significantly decreases total cholesterol in hypogonadal men Total cholesterol (mmol/L) Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Minnemann et al. 2007 -0.11 -0.71 0.49 0.72 Minnemann et al. 2008 -0.51 -1.18 0.16 0.14 Saad et al. 2007a -1.74 -2.16 -1.32 0.00 Saad et al. 2007b -1.58 -2.04 -1.12 Permpongkosol et al. 2010 -0.60 -0.77 -0.43 Moon et al. 2010 -0.23 -0.42 -0.04 0.02 Garcia et al. 2011 -1.51 -1.89 -1.13 Arafa et al. 2012 -1.08 -0.84 Saad et al. 2013 -2.40 -3.59 -1.21 Tirabassi et al. 2013 -0.47 -0.18 Zitzmann et al. 2013 -0.25 -0.34 -0.17 Francomano et al. 2014 -0.73 -1.15 -0.30 Yassin et al. 2014 -1.14 -1.37 -0.91 Overall -0.89 -1.19 -2 -1 1 2 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 13 studies reported data for change in total cholesterol. Meta-analysis of 13 studies reporting data for change in total cholesterol; CI, confidence interval Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Nebido® significantly increases HDL-C in hypogonadal men
Efficacy: dyslipidemia Nebido® significantly increases HDL-C in hypogonadal men HDL-C (mmol/L) Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Minnemann et al. 2007 0.31 0.17 0.45 0.00 Minnemann et al. 2008 -0.16 -0.32 -0.00 0.05 Saad et al. 2007 0.35 0.53 Saad et al. 2008 0.24 0.07 0.41 0.01 Fennell et al. 2010 0.12 0.10 0.14 Moon et al. 2010 -0.05 -0.17 0.40 Garcia et al. 2011 0.30 0.19 0.42 Arafa et al. 2012 0.03 -0.03 0.09 0.37 Saad et al. 2013 0.20 Tirabassi et al. 2013 0.13 0.29 0.11 Francomano et al. 2014 -0.01 0.27 0.06 Yassin et al. 2014 Overall 0.15 0.08 0.23 -0.50 -0.25 0.25 0.50 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 12 studies reported data for change in HDL-C. Meta-analysis of 12 studies reporting data for change in HDL-C CI, confidence interval; HDL-C, high-density lipoprotein cholesterol Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Nebido® significantly decreases triglycerides in hypogonadal men
Efficacy: dyslipidemia Nebido® significantly decreases triglycerides in hypogonadal men Triglycerides (mmol/L) Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Minnemann et al. 2007 0.27 -0.39 0.93 0.42 Minnemann et al. 2008 -0.26 -0.92 0.40 0.44 Saad et al. 2007 -1.19 -1.63 -0.75 0.00 Saad et al. 2008 -1.32 -1.77 -0.87 Moon et al. 2010 -0.04 -0.28 0.19 0.73 Garcia et al. 2011 -0.89 -1.22 -0.56 Arafa et al. 2012 -0.12 Saad et al. 2013 -0.90 -1.35 -0.45 Tirabassi et al. 2013 -0.11 -0.34 0.12 0.35 Zitzmann et al. 2013 -0.18 -0.25 -0.10 Francomano et al. 2014 -0.01 -0.23 0.21 0.92 Yassin et al. 2014 -0.58 -0.77 -0.40 Overall -0.44 -0.63 -0.24 -2 -1 1 2 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 12 studies reported data for change in triglycerides. Meta-analysis of 12 studies reporting data for change in triglycerides CI, confidence interval Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Waist circumference (cm) [mean +SD]
Efficacy: metabolic syndrome & diabetes Nebido® but not oral testosterone undecanoate has clinical benefit in hypogonadal men with metabolic syndrome Only Nebido® was significantly associated with improved metabolic and physical parameters after 6 and 12 months of treatment Placebo for 12 months (n=10) Nebido® for 12 months (n=32) Oral testosterone undecanoate for 6 months then switch to Nebido® for next 6 months (n=10) * HOMA-IR [mean +SD] ** Waist circumference (cm) [mean +SD] Randomized, double-blind, double-dummy study in men (N=52; mean age 57 years) with hypogonadism (mean testosterone <320 ng/dL) and metabolic syndrome. Men were randomized (1:1:3) to receive either: Nebido® every 12 weeks from week 6 for 12 months (n=32) . Oral testosterone undecanoate 2 capsules of 40 mg twice daily (equalling a total dose of 160 mg/day) for 6 months and continued with Nebido® for a further 6 months (n=10). Placebo 3–4 g/day for 12 months (n=10). *p<0.0001, **p<0.001 versus baseline N=52 men with hypogonadism [mean total T: <320 ng/dL (11.1 nmol/L)] and metabolic syndrome (mean age: 57 years) HOMA-IR, Homeostasis Model Assessment index of Insulin Resistance; SD, standard deviation; T, testosterone Aversa A et al. J Endocrinol Invest. 2010;33(11):776–83.

Fat-free mass (kg) [mean +SD]
Efficacy: metabolic syndrome & diabetes Nebido® but not oral testosterone undecanoate has clinical benefit in hypogonadal men with metabolic syndrome Only Nebido® was significantly associated with improved metabolic and physical parameters after 6 and 12 months of treatment Placebo for 12 months (n=10) Nebido® for 12 months (n=32) Oral testosterone undecanoate for 6 months then switch to Nebido® for next 6 months (n=10) Fat mass (%) [mean +SD] ** * Fat-free mass (kg) [mean +SD] Randomized, double-blind, double-dummy study in men (N=52; mean age 57 years) with hypogonadism (mean testosterone <320 ng/dL) and metabolic syndrome. Men were randomized (1:1:3) to receive either: Nebido® every 12 weeks from week 6 for 12 months (n=32) . Oral testosterone undecanoate 2 capsules of 40 mg twice daily (equalling a total dose of 160 mg/day) for 6 months and continued with Nebido® for a further 6 months (n=10). Placebo 3–4 g/day for 12 months (n=10). *p<0.0001, **p<0.001 versus baseline N=52 men with hypogonadism [mean total T: <320 ng/dL (11.1 nmol/L)] and metabolic syndrome (mean age: 57 years) SD, standard deviation; T, testosterone Aversa A et al. J Endocrinol Invest. 2010;33(11):776–83.

Efficacy: metabolic syndrome & diabetes, sexual function
Nebido® significantly improves clinical parameters and sexual function in hypogonadal men with type 2 diabetes No TTh group (n=31) Nebido® group (n=56) * Change from baseline Total T (ng/dL) +147 -9 HbA1c (%) Prospective, non-randomized study . Of 212 men with T2DM screened, 87 had testosterone levels <300 ng/dL. Nebido® was administered to 56 of these men, while 31 opted against treatment. An additional 23 patients with eugonadal testosterone levels were followed up after 3 months. All men were assessed after 3–6 months of treatment/no treatment. *p<0.05 versus baseline N=212 men with type 2 diabetes (mean age: 52.1 years), of whom 87 had total T levels <300 ng/dL (10.4 nmol/L) AMS, Aging Males’ Symptoms scale; HbA1c, glycated hemoglobin; IIEF-5, simplified International Index of Erectile Function; LDL-C, low-density lipoprotein cholesterol; T, testosterone; TTh, testosterone therapy Arafa M et al. Andrologia. 2012;44 Suppl 1:756–63.

Nebido® significantly improves HbA1c in hypogonadal men
Efficacy:diabetes Nebido® significantly improves HbA1c in hypogonadal men HbA1c (%) Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Arafa et al. 2012 -0.50 -0.65 -0.35 0.00 Saad et al. 2013 -0.90 -1.27 -0.53 Tirabassi et al. 2013 -0.10 -0.21 0.01 0.08 Francomano et al. 2014a -0.40 -0.97 0.17 Francomano et al. 2014b -1.60 -2.32 -0.88 Yassin et al. 2014 -0.92 -1.13 -0.71 Overall -0.68 -1.04 -0.32 -2.50 -1.25 1.25 2.50 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 6 studies reported data for change in HbA1c. Meta-analysis of 6 studies reporting data for change in HbA1c CI, confidence interval; HbA1c, glycated hemoglobin Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

General well-being and sexual function
Module 5: Nebido® clinical efficacy General well-being and sexual function

Ability to concentrate*
Efficacy: general well-being & sexual function IPASS: Nebido® markedly improves mental and psychosexual function in hypogonadal men Patients (%) Vigor* Ability to concentrate* General mood* High/very high Moderate Very low/low Positive/very positive Very negative/negative Good/very good Very poor/poor IPASS is the largest worldwide prospective, observational study of Nebido® conducted to date. A total of 1,493 men were enrolled in 23 countries, and data from 1,438 patients who received a total of 6,333 injections (up to 5 injections per patient) were analyzed. Nebido® was found to be effective and well tolerated in patients with hypogonadism. Clinical benefit was seen in both treatment-naive patients and those with prior androgen therapy experience. Marked improvements in mental and psychosexual health, waist circumference, blood pressure, and lipid profiles were observed during Nebido® treatment. The proportions of patients with low/very low sexual desire/libido and moderate-to-severe erectile dysfunction decreased from baseline after 4 doses (from 64% to 10% and from 67% to 19%, respectively). Most patients reported being satisfied or very satisfied with their treatment (89%). The drop-out rate was 17.5%, which was remarkably low considering that 155 centers were involved in this open-label study design. *For all 3 parameters, significant improvements (p<0.0001) were noted over each injection interval N=1,438 men with confirmed hypogonadism (mean age: 49.2 years); patients’ subjective assessment of erectile function, libido, vigor/vitality, mood and ability to concentrate was recorded by physician interview using items and 5-point Likert scales originating from the Aging Males’ Symptoms scale (AMS) and simplified International Index of Erectile Function (IIEF-5) Zitzmann M et al. J Sex Med. 2013;10(2):579–88.

Efficacy: general well-being & sexual function
Nebido® significantly improves mood, fatigue and related psychological parameters in hypogonadal men Agitation Time (weeks) * Good mood Fatigue Concentration Activation Testosterone therapy with Nebido® improves mood and sexual function in men with hypogonadism. Using a 10-cm visual analog scale, hypogonadal men rated 12 items related to mood and sexual function. Both Nebido® and parenteral testosterone enanthate were associated with rapid improvements in ability to concentrate, self-confidence, activity and more positive mood. Conversely, feelings of fatigue and exhaustion were reduced. Efficacy was maintained through 65 weeks. Efficacy was comparable between the two treatments, but Nebido® required less-frequent administration than testosterone enanthate. *p<0.05 versus baseline N=20 hypogonadal men (total testosterone: <5 nmol/L) aged 18–65 years, who received Nebido®; patients rated their weekly state concerning different items using a 10-cm visual analog scale Jockenhövel F et al. Aging Male. 2009;12(4):113–8.

Nebido® significantly improves health-related quality of life assessed by AMS score in hypogonadal men Placebo (n=58) Nebido® (n=56) Mean total AMS sum score Time (weeks) ** Mean psychological domain score Mean somatovegetative domain score * Mean sexual domain score NS Nebido® has been shown to improve overall HR-QoL) in men with hypogonadism. Assessment of HRQoL using the AMS scale in a placebo-controlled study in 120 men showed significant improvements in total score, and psychological and somatovegetative domain scores, and a non-significant improvement in sexual domain scores with Nebido® versus placebo recipients at week 48. *p<0.001, **p=0.017, §p=0.03 for improvement from baseline at 48 weeks versus placebo N=120 men aged >40 years with symptomatic hypogonadism (total testosterone: <12 nmol/L, total AMS score ≥27); n=58 and n=56 men who received placebo or Nebido®, respectively, and completed the study (48 weeks) AMS, Aging Males’ Symptoms scale; NS, not significant Ho CC et al. BJU Int. 2012;110(2):260–5.

Mental health composite scores Role functioning (physical)
Efficacy: general well-being & sexual function Nebido® significantly improves the mental health component and several other HR-QoL domains of the SF-12 in hypogonadal men Placebo (n=58) Nebido® (n=56) Mental health composite scores Time (weeks) ** Role functioning (physical) Time (weeks) Vitality Time (weeks) * Social functioning Time (weeks) # The 12-Item Short Form Survey (SF-12) showed a significant improvement in role functioning (physical), vitality, social functioning and mental health composite scores (but not physical health composite scores) with Nebido® versus placebo after adjustment for baseline differences (body mass index, systolic and diastolic blood pressure and total AMS scores. *p=0.002, **p=0.013, §p=0.015, #p=0.025 for improvement from baseline at 48 weeks versus placebo (data adjusted for baseline body mass index, systolic and diastolic blood pressure and total AMS score differences) N=120 men aged >40 years with symptomatic hypogonadism (total testosterone: <12 nmol/L, total AMS score ≥27); n=58 and n=56 men who received placebo or Nebido®, respectively, and completed the study (48 weeks) AMS, Aging Males’ Symptoms scale; HR-QoL, health-related quality of life; SF-12,12-Item Short Form Survey Tong SF et al. Asian J Androl. 2012;14(4):604–11.

Beck Depression Inventory score Aging Males’ Symptoms scale
Efficacy: general well-being & sexual function Nebido® improves depression, aging male symptoms and sexual dysfunction in hypogonadal men with metabolic syndrome Placebo (n=71) Nebido® (n=113) Beck Depression Inventory score Time (weeks) 6 7 8 9 10 11 p=0.027 Aging Males’ Symptoms scale p<0.001 IIEF-5 In a randomized, double-blind, placebo-controlled Phase III trial in 184 men with hypogonadism and metabolic syndrome, treatment with Nebido® produced significant improvements in depression, AMS and IIEF-5 scores compared with placebo at 30 weeks. The greatest effects on mood and sexual function were observed in men with the lowest baseline testosterone levels. N=184 obese, hypogonadal men (mean body mass index: 35.5 kg/m2, mean total testosterone: 8 nmol/L, mean age: 52.1 years) with metabolic syndrome IIEF-5, simplified International Index of Erectile Function Giltay EJ et al. J Sex Med. 2010;7(7):2572–82.

Nebido® significantly improves sexual function in hypogonadal men
Efficacy: general well-being & sexual function Nebido® significantly improves sexual function in hypogonadal men Satisfaction with sex life Time (weeks) * Sexual thought/ fantasy Sexual interest/ desire Ejaculations Total erections Spontaneous morning erections Testosterone therapy with Nebido® improves mood and sexual function in men with hypogonadism. Using a 10-cm visual analog scale, hypogonadal men rated 12 items related to mood and sexual function. Both Nebido® and parenteral testosterone enanthate were associated with rapid improvements in number of morning erections, total erections and number of ejaculations, as well as sexual fantasies, sexual desire and satisfaction with sexual life, from as early as 3 weeks. Efficacy was maintained through 65 weeks. Efficacy was comparable between the two treatments, but Nebido® required less-frequent administration than testosterone enanthate. *p<0.05 versus baseline N=20 hypogonadal men (total testosterone: <5 nmol/L) aged 18–65 years, who received Nebido®; patients rated their weekly state concerning different items using a 10-cm visual analog scale Jockenhövel F et al. Aging Male. 2009;12(4):113–8.

Nebido® significantly improves erectile function in hypogonadal men
Efficacy: general well-being & sexual function Nebido® significantly improves erectile function in hypogonadal men Erectile function standardized mean Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Saad et al. 2007 2.33 1.65 3.01 0.00 Kalinchenko et al. 2008 0.97 0.31 1.62 Kurbatov et al. 2008 8.67 7.01 10.33 Saad et al. 2008 2.03 1.37 2.68 Moon et al. 2010 0.74 0.49 0.99 Permpongkosol et al. 2010 0.15 -0.07 0.37 0.17 Garcia et al. 2011 8.86 7.17 10.55 Arafa et al. 2012 1.57 2.48 Zitzmann et al. 2013 0.07 0.22 Francomano et al. 2014 0.10 -0.52 0.72 0.76 Haider et al. 2014 2.18 2.77 Yassin et al. 2014 2.44 2.15 2.73 Overall 2.24 1.52 2.97 -4 -2 2 4 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 12 studies reported data for change in erectile function. Meta-analysis of 12 studies reporting data for change in erectile function CI, confidence interval Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Nebido® significantly improves penile health in obese men with adult-onset hypogonadism NPT: frequency of rigidity (times) Time (months) Night 2 Night 1 * NPT: duration of rigidity (min) IIEF-5 score Peak systolic velocity (cm/s) Right cavernous artery Left cavernous artery # End diastolic velocity (cm/s) ** Testosterone level (nmol/L) In a prospective study of 88 patients with erectile dysfunction due to adult-onset hypogonadism, Nebido® was shown to improve the objective and subjective parameters of andrological health. At the end of the 12-month treatment period, significant increases were observed in both the frequency (mean increase 1.27 times) and duration (mean increase 5.12 min) of nocturnal penile tumescence (p< for all measurements). In addition, blood flow through the cavernous arteries was altered, with a significant increase in peak systolic velocity and a significant decrease in end diastolic velocity detected after 12 months of treatment. Furthermore, significant improvements in IIEF scores were recorded at 6 and 12 months (p<0.0001). *p<0.0001, **p=0.004, §p=0.007, #p=0.016 versus baseline N=88 obese men with symptomatic adult-onset hypogonadism (mean body mass index: 34.6 kg/m2, mean total testosterone: 7.62 nmol/L, mean age: 51.1 years) and erectile dysfunction IIEF-5, simplified International Index of Erectile Function; NPT, nocturnal penile tumescence Canguven O et al. Aging Male. 2016;19(4):215–20.

Nebido® shows benefits on sexual function beyond caloric restriction alone in obese, hypogonadal men Placebo (n=51) Nebido® (n=49) Mean change from baseline after 10 weeks ‡ Mean change from baseline after 56 weeks * ** ‘Decrease in sexual desire/libido’ A pre-specified analysis of a randomized, double-blind, placebo-controlled study in 100 obese (body mass index ≥30 kg/m2) men aged 18–70 years with hypogonadism who undertook dietary restriction for 10 weeks followed by weight maintenance for 46 weeks. Men received 56 weeks of treatment with Nebido® (10-weekly) or matching placebo. Patients with more severe symptoms at baseline experienced greater improvements at the end of the study. After 56 weeks of treatment mean adjusted unit difference in AMS score was −0.34 (p=0.04). In patients with erectile dysfunction at baseline, Nebido® was associated with a significant improvement in IIEF-5 score compared with placebo (p=0.025). *p=0.0008, §p=0.003, ‡p=0.01, **p=0.025, ¤p=0.04 versus placebo group N=100 obese, hypogonadal men (body mass index: ≥30 kg/m2, total T: <12 nmol/L) (median age: 53 years) who undertook dietary restriction for 10 weeks followed by weight maintenance for 46 weeks AMS, Aging Males’ Symptoms scale; IIEF-5, simplified International Index of Erectile Function Ng Tang Fui M et al. Int J Obes (Lond). 2017;41(3):420–6.

Change in sexual desire (%)
Efficacy: general well-being & sexual function Nebido® significantly increases sexual desire independently of baseline testosterone levels in obese men with OSA Placebo (n=28) Nebido® (n=26) Change in sexual desire (%) Time (weeks) p=0.0039 A randomized, double-blind, placebo-controlled study of 67 obese men with sleep apnoea who received Nebido® for 12 weeks showed that those treated with testosterone had an increase in sexual desire versus placebo recipients. Other sexual function outcomes were not different between groups, and Nebido® therapy did not affect quality of life, measures of sleepiness, weight loss or neurocognitive function in these patients. N=54 obese men (body mass index: >30 kg/m2, mean age: 48.5 years) with OSA and a variety of baseline testosterone concentrations: <13, <11 and <8 nmol/L in 62%, 47% and 23% of men, respectively OSA, obstructive sleep apnea Melehan KL et al. Andrology. 2016;4(1):55–61.

Excluding PDE-5 inhibitor users (n=164)
Efficacy: general well-being & sexual function Nebido® improves erectile function, irrespective of PDE-5 inhibitor use or the presence of ED Placebo group Nebido® group Blinded treatment Open-label treatment Time (weeks) IIEF-EF score All patients (N=199) Excluding PDE-5 inhibitor users (n=164) Excluding PDE-5 inhibitor users and men with IIEF-EF score >25 (n=141) Randomized, double-blind, placebo-controlled BLAST study in men (N=199) with type 2 diabetes and total testosterone ≤12 nmol/L or free testosterone ≤250 pmol/L at baseline. For the first 30 weeks, men were treated with either Nebido® or placebo, followed by open-label treatment for 52 weeks. Sexual function parameters were measured at baseline and 30 weeks. In men taking PDE-5 inhibitors, there was no change in erectile function during the double-blind phase, but a 9-point improvement in erectile function occurred during open-label treatment. N=199 hypogonadal men (total testosterone: ≤12 nmol/L or free testosterone: ≤250 pmol/L) with type 2 diabetes, with or without depression, treated with Nebido® or placebo for 30 weeks (blinded) then for a further 52 weeks (open-label) ED, erectile dysfunction; IIEF-EF, erectile function domain of the International Index of Erectile Function; PDE-5, phosphodiesterase type 5 Hackett G et al. J Sex Med. 2013;10(6):1612–27.

Nebido® significantly improves erectile function and response to PDE-5 inhibitors in hypogonadal men with ED None (≤26) Mild (27–36) Hypogonadism severity (AMS score): Moderate (37–49) Severe (≥50) Mean AMS score * Patients (%) ** Mild (17–21) Mild to moderate (12–16) ED severity (IIEF-5 score): Moderate (8–11) Severe (1–7) Patients (%) # Mean IIEF-5 score ‡ *p≤0.001, **p=0.002, §p=0.003, #p=0.016, ‡p=0.033 versus baseline N=25 men with symptomatic adult-onset hypogonadism (total testosterone: <10.4 nmol/L; mean age: years) with ED receiving Nebido®; at week 12, if ED was not improved (assessed by IIEF-5 score or GAQ), vardenafil was added AMS, Aging Males’ Symptoms scale; ED, erectile dysfunction; GAQ, Global Assessment Question; IIEF-5, simplified International Index of Erectile Function; PDE-5, phosphodiesterase type 5 Permpongkosol S et al. Open J Urol. 2013;3:139–45.

Nebido® improves erectile function in hypogonadal men with ED that does not respond to PDE-5 inhibitors Time (weeks) Total testosterone (nmol/L) * ** IIEF-EF score: sexual desire domain IIEF-EF score: erectile function domain *p<0.05 versus baseline; **p<0.05 versus week 6; §p<0.05 versus week 18 N=29 hypogonadal men [total T: <12 nmol/L (350 ng/dL) or free T: <200 pmol/L (5 ng/dL)] (mean age: 59 years) with ED (mild to moderate: n=21, severe: n=8) that is refractory to PDE-5 inhibitor therapy ED, erectile dysfunction; IIEF-EF, erectile function domain of the International Index of Erectile Function; PDE-5, phosphodiesterase type 5; T, testosterone Garcia JA et al. Andrologia. 2011;43(5):293–6.

In hypogonadal men with ED, Nebido® plus daily tadalafil is significantly more effective than Nebido® and on-demand tadalafil Nebido® plus on-demand tadalafil (n=30) Nebido® plus daily tadalafil (n=30) Mean total IIEF score Time (weeks) * Mean total AMS score *p<0.05 versus Nebido® plus on-demand tadalafil group N=60 hypogonadal men [total testosterone: <12 nmol/L (350 ng/dL)] (mean age: years) with ED, treated with either Nebido® and on-demand tadalafil (10–20 mg) or combination therapy with Nebido® plus daily tadalafil (5 mg) for 30 weeks AMS, Aging Males’ Symptoms scale; ED, erectile dysfunction; IIEF, International Index of Erectile Function Yassin DJ et al. World J Urol. 2014;32(4):1049–54.

Testosterone (nmol/L)
Efficacy: general well-being & sexual function Nebido® achieves higher plasma T levels and shows greater improvements in erectile function than T gel T gel 50 mg daily (n=27) Nebido® (n=28) Testosterone (nmol/L) Time (months) +63.64% change % change** * SHBG (nmol/L) Time (months) +3.57% change** -20.51% change * IIEF score Time (months) +41.67% change % change** * Nebido® produced greater improvement in IIEF scores than that achieved with testosterone gel in elderly hypogonadal men with underlying conditions and sexual dysfunction. Testosterone levels significantly increased from baseline after 9 months of treatment with either testosterone gel or Nebido® (p<0.05). This suggests a dose-response relationship between achieved testosterone levels and sexual function. *p<0.05 versus baseline; **p<0.05 versus T gel N=55 men with adult-onset hypogonadism [total T: <10.4–29.8 nmol/L (3.0–8.6 ng/mL); mean age: 60.5 years] complaining of sexual dysfunction, most of whom had metabolic syndrome, CVD and/or type 2 diabetes CVD, cardiovascular disease; IIEF, International Index of Erectile Function; T, testosterone Saad F et al. J Androl. 2008;29(1):102–5.

Testosterone (nmol/L)
Efficacy: general well-being & sexual function Nebido® achieves higher plasma T levels and shows greater improvements in erectile function than T gel T gel 50 mg daily Nebido® Testosterone (nmol/L) Time (months) +63% change ** * IIEF score Time (months) +40% change +13% change * ** AMS score Time (months) -20% change -35% change * ** Nebido® produced greater improvements in AMS and IIEF scores than those achieved during 9 months of initial treatment with testosterone gel in elderly hypogonadal men with sexual dysfunction. Testosterone levels significantly increased from baseline after 9 months of testosterone gel treatment, and a further increase was observed after 3 months of treatment with Nebido® (p<0.05). This suggests a dose-response relationship between achieved testosterone levels and sexual function. *p<0.05 versus baseline; **p<0.05 versus T gel (9 months) N=27 men with adult-onset hypogonadism [mean total T: 7.8 nmol/L (2.24 ng/mL); mean age: 60 years] complaining of sexual dysfunction, who were treated with T gel for 9 months, and then Nebido® for 9 months AMS, Aging Males’ Symptoms scale; IIEF, International Index of Erectile Function; T, testosterone Saad F et al. Andrologia. 2008;40(1):44–8.

IIEF-5 score: libido domain IIEF-5 score: erectile function domain
Efficacy: general well-being & sexual function Nebido® can improve erectile function in hypogonadal men with ED due to venous leakage Penile cavernosography and MRI suggest that the improvement in erectile function with Nebido® in men with ED due to venous leakage is associated with erectile tissue structural remodelling1–3 IIEF-5 score: libido domain Time (weeks) * IIEF-5 score: erectile function domain AMS score Evidence comes from case series and a small study in 20 hypogonadal men with ED due to venous leakage. *p<0.05 versus baseline N=29 hypogonadal men [mean total testosterone: 10.6 nmol/L (300 ng/dL), mean age: 47 years) with ED non-responsive to PDE-5 inhibitor therapy, of whom n=20 had ED due to venous leakage (this subgroup is shown in the graphs above)3 AMS, Aging Males’ Symptoms scale; ED, erectile dysfunction; IIEF-5, simplified International Index of Erectile Function; MRI, magnetic resonance imaging; PDE-5, phosphodiesterase type 5 1. Yassin AA & Saad F. Andrologia. 2006;38(1):34–7. 2. Yassin AA et al. J Sex Med. 2006;3(4):727– Kurbatov D et al. J Androl. 2008;29(6):630–7.

BLAST: greater improvements in sexual function with Nebido® are seen in diabetic men with more severe hypogonadism Placebo group Nebido® group Mild hypogonadism Severe hypogonadism Change in mean IIEF score: intercourse satisfaction domain Time (weeks) ** ‡ Change in mean IIEF score: erectile function domain † Change in mean IIEF score: orgasmic function domain Change in mean IIEF score: sexual desire domain * Additional results from the BLAST study, investigating treatment with Nebido® in men with type 2 diabetes and mild or severe hypogonadism, showed that men with severe hypogonadism (total testosterone ≤8.0 nmol/L or free testosterone ≤0.18 nmol/L) reported an improvement in erectile function from baseline and versus placebo after 30 weeks’ treatment, according to IIEF-15 scores. Intercourse satisfaction and sexual desire scores also improved at 6, 18 and 30 weeks versus baseline and placebo in these men after Nebido® treatment. *p≤0.0001, **p=0.0002, §p=0.0017, †p=0.0036, ‡p=0.0051, ¤p=0.031 versus placebo N=189 men with type 2 diabetes (mean age: 61.8 years) and mild (total T: 8.1–12 nmol/L or free T: 0.181–0.25 nmol/L) or severe (total T: ≤8.0 nmol/L or free T: ≤0.18 nmol/L) hypogonadism, treated with Nebido® or placebo for 30 weeks IIEF, International Index of Erectile Function; T, testosterone Hackett G et al. BJU Int. 2016;118(5):804–13.

LUTS

Nebido® significantly improves LUTS in hypogonadal men
Efficacy: LUTS Nebido® significantly improves LUTS in hypogonadal men IPSS score * Nocturia † ** Obstructive symptoms ‡ Irritative symptoms Testosterone gel 50 mg (n=10) Nebido® (n=20) Pilot study in men (N=30; mean age 51 years) with hypogonadism (plasma testosterone levels <10.8 nmol/L) and symptoms of LUTS. At the time of the inclusion of the study, men were not using medications for LUTS. Men received either testosterone gel 50 mg (Androgel®/Testogel®) daily for 3 months (n=10) or Nebido® for 26 weeks (n=20). The International Prostate Symptoms Score (IPSS) was used to measure change in LUTS. *p< , **p<0.001, §p=0.004, †p=0.005, ‡p=0.018 versus before treatment N=30 hypogonadal men (plasma total testosterone: <10.8 nmol/L) with symptoms of LUTS, not receiving treatment for benign prostatic hyperplasia (mean age: 51 years) IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms Kalinchenko S et al. Aging Male. 2008;11(2):57–61.

Efficacy: LUTS Nebido® significantly improves moderate LUTS in men with suspected hypogonadism Before treatment After ≥1 year of Nebido® treatment Score * ** In this follow-up study, all men (N=246) had received Nebido® for at least 1 year. A subanalysis was conducted on 17 men (median age 53 years) who had moderate LUTS (i.e. initial IPSS >8 points but <19 with a maximal flow rate of ≥10 ml/s), but were not taking any benign prostatic hyperplasia medications while receiving testosterone therapy. The local institutional policy for initiation of testosterone therapy was a complaint of erectile dysfunction with a serum testosterone level <3.5 ng/ml. The primary end point was change in IPSS score. *p=0.028, **p=0.039, §p=0.048 versus before treatment N=17 men with suspected hypogonadism and moderate LUTS, not receiving treatment for benign prostatic hyperplasia (mean age: 51 years) IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms Ko YH et al. World J Mens Health. 2013;31(1):47–52.

Efficacy: LUTS Nebido® significantly improves LUTS, independently of other factors, in hypogonadal men Nebido® treatment significantly improved IPSS, independently of weight loss, PDE-5 inhibitor use or baseline age (p<0.05) Mean IPSS score Treatment visit No weight loss Weight loss No PDE-5 inhibitor use PDE-5 inhibitor use A 5-year prospective, observational and longitudinal registry study in in men (N=261; mean age 59.5 years) with hypogonadism (total testosterone concentration ≤3.5 ng/mL (12 nmol/L) on 2 blood samples). After reaching steady-state testosterone concentrations, men received Nebido® every 3 months for a median period of 42.3 months. The primary endpoint was mean reduction in IPSS from baseline at each treatment visit. Two subgroup analyses were conducted to test for confounding: (1) users versus non-users of the PDE-5 inhibitor, vardenafil and (2) weight losers versus non-losers. N=261 men with confirmed hypogonadism [total T: ≤12 nmol/L (3.5 ng/mL)] (mean age: 59.5 years) IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; PDE-5, phosphodiesterase type 5; T, testosterone Yassin DJ et al. World J Urol. 2014;32(4):1049–54.

Statistics for each study
Efficacy: LUTS Meta-analysis confirms that Nebido® significantly improves LUTS in hypogonadal men IPSS score Study Statistics for each study Difference in means and 95% CI Difference in means Lower limit Upper limit p value Saad et al. 2007 -2.90 -4.45 -1.35 0.00 Saad et al. 2008 -1.70 -3.25 -0.15 0.03 Kalinchenko et al. 2008 -5.50 -9.02 -1.98 Permpongkosol et al. 2010 -0.40 -1.77 0.97 0.57 Moon et al. 2010 -0.60 -1.58 0.38 0.23 Garcia et al. 2011 2.00 0.69 3.31 Ko et al. 2013 1.00 -4.14 6.14 0.70 Francomano et al. 2014 -2.00 -3.58 -0.42 0.01 Yassin et al. 2013 -3.77 -4.71 -2.83 Overall -1.54 -2.97 -0.10 0.04 -4 -2 2 4 Post-Nebido® Pre-Nebido® Meta-analysis of 33 studies (including 11 randomized, placebo-controlled trials) in 3,359 men who received Nebido® and 478 placebo-treated men. 9 studies reported data for change in IPSS score. Meta-analysis of 9 studies reporting data for change in IPSS score CI, confidence interval; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms Corona G et al. Expert Opin Pharmacother. 2014;15(13):1903–26.

Long-term studies

Waist circumference (cm) Fasting glucose (mmol/L)
Long-term efficacy Nebido® continues to significantly improve metabolic parameters in hypogonadal men over the long-term Waist circumference (cm) Time (years) * Fasting glucose (mmol/L) Time (years) * * Weight (kg) Time (years) * HbA1c (%) Time (years) * *p< versus baseline; §p< versus previous year N=262 hypogonadal men (total testosterone: ≤12 nmol/L) (mean age: years) receiving Nebido® for up to 10 years (mean follow-up: 7.56 years) HbA1c, glycated hemoglobin Yassin AA et al. Andrologia. 2016;48(7):793–9.

Total cholesterol (mg/dL) Triglycerides (mg/dL)
Long-term efficacy Nebido® continues to significantly improve metabolic parameters in hypogonadal men over the long-term Continued treatment with Nebido® leads to significant year-on-year improvements in metabolic parameters (p<0.0001) HDL-C (mg/dL) Time (years) * Total cholesterol (mg/dL) Time (years) * LDL-C (mg/dL) Time (years) * Triglycerides (mg/dL) Time (years) * *p< versus baseline; §p< versus previous year N=262 hypogonadal men (total testosterone: ≤12 nmol/L) (mean age: years) receiving Nebido® for up to 10 years (mean follow-up: 7.56 years) HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol Yassin AA et al. Andrologia. 2016;48(7):793–9.

Waist circumference (cm)
Long-term efficacy: obesity & diabetes Nebido® continues to significantly improve body composition in obese, hypogonadal men All subjects (n=181) Subjects with type 2 diabetes (n=72) Waist circumference (cm) Time (months) * Weight (kg) 16.44% weight change at 5 years versus baseline 15.97% weight change at 5 years versus baseline From a prospective registry study of 255 men aged 33–69 years (mean ± 6.06), a subgroup analysis of 181 men with obesity (mean serum testosterone ± 1.3 nmol/L, BMI ≥30 kg/m2) was performed. Of these 181 men, 72 (40%) had T2DM, which had been diagnosed before entering the study and was being treated by their primary care physician. All men received Nebido® every 12 weeks for up to 5 years. Data are available for 72 men for one year, 58 for two years, 50 for three years, 43 for four years and 33 for five years. Declining numbers do not reflect drop-outs but are a result of the registry design. *p< versus baseline; §p< versus previous year N=181 obese, hypogonadal men (body mass index: ≥30 kg/m2, mean total testosterone: nmol/L, mean age: 59.1 years), of whom 72 (40%) had type 2 diabetes Haider A et al. Obes Res Clin Pract. 2014;8(4):e339–49.

Waist circumference (cm) Change from baseline in weight (%)
Long-term efficacy: obesity Nebido® sustains weight loss in obese, hypogonadal men, irrespective of severity of obesity Class I obesity BMI: 30.0–34.9 kg/m2 (n=214) Class II obesity BMI: 35.0–39.9 kg/m2 (n=150) Class III obesity BMI: ≥40.0 kg/m2 (n=47) Waist circumference (cm) Time (year) * † ‡ Weight (kg) Change from baseline in weight (%) p< versus baseline for years 1–8 for all 3 groups *p< versus baseline; §p≤0.0001, ¤p=0.0009, †p<0.005, ‡p<0.05 versus previous year N=411 obese, hypogonadal men (BMI: kg/m2, total testosterone: ≤12 nmol/L) (mean age: years) receiving Nebido® for up to 8 years (mean follow-up: 6 years) BMI, body mass index Saad F et al. Int J Obes (Lond). 2016;40(1):162–70.

Glucose, HDL-C and LDL-C (mg/dL) Triglycerides and TC (mg/dL)
Long-term efficacy: metabolic syndrome & diabetes Sustained benefits with Nebido® in hypogonadal men with metabolic syndrome Significant improvements in liver enzyme levels and metabolic parameters with Nebido® were seen after 2 years of treatment [p< for all, except glucose (p=0.004)] AST and ALT (unit/L) CRP (mg/dL) Time (months) 3 4 7 6 5 CRP ALT AST Glucose, HDL-C and LDL-C (mg/dL) 180 200 260 240 220 Triglycerides and TC (mg/dL) HDL-C Triglycerides TC Glucose LDL-C A cohort of 122 men aged 18–83 years (mean 59.6 ± 8.0 years) with hypogonadism (baseline testosterone levels of 0.14–4.51 ng/mL) received 2 years of Nebido® treatment (administered at 0 and 6 weeks, and thereafter every 12 weeks). N=122 men with plasma total testosterone levels of 5.9–12.1 nmol/L (mean age: 59.6 years) ALT alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol Haider A et al. Horm Mol Biol Clin Invest. 2010;1(1):27–33.

Patients with NCEP-ATPII-defined metabolic syndrome (%)
Long-term efficacy: metabolic syndrome & diabetes Nebido® has clinical benefit in men with adult-onset hypogonadism and metabolic syndrome Placebo for 1 year then switch to Nebido® for following 1 year (n=10) Nebido® for 2 years (n=40) * Patients with NCEP-ATPII-defined metabolic syndrome (%) Patients (%) Fasting glucose Waist circumference Randomized, double-blind, double-dummy study in 50 men with metabolic syndrome and adult-onset hypogonadism. Men were randomized 4:1 to receive Nebido® 12-weekly or daily doses of placebo gel for 2 years. Nebido® significantly reduced waist circumference and fasting glucose levels from baseline, and significantly reduced the proportion of patients with metabolic syndrome after 1 year (p< for all). At 1 year, Nebido® recipients had significant improvements in insulin resistance (HOMA-IR, p<0.001) compared with those receiving placebo. As a result, the placebo-group patients were switched to Nebido® for the remainder of the study; at 2 years these patients also had a significant improvement in HOMA-IR (p<0.001) and significantly fewer were classified as having metabolic syndrome compared with baseline (p<0.0001). There was no significant change in BMI, and the reduced numbers of patients with metabolic syndrome were therefore considered primarily due to reductions in waist circumference and visceral fat mass, increased fat-free mass and improved HOMA-IR. *p< versus baseline N=50 men with adult-onset hypogonadism [total T: <3.0 ng/mL (11 nmol/L) or free T: <250 pmol/L (10 pg/mL)] plus metabolic syndrome defined according to NCEP-ATPIII criteria, with or without type 2 diabetes (mean age: 57 years) NCEP-ATPIII, National Cholesterol Education Program–Third Adult Treatment Panel; T, testosterone Aversa A et al. J Sex Med. 2010;7(10):3495–503.

Carotid intima media thickness (mm) High-sensitivity CRP (μg/nL)
Long-term efficacy: metabolic syndrome & diabetes Nebido® improves surrogate markers of endothelial function and atherosclerosis in hypogonadal men with metabolic syndrome Placebo for 1 year then switch to Nebido® for following 1 year (n=10) Nebido® for 2 years (n=40) Carotid intima media thickness (mm) * High-sensitivity CRP (μg/nL) ** ‡ Randomized, double-blind, double-dummy study in 50 men with metabolic syndrome and adult-onset hypogonadism. Men were randomized 4:1 to receive Nebido® 12-weekly or daily doses of placebo gel for 1 year (switching to Nebido® for the following 1 year). At 1 year, Nebido® recipients had significant improvements in carotid intima media thickness (p<0.0001) and hsCRP levels (p<0.001), which are surrogate markers of endothelial function and atherosclerosis progression, compared with those receiving placebo. The placebo-group patients who switched to Nebido® for the remainder of the study also had a significant improvement in these 2 surrogate markers. *p<0.0001, **p<0.001 versus baseline; §p<0.0001, ‡p<0.001 versus placebo/Nebido® switcher group N=50 men with adult-onset hypogonadism [total T: <3.0 ng/mL (11 nmol/L) or free T: <250 pmol/L (10 pg/mL)] plus metabolic syndrome defined according to NCEP-ATPIII criteria, with or without type 2 diabetes (mean age: 57 years) CRP, C-reactive protein; NCEP-ATPIII, National Cholesterol Education Program–Third Adult Treatment Panel; T, testosterone Aversa A et al. J Sex Med. 2010;7(10):3495–503.

Long-term efficacy: LUTS
Nebido® continues to significantly improve LUTS in obese, hypogonadal men Untreated group Nebido® group Adjusted difference** (Nebido® – Untreated) Nebido® group (n): Untreated group (n): Change from baseline in IPSS Year * This was an observational, prospective, cumulative registry study in 656 borderline obese/obese (mean body mass index: 29.3–33.1 kg/m2) men with total testosterone ≤12.1 nmol/L and hypogonadal symptoms (mean age: 60.7 years), seeking treatment for urological complaints. In total, 360 men received parenteral Nebido® 1,000 mg every 12 weeks after an initial 6-week interval for up to 10 years, and 296 men who had elected not to receive testosterone therapy served as untreated controls. Median follow-up in the 2 groups was 8 years. Patients completed the IPSS, AMS and IIEF-EF questionnaires. Assessments were taken 2–4 times per year, and the annual average was calculated. AMS, Aging Males’ Symptoms scale; IIEF-EF, erectile function domain of the International Index of Erectile Function; IPSS, International Prostate Symptom Score *p< for Nebido® versus untreated groups; **Adjusted for baseline age, waist circumference, weight, fasting glucose, systolic and diastolic blood pressure, total cholesterol, HDL-C, LDL-C, triglycerides and AMS N=656 borderline obese/obese (mean body mass index: 29.3–33.1 kg/m2) men with total testosterone ≤12.1 nmol/L (3.5 ng/mL) and hypogonadal symptoms (mean age: 60.7 years) seeking treatment for urological complaints AMS, Aging Males’ Symptoms scale; HDL-C, high-density lipoprotein cholesterol; IPSS, International Prostate Symptom Score; LDL-C, low-density lipoprotein cholesterol; LUTS, lower urinary tract symptoms Haider KS et al. J Urol. 2018;199(1):257–65.

Waist circumference (cm) Fasting glucose (mmol/L)
Long-term efficacy: diabetes Nebido® continues to significantly improve metabolic parameters in obese, hypogonadal men with type 2 diabetes Waist circumference (cm) Time (years) * ‡ Weight (kg) # Fasting glucose (mmol/L) ** † HbA1c (%) Data were collected from 2 observational, prospective and cumulative registry studies of 156 obese men (mean age ± 6.18 years; BMI ≥30 kg/m2) with symptomatic hypogonadism receiving Nebido® for up to 6 years. Long-term Nebido® treatment resulted in significant and sustained improvements in weight and other cardiometabolic risk factors. *p< versus baseline; §p≤0.0001, †p=0.0246, #p=0.0041, ¤p=0.0003, ‡p=0.0021, **p= versus previous year N=156 obese men (body mass index: ≥30 kg/m2) with symptomatic hypogonadism (mean total testosterone: 8.9 nmol/L) and type 2 diabetes (mean age: years) HbA1c, glycated hemoglobin Haider A et al. Int J Endocrinol. 2014;2014:

Total cholesterol (mg/dL) Triglycerides (mg/dL)
Long-term efficacy: diabetes Nebido® continues to significantly improve lipid profile in obese, hypogonadal men with type 2 diabetes HDL-C (mg/dL) Time (years) # * † LDL-C (mg/dL) Total cholesterol (mg/dL) Triglycerides (mg/dL) Data were collected from 2 observational, prospective and cumulative registry studies of 156 obese men (mean age ± 6.18 years; BMI ≥30 kg/m2) with symptomatic hypogonadism receiving Nebido® for up to 6 years. Long-term Nebido® treatment resulted in significant and sustained improvements in weight and other cardiometabolic risk factors. *p< versus baseline; §p<0.0001, †p=0.0056, #p= versus previous year N=156 obese men (body mass index: ≥30 kg/m2) with symptomatic hypogonadism (mean total testosterone: 8.9 nmol/L) and type 2 diabetes (mean age: years) HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol Haider A et al. Int J Endocrinol. 2014;2014:

Long-term efficacy: metabolic syndrome & diabetes
Nebido® significantly improves clinical parameters in hypogonadal, mostly obese men with underlying conditions Waist circumference (cm) Time (months) * Weight (kg) % weight change from baseline Correlation of % weight change with baseline T # A single-centre, open-label, cumulative prospective registry study in 255 men (aged 33–69 years, mean ± 6.30 years), with testosterone levels <12.13 nmol/L (mean: 9.93 ± 1.38). Men received Nebido® every 12 weeks after an initial interval of 6 weeks. Nebido® treatment produced significant and progressive reductions in body weight, waist circumference and BMI over 5 years (all p<0.0001). Significant improvements were also seen in lipid profiles (total, LDL- and HDL-cholesterol, triglycerides), blood pressure, HbA1c, blood glucose, CRP, and ALT and AST levels (all p<0.0001). Total testosterone increased to approximately 18 nmol/L during the first 12 months of treatment, and was maintained at physiological levels for the remainder of the study. *p<0.0001, #p<0.05 versus baseline; §p< versus previous year N=255 men [of whom 71% were obese (BMI: ≥30 kg/m2)] with symptomatic hypogonadism (mean total testosterone: 9.93 nmol/L) and various underlying conditions (hypertension 40%, type 2 diabetes 31%, dyslipidemia 18%, coronary artery disease 16%, inflammatory bowel disease 16%, post-myocardial infarction 15%, osteoporosis 14%) (mean age: years) BMI, body mass index; T, testosterone Saad F et al. Obesity (Silver Spring). 2013;21(10):1975–81.

Long-term efficacy: sexual function
Long-term Nebido® therapy can normalize erectile function in obese, hypogonadal men1 Nebido® group (n): Untreated group (n): Untreated group Nebido® group IIEF-EF score Year 17–21 Mild-to- moderate 11–16 Moderate 22–25 Mild 26–30 None Severity of erectile dysfunction2 * This was an observational, prospective, cumulative registry study in 656 borderline obese/obese (mean body mass index: 29.3–33.1 kg/m2) men with total testosterone ≤12.1 nmol/L and hypogonadal symptoms (mean age: 60.7 years), seeking treatment for urological complaints. In total, 360 men received parenteral Nebido® 1,000 mg every 12 weeks after an initial 6-week interval for up to 10 years, and 296 men who had elected not to receive testosterone therapy served as untreated controls. Median follow-up in the 2 groups was 8 years. Patients completed the IPSS, AMS and IIEF-EF questionnaires. Assessments were taken 2–4 times per year, and the annual average was calculated. AMS, Aging Males’ Symptoms scale; IIEF-EF, erectile function domain of the International Index of Erectile Function; IPSS, International Prostate Symptom Score *p< versus untreated group N=656 borderline obese/obese (mean body mass index: 29.3–33.1 kg/m2) men with total testosterone ≤12.1 nmol/L (3.5 ng/mL) and hypogonadal symptoms (mean age: 60.7 years) seeking treatment for urological complaints IIEF-EF, erectile function domain of the International Index of Erectile Function 1. Haider KS et al. J Urol. 2018;199(1):257– Cappelleri JC et al. Urology. 1999;54(2);346–51.

Long-term efficacy Nebido® significantly improves clinical and metabolic parameters in hypogonadal men with ED Age-matched control group (n=20) Nebido® group (n=40) Waist circumference (cm) Time (months) * Weight (kg) Time (months) * HbA1c (%) Time (months) ** Hematocrit (%) Time (months) Ratio of total cholesterol/HDL-C Time (months) * Triglycerides (mg/dL) Time (months) * Lumbar T-score Time (months) # * ** Neck T-score Time (months) # ** * *p<0.0001, §p<0.001, #p<0.005, **p<0.05 versus age-matched control group N=40 men aged 45–65 years with symptomatic hypogonadism [total testosterone: <11 nmol/L (320 ng/dL) or free testosterone: <255 pmol/L (74 pg/mL)] plus metabolic syndrome defined according to IDF criteria, with or without type 2 diabetes HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; IDF, International Diabetes Federation Francomano D et al. Int J Endocrinol. 2014;2014:

Long-term efficacy Nebido® significantly improves metabolic parameters in hypogonadal men with ED LDL-C (mg/dL) Time (years) * † ‡ Total cholesterol (mg/dL) HDL-C (mg/dL) # Triglycerides (mg/dL) HbA1c (%) ** Fasting glucose (mg/dL) A 5-year prospective, observational, and longitudinal registry study in 261 men (mean age 59.5 ± 8.4 years) diagnosed with hypogonadism [mean testosterone concentration at baseline = 2.23 ± 0.6 ng/mL (7.72 ± 2.07 nmol/L)] and ED. Men received Nebido® at day 1, at week 6, and every 3 months thereafter. Nebido® significantly improved body weight, waist circumference and BMI, as well as other cardiovascular-related endpoints, including lipid profile, blood glucose and blood pressure. Over the 5-year study, Nebido® treatment significantly improved body composition (body weight, waist circumference and BMI). Body weight decreased from ± 14.0 kg to 92.5 ± 11.2 kg (p<0.0001). Waist circumference was reduced from ± 10.0 cm to 99.0 ± 9.1 cm (p<0.0001). Nebido® also improved lipid profiles, fasting blood glucose, HbA1c and blood pressure. *p< versus baseline; §p≤0.0001, #p=0.0006, †p=0.0079, ‡p=0.0098, ¤p=0.0406, **p=0.049 versus previous year N=261 hypogonadal men [mean total testosterone: 7.72 nmol/L (2.23 ng/mL)] with ED (median age: 59.5 years) ED, erectile dysfunction; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol Yassin DJ et al. J Sex Med. 2014;11(6):1567–76.

Digit Span Test, forward score
Long-term efficacy: general well-being, younger age In younger hypogonadal men, long-term Nebido® therapy improves cognitive functioning 2-year Nebido® therapy in younger hypogonadal men was associated with significant improvements in executive function and psychomotor speed (Trail Making Test – B), attention capacity and psychomotor speed (Digit Span Test forward score), and attention and visual scanning abilities (Trail Making Test – A) Trail Making Test – A Time (years) Trail Making Test – B * Digit Span Test, forward score ** A study conducted over a 2-year period in young and middle-aged patients with hypogonadism (N=19; mean age: 30.5 years) showed no improvement in quality of life (measured by the World Health Organization’s Brief Quality of Life Questionnaire) or emotional state (assessed using the Profile of Mood States scale). It did, however, demonstrate that treatment with Nebido® resulted in significant improvements in executive function and psychomotor speed (Trail Making Test B, p=0.025) and attention capacity and psychomotor speed (Wechsler Adult Intelligence Scale, p=0.046), as well as marginally significant improvements in attention and visual scanning abilities (Trail Making Test A, p=0.050). *p=0.025, **p=0.046, §p=0.50 (borderline significance) versus baseline N=19 young and middle-aged hypogonadal men (mean total testosterone: 13.8 nmol/L, mean age: 30.5 years) Lašaitė L et al. Andrologia. 2017;49(3):Epub ahead of print.

Nebido® significantly improves HR-QoL in obese, hypogonadal men
Long-term efficacy: general well-being Nebido® significantly improves HR-QoL in obese, hypogonadal men Untreated group Nebido® group Adjusted difference** (Nebido® – Untreated) Nebido® group (n): Untreated group (n): Change from baseline in AMS Year * This was an observational, prospective, cumulative registry study in 656 borderline obese/obese (mean body mass index: 29.3–33.1 kg/m2) men with total testosterone ≤12.1 nmol/L and hypogonadal symptoms (mean age: 60.7 years), seeking treatment for urological complaints. In total, 360 men received parenteral Nebido® 1,000 mg every 12 weeks after an initial 6-week interval for up to 10 years, and 296 men who had elected not to receive testosterone therapy served as untreated controls. Median follow-up in the 2 groups was 8 years. Patients completed the IPSS, AMS and IIEF-EF questionnaires. Assessments were taken 2–4 times per year, and the annual average was calculated. AMS, Aging Males’ Symptoms scale; IIEF-EF, erectile function domain of the International Index of Erectile Function; IPSS, International Prostate Symptom Score *p< for Nebido® versus untreated groups; **Adjusted for baseline age, waist circumference, weight, fasting glucose, systolic and diastolic blood pressure, total cholesterol, HDL-C, LDL-C, triglycerides and AMS N=656 borderline obese/obese (mean body mass index: 29.3–33.1 kg/m2) men with total testosterone ≤12.1 nmol/L (3.5 ng/mL) and hypogonadal symptoms (mean age: 60.7 years) seeking treatment for urological complaints AMS, Aging Males’ Symptoms scale; HDL-C, high-density lipoprotein cholesterol; HR-QoL, health-related quality of life; LDL-C, low-density lipoprotein cholesterol Haider KS et al. J Urol. 2018;199(1):257–65.

Total T concentration (ng/mL)
Long-term efficacy: general well-being & sexual function Nebido® sustains physiological testosterone levels and improves ED and HR-QoL in hypogonadal men Total T concentration (ng/mL) Time (weeks) Mean AMS score Time (weeks) Mean total IPSS score Time (weeks) Mean IIEF-5 score Time (weeks) *p<0.001, **p<0.05 versus baseline N=261 men with symptomatic adult-onset hypogonadism [total T: <12 nmol/L (3.5 ng/mL); mean age: 58 years] and ED, treated with Nebido® for up to 5 years (average: 4.25 years) AMS, Aging Males’ Symptoms scale; ED, erectile dysfunction; HR-QoL, health-related quality of life; IIEF-5, simplified International Index of Erectile Function; IPSS, International Prostate Symptom Score; T, testosterone Almehmadi Y et al. Arab J Urol. 2016;14(1):31–6.

Waist circumference (cm) Total cholesterol (mg/dL)
Long-term efficacy: Asian ethnicity Nebido® has clinical benefit in men of Asian ethnicity with adult-onset hypogonadism Waist circumference (cm) Time (months) * Total cholesterol (mg/dL) Time (months) * HbA1c (%) Time (months) * Total lumbar (L1–L4) BMD Time (months) * Body fat (%) Time (months) * LDL-C (mg/dL) Time (months) * Hematocrit (%) Time (months) * Femoral neck BMD Time (months) * Nebido® did not produce differences in BMI, HDL-C or triglycerides from baseline. *p<0.05 versus baseline N=120 Thai men with symptomatic adult-onset hypogonadism [total testosterone: <12.1 nmol/L (300 ng/dL)] (mean age: 65.6 years) receiving Nebido® for a mean of months BMD, bone mineral density; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol Permpongkosol S et al. J Sex Med. 2016;13(8):1199–211.

Long-term efficacy: general well-being & sexual function, Asian ethnicity
Nebido® sustains improvements in sexual function in men of Asian ethnicity with adult-onset hypogonadism IIEF-5 score Time (months) * IIEF-15: orgasmic function domain IIEF-15: overall satisfaction domain IIEF-15: erectile function domain IIEF-15: intercourse satisfaction domain IIEF-15: overall IIEF-15: sexual desire domain *p<0.05 versus baseline N=120 Thai men with symptomatic adult-onset hypogonadism [total testosterone: <12.1 nmol/L (300 ng/dL)] (mean age: 65.6 years) receiving Nebido® for a mean of months IIEF-5, simplified International Index of Erectile Function; IIEF-15, International Index of Erectile Function Permpongkosol S et al. J Sex Med. 2016;13(8):1199–211.

Cardiovascular risk and mortality
Module 5: Nebido® clinical efficacy Cardiovascular risk and mortality

Long-term efficacy: CV risk & mortality
Nebido® is associated with a significantly reduced risk of cardiovascular events and mortality Untreated controls (n=296) Nebido® group (n=360) Events (n) * 10-year incidence of death Untreated controls: (95% CI: –0.1756; p<0.000) Nebido® group: (95% CI: –0.0368; p<0.000) Estimated between-group difference: (95% CI: –0.3431; p<0.001) Estimated reduction in mortality with Nebido®: 66–92% Patient characteristics, comorbidities and concomitant medication use at baseline for the study population are shown on the next slide (hidden). *Heart failure (n=7), MI (n=5), stroke (n=4), thromboembolism (n=2), lung embolism (n=1) N=656 men with symptomatic hypogonadism (total testosterone: <12.1 nmol/L) (mean age: 60.7 years) who either received Nebido® therapy (n=360) or chose to remain untreated (controls, n=296), followed up for a mean of months CVD, cardiovascular disease; MI, myocardial infarction Traish AM et al. J Cardiovasc Pharmacol Ther. 2017;22(5):414–33.

Efficacy: mortality Nebido® is associated with a significantly reduced risk of mortality in men with type 2 diabetes Untreated hypogonadal men (n=362) Nebido®-treated hypogonadal men (n=175) Untreated men with normal T (n=320) Mortality (%) Cox regression analysis with time to death/last visit as outcome [HR (95% CI)] Untreated hypogonadal men: Reference Untreated men with normal T: (95% CI: 0.41–0.94); p=0.023 Nebido®-treated hypogonadal men: (95% CI: 0.16–0.90); p=0.027 Another analysis of 857 men with T2DM who were initially screened as part of the BLAST study showed that low testosterone levels (total testosterone ≤12.0 nmol/L or free testosterone ≤0.25 nmol/L) were associated with increased mortality. Men with normal testosterone levels or men with low testosterone levels who received Nebido® had significantly reduced mortality (p<0.05); this association was independent of PDE-5 inhibitor therapy. N=857 men with type 2 diabetes from the BLAST study, of whom 537 were hypogonadal (total T: ≤12 nmol/L or free T: ≤0.25 nmol/L, mean age: 63.5 years), followed up for a mean of 3.8 years; 103 deaths occurred during the study, attributed to cardiovascular (n=52), respiratory (n=28), cancer (n=12) and other causes (n=11), including renal, liver or multiple organ failure, pancreatitis, esophageal varices, encephalitis and sepsis-related surgical events CI, confidence interval; HR, hazard ratio; T, testosterone Hackett G et al. Int J Clin Pract. 2016;70(3):244–53.

Interruption of Nebido® therapy
Module 5: Nebido® clinical efficacy Interruption of Nebido® therapy

Interrupting Nebido® therapy
Interrupting Nebido® therapy leads to loss of clinical benefits, but these return once therapy is resumed Interrupted Nebido® therapy (n=147) Continuous Nebido® therapy (n=115) Waist circumference (cm) Period 1 2 3 p<0.0001 Fasting glucose (mg/dL) p=NS p=0.0043 Total cholesterol (mg/dL) p=0.0004 LDL-C (mg/dL) Weight (kg) HbA1c (%) p=0.0012 HDL-C (mg/dL) p=0.0002 Triglycerides (mg/dL) N=226 men with symptomatic hypogonadism (total testosterone: <12 nmol/L) and erectile dysfunction (mean age: years); after receiving Nebido® for a mean of 65.5 months (Period 1), therapy was temporarily interrupted in a subgroup of men (n=147) for a mean of 16.9 months (Period 2) and then resumed for a mean of 14.5 months (Period 3) HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NS, not significant Yassin A et al. Clin Endocrinol (Oxf). 2016;84(1):107–14.

Residual voiding volume (mL) Bladder wall thickness (cm)
Interrupting Nebido® therapy Interrupting Nebido® therapy leads to loss of clinical benefits, but these return once therapy is resumed Interrupted Nebido® therapy (n=147) Continuous Nebido® therapy (n=115) Prostate volume (mL) Period 1 2 3 p=NS p<0.0001 p=0.0037 PSA (ng/mL) p=0.0018 p=0.0183 IPSS score Residual voiding volume (mL) AMS score p<0.0002 CRP (mg/dL) p=0.0359 Bladder wall thickness (cm) IIEF-EF score N=226 men with symptomatic hypogonadism (total testosterone: <12 nmol/L) and erectile dysfunction (mean age: years); after receiving Nebido® for a mean of 65.5 months (Period 1), therapy was temporarily interrupted in a subgroup of men (n=147) for a mean of 16.9 months (Period 2) and then resumed for a mean of 14.5 months (Period 3) AMS, Aging Males’ Symptoms scale; CRP, C-reactive protein; IIEF-EF, erectile function domain of the International Index of Erectile Function; IPSS, International Prostate Symptom Score; PSA, prostate-specific antigen; NS, not significant Yassin A et al. Aging Male. 2016;19(1):64–9.

Summary Nebido® is efficacious for the treatment of male hypogonadism alone or in the presence of underlying conditions, such as metabolic syndrome, type 2 diabetes, dyslipidemia and ED In hypogonadal men, TTh with Nebido®: Has a favorable effect on body composition by significantly increasing muscle mass and decreasing fat mass Significantly improves: Muscle strength Bone mineral density Dyslipidemia Can attenuate anemia Exerts a positive effect on mood, thus improving self-confidence and activity, and reduces fatigue and feelings of exhaustion LUTS Markers of cardiovascular disease Parameters of sexual function ED, erectile dysfunction; LUTS, lower urinary tract symptoms; TTh, testosterone therapy

Summary (2) In hypogonadal men with obesity, TTh with Nebido®:
Promotes and sustains weight loss, and reductions in waist circumference Significantly improves clinical and metabolic parameters, glycemic control, dyslipidemia, anemia, LUTS, sexual function and HR-QoL In hypogonadal men with diabetes, TTh with Nebido®: Significantly improves glycemic control and insulin resistance, clinical and metabolic parameters, and sexual function Is associated with a significantly reduced risk of cardiovascular events and mortality May reduce or improve disease-related complications HR-QoL, health-related quality of life; LUTS, lower urinary tract symptoms; TTh, testosterone therapy

Summary (3) Long-term TTh with Nebido® for hypogonadism:
Is associated with continuing, significant reductions in body weight, body mass index and waist circumference Is associated with continuing, significant improvements in lipid profile and glycemic control Is associated with continuing, significant improvements in LUTS Can restore erectile function to normal Significantly improves surrogate markers of endothelial function and atherosclerosis Significantly improves HR-QoL HR-QoL, health-related quality of life; LUTS, lower urinary tract symptoms; TTh, testosterone therapy

Nebido® clinical efficacy

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Nebido® clinical efficacy

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