A Randomized, Doubleblind, Placebocontrolled Trial on the Effect
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A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male BJUI Symptoms scale BJU INTERNATIONAL † ‡ Christopher C.K. Ho , Seng Fah Tong * , Wah Yun Low , Chirk Jenn Ng , ‡ § Ee Ming Khoo , Verna K.M. Lee , Zulkifl i Md Zainuddin and †¶ Hui Meng Tan Departments of Surgery and * Family Medicine, Universiti Kebangsaan Malaysia Medical Centre , † Medical Research and Development Unit and ‡ Department of Primary Care Medicine, Faculty of Medicine, University of Malaya , § Department of Family Medicine, Faculty of Medicine, International Medical University, Kuala Lumpur and ¶ Sime Darby Medical Centre, Selangor, Malaysia Accepted for publication 9 August 2011 Study Type – Therapy (RCT) What ’ s known on the subject? and What does the study add? Level of Evidence 1b Testosterone defi ciency syndrome can be treated with testosterone replacement in the form of injectable, transdermal, buccal and oral preparations. Long-acting i.m. testosterone undecanoate 1000 mg, which is given at 10− 14 week intervals, has been OBJECTIVE shown to be adequate for sustaining normal testosterone levels in hypogonadal men. This study confi rms that long-acting i.m. testosterone undecanoate is effective in • To evaluate the effect of i.m. injection of improving the health-related quality of life in men with testosterone defi ciency testosterone undecanoate 1000 mg over 12 syndrome as assessed by the improvement in the Aging Male Symptoms scale. months on the Aging Male Symptom (AMS) Testosterone treatment can be indicated in men who have poor health-related quality scale scores in men with testosterone of life resulting from testosterone defi ciency syndrome. defi ciency syndrome (TDS). RESULTS than in the placebo group ( − 2.8 vs − 1.2, PATIENTS AND METHODS P = 0.03; and − 3.2 vs − 1.8, P = 0.016). • Improvement in the total AMS score • The difference in change between the • A total of 120 men > 40 years old was signifi cantly greater in the treatment randomized groups for the sexual domain with TDS (total testosterone < 12 nmol/L group than in the placebo group (F: 4.576, scores followed the same trend, though the and total AMS scores ≥ 27) were P = 0.017) over the 48-week period. difference was not signifi cant. randomized into i.m. injection of either • The mean ( SD ) total AMS score was placebo or testosterone undecanoate 38.46 (11.85) at baseline and 33.59 (1.69) CONCLUSION 1000 mg. at 48 weeks for the placebo group, • In all, 56 and 58 participants from the and 41.73 (12.73) at baseline and 32.61 • Long-acting testosterone is effective in active treatment and placebo groups, (9.67) at 48 weeks for the treatment improving health-related quality of life as respectively completed the study. group. assessed by the AMS scale in men with TDS. • An i.m. injection of either placebo or • The mean change in the total AMS score testosterone undecanoate 1000 mg was was − 12.6% in the placebo group and KEYWORDS given at weeks 0, 6, 18, 30 and 48. − 21.9% in the treatment group. • Self-administered AMS questionnaires • The mean psychological and testosterone defi ciency , hypogonadism , were completed at weeks 0, week 18 and somatovegetative domain scores decreased testosterone undecanoate , injectable , week 48. signifi cantly more in the treatment group long-acting , AMS scale INTRODUCTION healthcare issues of the 21 st century are have reported that there is a consistent those related to aging and, with regard to decline in total testosterone levels at a rate Men ’ s health has become a key concern and men ’ s health, the aging male. Worldwide, of 1 – 2% per year starting from a man ’ s late challenge for healthcare professionals and the elderly population is growing faster than 30 s [ 1 ] .Testosterone defi ciency syndrome policy makers. Amongst the most prominent any other age group. Observational studies (TDS) in adult males is associated with © 2011 THE AUTHORS BJU INTERNATIONAL © 2011 BJU INTERNATIONAL | doi:10.1111/j.1464-410X.2011.10755.x 1 HO ET AL. numerous physical, psychological and sexual treatment) decreased after 12 weeks of RESEARCH TOOL symptoms. Testosterone replacement treatment, indicating a signifi cant therapy has been shown to improve improvement in symptoms and in HRQoL. We used the AMS scale, which measures symptoms as well as health-related quality These authors also showed that AMS severity of subjectively perceived complaints of life (HRQoL) related to TDS [ 2,3 ] . scale scores can predict subjective clinical in each of the 17 items on a scale of 1 – 5, a expert opinion on the effi cacy of the higher score meaning greater symptom There are many tools for the measurement treatment. severity [ 16 ] . The composite scores for each of HRQoL in hypogonadal men. These of the domains is based on adding up the include the Aging Male Symptom (AMS) Recently, a new preparation of long-acting scores of the items of the respective scale, the WHO quality-of-life scale, the injectable testosterone undecanoate domains. The composite score (total score) 12- and 36-item short-form health surveys, (Nebido ® , Bayer Schering, Leverkusen, is the sum of the domain scores. The and the androgen defi ciency in adult males Germany) has been brought onto the cumulative score can range from 17 to 85 (ADAM) scale. The AMS scale was originally market. This undecanoate ester formulation points. The severity of the symptoms are developed in Germany in 1991 [ 4 ] , with the of testosterone with castor oil, extends the defi ned as: no/low (17 – 26 points), mild aim of assessing aging symptoms among maximum dosing interval by about fourfold (27 – 36 points), moderate (37 – 49 points) and groups of males under different conditions, compared with that of other injectable severe ( ≥ 50 points). The three domains evaluating the severity of symptoms over formulations of testosterone [ 17 ] . Studies of the AMS scale are psychological, time, and measuring changes before and in Europe have reported that 1000 mg somatovegetative and sexual. Heinemann after androgen replacement therapy [ 5 ] . The testosterone undecanoate as an i.m. et al . [ 6 ] translated the original German development of the AMS scale at that time injection at 10 – 14-week intervals is AMS scale into the culturally adapted was in response to the lack of fully adequate for sustaining normal testosterone English-language scale and showed that standardized scales to measure the severity levels in hypogonadal men [ 18 ] . Similar there was cross-cultural equivalence. of aging symptoms and their impact on fi ndings were found in studies done in Asia HRQoL in males, specifi cally [ 6,7 ] . and Australia. SUBJECTS Many studies have shown that the AMS The objective of the present study was to Participants were recruited by phone-call scale correlates with testosterone levels and investigate the effect of i.m. injection of invitation to form a cohort of randomly predicts hypogonadism [ 8 – 13 ] . It also meets testosterone undecanoate 1000 mg over 12 selected men aged ≥ 40 years from an urban the requirements of clinical utility and months on the AMS scores for Malaysian community. Participants, who gave written outcomes sensitivity [ 8 ] . Heinemann et al . men with low serum testosterone levels. informed consent to participate, underwent [ 8 ] have also convincingly shown that the initial screening tests which included an AMS scale has the ability to measure early morning total testosterone test and treatment effects on HRQoL across the full PATIENTS AND METHODS the completion of the AMS questionnaire. If range of severity of complaints. In addition, the participant ’ s total testosterone level was the results of the AMS scale can predict STUDY DESIGN < 12 nmol/L and total AMS score was ≥ 27 subjective clinical expert opinion on (corresponding to mild to severe symptoms treatment effi ciency [ 14 ] . Weak correlations The present study was a double-blind, of TDS), he was called back for a formal were also reported between AMS scale parallel, randomized, placebo-controlled trial screening visit to establish whether he domain scores (psychological, somatic and with an allocation ratio of 1:1. It was fulfi lled the study criteria. The inclusion sexual) and testosterone levels [ 9,10 ] . approved by the Medical Ethics Committee, criteria were: age 40 – 70 years; having University of Malaya Medical Centre at least ‘ mild ’ symptoms for all three There are very few studies reporting the (approval number: 631.11) and was AMS domains (scores of ≥ 9 in the effect of testosterone therapy using the conducted in accordance with the ethical somatovegetative, ≥ 6 in the psychological AMS scale. In one of the largest placebo- principles of the Malaysian Good Clinical and ≥ 6 in the sexual domain) or total AMS controlled studies of testosterone therapy in Practice Guidelines that are based on the scores ≥ 27; having early morning total late-onset hypogonadism, it was found that Declaration of Helsinki and the International testosterone level < 12 nmol/L on two the effect of oral testosterone undecanoate Conference on Harmonization guideline E6: occasions; and a PSA level of < 4 ng/mL. The (Andriol Testocaps TM , Merck, Sharp and Good Clinical Practice. The primary endpoint exclusion criteria were: uncontrolled Dohme, Whitehouse Station, NJ, USA) on of the present study was treatment effect diabetes mellitus (HbA1c > 8%); clinical total AMS scores during 12 months of on AMS scores. The secondary endpoints hypothyroidism or hyperthyroidism; treatment was not signifi cantly different were adverse events, anthropometric haematocrit > 55%; known prostate cancer; from placebo, except for sexual symptoms, changes and changes in laboratory blood androgen-dependent carcinoma of the male where a modest improvement was reported results, i.e fasting lipid, fasting blood mammary gland; past or present liver with oral testosterone undecanoate 160 mg/ glucose, liver function tests, total tumours; other signifi cant medical day [ 15 ] .