Urimax D (Tamsulosin Hydrochloride Plus Dutasteride) Clinical Trial

Introduction

Management of Benign Prostatic Hyperplasia (BPH) has changed dramatically over years and there has been gradual shift from use of surgical therapy to medical therapy. Medical treatment includes use of an ?-blocker and/or 5 ?-reductase inhibitor. A fast and sustained improvement of bothersome urinary symptoms, maximum flow rate and quality of life are considered to be important short-term treatment goals in lower urinary tract symptoms suggestive of BPH. However, it is increasingly recognized that BPH is slowly progressing disease. Hence halting progression of disease and thus reducing occurrence of serious complications such as acute urinary retention (AUR) and need for surgery have become major treatment goals.

Alpha-blockers offer rapid symptomatic relief. However, alpha-blockers lack any effect on prostate volume. 5 alpha-reductase inhibitors (5-ARI) inhibit 5 alpha-reductase enzyme which is responsible for conversion of testosterone to dihydrotestosterone (DHT). DHT is an androgen primarily responsible for enlargement of prostate gland. Thus 5 alpha-reductase inhibitors reduce prostate size there by halting disease progression. However, symptomatic relief with 5ARIs may be delayed for 3-6 months. Combination of an alpha-blocker and 5 alpha-reductase inhibitor thus combines benefits of individual monotherapy and provides rapid symptomatic relief as well as reduces the risk of progression.

It was in 2003, that the landmark trial -Medical Therapy of Prostatic Symptoms- (MTOPS) showed for the first time that percentage reduction in overall risk of BPH progression was significantly greater with combination therapy than either monotherapy. Although MTOPS study contributed substantially to the understanding of the role of combination therapy for symptomatic BPH, some of the issues still remain unresolved. In MTOPS study, only a subset of patients was at heightened risk for progression. Also MTOPS study used finasteride as 5-ARI which blocks only type II 5 alpha reductase enzyme.

CombAT, combination of Avodart and Tamsulosin was the first long-term study which assessed the benefits of combination of tamsulodin and dutasteride over monotherapy in men who are at risk of progression by virtue of having prostate volume ≥30 cm³ and PSA ≥1.5 ng/ml. Tamsulosin hydrochloride is a subtype selective ?_1A-blocker which has 15 fold higher selectivity for ?_1A subtype than ?_1B subtype of adrenoreceptors. Higher ?_1A selectivity reduces the propensity for vasodilatory side effects. Dutasteride is a 5 ARI which blocks both type I and type II 5 alpha-reductase enzyme, whereas finasteride blocks only type II 5 alpha-reductase enzyme. Thus, treatment with dutasteride results in greater degree and consistency of dihydrotestosterone suppression compared with finasteride.

CombAT provides support for long-term use of dutasteride and tamsulosin combination therapy in men with moderate to severe LUTS due to BPH and prostatic enlargement at increased risk of progression.

Based on CombAT study results, fixed dose combination of tamsulosin and dutasteride was approved by US FDA.

Combination of Tamsulosin and Dutasteride : Clinical Efficacy

An open phase III multicenter prospective trial was conducted to evaluate the efficacy and safety of the fixed dose combination of dutasteride (0.5 mg) + tamulosin (0.4 mg) (Urimax D) in the treatment of patients with BPH. It was conducted at six centers across India.

Study Design

99 male patients in the age group of 40-80 years with lower urinary tract symptoms and clinical findings suggestive of BPH were included in this study.
Inclusion criteria were:
- Patients with International Prostate Symptom Score (IPSS) of 10 to 35.
- Patients with maximum urinary flow rate of 4 -15 ml/sec for a voided volume of ≥125 ml
- Patients with PSA (Prostate Specific Antigen) level <4 ng/ml. Those patients who have PSA levels between 4 and 10 ng/ml, should be proven negative for prostate cancer on biopsy
- Patients with prostate volume ≥20 ml
They received single tablet of combination of tamsulosin hydrochloride (0.4 mg) and dutasteride (0.5 mg) (Urimax D) after the same meal every day for 12 weeks.
At baseline screening visit, a detailed history along with thorough clinical examination was recorded. Laboratory tests including routine hematology, liver function tests, renal function tests, random blood sugar and serum PSA were also performed.
Subjects were followed up at 2 weeks, 4 weeks, 8 weeks and 12 weeks after the baseline visit (on this day patient received first dose of the study drug). At each study visit the patient underwent a clinical examination, IPSS evaluation and adverse event assessment. In addition at the last study visit (week 12), laboratory investigations were repeated. Transrectal Ultrasonography (TRUS) for prostate volume and uroflowmetry were done at baseline and week 12.
The efficacy parameters included IPSS, prostate volume, uroflowmetry and serum PSA. Efficacy was assessed by measuring these parameters at the end of 12 weeks then comparing with baseline.

Results

Efficacy Evaluation

Prostate Volume

Significant reduction in prostate volume was noted at 12 weeks.

IPSS Score

There was significant improvement in IPSS score as well as obstructive and irritative IPSS subscores.

Serun PSA

Significant reduction in serum PSA was noted at 12 weeks.

Uroflowmetry

There was significant increase in maximum urinary flow rate (Q_max) as well as average flow rate.

Safety Evaluation

Adverse events reported were ejaculatory dysfunction (2.02%), decreased libido (3.03%), gastritis (2.02%), fever (2.02%), palpitation (1.01 %), URTI (1%). Other adverse events observed were dizziness (1.01%), general itching (1.01 %), and backache (1.01 %).
There were no clinically relevant changes in blood pressure and pulse rate. Also no significant laboratory abnormalities were observed.

Conclusion

The results of the present study showed that the fixed dose combination of dutasteride and tamsulosin is effective and well tolerated in patients with benign prostatic hyperplasia.

References

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5. Data on file: Cipla Ltd.