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Phytotherapy of BPH with Cernilton ® - Results of a Controlled Prospective Study

H. Becker, L. Ebeling

Topic

The efficacy and benefit to risk ratio of Cernilton ® in the treatment of patients with BPH are documented in a controlled prospective study and the resulting consequences for long-term treatment are discussed.

Introduction

Among the various treatment options for benign prostatic hyperplasia (BPH), phytotherapy is established and recognized as a treatment alternative directed at the symptoms because of its high benefit to risk ratio. Follow-up examination during therapy allows physicians to monitor treatment response and to confirm the appropriateness of conservative therapy or revise the treatment strategy. In view of recent epidemiological studies documenting relatively rare indications for surgical treatment (2,11) and the critical re-evaluation of TURP (7,13) phytotherapy is a preferred treatment option in the initial stages of BPH (2,15,18).

Based on positive results with Cernilton ® in the treatment of benign prostatic diseases (6) we conducted a clinical trial in patients with BPH in stages IIand III over 24 weeks. The standardized pollen extract Cernilton ® was tested in a double-blind placebo controlled study with separate follow-up (phase II) in both groups of which the result in the double-blind phase (Phase I have already been published (3).

The trial was conducted in cooperation with six urologists in private practice on a representative patient population and documented the efficacy of Cernilton ®, which supposedly is based on anticongestive and anti-inflammatory properties of the pollen extract.

Patients and Methods

Concerning the basic characterization of this clinical trial (3) it can be stated that the results of the double-blind study were confirmed in the entire patient population. Results are therefore shown as a pre- to post-treatment comparison for the entire cohort. As an additional statistical method an analysis of the variance was utilized for the split-plot design of the time points before therapy, after phase I and after phase I I.

The definitions of BPH stages II and III are according to Vahlensieck (18), the symptoms were assessed according to the FDA recommendations (4), and the flow rate measurements were corrected for volume by using the uroflow index (14).

Following the double-blind study phase both drug and placebo groups were treated in an open-label trial with Cernilton ® over a 12-week period. Because of drop-out (TURP for urinary retention, lost drugs) and premature termination of treatment (complete elimination of symptoms) in phase I and unwillingness to participate in the follow-up treatment trial in seven patients, the data on 92 patients could be analyzed. Of these, 45 patients received active drug followed by Cernilton ®, while 47 patients received first placebo followed by Cernilton ®.

During phase II, participating physicians were blinded as to the prior treatment of the patients in phase I(active drug or placebo) and the results of the treatment to avoid biases in the interpretation of the results at the final examination at 24 weeks. The treatment plan was changed in three patients because of termination or interruption of therapy. Concomitant medication was changed between phase I and phase I I in only one case.

Results

Randomization resulted in well-matched groups and the initial status is identical to the status at the beginning of the published double-blind phase of the study (3). The clinical symptoms of patients with BPH are dominated by nocturia, which was reported by almost all patients. Comorbidities, mainly cardiovascular and metabolic diseases, were present in 54.3 % of the patients. Concomitant medications, mainly cardiovascular and antidiabetic drugs, were taken by 41.3 % of the patients.

Statistically significant differences were found during the double-blind phase of the study in nocturia, frequency (frequent daytime voiding; > 4 times abnormal), feeling of incomplete bladder emptying, residual urine volume, and global assessment of the outcome by both physician and patient (Table 1).

Tab. 1  Results of the double-blind study: significant differences in favor of Cernilton ® for symptoms, urodynamic parameters and global assessment of the overall outcome of therapy.

Follow-up Phase: Placebo - Cernilton ®

In comparison between the results at the end of the double-blind phase and the follow-up phase the following changes were noted in patients who were switched from placebo to Cernilton ® for 12 weeks each:

The overall response rate (defined as improvement or elimination of previously present symptoms or findings) is significantly increased for all tested parameters (Tables2 and 3).

Residual urine volume decreases significantly (Fig. 1), and the uroflow index increases further from 0.79±0.27 to 0.97±0.25 after it increased under placebo treatment from 0.70 ± 0.31 to 0.79 ± 0.27).

Fig. 1  Comparison of the treatment groups placebo - Cernilton ® and verum - Cernilton ®. Significant differences after the double-blind (phase I) study are eliminated after the subsequent Cernilton ® open-label follow-up trial.   Parallel responses are seen for verum-treated patients in comparison to Cernilton ® after intitial placebo treament. The residual urine volume is significantly different during both phases in the treatment arms (p = .008).

Correspondingly the global assessment of the overall outcome is judged by physicians and patients as very good or good in 63.8 % and 66.0 %, respectively (at the end of the double-blind phase this was found in 13.6 % and 27.3 %, respectively).

Tab. 2  Symptom response and improvement of rectal findings under placebo and subsequent Cernilton ® treatment.

Follow-up Phase: Verum - Cernilton ®

In those patients initially treated with active drug (Cernilton ®) followed by 12 additional weeks of Cernilton ® (phase II), the positive changes in regard to clinical symptoms, rectal findings, and urodynamic parameters in comparison to the findings at the end of phase I are rather minor (Fig. 1).

The global assessment of the overall outcome is judged as very good or good by physicians and patients after phase I verum treatment in 58.1 % and 72.1 %, respectively, and after subsequent Cernilton ® treatment in 62.2 % and 62.2 %, respectively. A poor result is reported after 24 weeks by 4.4 % of patients and 13.3 % of physicians.

Comparison of Treatment Groups

Nocturia and residual urine volume demonstrate that the results of Cemilton® treatment in previously placebo-treated patients are comparable to those achieved in verum treated patients (Fig. 1).

A comparison of the time points of changes in regard to the following symptoms and findings reveals a significant difference (earlier change in the verum. - Cernilton ® treated group): nocturia (p =.051), frequency (p =.039), feeling of incomplete emptying (p =.013), palpable enlargement of the prostate (p =.046), and prostatic congestion (p =.03).

Residual urine volume decreases during phase I significantly more under verum treatment than under placebo (p <.001). During phase II the volume decreases significantly (p =.002) in the placebo - Cernilton ® group).

Cernilton ® is tolerated well after phase II in 86 cases (93.5 %) and satisfactorily in 6 cases (6.5 %). Side-effects (nausea and stomach upset) are reported in three cases.

Discussion

The results of this controlled follow-up treatment study confirm the efficacy of the pollen extract Cernilton ® in patients with BPH.

Tab. 3  Symptom elimination and negative rectal findings under placebo and subsequent Cernilton ® treatment.

Significant differences in favor of Cernilton ® are found for nocturia, frequency, feeling of incomplete emptying, residual urine volume, and in a comparison of the treat ment groups also for prostatic enlargement and congestion. Furthermore, the results of patients treated with placebo - Cernilton ® parallel those of patients treated with verum.

No statistical significant differences are found for dysuria, urgency and flow rate parameters.

The placebo-treated patients show a significant improvement in their voiding pattern after conversion to Cernilton ® in the follow-up phase. The continuous treatment with Cernilton ® over 24 weeks leads to complete elimination of some of the symptoms in over 50 % of the patients. This is documented in particular for frequency and feeling of incomplete emptying. Nocturia improves in 3/4 of all patients.

Residual urine volume remains unchanged during follow-up after an initial decrease during the verum treatment in phase I. The uroflow index continues to increase. Despite increased voided volume (8, 9,14), voiding time and time to peak flow rate are reduced.

The efficacy of Cernilton ® in regard to symptoms and urodynamic parameters, which has also been documented in a 6-month placebo-controlled double-blind study in a patient population with more advanced BPH (5), corresponds with the positive global assessment of the treatment outcome by physicians and patients in 80 % and 90 %, respectively.

The clinical relevance of congestive and inflammatory changes in the context of BPH (2, 3,12,17,18) is confirmed by the study presented here if a cause-effect relationship with the irritative, and partially obstructive, symptoms is assumed. The importance of detrusor hyperactivity is pointed out by urodynamic testing, and residual urine in this context may also be viewed as a parameter of detrusor function (9). If in fact the effect of Cernilton ® is based on its antiedematous properties which may lead to a normalization of the pathophysiological changes in the innervation of the prostate, this may explain also the concomitant improvement in irritative symptoms and the residual urine. Furthermore, in the nude mice model an inhibitory effect of oral Cernilton ® on the hormonally stimulated growth of heterotransplanted BPH has been documented (19). Further studies are necessary to confirm the importance of these findings for clinical application.

Phytotherapy of BPH is characterized by a high benefit to risk ratio. Long-term treatment is justified in particular in patients with symptoms of frequency because of the limited indication for surgical intervention (2,7,9,11,13,18). It does not represent an alternative if surgical treatment is indicated ' however (10), but the improvement of subjective symptoms is the main goal of this treatment option. New drugs (1,16) must therefore have an efficacy similar to that of surgical treatment if their safety profile is poorer than that of phytotherapy drugs.

Summary

The efficacy and tolerance of the pollen extract Cernilton ® was studied in a controlled follow-up study in patients with stages II and III (according to Vahlensieck) BPH in six urology practices. In phase I Cernilton ® was tested in a double-blind fashion against placebo for 12 weeks, and in the 12 week follow-up open-label trial, both treatment groups were treated with Cernilton ® (phase II). Significant differences were found in the 92 patients at the end of phase I between the placebo- and verum-treated patients. At the end of the open-label followup study with Cernilton ®, the differences between the two groups are eliminated. Tolerance of Cernilton ® is judged as good in 93.5 % and satisfactory in 6.5 %. The results of this study in a representative patient population with BPH confirm the effectiveness of Cernilton ® for BPH stages II and III over a 24-week duration and document the long-term therapeutic efficacy of the pollen extract, which allows effective long-term drug treatment of BPH.

Practical Conclusions

The continuous effectiveness of Cernilton ® allows a low-risk, long-term treatment of BPH. Antiandrogens and other hormonal drugs must be compared to the high benefit to risk ratio achieved with this drug. Anticongestive treatment will remain at the center of conservative treatment efforts for BPH.

Acknowledgements

For making this study possible and for good cooperation we would like to thank our colleagues in Cologne Dr. R. G. Kahnnann, Dr. J. Nuding, Dr. L. Pausch, Dr. G.-H. Rautenbach, Dr. J. Thissen and Dr. W. P. Winkler as well as their office personnel.

Furthermore we would like to thank Dr. J. Schnitker and co-workers, Institute for Applied Statistics, Bielefeld, for the statistical analysis; Intramed GmbH, Hamburg, for the figures; Mrs. U. Buinke, Hamburg for typing.

References

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* Published in Urologe (B) 31 (19918) 113-116

¹Pharmaceutical Company: Pharma Stroschein (licensed by Cernitin SA, 6903 Lugano, Switzerland) 2000 Hamburg, Germany

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