International Urogynecology Journal

, Volume 16, Issue 4, pp 293–297

Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC)

Authors

    • Centre Hospitalier Universitaire de SherbrookeUniversité de Sherbrooke
  • Jacques Corcos
    • Jewish General HospitalMcGill University
  • Michel Camel
    • Centre Hospitalier Universitaire de SherbrookeUniversité de Sherbrooke
  • Yves Ponsot
    • Centre Hospitalier Universitaire de SherbrookeUniversité de Sherbrooke
  • Le Mai Tu
    • Centre Hospitalier Universitaire de SherbrookeUniversité de Sherbrooke
Original Article

DOI: 10.1007/s00192-005-1307-4

Cite this article as:
Chen, T.Y., Corcos, J., Camel, M. et al. Int Urogynecol J (2005) 16: 293. doi:10.1007/s00192-005-1307-4

Abstract

Objective: To determine the safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC) patients. Materials and Methods: IC patients were instilled with 50 cc of test solution containing either placebo, 0.05 μM or 0.10 μM RTX in the bladder. Plasma concentration of RTX and its degradant resiniferonol 9-, 13-, 14-orthophenylacetate was measured. Immediate post-treatment blood sampling and cystoscopy were performed. Symptoms were evaluated before treatment, at 4- and at 12-week follow-ups, using VAS indicator for pain, voiding diary, and O’Leary’s IC symptom/problem indices. Results: Among 22 patients observed (ten in 0.10 μM RTX, eight in 0.05 μM RTX, and four in placebo groups), the most commonly reported adverse event was pain during instillation (80.0%, 87.5%, and 25.0%). No serious adverse events were reported. Conclusions: Use of intravesical RTX in IC patients is associated with important tolerability issues but safe at 0.10 μM and 0.05 μM.

Keywords

Interstitial cystitisResiniferatoxin (RTX)Intravesical treatment

Introduction

Interstitial cystitis (IC) remains a diagnosis of exclusion and is one of the most challenging syndromes for the urologist. Infection, autoimmunity, urothelial leak, mast cells involvement, and neurogenic inflammation have all been suggested, and most authors support a multi-factorial aetiology [1, 2]. The recent use of 0.01 μM resiniferatoxin (RTX) in patients with hypersensitive bladder disorder has shown promising results [3]. Therapeutic effects, however, were attenuated one month post-treatment, and no safety datum was reported. While intravesical RTX is believed safe in humans, there has been no systematic evaluation of the safety and tolerability of RTX in IC patients. The present study seeks to address the safety, tolerability, and efficacy (as a secondary endpoint) of RTX in IC patients at a maximum desensitizing concentration of 0.10 μM.

Materials and methods

A prospective, randomized, parallel group, double blind, placebo-controlled study was designed to compare, first the safety and tolerability and secondly the efficacy of RTX with placebo in 22 patients (17 women and 5 men) diagnosed with IC for a minimum of 9 months, based on NIH-NIADDK criteria. This was a phase 1 trial, and a phase 2 trial is currently underway in the US. Participants were aged 18–85 (mean age: 43.7 for RTX groups, 56.6 for placebo) and had similar urologic history and demographics. Patients on medication to control irritative symptoms were included, provided dosage had not changed within the 30 days leading to the study. No dosage change was permitted during the protocol. Individuals were excluded if pregnant or nursing, or if they had other pathologies of the lower urinary tract (infection, detrusor overactivity, and urologic manifestation of neurologic diseases), ulcerative IC, intravesical therapy or bladder hydrodistension 6 weeks prior, current or previous malignancy, known chemical addiction, seizure or major psychiatric disorder, pertinent allergy, or significant medical conditions.

The study involved four clinic visits: screening, treatment (Day 1), and follow-ups at weeks 4 and 12 post-treatment. During screening, a complete medical history, physical examination, urodynamic assessment, cystoscopy, and clinical laboratory tests were done to confirm patient eligibility. Patients were randomized to one of three test solutions, which were identical in appearance and delivered in 10% ethanol in saline: 0.05 μM RTX (eight patients), 0.10 μM RTX (ten patients) and placebo (four patients) at a ratio of 2:2:1. The placebo consisted of the 10% ethanol in saline. RTX was supplied as a sterile stock solution 10 μM in 100% dehydrated alcohol. All solutions were prepared in polypropylene tubing and syringes, preventing absorption of RTX by the equipment. As an optional procedure, the investigator could administer 50 cc of 2% lidocaine in the bladder via a Foley catheter to be retained for 10 min. The lidocaine solution is then emptied and the bladder is rinsed with 50 cc of saline. An amount of 50 cc of the test solution was then to be administered intravesically at a rate of approximately 50 cc/min. The test solution was to be retained for 30 min; the bladder was then to be emptied and rinsed with approximately 50 cc of normal saline.

Safety and tolerability measurements included incidence and description of adverse events, physical examinations, vital signs, cystoscopy, and clinical laboratory tests [hematology, blood biochemistry, serum concentration of RTX and its primary degradant ROPA]. Hematology and blood biochemistry were performed on screening visit, immediately post-intravesical treatment, and by week 4. Serum concentration of RTX and ROPA were tested pre-instillation and 15, 30, 45 and 60 min after the start of the intravesical treatment.

The main efficacy variable used in the study protocol was IC-related pain. Participants were also asked to complete a voiding diary for a 3-day period at baseline and weeks 1, 4, 8 and 12. The interstitial cystitis symptom and problem questionnaire was also administered, at baseline and weeks 4 and 12.

Patients were randomized via a computer generated randomization schedule. A sequence of randomization numbers was assigned to each study centre. The size of the randomization blocks was not disclosed. Blinding information was contained in sealed envelopes and distributed to investigators. Breaking the blind was permitted on a case-by-case basis and only in the event of an emergency. Such activity was to be reported and documented.

All analyses, data listings and tables were produced using SAS Version 8.0. Descriptive statistics for continuous variables included mean, standard deviation, median, minimum, and maximum. Categorical variables were presented as counts and percentages. Analyses were based on intent to treat principle.

The study was approved by the Ethics Committee of participating institutions, and each patient expressed informed written consent.

Results

Nineteen of the 22 patients studied experienced at least one adverse event (90.0% in 0.10 μM RTX group, 87.5% in 0.05 μM RTX group, and 75.0% in the placebo group, respectively). The most commonly reported adverse event was pain during instillation (80.0, 87.5, and 25.0%, respectively). Mean VAS pain scores during instillation as assessed by the patients were 8.0, 9.4, and 4.5, respectively. Duration of pain was approximately 1 h in the RTX groups and 40 min in the placebo group. Other adverse events included abdominal pain, cystitis, dizziness, pallor, and urinary tract disorders.

Ten patients in the RTX groups, who received optional pre-instillation lidocaine, had a VAS score during treatment similar to eight in the RTX group who did not receive lidocaine (8.4 vs. 8.8). Of the patients who had received intravesical lidocaine prior to RTX, 4 (40%) discontinued early due to pain, compared to 5 (62%) of the patients with RTX who had not benefited lidocaine. The difference is not statistically significant.

No serious adverse event was reported, and no patient discontinued the study due to adverse events. No clinically significant change was observed during physical exam. Mild post-instillation changes in cystoscopy findings were observed in 5 (50%) patients in the 0.10 μM RTX group, 4 (50%) in the 0.05 μM group, and 2 (50%) patients in the placebo group. Changes included erythema, vascularization and petechia/glomerulation. There was no clinically significant change in results of hematology and biochemistry. Plasma concentrations of both RTX and ROPA were below the quantitative limit at all time points for all samples assessed. A flare of IC was reported in one patient each in the 0.10 μM RTX and placebo groups. Both incidents occurred several days after the instillation.

No statistically significant trend was observed in the efficacy data. The mean VAS pain score did not change significantly over time for any of the groups, and no significant trends were noted in voiding diary (Table 1). However, there seems to be a dose-dependent decrease in the overall score of the IC problem and Symptom Indices (Table 2). The change was present even at 12 weeks. It is important to note that the improvement did not reach statistical significance due to the small sample size in this phase 1 trial.
Table 1

Efficacy outcomes

Subject

Visit

Frequency

Nocturia

Urgency

VAS

ICSI

ICPI

0.10 μM RTX dose group

02

Day 1

36.7

4.3

5.7

4.7

13

13

Week 4

62.7

3.7

17.0

6.2

13

13

Week 12

65.7

3.7

19.7

6.5

15

14

04

Day 1

14.7

5.3

4.0

4.0

12

9

Week 4

12.0

5.0

0.7

0.0

7

3

Week 12

11.7

2.7

1.3

0.0

3

2

06

Day 1

31.0

10.3

31.0

9.3

20

16

Week 4

36.3

12.3

36.3

9.5

19

16

Week 12

36.7

13.0

36.7

10.0

20

16

07

Day 1

13.7

2.0

13.3

4.0

15

15

Week 4

12.7

2.3

0.0

1.7

9

9

Week 12

11.0

3.0

7.3

2.7

10

9

09

Day 1

16.3

2.3

7.7

2.7

14

12

Week 4

9.7

2.0

1.7

0.0

8

2

Week 12

9.3

0.7

1.0

0.0

3

4

11

Day 1

18.3

4.0

1.3

4.3

17

16

Week 4

25.3

4.0

3.3

8.0

18

15

Week 12

21.7

3.7

21.7

7.3

19

16

15

Day 1

18.7

3.7

4.0

2.0

17

14

Week 4

5.3

0.7

0.7

0.0

1

0

Week 12

7.0

0.3

0.7

0.0

2

1

17

Day 1

23.3

5.3

21.7

6.5

18

13

Week 4

27.0

7.0

27.0

5.2

18

12

Week 12

13.7

4.3

13.7

2.0

13

7

20

Day 1

13.0

2.0

8.3

7.3

14

11

Week 4

8.7

0.7

3.0

0.0

2

0

Week 12

7.3

0.0

3.3

3.1

9

7

24

Day 1

16.0

3.7

3.7

2.3

17

15

Week 4

10.3

2.3

1.0

1.3

13

12

Week 12

12.7

3.0

1.0

3.3

13

14

0.05 μM RTX dose group

01

Day 1

17.5

5.5

8.0

5.0

16

15

Week 4

20.0

8.5

18.0

7.0

18

16

Week 12

23.3

8.0

22.3

8.0

17

16

05

Day 1

14.3

3.0

12.3

9.0

17

16

Week 4

12

3.0

5.3

4.3

9

10

Week 12

11.3

2.7

4.7

4.7

6

3

10

Day 1

13.3

5.0

5.0

8.3

17

14

Week 4

11.3

4.3

2.3

6.0

12

13

Week 12

NR

NR

NR

NR

NR

NR

12

Day 1

14.0

3.0

14.0

8.0

18

16

Week 4

11.0

1.7

11.0

8.0

17

16

Week 12

13.3

2.0

5.3

5.0

18

16

14

Day 1

12.7

4.7

4.0

6.3

10

15

Week 4

13.0

3.7

8.0

7.7

12

15

Week 12

15.0

3.7

6.7

7.0

12

15

16

Day 1

17.0

3.3

6.7

6.7

13

12

Week 4

17.3

3.7

2.7

4.3

10

9

Week 12

15.3

3.0

3.3

6.8

14

12

19

Day 1

12.0

3.0

12.0

8.0

17

13

Week 4

9.7

0.3

2.3

4.3

6

8

Week 12

8.0

0.0

0.0

2.0

7

5

21

Day 1

14.0

3.3

3.0

3.7

13

13

Week 4

16.3

3.3

1.7

3.8

15

13

Week 12

14.0

4.0

0.0

0.3

11

7

Placebo group

03

Day 1

27.7

11.0

20.0

7.0

20

16

Week 4

27.3

11.7

12.3

1.7

16

13

Week 12

31.3

16.3

19.0

2.0

16

11

08

Day 1

9.0

1.7

3.7

7.8

13

12

Week 4

10.7

2.7

5.3

7.7

13

12

Week 12

12.3

3.7

7.0

6.7

12

13

13

Day 1

13.0

4.0

3.3

3.7

13

14

Week 4

14.7

3.7

1.7

1.3

10

14

Week 12

13.0

3.0

4.3

1.7

12

15

18

Day 1

9.3

1.7

8.3

3.3

13

13

Week 4

10.3

0.3

8.0

3.3

13

12

Week 12

11.0

0.0

10.3

3.3

12

12

One patient did not complete all week 12 assessments due to problems with transportation

Table 2

Changes in IC Symptom and Problem indices, according to concentration groups

 

Placebo

0.05 mM RTX

0.10 mM RTX

ΔIC S × index by week 4

−1.8

−2.8

−4.9

ΔIC S × index by week 12

−1.8

−2.0

−5.0

ΔIC Pb index by week 4

−1.0

−1.8

−5.2

ΔIC Pb index by week 12

−1.0

−3.3

−4.4

Discussions

Micturition is a process that involves both the central nervous system and peripheral neurologic elements in the lower urinary tract: small myelinated A-delta fibres that transmit mechano-receptor information and unmyelinated C-fibres that detect irritants and provoke painful sensation [4]. Under normal circumstances, signals regarding wall tension, and hence bladder volume, are transmitted via A-delta fibres that allow micturition at an appropriate time; C-fibres remain relatively silent. In certain pathologic conditions, however, C-fibres become activated and may be implicated in a defence mechanism that allows the bladder to reflexively eliminate irritants by triggering voiding [5]. Some evidence suggests that IC may be a neurogenic inflammatory disorder. Findings from electron microscopy and urinary cytology support the presence of neurogenic inflammation in patients with IC [68].

The neurogenic inflammatory model of IC has brought capsaicin (CAP) and its ultra-potent analogue, RTX, into the spotlight as potential therapy for the treatment of IC. Although RTX and CAP differ significantly in structure, they share a homovanillyl group that confers analogous biological activities [9]. This similarity in biological activities of CAP and RTX is substantiated by a variety of studies [1012].

It is important to note that RTX has no carcinogenic activity, despite its structural resemblance to phorbol ester, a tumour-inducing agent. In order for RTX to behave like phorbol ester, it must lose the homovanillyl group and become ROPA [13, 14]. Our study, however, did not detect the presence of this substance in all plasma specimens for all time periods. In other words, intravesical instillation of RTX is safe up to the upper limit of this study, which is 0.10 μM.

RTX offers certain distinct advantages over CAP. The magnitude of C-fibre desensitization by capsaicin is dependent on concentration, duration and interval of exposure, and temperature [15, 16]. RTX has a longer duration of action than CAP [17]. Bladder tissue exposed to RTX recovers faster from inflammatory changes [18]. The use of topical CAP is also associated with the risk of autonomic dysreflexia in certain patients, which has not yet been observed with RTX to our knowledge [19, 20].

The most important advantage of RTX lies in its ability to desensitize without significant initial burning. RTX is estimated to be 1,000 times more potent than CAP in desensitizing power, but only 100–300 times more potent in causing inflammation [10, 18]. One explanation for this may be a small difference in the spectrum of activity between CAP and RTX [10]. Another explanation may lie in the existence of subgroups of vanilloid receptors or C-fibres, for which CAP and RTX may have different affinities [21]. An interesting third alternative theory attributes the difference in initial irritation to ethanol, a solvent used in the vehicle to deliver CAP and RTX [22]. CAP is virtually insoluble in water and necessitates a considerable concentration of ethanol (30%) to solve into the required concentration. RTX, on the other hand, is slightly soluble in water, so the concentration of ethanol concentration in RTX solutions is usually lower than in CAP solutions. Ethanol is known to cause bladder irritation, inflammation, and tissue damage at higher concentrations such as 90% [23].

In our study, a substantial proportion of patients reported pain during intravesical instillation. We chose to use 10% ethanol (a higher concentration than in previous studies in which RTX was better tolerated) as the vehicle for delivery because of the higher concentration of RTX in the treatment solution. This has resulted in more important tolerability issues. However, it is important to note that no serious adverse events occurred during the study. In our experience, support from the staff has an important role. For instance, our research nurse engaged in more conversation with patients during treatment administration. This distracts patients and, in our opinion, contributes to higher completion rate in our centre compared with other collaborators, despite similar intensity of pain during administration.

The primary objective of our study was to evaluate the safety and tolerability of RTX in patients. The chosen concentrations were based on previous animal and human studies that showed that the desensitization effect of RTX was dose-dependent, and maximum efficacy was reached at 0.10 μM [21, 22, 24]. RTX concentration as high as 10 μM was used in patients with refractory detrusor hyperreflexia, with apparently few side effects [25]. A different range might have been of little clinical use or we may have exposed our patients to unnecessarily high dose of RTX. Nonetheless, further study is needed to determine the optimum efficacious dose for RTX in the treatment of IC.

The efficacy result was less conclusive than the safety data. While the VAS and voiding diary showed no noticeable trend, the percentage of patients showing improvement in these elements was generally higher in the RTX groups than the placebo group. The small number of study participants might help explain this: a few patients with an extreme response can easily distort the results of the majority and mask the general trend of the group. This also underlines another difficulty in research for IC patients, which is how to choose the best outcome measure. As demonstrated by our study, different instruments seemingly measuring the same symptoms can have discordant results. Currently, there is a phase 2 trial with 150 patients evaluating the efficacy of intravesical RTX at various concentrations in IC patients. The results of this study are anxiously awaited.

Our efficacy results were not as encouraging as those of Dr Lazerri et al. [3]. Our use of a higher RTX concentration showed that therapeutic effect might last longer than 4 weeks (persistent improvement in the ICPI/ICSI score at the 12-week follow-up), but we were unable to confirm efficacy results as conclusively at the 4-week follow-up. Differences such as the study population, randomization ratios, and choice of analytical statistical methods may contribute to the difference.

Conclusions

RTX at 0.10 μM and 0.05 μM is safe to administer intravesically in patients with IC. Intravesical instillation of RTX at these concentrations with 10% ethanol is associated with significant tolerability issues. However, no serious adverse events were reported. Lidocaine pre-instillation may be beneficial, especially in IC patients whose main complaint is pain. A larger clinical study is needed to confirm the clinical efficacy of RTX and to determine the optimum concentration and appropriate timing for repeated instillation, if indicated, of RTX in IC patients.

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© International Urogynecology Journal 2005