2. Zelmac: phase III study designs
Baseline
period
Treatment period
6 mg b.i.d.
or placebo
Withdrawal
period
Baseline
period
Treatment period
2 mg b.i.d., 6 mg b.i.d.
or placebo
4 weeks 12 weeks 4 weeks
Studies
1 and 2
Study 3
3. How can you “measure” drug response?
Abdominal pain?
Bloating??
Constipation?
4. Subject’s Global Assessment of Relief
Please consider how you felt this past week in regard to your IBS, in
particular your overall wellbeing, and symptoms of abdominal
discomfort, pain and altered bowel habit
Compared to the way you usually felt before entering the study, how
would you rate your relief symptoms during the past week?
Completely relieved
Considerably relieved
Somewhat relieved
Unchanged
Worse
Response: ≥50% complete/considerable relief or 100% somewhat
relief at study endpoint
Novartis, data on file
5. Validation of Subject’s
Global Assessment of Relief
Last study week
Efficacy variable
change from baseline (%) Complete Considerable Somewhat Unchanged Worse
Abdominal pain/discomfort –79 –50 –23 –5 8
Days with significant pain –73 –40 –7 18 3
Daily pain score –72 –44 –16 4 8
Days with significant
bloating –61 –37 –7 6 3
Daily bloating score –64 –41 –16 1 7
Bowel habit –75 –50 –23 –3 6
Days with no bowel
movement –62 –46 –28 –10 –16
Days with hard or
very hard stool –71 –70 –50 –19 3
Study 2
n=799 Novartis, data on file
6. Demographics and baseline
characteristics
Studies 1, 2 and 3
Variable
Mean age (years) 42.9
Gender (% female) 91.8
Race (% Caucasian) 85.5
Mean days with abdominal pain/discomfort (%) 89.0
Mean days with bloating (%) 89.9
Mean no. of bowel movements/week 5.6
Mean stool consistency score 4.8
Mean duration of IBS (years) 14.6
Novartis, data on file
17. Several clinical trials in functional GI
disorders have shown a high placebo
response rate, defined as the
“psychological or psychophysiologic
effect produced by placebo”
IBS is a functional Disease
18. In a meta-analysis, Spiller reported placebo response
rates of up to 84% in 25 randomized, controlled studies
in IBS, conducted during a 22-year period.
He found that, on average, the placebo response is
approximately three times the size of the difference
between drug and placebo response
Spiller Asked the same question
19. But Why??
Can you explain the phenomena
based on the nature of the
disease?
20. No One still knows
“patient- care effect”
Patient
Research Staff
Symptoms,
worries,
concerns
accept and validate
comfort
decrease anxiety
21. Summary of Zelmac efficacy
Zelmac 6 mg b.i.d. provides rapid and sustained relief
of three key symptoms of IBS with constipation
– abdominal pain/discomfort
– bloating
– constipation
Zelmac provides a significant improvement in
the Subject’s Global Assessment of Relief
These improvements occur within the first week
of treatment and are sustained for the duration of
treatment
Notas do Editor
Slide 8. Zelmac: Phase III study designs
Data from three Phase III studies are included in this slide set: a European Study (Study 1/B301), and two North American Studies (Study 2/B351 and Study 3/B358). In all three studies, medication was taken by the patients b.i.d., 30 minutes before morning and evening meals. A double-dummy technique was used and patients remained on the same dosage throughout the studies.
Studies 1 and 2 had the same design. Both were randomized, placebo-controlled and double-blind and included both male and female IBS patients. All patients enrolled in each study entered a pre-treatment 4-week baseline period. During this period (in which no study medication nor placebo was given), patients recorded their IBS symptoms in a diary. Following completion of the 4-week baseline period, patients (if judged eligible) were randomized to receive either placebo or Zelmac at doses of 2 or 6 mg b.i.d. for 12 weeks. Visits were scheduled on a monthly basis, at Day –28 (Month –1), Day 1 (randomization), Day 29 (Month 1), Day 57 (Month 2) and Day 85 (Month 3).
Study 3 enrolled only women with IBS. This was because IBS is a disease with a female preponderance (Everhart and Renault, 1991). A dose of 6 mg b.i.d. Zelmac was compared with placebo, because in Studies 1 and 2 this dose had been shown to be the most effective and well tolerated. In addition to a 4-week baseline period and 12-week treatment period, Study 3 featured a 4-week withdrawal period during which efficacy and safety data were recorded but no study medication was given. This allowed determination of the time period for the recurrence of IBS symptoms and an evaluation of the occurrence of any withdrawal symptoms.
In Studies 1 and 2 patients used paper diaries to record their IBS symptoms on a daily and weekly basis, while in Study 3 the paper diaries were replaced with a touch-tone telephone electronic diary. This data collection system has been shown to be reliable and ensures that the patients’ responses are collected at a specified interval (Harding et al., 1997).
For consistency, only the Zelmac 6 mg b.i.d. data are presented in the following efficacy slides.
Slide 9. Subject’s Global Assessment of Relief
In a meeting with the FDA in August 1997, the use of an outcome measure that encompasses overall well-being, abdominal pain/discomfort and altered bowel function was agreed upon for use in the Zelmac clinical trials.
Patients answered the resulting question (shown in the slide, with possible answers given using a five-point ordinal scale) on a weekly basis, in a self-assessed manner. This global assessment measure (termed the ‘Subject’s Global Assessment [SGA] of Relief’) reflects the key aspects of IBS from a patient’s perspective (i.e. overall well-being, abdominal pain/discomfort, bloating and altered bowel function). In the clinical trials, a responder was defined as a patient experiencing either ‘complete’ or ‘considerable’ relief at least 50% of the time, or at least ‘somewhat’ relief 100% of the time, over the last 4 weeks for which records were available (or all weeks if less than four). This definition captures both the magnitude and persistence of the drug effect.
Despite the recent advances in the diagnosis of IBS, the condition remains poorly understood. The lack of pathologic or biochemical markers makes the subjective assessment of symptom improvement during IBS clinical trials difficult. In 1988, Kenneth Klein assessed the effectiveness of randomized, controlled treatment trials for IBS. He commented, “A study should include measures of improvement of each of the relevant elements in the operational definition [of IBS] . . . Thus, it is desirable to have an overall measure of improvement that ideally would integrate change in all relevant symptoms” (Klein, 1988).
The symptoms that result in the diagnosis of IBS are varied and interact in a complicated manner. It was, therefore, felt that the main outcome measure in the Zelmac clinical trials should allow the patient to “integrate the contribution of a disparate group of symptoms into a single global clinical rating”. This general recommendation for primary outcome measures in trials of functional GI disorders was made in the Rome II recommendations (Veldhuyzen van Zanten et al., 1999).
Slide 10. Validation of Subject’s Global Assessment of Relief
For comparison with the SGA of Relief, and to assess concurrent validity, measurements of relevant and representative symptoms of IBS (e.g. abdominal pain/discomfort, bloating and days with hard/very hard stools) were also made and recorded by patients in the same diary.
A consistency in the relative magnitude of response across each response parameter of the SGA of Relief was demonstrated. Patients classified as ‘responders’ on the SGA of Relief (i.e. those with ‘complete’, ‘considerable’ or ‘somewhat’ relief) experienced a similar magnitude of improvement in their individual IBS symptoms, which were assessed separately through the secondary endpoints. In addition, those who were ‘unchanged’ or ‘worse’ on the SGA of Relief experienced a progressively lesser degree of improvement in individual IBS symptoms.
The data in this slide confirm the clinical validity of the global assessment measure used in the the Zelmac Phase III studies and indicate that the definition of a responder is robust and clinically relevant.
An alternative way to present these data is shown in Slide 30.
Slide 11. Demographics and baseline characteristics
The mean values for patient demographics and baseline characteristics were calculated for all patients in Studies 1, 2 and 3. The patients enrolled in the three studies were similar except Study 3 enrolled only women, whereas Studies 1 and 2 enrolled both men and women. Overall, the majority of patients were female.This is consistent with the observation that IBS is more common in women. The mean age of the patient population was approximately 43 years. Approximately 86% of patients were Caucasian.
Patients entering the three clinical trials typically had a long duration of IBS symptoms upon study entry (mean 14.6 years). This reflects the current lack of medication for treating multiple symptoms of IBS (abdominal pain/discomfort, bloating and constipation).
The patients enrolled in the Phase III studies experienced abdominal pain/ discomfort on the majority of days during the baseline period (89% of the 28 days), indicating that this was a major problem for the patients selected. The mean weekly number of bowel movements (5.6/week) indicates incomplete evacuation and the mean stool consistency score (approximately 5) showed a patient group with hard stools and constipation.
Patients also experienced bloating on most days during the baseline period (89.9%).
Slide 12. Global assessment: responders
In Study 1, the proportion of patients who had a global assessment of relief of at least ‘somewhat’ relieved remained constant, at around 10%, during the baseline period. Immediately after starting treatment a substantial treatment effect was observed. At Week 1, the proportion of patients at least ‘somewhat’ relieved was higher in the Zelmac 6 mg b.i.d. group (48.1%), compared with the placebo group (35.0%). This difference was statistically significant (p<0.05).
In the Zelmac 6 mg b.i.d. treatment group the number of patients with at least ‘somewhat’ relief was consistently higher than in the placebo group during the entire treatment period and the difference was statistically significant at most time points.
There was also a similar improvement with Zelmac 6 mg b.i.d. in global assessment in Studies 2 and 3. Results from Study 3, including data from the withdrawal period, are shown in Slide 13.
As with all studies in IBS there is a marked placebo response seen in this study and in the other Zelmac Phase III studies. In a review, Spiller reported placebo response rates of up to 84% in 25 randomized, controlled studies conducted during a 22-year period (Spiller, 1999). He found that, on average, the placebo response is approximately three times the size of the difference between drug and placebo response. The reasons behind the placebo response phenomenon are poorly understood, although several researchers have proposed that the actual care effect in the clinical trial process, whereby patients are in frequent contact with research staff, contributes to overall improvement. It could also be due, at least in part, to the spontaneous regression of symptoms, which is common in a cyclical disorder such as IBS.
It has been argued that a high placebo response may suggest that psychologic factors are important in the pathophysiology of IBS. However, this is not the whole story, because trials conducted in peptic ulcer, a disorder with a clear-cut pathophysiology, also show a high response to placebo. In clinical trials, ulcer healing obtained with placebo in various studies ranged from 5% to 80% (Gudjonsson and Spiro, 1978).
Slide 13. Global assessment: responders
In Study 3, patients receiving Zelmac 6 mg b.i.d. showed a consistently superior response on the global assessment of relief than patients receiving placebo. This was evident from the first week of treatment (p<0.05) and was sustained throughout the 12-week treatment period (significant at most time points).
As mentioned in Slide 8, Study 3 differed from Studies 1 and 2 by having a 4-week withdrawal period after the 12-week treatment period, where no medication was taken. This allowed determination of the time period for the recurrence of IBS symptoms and an evaluation of the occurrence of any withdrawal symptoms. As soon as treatment was stopped, response rapidly declined, although it did not return to baseline levels and there was no rebound.
Slide 14. Early onset of action: bowel movements
Altered or abnormal frequency of bowel movements is one of the key diagnostic criteria for identifying IBS. One of the Rome Criteria for diagnosis of IBS is altered stool frequency of three/day or <three/week at least 25% of the time (Thompson WG et al., 1992).
In Studies 1 and 2, patients treated with Zelmac 6 mg b.i.d. reported a rapid increase in the number of bowel movements per day from the first day of treatment. This difference between Zelmac and placebo groups was statistically significant at Days 1–13.
After approximately 1 week of treatment the effect stabilized and the patients continued to have approximately one bowel movement per day throughout the 12 weeks of treatment. Patients who received placebo reported little change in the number of bowel movements during the study, although there was a slight increase in the number of bowel movements around Days 2–4 of treatment.
A similar effect of Zelmac 6 mg b.i.d. was also seen in Study 3.
Slide 15. Sustained action: bowel movements
In Study 1, patients who received Zelmac 6 mg b.i.d. had a greater number of bowel movements throughout the 12 weeks of treatment compared with patients who received placebo. The effect occurred early (Slide 14) and was maintained throughout the study duration. The difference between the Zelmac and placebo groups was statistically significant for the majority of weeks.
A similar effect of Zelmac 6 mg b.i.d. was also observed in both Study 2 and Study 3.
Slide 16. Early onset of action: stool consistency
In the Phase III Zelmac clinical trials stool consistency was monitored daily by the patient using a 7-point ordinal scale (whereby 1=watery and 7=very hard). This scale is the reverse of the Bristol stool form scale.
Abnormal stool form is one of the features that is supportive of IBS. The Rome Criteria (Thompson WG et al., 1992) define abnormal stool form as ‘lumpy/hard or loose/watery.’
In Studies 1 and 2, patients treated with Zelmac 6 mg b.i.d. showed a rapid and statistically significant improvement in their stool consistency score compared with those patients assigned placebo. This was evident from the first day of treatment and was sustained throughout the 12 weeks of the study.
The effect during the first few days of treatment showed a rapid reduction in stool consistency due to the pharmacodynamic nature of Zelmac. This effect stabilized after a few days of treatment.
A similar effect of Zelmac was also seen in Study 3.
Slide 17. Early onset of action: abdominal pain/discomfort
The intensity of abdominal pain/discomfort (mean pain score) was significantly reduced in patients treated with Zelmac 6 mg b.i.d. compared with patients who received placebo. This effect was observed early, within 2 days of starting treatment. Similar effects were also seen in Study 3.
‘Abdominal pain is usually an unpleasant experience with sensory and affective components, and is a central feature of IBS’, commented Talley et al. in 1993. Several studies have investigated the effects of abdominal pain in IBS patients and have found that for many patients, it is the most predominant symptom in their condition (Manning et al., 1978; Drossman et al., 1990). It is also a predictor of physician visits (Whitehead et al., 1992) and correlates highly with symptom severity (Heaton et al., 1992; Sandler et al., 1984).
Abdominal pain is a sensation that can only be quantified by the individual, and, therefore, it can only be assessed by verbal and non-verbal observations. Pain can be considered to have three main dimensions: intensity, duration and frequency.
In Studies 1 and 2, the intensity of abdominal pain and discomfort was assessed daily by the patient using a 6-point ordinal severity scale (0=absent and 5=very severe).
Slide 18. Sustained action: abdominal pain/discomfort
In Study 1, patients treated with Zelmac 6 mg b.i.d. showed a consistently greater reduction in intensity of abdominal pain/discomfort (mean change in pain score from baseline) compared with patients who received placebo. This effect was statistically significant within 1 week of the initiation of treatment and was maintained throughout the study up to Week 12 of treatment (p<0.05).
Similar effects of Zelmac were also observed in Studies 2 and 3.
Results from Study 3, including data from the withdrawal period, are shown in Slide 19.
Slide 19. Sustained action: abdominal pain/discomfort
This slide again demonstrates the positive effect of Zelmac on the intensity of abdominal pain/discomfort (shown as a change from baseline). In Study 3, where there was a 4-week treatment-free withdrawal period, the mean abdominal pain/discomfort score (change from baseline) began to decrease as soon as treatment was discontinued at Week 12. Although there was a marked deterioration in both placebo and Zelmac groups there was no rebound or worsening of symptoms and the pain score did not return to baseline levels.
Slide 20. Sustained action: bloating
Bloating is an extremely common symptom of IBS and was experienced on approximately 90% of days during the baseline period in the Zelmac Phase III studies (Slide 11). Bloating can be a particular problem for IBS patients, especially in view of the fact that, before now, no IBS treatment has proven effective against the symptoms of bloating. As one patient explained: “Abdominal bloating may be so severe that it makes me look 6 months pregnant”.
Intensity of bloating was measured using a 6-point ordinal severity scale: (0=none and 5=very severe). In Study 1, patients who received Zelmac 6 mg b.i.d. showed a greater reduction in the mean bloating score (shown as a change from baseline) than patients who received placebo. This difference was apparent after 1 week of treatment and was maintained throughout the 12-week treatment period. The difference was statistically significant at Weeks 3–10 and Week 12 (p<0.05).
A similar effect on bloating score was also seen in Study 2 and Study 3.
Bloating or a sensation of fullness may be associated with borborygmi and flatulence. It is usually absent on awakening and worsens throughout the day. Clinical observations using inflation of balloons in the gut suggest that the sensation of bloating can arise at any level of the intestine and that it may have the same origin as gut pain. There is also evidence that bloating may be associated with slow intestinal transit (Thompson WG et al., 1992).
Slide 21. Summary of Zelmac efficacy
Zelmac 6 mg b.i.d. has a rapid and sustained action in improving some of the key symptoms of IBS with constipation: abdominal pain/discomfort, bloating and constipation.
Improvements in stool consistency and bowel movements are observed as early as Day 1, and relief of abdominal pain/discomfort is recorded by Day 2 (pooled data from Studies 1 and 2). These effects are sustained throughout the 12-week treatment period. Furthermore, improvement in individual symptoms correlates well with the global assessment parameter (the primary efficacy variable in Phase III studies).
Additional data collected during the withdrawal period in Study 3 indicate that the treatment effect rapidly diminishes after Zelmac is stopped, although there is no rebound and symptoms do not worsen compared with the baseline period.
Zelmac 6 mg b.i.d. has been shown to be consistently effective across multiple symptoms of IBS with constipation (abdominal pain/discomfort, bloating and constipation) and is recommended as the usual therapeutic dose to be taken just prior to meals.
