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Keywords:

  • abdominal bloating;
  • abdominal discomfort;
  • abdominal pain;
  • guanylate cyclase type-C receptor;
  • guanylin;
  • MD-1100

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Background

Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS-C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report ≥30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of ≥1 from baseline.

Methods

Anchor-based methodology was used to estimate thresholds of clinically meaningful change using symptom-specific patient rating of change questions (PRCQs) and symptom severity questions. The diagnostic accuracy of the FDA Responder Endpoint was assessed using sensitivity/specificity-based methods.

Key Results

Using anchor-based methods, the estimates of the clinically meaningful improvement thresholds for Abdominal Pain ranged from 25.9% to 32.4% and thresholds for increase in weekly CSBM rate ranged from 1.4 to 1.6 CSBMs per week. Compared with the symptom-specific PRCQs for patient rating of relief, the FDA Responder Endpoint has a sensitivity of 60.7%, a specificity of 93.5%, and an accuracy of 82.0%. Changing the number of weeks required to be a responder or the percentage improvement in the Abdominal Pain criteria did not result in notable improvement in the accuracy of the FDA Responder Endpoint.

Conclusions & Inferences

The FDA Responder Endpoint for IBS-C clinical trials represents clinically meaningful improvements in IBS-C symptoms for patients with excellent specificity and reasonable sensitivity.

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder, characterized by recurrent episodes of abdominal pain or abdominal discomfort associated with altered bowel movements, which affects between 9% and 15% of the adult population.[1-4] IBS with constipation (IBS-C) occurs more commonly in women than men, and frequently includes additional symptoms such as abdominal bloating, hard stools, straining, and sensation of incomplete evacuation.[5] The diagnosis of IBS is based on identifying typical symptoms, evaluating for ‘alarm features’, and excluding organic diseases when appropriate.[6, 7]

The US Food and Drug Administration (FDA)'s guidance for assessing the efficacy of pharmacological treatments in IBS-C recommends use of an endpoint that measures two major IBS symptoms—abdominal pain and abnormal defecation.[8] In particular, this guidance recommends that an IBS-C responder definition includes a ≥ 30% reduction from baseline in the weekly mean of the daily scores for worst Abdominal Pain and an increase of ≥1 Complete Spontaneous Bowel Movement (CSBM) per week from baseline, both in the same week, for at least 50% of the Treatment Period weeks. However, the meaningfulness of these thresholds to define Abdominal Pain and CSBM Responders has not yet been evaluated.

The objective of this study is to evaluate the performance of the FDA Responder Endpoint for clinical trials in IBS-C, using data from two large Phase 3 clinical trials of linaclotide, a guanylate cyclase-C agonist (GCCA).

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Clinical trial design

Two large Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, clinical trials (Trials 31 and 302) were conducted to assess the efficacy of oral linaclotide in patients with IBS-C. Further details and results of these trials have been published elsewhere.[9, 10] A total of 1,602 IBS-C patients were included in the Pooled ITT Population. Both trials included a 2-week Baseline Period, after which patients were randomized to receive either placebo or linaclotide 290 μg once daily during a Treatment Period of 12 weeks (Trial 31) or 26 weeks (Trial 302). In both trials, the primary endpoints were evaluated using data collected during the first 12 weeks of treatment. The current analyses were also limited to the first 12 weeks of Trials 31 and 302.

Study population

Patients were men and women aged 18 years or older who met Rome II criteria for IBS. Patients entering the Baseline Period were required to report <3 spontaneous bowel movements (SBM = a bowel movement [BM] occurring in the absence of laxative, enema, or suppository use in the previous 24 h, defined in these trials as the calendar day of the BM or the calendar day before the BM) per week and had one or more of the following symptoms for at least 12 weeks, which need not have been consecutive, in the preceding 12 months: (i) straining during >25% of BMs, (ii) lumpy or hard stools during >25% of BMs, and (iii) a sensation of incomplete evacuation during >25% of BMs. During the 14-day Baseline Period, patients eligible for randomization needed to report an average score of ≥3 for daily Abdominal Pain at its worst on a 0–10-point numeric rating scale (NRS) and an average of ≤5 SBMs per week and <3 CSBMs per week (CSBM = an SBM that is associated with a sensation of complete emptying).

Clinical assessments

Efficacy assessments

Each day during the Baseline and Treatment Periods, patients were asked to call into an interactive voice response system (IVRS) to record their IBS-C symptoms. Although a number of symptoms were assessed, those used in these analyses included Abdominal Pain at its worst using an 11-point NRS, the number of BMs, and whether rescue medication was used. In addition, each BM was assessed for sensation of complete bowel emptying (yes/no).

Anchor questions

Symptom-specific patient rating of change questions (PRCQs) for Abdominal Pain Relief and CSBM Frequency Improvement were assessed at all visits following randomization (i.e., weeks 2, 4, 8, and 12). For Abdominal Pain Relief, patients responded to the following PRCQ: ‘Compared to before you started this study, how would you rate your abdominal pain at its worst during the past 7 days?’ For CSBM Frequency Improvement, patients responded to the following PRCQ: ‘Compared to before you started this study, in the absence of laxative use, how would you rate your frequency of complete bowel movements (i.e., bowel movements where you felt like you completely emptied your bowels) during the past 7 days?’ Finally, the Degree of Relief of IBS symptoms PRCQ was assessed weekly via IVRS with the following question: ‘Compared to before you started this study, how would you rate your IBS symptoms during the past 7 days?’ For all three PRCQs, the response options were as follows: 1 = Completely relieved/improved, 2 = Considerably relieved/improved, 3 = Somewhat relieved/improved, 4 = Unchanged, 5 = Somewhat worse, 6 = Considerably worse, 7 = As bad as I can imagine.

Patients rated their current IBS and Constipation Symptom Severity weekly via IVRS using the following questions: ‘On average, how would you rate your IBS symptoms during the past 7 days?’ and ‘On average, how would you rate your constipation during the past 7 days’, respectively. For both questions, the response options were as follows: 1 = None, 2 = Mild, 3 = Moderate, 4 = Severe, 5 = Very severe. For these assessments, patients did not need to reflect back to before the study started, but rather rate their current symptoms during the past 7 days.

FDA Responder Endpoint

The FDA Responder Endpoint for IBS-C trials defines a responder as a patient who, during the same week for at least 50% of the weeks of a Treatment Period (i.e., 6 of 12 weeks), reports: (i) an improvement of ≥30% from baseline in the average of the daily worst Abdominal Pain score, and (ii) an increase of ≥1 CSBM from baseline. Patients were required to complete at least 4 IVRS calls during the week to qualify as a responder.

Endpoint Evaluation Methods

Anchor-based Estimates of Meaningful Change: An anchor-based methodology[11] was used to estimate thresholds of meaningful change using the following assessments as anchors: symptom-specific (i.e., Abdominal Pain Relief and CSBM Frequency Improvement) PRCQs, global (i.e., Degree of Relief of IBS) PRCQs, and the IBS and Constipation Symptom Severity questions. Whereas the PRCQs require the patient to compare their current status with their status prior to starting the study, the IBS and Constipation Symptom Severity questions (these items will be referred to as ‘Current Severity Questions’) require patients to rate their current status over the past 7 days.

The anchor-based clinically meaningful threshold estimates were the change-from-baseline scores in Abdominal Pain or CSBMs averaged over those weeks the patient responded ‘Somewhat relieved/improved’ for the PRCQs.[12, 13] Similarly, the threshold estimates for the Current Severity Questions were the change-from-baseline scores in Abdominal Pain or CSBMs averaged over those weeks the patient had an improvement of one category. As a patient can have multiple weeks in which the anchor criterion was met (for either the PRCQs or the Current Severity Questions), a repeated measures mixed-model approach[14] was performed with the use of the PROC MIXED procedure in sas software, version 9.1 (sas Institute) to estimate the mean of the change-from-baseline scores on those weeks when a patient met the anchor criterion. The mixed model had a fixed intercept, Gaussian distribution random intercepts for each patient, and the covariance pattern for the within-patient observations was unstructured. For CSBMs, as the distribution of the change-from-baseline data was non-Gaussian (i.e., the underlying distribution was skewed), clinically meaningful thresholds based on median scores were estimated in addition to the thresholds based on mean scores. For this CMC estimate, the median change-from-baseline score in CSBMs over those weeks the patient met the anchor criterion was used. If a patient had multiple weeks meeting the anchor criterion, the patient's median score was used to determine the overall change-from-baseline median score.

Sensitivity/Specificity: The diagnostic accuracy of the FDA Responder Endpoint was assessed using sensitivity/specificity-based methods. Sensitivity is defined as the ability of a measure to correctly identify patients who have a condition; [15]it is the percentage of true positives (i.e., responders) classified as positive by the measure being evaluated. Specificity is the ability of a measure to correctly identify patients who do not have a condition; it is the percentage of true negatives (i.e., non-responders) classified as negative by the measure being evaluated. Accuracy is the percentage of true results, both true positives and true negatives.

The two symptom-specific PRCQs, Abdominal Pain Relief, and CSBM Frequency Improvement, averaged across the 12-week Treatment Period, were used as gold standards for categorizing each patient's status (improved or not improved) in the assessment of the diagnostic accuracy of the FDA Responder Endpoint. A patient's status was defined as ‘improved’ if his/her average response to both the Abdominal Pain Relief and CSBM Frequency Improvement PRCQs was ≤3.0 on the 7-point balanced scale (i.e., an average score of somewhat, considerably, or completely relieved/improved across the 12-week Treatment Period) and, conversely, ‘not improved’ if his/her average response to both the Abdominal Pain Relief and CSBM Frequency Improvement PRCQs was >3.0. In addition, the patient would be categorized as ‘not improved’ if any of the following occurred in the 12 weeks of treatment: the patient withdrew from the trial due to lack of efficacy, the patient withdrew from the trial due to a gastrointestinal adverse event, or the patient completed less than 6 weeks of treatment.

Therefore, the FDA Responder Endpoint is considered sensitive if it identifies as responders a large percentage of individuals who are categorized as improved based on PRCQ Abdominal Pain Relief and PRCQ CSBM Frequency Improvement (i.e., patients with an average score of at least ‘somewhat relieved’), and specific if it does not classify a large number of patients as responders who did not indicate relief of Abdominal Pain and improvement in CSBM Frequency. Accuracy is the percentage of patients who are categorized as both ‘improved’ and ‘responders’ or ‘not improved’ and ‘non-responders.’

To further assess the rigor of the FDA Responder Endpoint, we also evaluated its sensitivity, specificity, and accuracy while separately varying the number of weeks (from ≥6/12 weeks), the percentage change in Abdominal Pain (from ≥30%), and the increase in CSBMs from baseline (from ≥1) required to be identified as a responder. While varying one of these criteria, the other two criteria remained at the values defined for the FDA endpoint.

Percentage of Responders Based on Incremental Abdominal Pain and Weekly CSBM Criteria by Treatment Group: The percentages of patients meeting the FDA Responder Endpoint in the linaclotide and placebo treatment groups were compared using a Cochran-Mantel-Haenszel (CMH) test controlling for trial geographic region. In addition, the percentages of patients meeting incremental thresholds of reduction in Abdominal Pain and improvements in CSBM Frequency for at least 6 of the first 12 weeks of the Treatment Period in the linaclotide and placebo treatment groups were compared using Fisher's exact test.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Clinically meaningful change thresholds for Abdominal Pain and CSBMs

Estimates of clinically meaningful improvement thresholds based on the anchor-based approaches are presented in Table 1. An average response of ‘somewhat relieved’ for the symptom-specific PRCQ Abdominal Pain Relief anchor corresponded to an improvement in Abdominal Pain of 25.8%, whereas for the PRCQ CSBM Frequency Improvement anchor, the threshold for improvement in CSBMs per week was 1.4 (1.0 using median-based methods). Using a more global anchor, the Degree of Relief of IBS PRCQ, the threshold for improvement in Abdominal Pain was 27.6%, whereas the threshold for improvement in CSBMs per week was 1.4 (0.5 using median-based methods). The clinically meaningful improvement threshold values based on the patients’ ratings of Current Severity questions (IBS and Constipation Symptom Severity) over the past 7 days were similar to the PRCQ results, with estimates of 30.4% and 28.4%, respectively, for Abdominal Pain, and 1.5 and 1.3, respectively, for CSBMs (0.5 for both IBS and Constipation Severity items using median-based methods) (Table 1).

Table 1. Thresholds for clinical meaningfulness estimates based on anchor-based methods
  Anchors
PRCQsCurrent severity questions
Symptom-specific patient rating of changebDegree relief of IBS symptomsIBS symptom severityConstipation symptom severity
  1. a

    CMC estimates and 95% confidence intervals.

  2. b

    PRCQ Abdominal Pain Relief was the anchor for the percent improvement in Abdominal Pain; PRCQ CSBM Frequency Improvement was the anchor for increase in weekly CSBM Frequency.

  3. c

    Median-based CMC estimates and 95% CIs; as the CSBM change from baseline distribution is non-Gaussian, both median- and mean-based CMC estimates are presented.

Improvement in Abdominal Pain (%)a25.8 (24.1, 27.5)27.6 (26.0, 29.1)30.4 (28.7, 32.0)28.4 (26.7, 30.1)
Increase in weekly CSBM frequencya
Mean1.4 (1.2, 1.5)1.4 (1.3, 1.5)1.5 (1.3, 1.6)1.3 (1.2, 1.4)
Median[1.0 (0.6,1.0)]c[0.5 (0.5,0.6)]c[0.5 (0.0, 0.5)]c[0.5 (0.0, 0.5)]c

The results of these analyses indicate that the criteria of ≥30% improvement in Abdominal Pain and an increase of ≥1 CSBM for 6 of 12 weeks recommended in the FDA Responder Endpoint are consistent with the threshold estimates for clinical meaningfulness, across different anchors.

Sensitivity and specificity of the FDA Responder Endpoint

Table 2 shows the number of patients who were responders and non-responders for the FDA Responder Endpoint compared with the number of patients who were categorized as ‘improved’ or ‘not improved’ based on a patient reporting, on average, at least ‘somewhat improved’ on both the Abdominal Pain Relief and CSBM Frequency Improvement PRCQs. Using these PRCQ criteria, the FDA Responder Endpoint has a sensitivity of 60.7%, a specificity of 93.5%, and an accuracy of 82.0%. The FDA Responder Endpoint could be considered conservative given the moderate sensitivity of 60.7%, which implies that 39.3% of patients reporting improvement on the symptom-specific PRCQs did not meet the FDA Responder Endpoint, whereas, due to the very high specificity, only 6.5% of patients not reporting improvement were responders.

Table 2. Comparison of FDA Responder Endpoint by patient rating of change questions for Abdominal Pain relief and CSBM improvement
 Patient rating of Abdominal Pain relief and CSBM improvementa
YesNoTotal
  1. Pooled IBS-C Phase 3 ITT Population.

  2. a

    A patient was defined as having Abdominal Pain relief and CSBM improvement if the average response to the Abdominal Pain and CSBM Frequency PRCQs was both ≤3.0 (on the 7-point balanced scale) across the 12-week Treatment Period. In addition, the patient could not have withdrawn from the trial due to lack of efficacy, a gastrointestinal adverse event, or completed less than 6 weeks of the Treatment Period.

  3. b

    The FDA Responder Endpoint for IBS-C trials defines a responder as a patient who, during the same week for at least 50% of the weeks of a Treatment Period (i.e., 6 of 12 weeks), reports: (i) an improvement of ≥30% from baseline in the average of the daily worst Abdominal Pain score and (ii) an increase of ≥1 CSBM from baseline.

FDA Responder EndpointbResponder34268410
Non-responder2219711192
Total56310391602

Percentage of patients who met the FDA Responder Endpoint: 25.6%(410/1602)

Percentage of patients with Abdominal Pain Relief and CSBM Improvement: 35.1% (563/1602)

Sensitivity = 60.7% (342/563); Specificity = 93.5% (971/1039); Accuracy = 82.0% (342 + 971)/1602)

Similar analyses were performed based on a patient reporting, on average, at least ‘considerably relieved/improved’ (i.e., rather than ‘somewhat relieved/improved’ as in Table 2) on both the Abdominal Pain Relief and CSBM Frequency Improvement PRCQs. Using these modified PRCQ criteria, the FDA Responder Endpoint has a sensitivity of 84.7%, a specificity of 80.1%, and an accuracy of 81.2%. Thus, using these more conservative PRCQ criteria resulted in an increase in the sensitivity but also a corresponding decrease in specificity without change in accuracy. Notably, only 9.8% (157/1602) of patients met these more conservative PRCQ criteria.

Fig. 1A illustrates the impact on the sensitivity, specificity, and accuracy of variations on the FDA Responder Endpoint in which the criterion for the number of weeks a patient needs to be identified as a responder is modified. As discussed above, the FDA Responder Endpoint, which requires that the criteria be met for at least 50% of the Treatment Period weeks (i.e., ≥6 of 12 weeks), yields a sensitivity, specificity, and accuracy of 60.7%, 93.5%, and 82.0%, respectively, compared with the PRCQ criteria. If the number of weeks required to meet this criterion is increased to at least 75% of the Treatment Period weeks (i.e., ≥9 of 12 weeks), the sensitivity decreases markedly to 37.8%, the specificity increases slightly to 98.7%, and the accuracy decreases to 77.3%. A maximum accuracy of 82.5% is achieved when requiring at least 5 weeks, which is only slightly better accuracy than at the FDA responder requirement of at least 6 of 12 weeks (Fig. 1A).

image

Figure 1. Variations on the FDA Responder Endpoint. (A) Impact of varying the number of weeks needed to meet the Responder Endpoint on endpoint sensitivity and specificity. Note: FDA Responder Endpoint criterion is ≥6/12 weeks. Pooled IBS-C Phase 3 ITT population. (B) Impact of varying the percent improvement (weekly average) in Abdominal Pain threshold on endpoint sensitivity and specificity. Note: FDA Responder Endpoint criterion is 30%. Pooled IBS-C Phase 3 ITT population.

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Fig. 1B illustrates the impact on sensitivity, specificity, and accuracy of variations on the FDA Responder Endpoint in which the weekly Abdominal Pain criterion (i.e., ≥30% improvement) is modified. Increasing the mean percentage improvement in weekly Abdominal Pain requirement beyond the 30% required for the FDA Responder Endpoint threshold results in small increases in specificity while decreasing both sensitivity and accuracy. For example, at the 50% reduction in Abdominal Pain threshold, the specificity increases slightly to 97.0%, but the sensitivity and accuracy decrease to 47.1% and 79.5%, respectively (Fig. 1B).

Table 3 reports the sensitivity, specificity, and accuracy of variations on the FDA Responder Endpoint in which the weekly CSBM Frequency criterion is modified from an increase of ≥1 CSBM to ≥2 or ≥3. The accuracy is lower for both the ≥2 and ≥3 CSBM criteria (79.6% and 76.4% accuracy, respectively) compared with the ≥1 CSBM criterion (82.0% accuracy). In addition, the sensitivity notably decreases when increasing the CSBM criterion, whereas the specificity only slightly increases (Table 3).

Table 3. Variations on the FDA Responder Endpoint: impact of varying the weekly increase in CSBM criterion on endpoint sensitivity and specificity
Endpoint (Criterion)aSensitivitySpecificityAccuracy
  1. Pooled IBS-C Phase 3 ITT Population.

  2. a

    Abdominal Pain and CSBM criteria must be met in the same week for at least 50% of the treatment weeks.

Improvement of ≥30% Abdominal Pain + ≥1 increase in CSBM per week (FDA Responder Endpoint)60.7% (342/563)93.5% (971/1039)82.0% (1313/1602)
Improvement of ≥30% Abdominal Pain + ≥2 increase in CSBM per week47.6% (268/563)96.9% (1007/1039)79.3% (1275/1602)
Improvement of ≥30% Abdominal Pain + ≥3 increase in CSBM per week35.7% (201/563)98.5% (1023/1039)76.4% (1224/1602)

Distribution of results by treatment group

While the results described above have evaluated the entire ITT Population (placebo and linaclotide) from the two Phase 3 clinical trials, Table 4 presents the results of the FDA Responder Endpoint by treatment group (i.e., linaclotide 290 μg or placebo). The responder rate for the linaclotide treatment group was 33.7%, as compared to 17.4% for the placebo group (P < 0.0001).

Table 4. FDA Responder Endpoint results for linaclotide and placebo treatment groups
FDA Responder EndpointaPlaceboLinaclotide 290 μgDifference
  1. Pooled IBS-C Phase 3 ITT Population.

  2. a

    The FDA Responder Endpoint for IBS-C trials defines a responder as a patient who, during the same week for at least 50% of the weeks of a Treatment Period (i.e., 6 of 12 weeks), reports: (i) an improvement of ≥30% from baseline in the average of the daily worst Abdominal Pain score and (ii) an increase of ≥1 CSBM from baseline.

Percentage of responders17.4% (139/797)33.7% (271/805)16.2%, P < 0.0001
95% Confidence interval14.9%–20.3%30.4%–37.0%12.0%–20.4%

Fig. 2 shows the distribution of patients achieving increasing levels of percent improvement from baseline in Abdominal Pain (Fig. 2A) and increases in weekly CSBM rates (Fig. 2B) by treatment group for at least 6 of the first 12 weeks of the Treatment Period. These figures show a clear and consistent separation of linaclotide over placebo across the entire range of responses presented.

image

Figure 2. Percentage of patients with specified improvements in Abdominal Pain and CSBM frequency for at least 6 of the first 12 weeks of treatment in Phase 3 IBS-C trials, by treatment group. Note: pooled IBS-C Phase 3 ITT population. P < 0.0001 comparing linaclotide with placebo at each threshold. (A) Abdominal pain. (B) CSBM frequency.

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Using pooled data from two Phase 3 linaclotide clinical trials in IBS-C patients, we employed anchor-based methods which ‘anchor’ or map a difference score onto specific level(s) of patient-reported improvement to estimate thresholds of clinically meaningful change from baseline for reduction in Abdominal Pain and increase in weekly CSBMs. Clinically meaningful change thresholds should ideally be the smallest difference in the domain of interest which patients perceive as beneficial. The threshold for clinically meaningful change used in these trials was patients reporting on average ‘somewhat relieved/improved’ answers to the PRCQs for Abdominal Pain Relief, CSBM Frequency Improvement, and Degree of Relief of IBS Symptoms, or an improvement of one point on a 5-point scale for the Current Severity Items (IBS and Constipation Symptom Severity). Thresholds for clinically meaningful change were similar among all methods used in these analyses. Anchor-based approaches have commonly been used to determine clinically meaningful change in clinical studies, and are generally considered to be superior to distribution-based methods.[12, 13] Our threshold estimates using anchor-based methods for clinically meaningful change in Abdominal Pain (i.e., 25.8% and 27.6% for the PRCQs, and 30.4% and 28.4% for the Current Severity Items) and weekly CSBM Frequency (i.e., ranging from 0.5 to 1.4 for the PRCQs, and 0.5 to 1.5 for the Current Severity Items) provide evidence to support the clinical relevance of the current FDA Responder Endpoint (i.e., a 30% decrease in Abdominal Pain and an increase of ≥1 CSBM for 6 of 12 weeks). Interestingly, an analysis conducted across 10 studies of other chronic pain conditions also has shown that a 30% change on a 0–10 numerical rating scale has also been associated with a clinically meaningful change, using a similar, patient-based rating scale. An analysis of the use of a numerical rating scale for Abdominal Pain in IBS produced similar results.[16].

We found the FDA Responder Endpoint to be somewhat conservative, in that the specificity was high (i.e., 93.5%) and the sensitivity moderate (i.e., 60.7%). Consistent with this endpoint being conservative, when the stricter criterion of ‘considerably relieved/improved’ was used as the PRCQ threshold for defining improvement, the specificity was lower (80.1%) and the sensitivity was higher by approximately the same magnitude (84.7%). Given the chronic non-life-threatening nature of IBS-C, a higher specificity, even if associated with a lower sensitivity, may be a desirable property for a primary endpoint of a clinical trial, thereby ensuring that there is relative certainty that patients meeting the endpoint have experienced a clinically meaningful benefit. However, it needs to be acknowledged that there will be patients who experience benefit who do not meet the FDA Responder Endpoint.

The impact of modifying the criteria requirements of the FDA Responder Endpoint was examined [i.e., the number of weeks needed to meet this endpoint (6 of 12 weeks), the weekly Abdominal Pain improvement of at least 30%, and the weekly increase in CSBMs of at least one per week]. We found that the current FDA Responder Endpoint appears to be an appropriate endpoint for clinical trials. In the case of the number of weeks requirement (i.e., at least 6 of 12 weeks), increasing the number of weeks criterion beyond at least 6 weeks resulted in only slightly increasing specificity whereas greatly decreasing sensitivity. The accuracy when varying the number of weeks criterion was maximized when requiring patients to be responders for at least 5 weeks; however, this accuracy was only slightly higher than that for the FDA's requirement of at least 6 of 12 weeks. In addition, the results of the analyses varying the Abdominal Pain and CSBM weekly criteria indicate no benefit to modifying the current FDA weekly responder criteria of a ≥ 30% reduction in Abdominal Pain and an increase of ≥1 CSBMs. For both of these criteria, increasing the threshold results in decreases in sensitivity and accuracy with only slight increases in specificity.

In summary, this study suggests that the current FDA Responder Endpoint for IBS-C clinical trials represents clinically meaningful improvements in IBS-C symptoms for patients with excellent specificity and reasonable sensitivity.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Jacquelyn Cronin of Ironwood Pharmaceuticals provided medical writing support for this manuscript.

Funding

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

This trial was funded by Forest Research Institute and Ironwood Pharmaceuticals, Inc. RTI received financial support from Forest Research Institute and Ironwood Pharmaceuticals for these analyses.

Disclosure

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Jeffrey Johnston, James MacDougall, Bernard Lavins, Caroline Kurtz, Mollie Baird, and Mark Currie are employees of Ironwood Pharmaceuticals and own stock/stock options in Ironwood Pharmaceuticals. Robyn Carson, Steven Shiff, and Kelvin Shi are employees of Forest Laboratories and own stock/stock options in Forest Laboratories. Anthony Lembo is a paid consultant to Ironwood Pharmaceuticals and Forest Laboratories. Valerie Williams and Lauren Nelson are paid consultants to Ironwood Pharmaceuticals and Forest Laboratories.

Author Contribution

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References

Analyses were designed by JEM, KS, LMN, and VSLW. Data were interpreted by JEM, KS, LMN, VSLW, JMJ, BJL, RTC, SJS, CBK, MJB, MGC, and AJL. AJL wrote the manuscript. All authors provided critical review of the manuscript. All authors approved the submitted version of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Funding
  8. Disclosure
  9. Author Contribution
  10. References