Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders

In these post hoc analyses, data from the clinical development program for each indication (Table 1; Figure S1) were combined. Only data for patients assigned to receive placebo or the currently approved doses of lubiprostone were included in the present analyses (Figure S1). All randomized controlled trials (RCTs) analyzed in these post hoc analyses fulfilled criteria on the Jadad scale assessing the quality of studies [17]. For CIC treatment, data were from six studies. Three of the CIC studies were randomized, double-blind, placebo-controlled trials lasting 3–4 weeks [5, 7, 8], and two were open-label 24- and 48-week extension studies [9, 10]. The sixth CIC study included 4 weeks of active treatment, a 3-week randomized withdrawal, and a 48-week open-label period [6]. Lubiprostone was administered at 24 mcg BID in all of the studies except the 3-week study, in which patients were treated with 24, 48, or 72 mcg (total dose). For OIC treatment, data were from three randomized, double-blind, 12-week, placebo-controlled studies (registered on ClinicalTrials.gov as NCT01298219 [11], NCT00595946, and NCT00597428) and one 36-week open-label extension study (NCT00620061) [16]. In all of these OIC studies, patients were treated with 24 mcg BID lubiprostone. For IBS-C treatment, data were from three randomized, double-blind, 12-week, placebo-controlled studies (NCT00380250 and NCT00399542 [13], and a third study [14]) and one 36-week open-label extension study (continuation of NCT00380250 and NCT00399542) [15]. In one of the IBS-C studies [14], patients were treated orally with 8, 16, or 24 mcg BID lubiprostone; the treatment dose was 8 mcg BID in all of the other studies. In all of the studies, patients were instructed to take their medications with the morning and evening meals.

Patient criteria specific to the clinical studies have been described previously [5‐16]. In all of the lubiprostone development programs (CIC, OIC, and IBS-C), patients were required to be ≥18 years of age and to meet criteria with respect to the maximum weekly frequency of spontaneous bowel movements (SBMs) and symptoms of constipation. “Spontaneous” was defined as a bowel movement occurring without the use of laxatives or stool softeners within the prior 24-h period. Signs and symptoms of constipation comprised ≥1 of the following, which had to be present for ≥25% of the SBMs during each week of the baseline washout period: hard or very hard stools, sensation of incomplete evacuation (for CIC and OIC studies), and/or moderate to very severe straining associated with the SBMs. Exclusion criteria included documented mechanical obstruction; organic bowel disorders; constipation secondary to a documented cause; clinically significant cardiovascular, liver, lung, neurologic, or psychiatric disorder; or significant laboratory abnormalities.

Patients in the CIC studies had a documented history of constipation and, during the baseline washout period, <3 SBMs per week and signs and symptoms of constipation. Patients in the OIC studies had chronic non-cancer-related pain being treated consistently with an opioid for ≥30 days before the baseline washout and that would require continued opioid treatment during the study. Patients had <3 SBMs per week and signs and symptoms of constipation during the baseline washout period. Patients with a history of chronic constipation (≥90 days) could be included if they experienced an exacerbation in constipation after the initiation of opioid therapy. Patients receiving opioid treatment for cancer-related pain, abdominal pain, or scleroderma, or for the management of drug addiction were excluded. “Study 1” (NCT01298219) in patients with OIC excluded patients who were receiving opioids of the diphenylheptane class (e.g., methadone). Specific inclusion criteria for IBS-C studies were that patients meet Rome II Diagnostic Criteria for IBS assessed using the Rome II Modular Questionnaire Criteria for IBS, have abdominal discomfort/pain of at least mild severity, and experience any two of the following: <3 SBMs per week ≥25% of the time, ≥25% of SBMs associated with moderate or greater straining, and ≥25% of SBMs associated with hard or very hard stool consistency. For two of the studies, patients with no SBMs during the baseline period did not have to meet the straining or stool consistency criteria. Patients were excluded from the IBS-C studies if they had diarrhea-predominant or alternating IBS, certain gastrointestinal or abdominal surgeries, known or suspected organic disorders of the small or large bowel, mechanical bowel obstruction or pseudo-obstruction, significant unexplained weight loss, unexplained rectal bleeding, and/or a diagnosis of constipation other than IBS.

Adverse events were noted and recorded at each study visit. Nausea was considered a treatment-emergent AE if it occurred after the initiation of treatment in patients without nausea at baseline or if it was present at baseline and subsequently worsened. The incidence, severity (mild, moderate, and severe), and duration of treatment-emergent AEs of nausea were categorized, as well as whether the events of nausea were associated with study discontinuation. The prebaseline nausea profile for patients in each of the three indications was determined by medical history and use of concomitant medications.

Patients who entered the treatment period of a specific study and received ≥1 dose of study medication were included in the analyzed study population. Data were pooled in two ways: data from RCTs only and “all trials.” Only patients who received lubiprostone were included in the “all trials” analyses, because comparisons between placebo and active treatment for “all trials” would be inappropriate due to the substantially shorter exposure to placebo compared with lubiprostone administered in open-label extension studies. The incidence of nausea was summarized descriptively, and differences between the placebo and lubiprostone groups were determined by the Fisher’s exact test for the RCT analyses only. A Cox proportional hazards regression model was used for analysis of incidence rates for the time to the first occurrence of nausea in RCTs for each indication. Categorical variables analyzed for their effects on the Cox proportional hazard ratios included treatment (active vs placebo), age (≥65 vs <65 years), and sex. Kaplan–Meier analysis was used to evaluate the cumulative occurrence of nausea AEs over time. Conditions that could predispose patients to nausea [18] were coded using standard preferred terms and used to search patient medical history.

A summary of analyzed populations is listed in Table 2. The RCT CIC study population consisted of 240 patients who received placebo and 239 who received lubiprostone (24 mcg BID); for OIC, 652 and 663 patients, respectively, received those treatments. For IBS-C, the 832 patients in the lubiprostone group received an 8-mcg BID dose and 435 received placebo. The “all trials” populations consisted of 1113 patients with CIC, 889 with OIC, and 1011 with IBS-C. Most patients in each clinical development program were women.

For each indication, the percentages of patients in RCTs reporting nausea at baseline or who had received treatment for nausea before randomization were statistically similar between patients who received placebo and lubiprostone. However, patients with OIC had a higher incidence of pretreatment nausea than those with CIC or IBS-C (Table 2).

The crude incidence of treatment-emergent nausea in the RCT populations was significantly higher in patients who received lubiprostone (24 mcg BID for CIC and OIC; 8 mcg BID for IBS-C) compared with placebo for each indication (CIC, 29.3 vs 6.3%, respectively; OIC, 13.4 vs 6.4%; IBS-C, 10.9 vs 6.4%; Table 2). The crude incidences of nausea in the RCT and “all trials” lubiprostone-treated patients were similar within each indication (Table 2).

For CIC analysis, the percentages of patients in RCTs reporting mild, moderate, and severe nausea were significantly higher with lubiprostone (24 mcg BID) than placebo (19.2 vs 3.3%, 7.9 vs 2.9%, and 2.1 vs 0%, respectively; Table 2). For the OIC analysis, the percentages of patients in RCTs reporting mild (8.0 vs 3.7%) and moderate (4.4 vs 1.7%), but not severe (1.1 vs 1.1%) nausea, were significantly higher for lubiprostone (24 mcg BID) compared with placebo. For IBS-C analysis, the percentage of patients in RCTs reporting moderate nausea was significantly higher with lubiprostone (8 mcg BID) than placebo (4.0 vs 1.4%), but the percentages of patients reporting mild or severe nausea were similar (6.4 vs 4.8% and 0.6 vs 0.2%, respectively). In the “all trials” CIC population, who were treated with lubiprostone for longer periods, incidences of moderate and severe nausea were slightly higher than observed for RCTs. Similar incidences of mild, moderate, and severe nausea were observed in the lubiprostone-treated “all trials” OIC population compared with the RCT population. The lubiprostone-treated “all trials” IBS-C population reported similar nausea rates by severity compared with the RCT population.

The percentage of patients discontinuing treatment owing to nausea in RCTs was low but significantly greater in patients who received lubiprostone 24 mcg BID compared with placebo in the CIC and OIC studies. On the other hand, patients who received lubiprostone 8 mcg BID had similar rates of discontinuation to placebo (Table 2). In the CIC and IBS-C studies, no AEs of nausea met the criteria to be considered as serious events (e.g., hospitalization). In the OIC studies, one patient treated with lubiprostone experienced a serious AE of nausea; however, this event was considered unrelated to study medication by the study investigator.

In patients who reported severe nausea, 40–80% of patients in each group had a history of medical conditions predisposing them to nausea, though few had a medical history of preexisting nausea (Table 3). Discontinuations due to severe nausea were more common in the longer “all trials” analysis of lubiprostone than in the shorter RCTs.

Among lubiprostone-treated patients in the “all trials” populations who reported any AE of nausea (CIC [24 mcg BID], n = 346; OIC [24 mcg BID], n = 124; IBS-C [(8 mcg BID], n = 115), 83.5–88.7% reported only one nausea event (Fig. 1a–c). More than 70% (70.7–73.8%) of patients reporting a single event of nausea who did not have a dose adjustment completed the full treatment period. Across the three indications, 8.3–17.7% of patients who reported a single nausea event required lubiprostone dose reduction to once daily or a temporary interruption of lubiprostone treatment, which allowed the majority of these patients to complete the full treatment period. Among patients who reported ≥1 event of nausea (CIC, n = 69; OIC, n = 18; IBS-C, n = 10), 55% with CIC, 78% with OIC, and 100% with IBS-C remained in the study.

In the “all trials” population, 64.3% of overall nausea events (393/611) occurred during the first 5 days of treatment with lubiprostone (CIC, 77.2% [267/346]; OIC, 45.2% [56/124]; IBS-C, 49.6% [70/141]). In RCTs, the median (range) for the first report of nausea was 2 (1–27), 5 (1–84), and 3 (1–90) days for the CIC, OIC, and IBS-C studies, respectively (Fig. 2). Median values for the first report of nausea in the long-term extension studies ranged from 2 to 8.5 days.

In the CIC, OIC, and IBS-C RCTs, comparisons between patients who received lubiprostone or placebo found that nausea rates were not significantly different between women or men, or for those aged <65 or ≥65 years of age or with body mass index (BMI) <25 or ≥25 (all P values >0.394; Table 4). Rates of severe nausea were low overall. Rates of nausea by sex, age, and BMI were also analyzed within the group of patients in RCTs who received lubiprostone treatment. In patients with CIC who received lubiprostone, a significantly higher rate of nausea was observed in women compared with men (P = 0.007), and in patients aged <65 versus ≥65 years of age (P = 0.028) (Table 4). There were no significant differences in the rates of severe nausea in any of these subgroups. In patients with OIC who received lubiprostone, there were no significant differences in the rates of nausea by sex, age group, or BMI, although there was a significantly higher rate (P = 0.050) of severe nausea in women compared with men (Table 4). In patients with IBS-C who received lubiprostone, the rates of nausea (P = 0.0140) and severe nausea (P = 0.0160) were significantly higher in patients with BMI <25 compared with those with BMI ≥25 (Table 4).