Safety Study of CB-5945 for the Treatment of Opioid-Induced Constipation

A TEAE was defined as any adverse event (AE) that occurred from the time of first dose of the study drug through the last study evaluation or pre-existing AEs that were aggravated in severity or frequency during the dosing period. The percentages of participants with at least 1 TEAE, with at least 1 drug-related TEAE (drug-related included possibly related or related as deemed by the Investigator; it also included events if causality was missing), and who discontinued from treatment due to a TEAE are presented. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Time frame: Baseline through Week 56

Population: All randomized participants who received at least 1 dose of study drug. Two participants were randomized to the Placebo Arm but were administered CB-5945 instead. As a result, these 2 participants were included in the CB-5945 Arm for analysis.

Throughout the study, participants were asked to record changes in maintenance opioid consumption and use of opioid analgesics for breakthrough or exacerbation of pain in a paper diary. Opioid consumption (including rescue opioids) of each participant was converted to an oral morphine-equivalent total daily dose (METDD). Opioid consumption (in milligrams of METDD) was summarized in 4-week intervals. The change from baseline to Weeks 49-52 is summarized.

Time frame: Baseline, Weeks 49-52

Population: All randomized participants who received at least 1 dose of study drug and had evaluable METDD data. Two participants were randomized to the Placebo Arm but were administered CB-5945 instead. As a result, these 2 participants were included in the CB-5945 Arm for analysis.

The PAC-QOL questionnaire contains a total of 28 items, each rated within 4 subscales: physical discomfort, psychosocial discomfort, worries and concerns, and satisfaction. Each item was rated on a 5-point Likert scale with the following score definitions, depending on the question: 0 = not at all (or none of the time), 1 = a little bit (or a little of the time), 2 = moderately (or some of the time), 3 = quite a bit (or most of the time), and 4 = extremely (or all of the time). The total score is the mean of all non-missing items. The range of the total score is 0 (response is 'not at all' for each item) to 4 (response is 'extremely' for each item). Negative change from baseline values indicate improvement in constipation quality of life. Each participant completed the PAC-QOL at Baseline and Week 52 using a 2-week recall period.

Time frame: Baseline, Week 52

Population: All randomized participants who received at least 1 dose of study drug and had evaluable PAC-QOL data. Two participants were randomized to the Placebo Arm but were administered CB-5945 instead. As a result, these 2 participants were included in the CB-5945 Arm for analysis.

The PCSA asked participants to rate the severity of their overall constipation during the 24 hours prior to the assessment, using a scale of 0 to 10, where 0 is no constipation and 10 is the worst constipation imaginable.

Time frame: Baseline, Week 52

Population: All randomized participants who received at least 1 dose of study drug and had evaluable PCSA data. Two participants were randomized to the Placebo Arm but were administered CB-5945 instead. As a result, these 2 participants were included in the CB-5945 Arm for analysis.

Blood samples for trough concentrations of CB-5945 were collected before the participant's morning dose of study drug at Weeks 4, 12, 24, 36, and 52. Overall concentration was based on the mean trough level for each participant across all weeks.

Time frame: Weeks 4, 12, 24, 36, and 52

Population: All participants randomized to CB-5945 who received at least 1 dose of study drug and had evaluable CB-5945 concentration data. Two participants were randomized to the Placebo Arm but were administered CB-5945 instead. As a result, these 2 participants were included in the CB-5945 Arm for analysis.

Cardiovascular (CV) events of interested included mycardial infarction, unstable angina, CV accident, congestive heart failure, serious arrhythmia, resuscitated cardiac arrest, and death. Gastrointestinal (GI) events of interest included emergency department visits for the serious adverse events of gastroenteritis, hepatitis, pancreatitis, nausea, vomiting, diarrhea, and abdominal pain or cramping. Central opioid withdrawal (OW) events of interest included opioid withdrawal syndrome. The adverse events that indicated central OW included, but were not limited to, hyperhidrosis, tremor, dysphoria, and myalgia. The number of participants with at least 1 confirmed CV, GI, or Central OW event is presented.

Time frame: Baseline through Week 56

Population: All randomized participants who received at least 1 dose of study drug. Two participants were randomized to the Placebo Arm but were administered CB-5945 instead. As a result, these 2 participants were included in the CB-5945 Arm for analysis.