Chronic Intestinal Pseudo-obstruction
Conditions
Brief summary
This is a phase II, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of velusetrag once a day, compared to placebo, in subjects with CIPO.
Interventions
DRUGVelusetrag 15 mg once daily for 4 weeks.
Subjects will be randomly allocated in a blinded fashion to 1 out of the 4 treatment sequences (each sequence include 4 periods, 2 periods with velusetrag and 2 periods with placebo). There will be a wash-out period between each treatment period.
DRUGPlacebo once daily for 4 weeks.
Subjects will be randomly allocated in a blinded fashion to 1 out of the 4 treatment sequences (each sequence include 4 periods, 2 periods with velusetrag and 2 periods with placebo). There will be a wash-out period between each treatment period.
Sponsors
Alfasigma S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with history of chronic idiopathic intestinal pseudo-obstruction or CIPO secondary to neurodegenerative or demyelinating disease. * Subjects with estimated oral caloric intake of at least 30% of the daily age- and sex-recommended caloric intake. * Subjects with at least 2 out of 4 CIPO gastrointestinal symptoms each of the 2 with a score ≥3 (on a 0 to 4 scale) at Day -1 * Subjects accepting to provide and legally capable of providing free and informed consent to all procedures included in the protocol. * All sexually active male participants who are partner of women of childbearing potential must use condom during intercourse until the 90th day after the end of the entire study. * Female participants are eligible if they are: i) of non-childbearing potential or ii) of childbearing potential with a negative pregnancy test result at screening and randomization AND agreeing to use a highly effective method of contraception (i.e., with failure rate of less than 1% per year) until the end of the entire study.
Exclusion criteria
* Subjects with primary CIPO or CIPO secondary to other known endocrine/metabolic, autoimmune diseases and neurologic conditions other than neurodegenerative or demyelinating diseases. * Subjects with conditions characterized by mechanical intestinal obstruction. * Nasogastric tube, gastrostomy tube, or jejunostomy feeding tube in place at randomization or planned throughout the duration of the study, or artificial food need scale stage 3. * Presence of untreated clinically relevant thyroid dysfunction or known thyroid dysfunction not well controlled by treatment deemed clinically significant by the Investigator. * Subjects with history of diabetes at screening. * Clinically significant ECG abnormalities at screening and randomization. * Screening ECG with a QTcF \>450 msec in males or \>470 msec in females or family history of sudden cardiac death. * Subjects requiring a low galactose diet. * Hypersensitivity or documented intolerance to lactulose, lactose or any excipient of the lactulose preparation to be used for L-BT. * History of sensitivity to velusetrag, or any of the velusetrag or placebo excipients. * Use of scopolamine or erythromycin within 2 weeks prior to screening and/or planned throughout the duration of the study. * Use of 5-HT4 receptor agonists within 5 days prior to randomization and/or planned throughout the duration of the study * Use of opioids within 8 weeks from screening and/or planned throughout the duration of the study. * Received strong cytochrome P450-isozyme 3A4 (CYP3A4) inhibitors within 2 weeks prior to screening and/or planned throughout the duration of the study. * Received strong P-glycoprotein (P-gp) transporter inhibitors within 2 weeks prior to Screening and/or planned throughout the duration of the study. * Received strong breast cancer resistance protein transporter inhibitors within 2 weeks prior to screening and/or planned throughout the duration of the study. * Current swab-positive or suspected (under investigation) COVID-19 infection. * Cancer (excluding non-melanoma skin cancer) and/or need of any anti-cancer treatment (also including radiotherapy) within the last 5 years. * Severe kidney impairment. * Aspartate aminotransferase (AST) or alanine transaminase (ALT) levels \>2.5 times the upper limit of normal (ULN); bilirubin (unless deemed to be due to Gilbert's Syndrome) or alkaline phosphatase (ALP) \>1.5 times ULN. * Severe hepatic impairment defined as Child-Pugh C. * History of any of the following cardiac disorders: i) torsade de pointes, ventricular tachycardia, ventricular fibrillation; ii) previous myocardial infarction, unstable angina pectoris, acute coronary syndrome, coronary artery or cerebral revascularization procedure or stroke within the previous 18 months; iii) angina pectoris class 2-4 during the last 12 months prior to screening; iv) congestive heart failure NYHA class III-IV during the last 18 months prior to screening. * History of any alcohol or drug abuse or dependence within the last year (Investigator's judgement). * Any current significant health condition that in the Investigator's judgement may: i) jeopardize the patient's safe participation in the trial or ii) make unlikely the patient's completion of the study or iii) make unlikely the patient's compliance with the study procedures. * Pregnant or breastfeeding woman. * Use of any experimental drug within 12 weeks prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Weekly Global Gastrointestinal Symptoms Average Index Score (WGGSAIS). | 4 weeks. The change is derived as the end of treatment period minus the pre-treatment value of the period, for each period. | Mean change in weekly global gastrointestinal symptoms average index score (WGGSAIS) from pretreatment (PRE) to the end of each treatment period (EOT). The weekly global gastrointestinal symptoms average index score is obtained by averaging the scores for each of the 4 symptoms, abdominal pain, bloating, nausea and vomiting, assessed using a subject's e-diary. Each symptom was rated using a recall period of 7 days and a Likert scale with the following categories: 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe according to its influence on usual activity. The WGGSAIS thus ranges between 0 and 4 with lower scores representing better health. |
Countries
Belgium, Italy, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall demographic characteristics are summarized descriptively overall | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 57.5 years STANDARD_DEVIATION 10.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment Italy | 11 participants |
| Region of Enrollment Spain | 6 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 7 / 17 | 10 / 17 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 |
Outcome results
Primary
Mean Change in Weekly Global Gastrointestinal Symptoms Average Index Score (WGGSAIS).
Mean change in weekly global gastrointestinal symptoms average index score (WGGSAIS) from pretreatment (PRE) to the end of each treatment period (EOT). The weekly global gastrointestinal symptoms average index score is obtained by averaging the scores for each of the 4 symptoms, abdominal pain, bloating, nausea and vomiting, assessed using a subject's e-diary. Each symptom was rated using a recall period of 7 days and a Likert scale with the following categories: 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe according to its influence on usual activity. The WGGSAIS thus ranges between 0 and 4 with lower scores representing better health.
Time frame: 4 weeks. The change is derived as the end of treatment period minus the pre-treatment value of the period, for each period.
Population: Modified Full Analysis Set 1 (mFAS1): the set of subjects responder/naïve to 5-HT4 agonist randomized and treated who reported data on the primary endpoint at least once during a velusetrag treatment period and at least once during a placebo treatment period. Arms were not mutually exclusive.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Modified Full Analysis Set 1 Velusetrag | Mean Change in Weekly Global Gastrointestinal Symptoms Average Index Score (WGGSAIS). | -0.424 score | Standard Deviation 0.6926 |
| Modified Full Analysis Set 1 Placebo | Mean Change in Weekly Global Gastrointestinal Symptoms Average Index Score (WGGSAIS). | -0.185 score | Standard Deviation 0.6876 |
Comparison: Subjects in this analysis are 15 and not 30 (this happens because arms are not mutually exclusive, as explained in previous sections). Each subject can contribute with 0, 1, 2 pairs. Only data that constitute pairs evaluable for primary endpoint are considered in the analysis; the pairs evaluable for primary endpoint were 23.p-value: =0.127995% CI: [-0.553, 0.074]paired T-test