Gastroesophageal Reflux Disease
Conditions
Brief summary
The aim of this study is to establish a dose-related effect of a selective 5-HT4 receptor agonist compared to placebo on residual symptoms (regurgitation with or without heartburn) in subjects with GERD who have persistent symptoms while on PPI therapy.
Interventions
DRUGSSP-002358 (0.1 mg) + PPI
0.1 mg tablet three times daily (t.i.d.) taken in addition to a PPI
DRUGSSP-002358 (0.5 mg) + PPI
0.5 mg tablet t.i.d. taken in addition to a PPI
DRUGSSP-002358 (2.0 mg) + PPI
2.0 mg tablet t.i.d. taken in addition to a PPI
DRUGPlacebo + PPI
Placebo t.i.d. taken in addition to a PPI
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Written Informed Consent Form signed voluntarily before the first study-related activity. 2. Aged between 18 and 70 years, inclusive. 3. Subjects with a history of the cardinal symptoms of GERD (both heartburn and regurgitation) prior to PPI therapy. 4. Subjects with symptoms of GERD for at least 6 months prior to the Screening Visit. 5. Subjects who have persistent symptoms of regurgitation for 3 or more days over the past week with or without heartburn while on PPI. 6. Subjects have at least some improvement to the symptom of heartburn while on PPI therapy. 7. Subjects on PPI therapy for at least 8 weeks prior to the Screening Visit of which the last 4 weeks are on a stable labeled dose for any GERD indication according to the country label, where a change of PPI therapy would not impact the symptoms (twice-daily dosing of PPI is not allowed in the last 4 weeks)
Exclusion criteria
1. Subjects who show no response to heartburn while on PPI therapy. 2. Subjects with dyspepsia symptoms that are more predominant than their GERD symptoms (heartburn and/or regurgitation). 3. Subjects with prior endoscopic anti-reflux procedure or major GI surgery or subjects with major GI disorders. 4. Presence of severe and clinically uncontrolled cardiovascular, liver, lung or neurologic disease, cancer or AIDS. 5. Alarm symptoms suggestive of malignancies or organic disease.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Percent Regurgitation-Free Days Over Weeks 5-8 | Baseline and over weeks 5-8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Heartburn-Free Days Over Weeks 5-8 | Baseline and over weeks 5-8 | — |
| Change From Baseline in the Persistent Reflux Integrated Symptom Measurement (PRISM) Liquid and Food Domain Scores Over Weeks 5-8 | Baseline and over weeks 5-8 | PRISM is a 21 item patient-reported outcome instrument with 4 domains. Items are scored using various scales. Total score ranges from 0-100. Higher scores indicate more severe or frequent symptoms. |
| Area Under the Steady-state Plasma Concentration-time Curve (AUC) of SSP-002358 | Over 8 hours post-dose (week 2 or later) | Area under the plasma concentration versus time curve can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. |
| Steady State Maximum Plasma Concentration (Cmax) of SSP-002358 | Over 8 hours post-dose (week 2 or later) | Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administered. |
| Time to Maximum Plasma Concentration (Tmax) of SSP-002358 | Over 8 hours post-dose (week 2 or later) | — |
Countries
Czechia, Germany, Latvia, Poland, Romania, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo + PPI Placebo taken three times daily (TID) in addition to a PPI | 122 |
| SSP-002358 0.1mg + PPI 0.1 mg tablet taken TID in addition to a PPI | 119 |
| SSP-002358 0.5mg + PPI 0.5 mg tablet taken TID in addition to a PPI | 118 |
| SSP-002358 2.0mg + PPI 2.0 mg tablet taken TID in addition to a PPI | 118 |
| Total | 477 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 | 7 | 14 |
| Overall Study | Clinically Significant Pre-Dose ECG | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 0 | 2 | 0 |
| Overall Study | Prohibited Medication | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 3 | 3 | 0 | 1 |
| Overall Study | Withdrawal By PI | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 3 | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo + PPI | SSP-002358 0.1mg + PPI | SSP-002358 0.5mg + PPI | SSP-002358 2.0mg + PPI | Total |
|---|---|---|---|---|---|
| Age, Continuous | 46.2 Years STANDARD_DEVIATION 12.1 | 48.8 Years STANDARD_DEVIATION 12.59 | 49.2 Years STANDARD_DEVIATION 12.31 | 47.6 Years STANDARD_DEVIATION 11.3 | 47.9 Years STANDARD_DEVIATION 12.11 |
| Age, Customized 18 - 40 | 40 Participants | 35 Participants | 29 Participants | 32 Participants | 136 Participants |
| Age, Customized 41 - 50 | 35 Participants | 23 Participants | 32 Participants | 32 Participants | 122 Participants |
| Age, Customized 51 - 65 | 41 Participants | 52 Participants | 49 Participants | 51 Participants | 193 Participants |
| Age, Customized >65 | 6 Participants | 9 Participants | 8 Participants | 3 Participants | 26 Participants |
| Region of Enrollment CZECH REPUBLIC | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Region of Enrollment FRANCE | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 7 Participants |
| Region of Enrollment GERMANY | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 17 Participants |
| Region of Enrollment HUNGARY | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 7 Participants |
| Region of Enrollment LATVIA | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 17 Participants |
| Region of Enrollment POLAND | 6 Participants | 7 Participants | 7 Participants | 8 Participants | 28 Participants |
| Region of Enrollment ROMANIA | 9 Participants | 8 Participants | 8 Participants | 8 Participants | 33 Participants |
| Region of Enrollment UNITED STATES | 92 Participants | 92 Participants | 92 Participants | 91 Participants | 367 Participants |
| Sex: Female, Male Female | 74 Participants | 78 Participants | 72 Participants | 65 Participants | 289 Participants |
| Sex: Female, Male Male | 48 Participants | 41 Participants | 46 Participants | 53 Participants | 188 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 122 | 22 / 119 | 35 / 118 | 45 / 118 |
| serious Total, serious adverse events | 0 / 122 | 0 / 119 | 0 / 118 | 1 / 118 |
Outcome results
Primary
Change From Baseline in Percent Regurgitation-Free Days Over Weeks 5-8
Time frame: Baseline and over weeks 5-8
Population: Full Analysis Set consisted of all subjects in the Safety Analysis Set who had at least 1 post-baseline value for the primary efficacy assessment. Safety Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + PPI | Change From Baseline in Percent Regurgitation-Free Days Over Weeks 5-8 | 36.96 percentage of days | Standard Error 3.598 |
| SSP-002358 0.1mg + PPI | Change From Baseline in Percent Regurgitation-Free Days Over Weeks 5-8 | 43.01 percentage of days | Standard Error 3.678 |
| SSP-002358 0.5mg + PPI | Change From Baseline in Percent Regurgitation-Free Days Over Weeks 5-8 | 44.37 percentage of days | Standard Error 3.667 |
| SSP-002358 2.0mg + PPI | Change From Baseline in Percent Regurgitation-Free Days Over Weeks 5-8 | 38.79 percentage of days | Standard Error 3.728 |
p-value: 0.12895% CI: [-1.743, 13.862]Mixed Models Repeated Measures Analysis
p-value: 0.06295% CI: [-0.378, 15.212]Mixed Models Repeated Measures Analysis
p-value: 0.6595% CI: [-6.1, 9.765]Mixed Models Repeated Measures Analysis
Secondary
Area Under the Steady-state Plasma Concentration-time Curve (AUC) of SSP-002358
Area under the plasma concentration versus time curve can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.
Time frame: Over 8 hours post-dose (week 2 or later)
Population: Full Pharmacokinetic Subset consisted of a subset of subjects who underwent the detailed pharmacokinetic assessments. Subjects who vomited within the blood sampling period may have been excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + PPI | Area Under the Steady-state Plasma Concentration-time Curve (AUC) of SSP-002358 | 1650 pg*h/ml | Standard Deviation 729 |
| SSP-002358 0.1mg + PPI | Area Under the Steady-state Plasma Concentration-time Curve (AUC) of SSP-002358 | 8352 pg*h/ml | Standard Deviation 2564 |
| SSP-002358 0.5mg + PPI | Area Under the Steady-state Plasma Concentration-time Curve (AUC) of SSP-002358 | 42613 pg*h/ml | Standard Deviation 4971 |
Secondary
Change From Baseline in Heartburn-Free Days Over Weeks 5-8
Time frame: Baseline and over weeks 5-8
Population: Full Analysis Set consisted of all subjects in the Safety Analysis Set who had at least 1 post-baseline value for the primary efficacy assessment. Safety Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + PPI | Change From Baseline in Heartburn-Free Days Over Weeks 5-8 | 21.76 percentage of days | Standard Error 3.623 |
| SSP-002358 0.1mg + PPI | Change From Baseline in Heartburn-Free Days Over Weeks 5-8 | 28.52 percentage of days | Standard Error 3.686 |
| SSP-002358 0.5mg + PPI | Change From Baseline in Heartburn-Free Days Over Weeks 5-8 | 30.68 percentage of days | Standard Error 3.688 |
| SSP-002358 2.0mg + PPI | Change From Baseline in Heartburn-Free Days Over Weeks 5-8 | 27.47 percentage of days | Standard Error 3.756 |
p-value: 0.10295% CI: [-1.344, 14.85]Mixed Models Repeated Measures Analysis
p-value: 0.03195% CI: [0.814, 17.021]Mixed Models Repeated Measures Analysis
p-value: 0.17595% CI: [-2.54, 13.957]Mixed Models Repeated Measures Analysis
Secondary
Change From Baseline in the Persistent Reflux Integrated Symptom Measurement (PRISM) Liquid and Food Domain Scores Over Weeks 5-8
PRISM is a 21 item patient-reported outcome instrument with 4 domains. Items are scored using various scales. Total score ranges from 0-100. Higher scores indicate more severe or frequent symptoms.
Time frame: Baseline and over weeks 5-8
Population: Full Analysis Set consisted of all subjects in the Safety Analysis Set who had at least 1 post-baseline value for the primary efficacy assessment. Safety Analysis Set consisted of all randomized subjects who took at least 1 dose of investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + PPI | Change From Baseline in the Persistent Reflux Integrated Symptom Measurement (PRISM) Liquid and Food Domain Scores Over Weeks 5-8 | -13.29 units on a scale | Standard Error 1.206 |
| SSP-002358 0.1mg + PPI | Change From Baseline in the Persistent Reflux Integrated Symptom Measurement (PRISM) Liquid and Food Domain Scores Over Weeks 5-8 | -15.77 units on a scale | Standard Error 1.228 |
| SSP-002358 0.5mg + PPI | Change From Baseline in the Persistent Reflux Integrated Symptom Measurement (PRISM) Liquid and Food Domain Scores Over Weeks 5-8 | -16.49 units on a scale | Standard Error 1.235 |
| SSP-002358 2.0mg + PPI | Change From Baseline in the Persistent Reflux Integrated Symptom Measurement (PRISM) Liquid and Food Domain Scores Over Weeks 5-8 | -15.44 units on a scale | Standard Error 1.25 |
p-value: 0.06495% CI: [-5.087, 0.141]Mixed Models Repeated Measures Analysis
p-value: 0.01795% CI: [-5.818, -0.573]Mixed Models Repeated Measures Analysis
p-value: 0.11495% CI: [-4.813, 0.519]Mixed Models Repeated Measures Analysis
Secondary
Steady State Maximum Plasma Concentration (Cmax) of SSP-002358
Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administered.
Time frame: Over 8 hours post-dose (week 2 or later)
Population: Full Pharmacokinetic Subset consisted of a subset of subjects who underwent the detailed pharmacokinetic assessments. Subjects who vomited within the blood sampling period may have been excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + PPI | Steady State Maximum Plasma Concentration (Cmax) of SSP-002358 | 648 pg/ml | Standard Deviation 302 |
| SSP-002358 0.1mg + PPI | Steady State Maximum Plasma Concentration (Cmax) of SSP-002358 | 3374 pg/ml | Standard Deviation 1175 |
| SSP-002358 0.5mg + PPI | Steady State Maximum Plasma Concentration (Cmax) of SSP-002358 | 17900 pg/ml | Standard Deviation 3573 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of SSP-002358
Time frame: Over 8 hours post-dose (week 2 or later)
Population: Full Pharmacokinetic Subset consisted of a subset of subjects who underwent the detailed pharmacokinetic assessments. Subjects who vomited within the blood sampling period may have been excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + PPI | Time to Maximum Plasma Concentration (Tmax) of SSP-002358 | 5.00 hours |
| SSP-002358 0.1mg + PPI | Time to Maximum Plasma Concentration (Tmax) of SSP-002358 | 5.07 hours |
| SSP-002358 0.5mg + PPI | Time to Maximum Plasma Concentration (Tmax) of SSP-002358 | 4.51 hours |