Diabetes Mellitus, Diabetes Mellitus Complications, Gastroparesis
Conditions
Keywords
Diabetes Mellitus, Delayed Gastric Emptying, Vomiting, Gastroparesis, Gastrointestinal Motility Disorder
Brief summary
The purpose of this study is to evaluate the effects of multiple dose regimens of relamorelin on vomiting episodes, gastric emptying and gastroparesis symptoms in participants with Type 1 and Type 2 diabetes mellitus and gastroparesis. Study drug (relamorelin and placebo) will be administered subcutaneously in a blinded fashion.
Interventions
DRUGRelamorelin
Double blind relamorelin was given subcutaneously BID for 12 weeks.
DRUGPlacebo
Placebo given subcutaneously for 12 weeks.
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes mellitus (T1DM) or Type 2 diabetes mellitus (T2DM) with stable glycemic control and Hemoglobin A1c (HbA1c) ≤11% at screening. * Diabetic gastroparesis (DG), defined as at least a 3-month history of symptoms suggestive of gastroparesis on an ongoing basis (e.g., vomiting, nausea, early satiety, bloating, or epigastric or abdominal pain). * Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD) score ≥2.6 at least once during the Screening Period (Visits 1-2). * At least 2 vomiting episodes during the \ 2 weeks prior to the first screening visit (Visit 1), as ascertained by patient history. * Delayed Gastric Emptying (GE) confirmed at screening by abnormal Gastric Emptying Breath Test (GEBT), defined as GE half-time (t1/2) ≥79 minutes (the 80th percentile of normative data). At least 50% of patients enrolled will have a t1/2 ≥97 minutes (i.e., the 95th percentile). * Stable concomitant medications, defined as no changes in regimen for at least 2 weeks prior to Visit 2 (daily adjustments of insulin doses are permitted). * No use of metoclopramide, erythromycin, domperidone, or other gastrointestinal (GI) motility agents, or anti-emetics for at least 2 weeks prior to Visit 2, and willingness to remain off these medications (except as used as part of protocol-specific rescue medication) during the course of the clinical trial. * Body mass index \>18 kg/m2. * If female, has a negative serum or urine pregnancy test and is not lactating. For females able to bear children, a hormonal (i.e., oral, implantable, or injectable) and single-barrier method, or a double-barrier method of birth control must be used throughout the study. Female patients unable to bear children must have this documented in the electronic case report form (eCRF) (i.e., tubal ligation, hysterectomy, or post-menopausal \[defined as a minimum of 1 year since the last menstrual period\]). Post-menopausal status will be confirmed by measurement of follicle stimulating hormone (FSH). * Able to provide written informed consent prior to any study procedures and willing and able to comply with study procedures. Additional inclusion criteria for randomization after the 2-week single-blind placebo run-in period: * Compliance with the completion of the Diabetic Gastroparesis Symptom Severity Diary (DGSSD) and study drug injections, defined as approximately 80% diary completions and approximately 80% administration of injections, during the 2-week single-blind placebo run-in period. For those patients whose compliance is measured to be \<80%, the final decision to randomize a patient will be made by the Investigator and the Sponsor (or designee). * At least one vomiting episode at any time during the 2-week single-blind placebo run-in period, as recorded in the DGSSD.
Exclusion criteria
* Currently receiving parenteral feeding or presence of a nasogastric or other enteral tube \[e.g., Percutaneous Endoscopic Gastrostomy (PEG) tube\] for feeding or decompression. * History of gastric surgery such as fundoplication, gastrectomy, gastric pacemaker placement, vagotomy, or bariatric procedure. (A history of diagnostic endoscopy is not exclusionary.) * History of pyloric injection of botulinum toxin within 6 months of screening. * Patients with clinical suspicion of upper GI obstruction (e.g., peptic stricture) must have been evaluated per standard of care and obstruction ruled out before screening. * Currently taking opiates, or expecting to use opiates during the course of the clinical trial. * Currently taking Glucagon-like peptide-1 (GLP-1) agonists, Sodium-glucose co-transporter 2 (SGLT2) inhibitors or pramlintide. * Allergic or intolerant of egg, wheat, milk, or algae, as these are components of the Gastric emptying breath test (GEBT) study meal. (Gluten-free crackers can be provided.) * History of anorexia nervosa, binge-eating, or bulimia within 5 years of screening. * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 × upper limit of normal (ULN) at Visit 1. * History of intestinal malabsorption or pancreatic exocrine disease. * Requires hemodialysis or has end-stage renal disease. * History of human immunodeficiency virus (HIV) infection. * Clinically significant neurologic or psychiatric disorders that are likely to impact compliance with protocol requirements. * Poor venous access or inability to tolerate venipuncture. * Participation in a clinical study within the 30 days prior to dosing in the present study. * Any other reason that, in the Investigator's opinion, would confound proper interpretation of the study or expose a patient to unacceptable risk, including renal, hepatic or cardiopulmonary disease, or significant acute electrocardiogram (ECG) abnormalities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Weekly Vomiting Episodes | 7 days prior to Day 1 for Baseline to 7 days prior to Week 12 | Vomiting episodes were assessed via the Diabetic Gastroparesis Symptoms Severity Diary (DGSSD). The DGSSD is a 7-item, participant-reported daily diary designed to assess the severity of 6 core signs and symptoms of Diabetic Gastroparesis (DG) (nausea, abdominal pain, postprandial fullness, bloating, vomiting, and early satiety) and the frequency of vomiting episodes. Each day, the participant recorded the number of vomiting episodes in the past 24 hours in the diary. Higher scores indicate more vomiting episodes. Weekly scores were averaged across the 12 weeks period. A negative change from Baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | 7 days prior to Day 1 for Baseline to 7 days prior to Week 12 | The DGSSD is a 7-item, participant-reported daily diary designed to assess the severity of 6 core signs and symptoms of DG (nausea, abdominal pain, postprandial fullness, bloating, vomiting, and early satiety) and the frequency of vomiting episodes. Severity of nausea, bloating and abdominal pain, were assessed on a numerical rating scale of 0 to 10, with 0 equating to no (symptom) and 10 equating to worst possible (symptom). Early satiety was assessed on a 5-item scale with 1 being Only 1 or 2 bites and 5 being All of a normal-sized meal; symptom severity scores for this item were reversed and normalized to a range 0 to 10 for the development of the DGSSD 4-symptom Composite Score. The DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal pain) range is 0 to 40. Higher scores indicate worse condition. Weekly scores were averaged across 12 weeks period. A negative change from Baseline indicates improvement. |
| Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Baseline (Day 1) to Week 12 | GE was measured via the GEBT and was reported as a time to half (t1/2) of the theoretical total GE. GEBT is a non-radioactive stable isotope breath test intended for measurement of GE of solids in participants. A negative change from Baseline indicates improvement. |
Countries
Belgium, Germany, Israel, Poland, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
A total 393 participants were randomized and received study treatment, and 334 participants completed the study. Five participants who received study drug but discontinued prematurely were summarized as completing the study because they fulfilled the Visit 8 (Week 12) assessments as per protocol.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo-matching relamorelin was administered subcutaneously (SC) by injection twice daily (BID) for 12 weeks. | 104 |
| Relamorelin 10 μg Relamorelin 10 microgram (μg) was administered SC by injection BID for 12 weeks. | 98 |
| Relamorelin 30 μg Relamorelin 30 μg was administered SC by injection BID for 12 weeks. | 109 |
| Relamorelin 100 μg Relamorelin 100 μg was administered SC by injection BID for 12 weeks. | 82 |
| Total | 393 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 | 8 | 9 |
| Overall Study | Investigator Decision | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 0 | 2 | 3 |
| Overall Study | Prohibited Medication | 1 | 1 | 0 | 0 |
| Overall Study | Protocol Non-compliance | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawn Consent | 4 | 8 | 6 | 6 |
Baseline characteristics
| Characteristic | Placebo | Relamorelin 10 μg | Relamorelin 30 μg | Relamorelin 100 μg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 11.9 | 59.3 years STANDARD_DEVIATION 10.2 | 56.0 years STANDARD_DEVIATION 11.7 | 57.1 years STANDARD_DEVIATION 11 | 57.0 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 64 Participants | 59 Participants | 65 Participants | 57 Participants | 245 Participants |
| Sex: Female, Male Male | 40 Participants | 39 Participants | 44 Participants | 25 Participants | 148 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 | 0 / 104 | 0 / 98 | 0 / 109 | 1 / 82 |
| other Total, other adverse events | 13 / 104 | 21 / 98 | 30 / 109 | 28 / 82 |
| serious Total, serious adverse events | 8 / 104 | 7 / 98 | 10 / 109 | 6 / 82 |
Outcome results
Primary
Change From Baseline to Week 12 in Weekly Vomiting Episodes
Vomiting episodes were assessed via the Diabetic Gastroparesis Symptoms Severity Diary (DGSSD). The DGSSD is a 7-item, participant-reported daily diary designed to assess the severity of 6 core signs and symptoms of Diabetic Gastroparesis (DG) (nausea, abdominal pain, postprandial fullness, bloating, vomiting, and early satiety) and the frequency of vomiting episodes. Each day, the participant recorded the number of vomiting episodes in the past 24 hours in the diary. Higher scores indicate more vomiting episodes. Weekly scores were averaged across the 12 weeks period. A negative change from Baseline indicates improvement.
Time frame: 7 days prior to Day 1 for Baseline to 7 days prior to Week 12
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study treatment and provided at least 1 postbaseline primary efficacy measurement (DGSSD). Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Baseline | 5.7 vomiting episodes per week | Standard Deviation 6 |
| Placebo | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Change from Baseline to Week 12 | -2.9 vomiting episodes per week | Standard Deviation 5.8 |
| Relamorelin 10 μg | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Change from Baseline to Week 12 | -3.7 vomiting episodes per week | Standard Deviation 12.5 |
| Relamorelin 10 μg | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Baseline | 7.7 vomiting episodes per week | Standard Deviation 17.2 |
| Relamorelin 30 μg | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Baseline | 6.9 vomiting episodes per week | Standard Deviation 10.3 |
| Relamorelin 30 μg | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Change from Baseline to Week 12 | -3.8 vomiting episodes per week | Standard Deviation 7.6 |
| Relamorelin 100 μg | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Baseline | 4.8 vomiting episodes per week | Standard Deviation 5.2 |
| Relamorelin 100 μg | Change From Baseline to Week 12 in Weekly Vomiting Episodes | Change from Baseline to Week 12 | -1.1 vomiting episodes per week | Standard Deviation 13.5 |
p-value: 0.36Measures mixed effects model (MMRM)
p-value: 0.25MMRM
p-value: 0.59MMRM
Secondary
Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time
GE was measured via the GEBT and was reported as a time to half (t1/2) of the theoretical total GE. GEBT is a non-radioactive stable isotope breath test intended for measurement of GE of solids in participants. A negative change from Baseline indicates improvement.
Time frame: Baseline (Day 1) to Week 12
Population: FAS included all randomized participants who received at least 1 dose of study treatment and provided at least 1 postbaseline primary efficacy measurement (DGSSD). Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Baseline | 127.1 minutes | Standard Deviation 36.5 |
| Placebo | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Change from Baseline to Week 12 | 0.0 minutes | Standard Deviation 38.5 |
| Relamorelin 10 μg | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Change from Baseline to Week 12 | -12.7 minutes | Standard Deviation 38.1 |
| Relamorelin 10 μg | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Baseline | 126.8 minutes | Standard Deviation 37.6 |
| Relamorelin 30 μg | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Baseline | 128.6 minutes | Standard Deviation 35.9 |
| Relamorelin 30 μg | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Change from Baseline to Week 12 | -12.8 minutes | Standard Deviation 36.5 |
| Relamorelin 100 μg | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Baseline | 133.6 minutes | Standard Deviation 35.4 |
| Relamorelin 100 μg | Change From Baseline to Week 12 for Gastric Emptying (GE) as Measured by the Gastric Emptying Breath Test (GEBT) Half-time | Change from Baseline to Week 12 | -13.6 minutes | Standard Deviation 40.5 |
Secondary
Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain)
The DGSSD is a 7-item, participant-reported daily diary designed to assess the severity of 6 core signs and symptoms of DG (nausea, abdominal pain, postprandial fullness, bloating, vomiting, and early satiety) and the frequency of vomiting episodes. Severity of nausea, bloating and abdominal pain, were assessed on a numerical rating scale of 0 to 10, with 0 equating to no (symptom) and 10 equating to worst possible (symptom). Early satiety was assessed on a 5-item scale with 1 being Only 1 or 2 bites and 5 being All of a normal-sized meal; symptom severity scores for this item were reversed and normalized to a range 0 to 10 for the development of the DGSSD 4-symptom Composite Score. The DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal pain) range is 0 to 40. Higher scores indicate worse condition. Weekly scores were averaged across 12 weeks period. A negative change from Baseline indicates improvement.
Time frame: 7 days prior to Day 1 for Baseline to 7 days prior to Week 12
Population: FAS included all randomized participants who received at least 1 dose of study treatment and provided at least 1 postbaseline primary efficacy measurement (DGSSD). Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Baseline | 21.4 score on a scale | Standard Deviation 6.7 |
| Placebo | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Change from Baseline to Week 12 | -5.4 score on a scale | Standard Deviation 8.1 |
| Relamorelin 10 μg | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Change from Baseline to Week 12 | -7.7 score on a scale | Standard Deviation 7.8 |
| Relamorelin 10 μg | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Baseline | 21.8 score on a scale | Standard Deviation 6.9 |
| Relamorelin 30 μg | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Baseline | 21.1 score on a scale | Standard Deviation 6 |
| Relamorelin 30 μg | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Change from Baseline to Week 12 | -7.5 score on a scale | Standard Deviation 7.4 |
| Relamorelin 100 μg | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Baseline | 22.3 score on a scale | Standard Deviation 6.2 |
| Relamorelin 100 μg | Change From Baseline to Week 12 in Weekly DGSSD 4-symptom Composite Score (Nausea, Bloating, Early Satiety, Abdominal Pain) | Change from Baseline to Week 12 | -8.9 score on a scale | Standard Deviation 8.3 |