Colon Cancer, Colorectal Carcinoma, Colon Cleansing
Conditions
Brief summary
This study evaluates the efficacy, safety and tolerability of NER1006 versus Trisulfate Solution (TS) in adult patients requiring bowel cleansing prior to any procedure that requires a clean bowel, using a 2-Day evening/morning Split-Dosing regimen. Approximately 540 patients will be randomised with the aim of achieving a minimum of 245 patients in each of the 2 groups.
Interventions
DRUGNER1006
The subject will self-administer the first dose of the assigned investigational product in the evening prior to the scheduled colonoscopy and take mandatory additional clear fluid. Subject will take the second dose together with mandatory additional clear fluids on the morning of the colonoscopy.
DRUGTrisulfate solution
The subject will self-administer the first dose of the assigned investigational product in the evening prior to the scheduled colonoscopy and take mandatory additional clear fluid. Subject will take the second dose together with mandatory additional clear fluids on the morning of the colonoscopy.
Sponsors
Norgine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SCREENING
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Male and female outpatients and inpatients aged ≥18 to ≤85 years undergoing a screening, surveillance, or diagnostic colonoscopy * Females of child bearing potential must have a negative pregnancy test at Screening and at Visit 2 and must be practising one of the following methods of birth control and agree to continue with the regimen throughout the study period: Oral, implantable, or injectable contraceptives (for a minimum of three months before study entry) in combination with a condom; Intrauterine device in combination with a condom; Double barrier method (condom\* and occlusive cap \[diaphragm or cervical/vault caps\] with spermicidal foam/gel/film/cream/suppository) * Willing, able and competent to complete study and comply with instructions.
Exclusion criteria
* Patients with past history within last 12 months or current episode of severe constipation (requiring repeated use of laxatives/enema or physical intervention before resolution), known or suspected ileus, gastrointestinal obstruction, gastric retention, bowel perforation, toxic colitis or megacolon. * Patients with ongoing severe acute Inflammatory Bowel Disease (IBD). * Patients who have had previous significant gastrointestinal surgeries, including colonic resection, sub-total colectomy, abdomino-perineal resection, de-functioning colostomy, Hartmann's procedure and de-functioning ileostomy or other similar surgeries involving structure and function of the small or large colon. * Regular use of laxatives or colon motility altering drugs in the last month (i.e. more than 2-3 times per week) and/or laxative use within 72 hours prior to administration of the preparation. * Patients with active intestinal bleeding episodes or with a clinically significant low hemoglobin level \<9 g/dL for women and \<11 g/dL for men at screening. * Known glucose-6-phosphate dehydrogenase (G6PD) deficiency. * Known phenylketonuria. * Known hypersensitivity to polyethylene glycols, ascorbic acid and sulfates (not including sulfa-based products) or any other component of the investigational product or comparator. * Past history within the last 12 months or evidence of any on-going clinically relevant electrocardiogram (ECG) abnormalities (e.g. arrhythmias). * History of uncontrolled hypertension with systolic blood pressure \>170 mmHg and diastolic blood pressure \>100 mmHg. * Patients with cardiac insufficiency NYHA grades III or IV. * Patients with moderate to severe renal insufficiency (i.e. with GFR, \<60 mL/min/1.73m2). * Patient with serum albumin \< 3.4 g/dL. * Patients with liver disease of grades B and C according to the Child Pugh classification. * Patients suffering from dehydration at screening as evaluated by the Investigator from physical examination and laboratory investigations. * Patients with clinically significant electrolyte abnormalities, whether pre-existing or noted at screening, such as hypernatremia, hyponatremia, hyperphosphatemia, hypermagnesemia, hypokalemia, hypocalcaemia, dehydration, or those secondary to the use of diuretics or angiotensin converting enzyme (ACE) inhibitors. * Patients with any other clinically significant hematological parameters including coagulation profile at screening. * Patients with impaired consciousness that might predispose them to pulmonary aspiration. * Patients undergoing colonoscopy for foreign body removal and/or decompression. * Patients who are pregnant or lactating, or intending to become pregnant during the study. * Clinically relevant findings on physical examination based on the Investigator's judgment. * History of drug or alcohol abuse within the 12 months prior to dosing. * Concurrent participation in an investigational drug or device study or participation within three months of study entry. * Patients who, in the opinion of the Investigator, should not be included in the study for any reason, including inability to follow study procedures, e.g. cognitively impaired, debilitated or fragile patients. * Patients who are ordered to live in an institution on court or authority order.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Successful Bowel Cleansing (Overall Colon) | Two days (from day of first dosing to day of colonoscopy) | The overall quality of bowel cleansing was assessed by a blinded central reader (an experienced and trained colonoscopist) using the segmental scores of the Harefield Cleansing Scale (HCS). A final HCS grading of A, B, C or D was derived. Grades A and B are classified as successful (i.e., all mucosa could be visualised) and C and D are classified as unsuccessful. Comparison of overall success of cleansing with NER1006 versus Trisulfate solution was evaluated using a non-inferiority study design. |
| Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Two days (from day of first dosing to day of colonoscopy) | The overall quality of bowel cleansing was assessed by a blinded central reader (an experienced and trained colonoscopist) using the segmental scores of the Harefield Cleansing Scale (HCS). Highly effective cleansing in the colon ascendens corresponded to scores 3 (Good) or 4 (Excellent) of the HCS. Adequate plus failure of cleansing corresponded to score 0-2. Comparison of 'Excellent plus good' cleansing of the colon ascendens using NER1006 versus Trisulfate Solution was evaluated using a non-inferiority study design. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adenoma Detection Rate (Colon Ascendens) | Two days (from day of first dosing to day of colonoscopy) | Comparison of the number of patients with at least one adenoma detected in the colon ascendens when NER1006 is used for bowel cleansing versus Trisulfate Solution. Adenoma detection rate (ADR) defined as the number of patients with at least one adenoma in the colon ascendens. |
| Adenoma Detection Rate (Overall Colon) | Two days (from day of first dosing to day of colonoscopy) | Comparison of the number of patients with at least one adenoma detected in the overall colon when NER1006 is used for bowel cleansing versus Trisulfate Solution. ADR defined as the number of patients with at least one adenoma in the overall colon. |
| Polyp Detection Rate (Colon Ascendens) | Two days (from day of first dosing to day of colonoscopy) | Comparison of the number of patients with at least one polyp detected in the colon ascendens when NER1006 is used for bowel cleansing versus Trisulfate Solution. Polyp detection rate (PDR) defined as the number of patients with at least one polyp in the colon ascendens. |
| Polyp Detection Rate (Overall Colon) | Two days (from day of first dosing to day of colonoscopy) | Comparison of the number of patients with at least one polyp detected in the overall colon when NER1006 is used for bowel cleansing versus Trisulfate Solution. PDR defined as the number of patients with at least one polyp in the overall colon. |
Countries
United States
Participant flow
Recruitment details
The trial recruited out/in-patients at 12 medical centres in the USA, from September 2014 to May 2015.
Participants by arm
| Arm | Count |
|---|---|
| Trisulfate Solution 2-Day Split-Dosing Trisulfate solution: Trisulfate solution 2-Day Split-Dosing Regimen (to commence in the evening of the day before the colonoscopy) | 311 |
| NER1006 2-Day Split-Dosing NER1006: NER1006 2-Day Split-Dosing Regimen (to commence in the evening of the day before the colonoscopy) | 310 |
| Total | 621 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | GFR<60mL/min | 16 | 21 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Various | 12 | 12 |
| Overall Study | Withdrawal by Subject | 17 | 15 |
Baseline characteristics
| Characteristic | Trisulfate Solution 2-Day Split-Dosing | NER1006 2-Day Split-Dosing | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 72 Participants | 67 Participants | 139 Participants |
| Age, Categorical Between 18 and 65 years | 238 Participants | 243 Participants | 481 Participants |
| Age, Continuous | 57.3 Years STANDARD_DEVIATION 10.56 | 57.7 Years STANDARD_DEVIATION 10.36 | 57.5 Years STANDARD_DEVIATION 10.44 |
| Sex: Female, Male Female | 142 Participants | 152 Participants | 294 Participants |
| Sex: Female, Male Male | 169 Participants | 158 Participants | 327 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 265 | 0 / 262 |
| other Total, other adverse events | 32 / 265 | 73 / 262 |
| serious Total, serious adverse events | 1 / 265 | 1 / 262 |
Outcome results
Primary
Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens)
The overall quality of bowel cleansing was assessed by a blinded central reader (an experienced and trained colonoscopist) using the segmental scores of the Harefield Cleansing Scale (HCS). Highly effective cleansing in the colon ascendens corresponded to scores 3 (Good) or 4 (Excellent) of the HCS. Adequate plus failure of cleansing corresponded to score 0-2. Comparison of 'Excellent plus good' cleansing of the colon ascendens using NER1006 versus Trisulfate Solution was evaluated using a non-inferiority study design.
Time frame: Two days (from day of first dosing to day of colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients, except any patient who (i) was randomized but subsequently failed to meet entry criteria and (ii) in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trisulfate Solution 2-Day Split-Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Excellent plus good | 82 Participants |
| Trisulfate Solution 2-Day Split-Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Adequate plus failure | 198 Participants |
| NER1006 2-Day Split-Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Excellent plus good | 99 Participants |
| NER1006 2-Day Split-Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Adequate plus failure | 177 Participants |
Comparison: The hypothesis was to demonstrate NI of NER1006 to Trisulfate Solution (TS) (10% margin). Success rate was number of patients with successful overall bowel cleansing as proportion of number of patients in each group. Treatment effect was NER1006 success rate - TS success rate. A Hochberg procedure was used to control Type I error since there were 2 alternative primary endpoints. An alpha level of 1.25% 1-sided was used. A closed testing procedure used to evaluate superiority if NI was met.p-value: 0.059Fisher Exact
Primary
Number of Patients With Successful Bowel Cleansing (Overall Colon)
The overall quality of bowel cleansing was assessed by a blinded central reader (an experienced and trained colonoscopist) using the segmental scores of the Harefield Cleansing Scale (HCS). A final HCS grading of A, B, C or D was derived. Grades A and B are classified as successful (i.e., all mucosa could be visualised) and C and D are classified as unsuccessful. Comparison of overall success of cleansing with NER1006 versus Trisulfate solution was evaluated using a non-inferiority study design.
Time frame: Two days (from day of first dosing to day of colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients, except any patient who (i) was randomized but subsequently failed to meet entry criteria and (ii) in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trisulfate Solution 2-Day Split-Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Successful | 238 Participants |
| Trisulfate Solution 2-Day Split-Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Failure | 42 Participants |
| NER1006 2-Day Split-Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Successful | 235 Participants |
| NER1006 2-Day Split-Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Failure | 41 Participants |
Comparison: The hypothesis was to demonstrate NI of NER1006 to Trisulfate Solution (TS) (10% margin). Success rate was number of patients with successful overall bowel cleansing as proportion of number of patients in each group. Treatment effect was NER1006 success rate - TS success rate. A Hochberg procedure was used to control Type I error since there were 2 alternative primary endpoints. An alpha level of 1.25% 1-sided was used. A closed testing procedure used to evaluate superiority if NI was met.p-value: 0.528Fisher Exact
Secondary
Adenoma Detection Rate (Colon Ascendens)
Comparison of the number of patients with at least one adenoma detected in the colon ascendens when NER1006 is used for bowel cleansing versus Trisulfate Solution. Adenoma detection rate (ADR) defined as the number of patients with at least one adenoma in the colon ascendens.
Time frame: Two days (from day of first dosing to day of colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients, except any patient who (i) was randomized but subsequently failed to meet entry criteria and (ii) in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trisulfate Solution 2-Day Split-Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with no adenomas detected | 232 Participants |
| Trisulfate Solution 2-Day Split-Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with at least one adenoma detected | 48 Participants |
| NER1006 2-Day Split-Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with no adenomas detected | 237 Participants |
| NER1006 2-Day Split-Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with at least one adenoma detected | 39 Participants |
Comparison: If at least one of the alternative primary endpoints was met, then key secondary endpoints for the same colon region as met by the primary endpoint were evaluated hierarchically in a pre-specified order. The difference in ADR was calculated as NER1006 rate - TS rate using 1-sided 97.5% confidence limits. Formal testing was to proceed in the hierarchy if preceding key secondary endpoint met non-inferiority. This procedure ensured overall Type I error control at 2.5% 1-sided.p-value: 0.86395% CI: [-11.36, 5.28]Fisher Exact
Secondary
Adenoma Detection Rate (Overall Colon)
Comparison of the number of patients with at least one adenoma detected in the overall colon when NER1006 is used for bowel cleansing versus Trisulfate Solution. ADR defined as the number of patients with at least one adenoma in the overall colon.
Time frame: Two days (from day of first dosing to day of colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients, except any patient who (i) was randomized but subsequently failed to meet entry criteria and (ii) in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trisulfate Solution 2-Day Split-Dosing | Adenoma Detection Rate (Overall Colon) | Patients with no adenomas detected | 182 Participants |
| Trisulfate Solution 2-Day Split-Dosing | Adenoma Detection Rate (Overall Colon) | Patients with at least one adenoma detected | 98 Participants |
| NER1006 2-Day Split-Dosing | Adenoma Detection Rate (Overall Colon) | Patients with no adenomas detected | 183 Participants |
| NER1006 2-Day Split-Dosing | Adenoma Detection Rate (Overall Colon) | Patients with at least one adenoma detected | 93 Participants |
Comparison: If at least one of the alternative primary endpoints was met, then key secondary endpoints for the same colon region as met by the primary endpoint were evaluated hierarchically in a pre-specified order. The difference in ADR was calculated as NER1006 rate - TS rate using 1-sided 97.5% confidence limits. Formal testing was to proceed in the hierarchy if preceding key secondary endpoint met non-inferiority. This procedure ensured overall Type I error control at 2.5% 1-sided.p-value: 0.66Fisher Exact
Secondary
Polyp Detection Rate (Colon Ascendens)
Comparison of the number of patients with at least one polyp detected in the colon ascendens when NER1006 is used for bowel cleansing versus Trisulfate Solution. Polyp detection rate (PDR) defined as the number of patients with at least one polyp in the colon ascendens.
Time frame: Two days (from day of first dosing to day of colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients, except any patient who (i) was randomized but subsequently failed to meet entry criteria and (ii) in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trisulfate Solution 2-Day Split-Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with no polyps detected | 213 Participants |
| Trisulfate Solution 2-Day Split-Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with at least one polyp detected | 67 Participants |
| NER1006 2-Day Split-Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with no polyps detected | 225 Participants |
| NER1006 2-Day Split-Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with at least one polyp detected | 51 Participants |
Comparison: If at least one of the alternative primary endpoints was met, then key secondary endpoints for the same colon region as met by the primary endpoint were evaluated hierarchically in a pre-specified order. The difference in PDR was calculated as NER1006 rate - Trisulfate Solution rate using 1-sided 97.5% confidence limits. Formal testing was to proceed in the hierarchy if preceding key secondary endpoint met non-inferiority. This procedure ensured overall Type I error control at 2.5% 1-sided.p-value: 0.953Fisher Exact
Secondary
Polyp Detection Rate (Overall Colon)
Comparison of the number of patients with at least one polyp detected in the overall colon when NER1006 is used for bowel cleansing versus Trisulfate Solution. PDR defined as the number of patients with at least one polyp in the overall colon.
Time frame: Two days (from day of first dosing to day of colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients, except any patient who (i) was randomized but subsequently failed to meet entry criteria and (ii) in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trisulfate Solution 2-Day Split-Dosing | Polyp Detection Rate (Overall Colon) | Patients with no polyps detected | 144 Participants |
| Trisulfate Solution 2-Day Split-Dosing | Polyp Detection Rate (Overall Colon) | Patients with at least one polyp detected | 136 Participants |
| NER1006 2-Day Split-Dosing | Polyp Detection Rate (Overall Colon) | Patients with no polyps detected | 150 Participants |
| NER1006 2-Day Split-Dosing | Polyp Detection Rate (Overall Colon) | Patients with at least one polyp detected | 126 Participants |
Comparison: If at least one of the alternative primary endpoints were met, then key secondary endpoints were evaluated hierarchichally in a pre-specified order. Non-inferiority was concluded if the 1-sided 97.5% confidence limit (CL) for difference in proportion of events between 2 groups excluded a 10% or greater difference was in favor of Trisulate Solution. Formal testing was to proceed in the hierarchy if preceding key secondary endpoint had at least met non-inferiority.p-value: 0.781Fisher Exact