Colon Cleansing, Colorectal Cancer, Colorectal Carcinoma
Conditions
Brief summary
This study evaluates the efficacy, safety and tolerability of NER1006 versus a sodium picosulfate and magnesium salt solution (SP + MS) in adult patients requiring bowel cleansing prior to any procedure that requires a clean bowel, using a Day Before Only Dosing regimen. Approximately 484 patients will be randomised with the aim of achieving a minimum of 220 patients in each of the 2 groups.
Interventions
DRUGNER1006, Day Before-Only Dosing
The subject will self-administer both doses of NER1006 in the evening of Day 1 with 1-2 hours interval. Subject will take mandatory additional clear fluid after each dose.
DRUGSP+MS, Day Before-Only Dosing
The subject will self-administer SP+MS in the morning of Day 1 and afternoon of Day 1. Subject will take mandatory additional clear fluid after each dose.
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
* Patients must provide 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 (unless postmenopausal or surgically sterile, or whose sole sexual partner has had a successful vasectomy): * 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 the entire study and to 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. * 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), sodium picosulfate and magnesium salt compounds, or any other component of the study drug or comparator * Past history within the last 12 months or evidence of any on-going clinically relevant electrocardiogram 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 are ordered to live in an institution on court or authority order. * Patients with history of rhabdomyolysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Successful Bowel Cleansing (Overall Colon) | One day (day before 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 visualized) and C and D are classified as unsuccessful. Comparison of overall success of cleansing with NER1006 versus SP+MS was evaluated using a non-inferiority study design. |
| Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | One day (day before 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 SP+MS was evaluated using a non-inferiority study design. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adenoma Detection Rate (Colon Ascendens) | One day (day before 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 SP+MS. Adenoma detection rate (ADR) defined as the number of patients with at least one adenoma in the colon ascendens. |
| Adenoma Detection Rate (Overall Colon) | One day (day before 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 SP+MS. Adenoma detection rate (ADR) defined as the number of patients with at least one adenoma in the overall colon. |
| Polyp Detection Rate (Colon Ascendens) | One day (day before 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 SP+MS. Polyp detection rate (PDR) defined as the number of patients with at least one polyp in the colon ascendens. |
| Polyp Detection Rate (Overall Colon) | One day (day before 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 SP+MS. Polyp detection rate (PDR) defined as the number of patients with at least one polyp in the overall colon. |
Countries
Germany, Italy, Netherlands, Poland, Spain, United Kingdom
Participant flow
Recruitment details
The trial recruited out/in-patients at 19 medical centres in Europe, from November 2014 to July 2015.
Participants by arm
| Arm | Count |
|---|---|
| SP+MS, Day Before-Only Dosing SP+MS 1-Day Day Before-Only Split-Dosing Regimen (to commence on the moring of the day before colonoscopy). | 257 |
| NER1006, Day Before-Only Dosing NER1006 1-Day Day Before-Only Split-Dosing Regimen (to commence on the evening of the day before colonoscopy). | 258 |
| Total | 515 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Various | 6 | 6 |
| Overall Study | Withdrawal by Subject | 10 | 15 |
Baseline characteristics
| Characteristic | Total | SP+MS, Day Before-Only Dosing | NER1006, Day Before-Only Dosing |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 104 Participants | 50 Participants | 54 Participants |
| Age, Categorical Between 18 and 65 years | 410 Participants | 207 Participants | 203 Participants |
| Age, Continuous | 53.8 years STANDARD_DEVIATION 12.5 | 52.9 years STANDARD_DEVIATION 13.35 | 54.6 years STANDARD_DEVIATION 11.64 |
| Sex: Female, Male Female | 342 Participants | 174 Participants | 168 Participants |
| Sex: Female, Male Male | 173 Participants | 83 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 241 | 0 / 235 |
| other Total, other adverse events | 9 / 241 | 32 / 235 |
| serious Total, serious adverse events | 0 / 241 | 1 / 235 |
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 SP+MS was evaluated using a non-inferiority study design.
Time frame: One day (day before 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) |
|---|---|---|---|
| SP+MS, Day Before-Only Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Excellent plus good | 3 Participants |
| SP+MS, Day Before-Only Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Adequate plus failure | 248 Participants |
| NER1006, Day Before-Only Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Excellent plus good | 11 Participants |
| NER1006, Day Before-Only Dosing | Number of Patients With 'Excellent Plus Good' (Highly Effective) Bowel Cleansing (Colon Ascendens) | Adequate plus failure | 239 Participants |
Comparison: Hypothesis was to demonstrate NI of NER1006 regimen to SP+MS (10% margin). Success rate was no. of patients with highly effective cleansing of the colon ascendens as proportion of no. of patients in each group. Treatment effect was NER1006 success rate - SP+MS 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: 0.027Fisher 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 visualized) and C and D are classified as unsuccessful. Comparison of overall success of cleansing with NER1006 versus SP+MS was evaluated using a non-inferiority study design.
Time frame: One day (day before 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) |
|---|---|---|---|
| SP+MS, Day Before-Only Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Successful | 135 Participants |
| SP+MS, Day Before-Only Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Failure | 116 Participants |
| NER1006, Day Before-Only Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Successful | 155 Participants |
| NER1006, Day Before-Only Dosing | Number of Patients With Successful Bowel Cleansing (Overall Colon) | Failure | 95 Participants |
Comparison: The hypothesis was to demonstrate non-inferiority (NI) of NER1006 regimen to SP+MS (10% margin). Success rate was no. of patients with successful overall bowel cleansing as proportion of no. of patients in each group. Treatment effect was NER1006 success rate - SP+MS 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: 0.038Fisher 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 SP+MS. Adenoma detection rate (ADR) defined as the number of patients with at least one adenoma in the colon ascendens.
Time frame: One day (day before 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) |
|---|---|---|---|
| SP+MS, Day Before-Only Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with no adenomas detected | 241 Participants |
| SP+MS, Day Before-Only Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with at least one adenoma detected | 10 Participants |
| NER1006, Day Before-Only Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with no adenomas detected | 234 Participants |
| NER1006, Day Before-Only Dosing | Adenoma Detection Rate (Colon Ascendens) | Patients with at least one adenoma detected | 16 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 - SP+MS 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: 0.15495% CI: [-6.35, 11.12]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 SP+MS. Adenoma detection rate (ADR) defined as the number of patients with at least one adenoma in the overall colon.
Time frame: One day (day before colonoscopy)
Population: The overall number of participants analyzed was based on the mFAS. This included all randomized patients with the exception of any patient who was randomized but subsequently failed to meet entry criteria and in whom it was confirmed (from their patient diary) that the same patient did not receive any study drug (n=501).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SP+MS, Day Before-Only Dosing | Adenoma Detection Rate (Overall Colon) | Patients with no adenomas detected | 204 Participants |
| SP+MS, Day Before-Only Dosing | Adenoma Detection Rate (Overall Colon) | Patients with at least one adenoma detected | 47 Participants |
| NER1006, Day Before-Only Dosing | Adenoma Detection Rate (Overall Colon) | Patients with no adenomas detected | 195 Participants |
| NER1006, Day Before-Only Dosing | Adenoma Detection Rate (Overall Colon) | Patients with at least one adenoma detected | 55 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 - SP+MS 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: 0.21295% CI: [-5.56, 11.91]Fisher 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 SP+MS. Polyp detection rate (PDR) defined as the number of patients with at least one polyp in the colon ascendens.
Time frame: One day (day before 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) |
|---|---|---|---|
| SP+MS, Day Before-Only Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with no polyps detected | 232 Participants |
| SP+MS, Day Before-Only Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with at least one polyp detected | 19 Participants |
| NER1006, Day Before-Only Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with no polyps detected | 220 Participants |
| NER1006, Day Before-Only Dosing | Polyp Detection Rate (Colon Ascendens) | Patients with at least one polyp detected | 30 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 - SP+MS 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: 0.06495% CI: [-4.36, 13.1]Fisher 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 SP+MS. Polyp detection rate (PDR) defined as the number of patients with at least one polyp in the overall colon.
Time frame: One day (day before 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) |
|---|---|---|---|
| SP+MS, Day Before-Only Dosing | Polyp Detection Rate (Overall Colon) | Patients with no polyps detected | 160 Participants |
| SP+MS, Day Before-Only Dosing | Polyp Detection Rate (Overall Colon) | Patients with at least one polyp detected | 91 Participants |
| NER1006, Day Before-Only Dosing | Polyp Detection Rate (Overall Colon) | Patients with no polyps detected | 152 Participants |
| NER1006, Day Before-Only Dosing | Polyp Detection Rate (Overall Colon) | Patients with at least one polyp detected | 98 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 - SP+MS 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: 0.27895% CI: [-5.96, 11.51]Fisher Exact