Proctitis, Ulcerative
Conditions
Keywords
Ulcerative proctitis, Proctocolitis, Inflammatory Bowel Disease, Gastrointestinal Diseases, Colonic Diseases, Mesalamine, 5-ASA
Brief summary
This is a prospective, multicenter, double-blind (DB), controlled, randomized, parallel group comparison Phase 3a study to evaluate the efficacy and safety of new mesalamine suppositories (MAX-002) as compared to placebo and active medicine after 6 weeks of treatment in adults with mild to moderate ulcerative proctitis (UP).
Detailed description
The present study consists of screening period (2 weeks before randomization), DB phase (6 weeks), OL phase (8 weeks) and follow-up visits at Week 3, Week 6 and Week 14. Participants who are eligible will be randomized to receive 1g MAX-002, 1g Canasa® and placebo suppository once daily in the DB phase. Participants who complete or discontinue the study at Week 6 will either receive 1g MAX-002 suppositories on a voluntary basis, standard care treatment as per investigator's discretion or no treatment during the next 8 weeks of the OL phase. Total duration of treatment will be of 14 weeks. Efficacy will primarily be evaluated by percentage of participants who show response as per Mayo DAI Score at Week 6. Participants' safety will be monitored throughout the study.
Interventions
DRUGMAX-002
MAX-002 suppository 1 gram (g) rectally once daily at bedtime for 6 weeks during the DB phase. Participants will then receive either MAX-002 suppository, standard care treatment or no treatment (as per Investigator's judgment) for 8 weeks during the open-label (OL) phase.
DRUGPlacebo
Matching placebo suppository rectally once daily at bedtime for 6 weeks during the DB phase. Participants will then receive either MAX-002 suppository, standard care treatment or no treatment (as per Investigator's judgment) for 8 weeks during the OL phase.
DRUGCanasa®
Canasa® suppository 1 g rectally once daily at bedtime for 6 weeks during the DB phase. Participants will then receive either MAX-002 suppository, standard care treatment or no treatment (as per Investigator's judgment) for 8 weeks during the OL phase.
Sponsors
Forest Laboratories
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Participants who are 18 years old or older * Participants with total Mayo DAI score between 5 to 10 at Screening and participants with score of 2 or more for the rectal bleeding and for the findings of flexible proctosigmoidoscopy or colonoscopy sub-scores of the Mayo DAI * Participants with confirmed mild to moderate active UP not extending above rectum as evidenced by flexible proctosigmoidoscopy and histopathology assessments * Female participants of child-bearing age who have negative serum beta-human chorionic gonadotropin (β-HCG) at the time of entry into the study * Female participants of child-bearing age who use medically acceptable form of birth control * Participants who are smokers and non-smokers must not change their smoking habits or nicotine use during the DB treatment period * Participants who are literate and have legal ability to sign informed consent form
Exclusion criteria
* Participants with other digestive diseases interfering with the measurement of any sub-score of the Mayo DAI * Participants with known presence or suspicion of malignant disease of the digestive system or presence or history of neoplasms other than carcinoma in situ of the cervix or basal carcinoma of the skin * Participants with clinically significant electrocardiographic abnormalities that would compromise its participation in the study * Participants who are chronically using oral 5-aminosalicylic acid (5-ASA) at a dose greater than 4g daily, change in the oral 5-ASA dosing, or use of any form of rectal 5-ASA formulations during the 30 days prior to randomization * Participants with significant use of corticosteroids ,immunosuppressant's or biologic response modifiers that may have a therapeutic effect on ulcerative proctitis during the 45 days before the date of consent * Participants who use any rectally administered medicine during the 30 days prior to randomization * Participants who have contraindication to the use of mesalamine or suppository vehicle, analgesia, flexible proctosigmoidoscopy or colonoscopy * Participants who have blood parameters of grade 3 or higher on the common terminology criteria for adverse events (CTCAE) 5-point scale * Participants with severe renal or hepatic impairment with parameters of grade 3 or higher on the CTCAE * Participants with clinically significant urinary tract obstruction and history of idiopathic pancreatitis * Participants with presence of other known clinically significant medical and/or psychological illnesses precluding participation * Participants who participate in clinical studies other than observational studies during the 90 days before the date of the informed consent form signature * Participants who are unable or unwilling to complete the follow-up evaluations required for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Were Responders at Week 6 | Week 6 | Participants were considered as responders if they had total Mayo Disease Activity Index (DAI) score less than 3 points and no individual sub-scores greater than or equal to 2. Mayo DAI is a semi-quantitative scale which consists of 4 sub-scales: stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy or colonoscopy and physician global assessment, each sub-scale ranged from 0 to 3 (0=normal, 3=severe). The total Mayo DAI score ranges from 0 (normal or inactive disease) to 12 (severe disease). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Were Responders at Week 3 | Week 3 | Participants considered as responders if they had total Mayo DAI score less than 3 points and no individual sub-scores greater than or equal to 2. Mayo DAI is a semi-quantitative scale which consists of 4 sub-scales: stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy or colonoscopy and physician global assessment, each sub-scale ranged from 0 to 3 (0=normal, 3=severe). The total Mayo DAI score ranges from 0 (normal or inactive disease) to 12 (severe disease). |
| Time to Relief of Rectal Bleeding | Day 1 up to Week 6 | Time to relief of rectal bleeding was defined as number of days from randomization (Day 1) up to the first date of 3 consecutive days without observation of rectal bleeding during the double-blind phase. |
| Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Baseline, Week 6 | The IBDQ is used to measure disease specific quality of life. The IBDQ consists of a self-administered 32-item questionnaire that evaluates quality of life across 4 domains of wellness: bowel symptoms (10 questions), systemic symptoms (5 questions), social symptoms (5 questions) and emotional function (12 questions). The response to each question is graded on 7-point likert scale, ranging from 1 (worst aspect) to 7 (best aspect). The total IBDQ is computed as the sum of the responses to the individual IBDQ questions. The total score ranges from 32 to 224 with higher scores indicating a better quality of life. |
| Time to Relief of Tenesmus | Day 1 up to Week 6 | Time to relief of tenesmus (feeling of constantly needing to pass stools, even if the bowels are already empty) was defined as the number of days from randomization (Day 1) up to the first date of 3 consecutive days without observation of tenesmus during the double-blind phase. |
Countries
Canada, Poland, United States
Participant flow
Pre-assignment details
Out of a total 119 double-blind phase participants, 116 participants (including 9 of the 11 participants that terminated early) further continued in the open-label (OL) phase where, under the amended protocol versions 3 and 4, they were provided the opportunity to voluntarily receive MAX-002, standard care treatment, or no treatment
Participants by arm
| Arm | Count |
|---|---|
| MAX-002 (Double-blind Phase) MAX-002 suppository 1 gram (g) rectally once daily at bedtime for 6 weeks during the DB phase. Participants then received either MAX-002 suppository, standard care treatment or no treatment (as per Investigator's judgment) for 8 weeks during the OL phase. | 41 |
| Canasa® (Double-blind Phase) Canasa® suppository 1 g rectally once daily at bedtime for 6 weeks during the DB phase. Participants then received either MAX-002 suppository, standard care treatment or no treatment (as per Investigator's judgment) for 8 weeks during the OL phase. | 39 |
| Placebo (Double-blind Phase) Matching placebo suppository rectally once daily at bedtime for 6 weeks during the DB phase. Participants then received either MAX-002 suppository, standard care treatment or no treatment (as per Investigator's judgment) for 8 weeks during the OL phase | 39 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double-blind Phase | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Double-blind Phase | Disease Progression | 0 | 1 | 2 | 0 | 0 | 0 |
| Double-blind Phase | Lack of Efficacy | 1 | 0 | 5 | 0 | 0 | 0 |
| Double-blind Phase | Withdrawal of Informed Consent | 0 | 0 | 1 | 0 | 0 | 0 |
| Open-Label Phase | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Open-Label Phase | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 | 0 |
| Open-Label Phase | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Open-Label Phase | Withdrawal of Informed Consent | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | MAX-002 (Double-blind Phase) | Canasa® (Double-blind Phase) | Placebo (Double-blind Phase) | Total |
|---|---|---|---|---|
| Age, Continuous | 44.3 years STANDARD_DEVIATION 13.55 | 44.8 years STANDARD_DEVIATION 11.7 | 41.8 years STANDARD_DEVIATION 12.84 | 43.7 years STANDARD_DEVIATION 12.69 |
| Sex: Female, Male Female | 19 Participants | 19 Participants | 23 Participants | 61 Participants |
| Sex: Female, Male Male | 22 Participants | 20 Participants | 16 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 41 | 0 / 38 | 0 / 44 | 0 / 52 | 0 / 20 |
| other Total, other adverse events | 14 / 40 | 16 / 41 | 20 / 38 | 20 / 44 | 20 / 52 | 9 / 20 |
| serious Total, serious adverse events | 0 / 40 | 1 / 41 | 0 / 38 | 1 / 44 | 0 / 52 | 0 / 20 |
Outcome results
Primary
Percentage of Participants Who Were Responders at Week 6
Participants were considered as responders if they had total Mayo Disease Activity Index (DAI) score less than 3 points and no individual sub-scores greater than or equal to 2. Mayo DAI is a semi-quantitative scale which consists of 4 sub-scales: stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy or colonoscopy and physician global assessment, each sub-scale ranged from 0 to 3 (0=normal, 3=severe). The total Mayo DAI score ranges from 0 (normal or inactive disease) to 12 (severe disease).
Time frame: Week 6
Population: ITT population included all randomized participants. Missing values were imputed using non-responder (NR) imputation method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MAX-002 (Double-blind Phase) | Percentage of Participants Who Were Responders at Week 6 | 56.1 percentage of participants |
| Canasa® (Double-blind Phase) | Percentage of Participants Who Were Responders at Week 6 | 46.2 percentage of participants |
| Placebo (Double-blind Phase) | Percentage of Participants Who Were Responders at Week 6 | 23.1 percentage of participants |
Comparison: The comparison between MAX-002 and placebo during the DB phase with respect to the primary outcome measure was the single pre-specified primary analysis, and the null hypothesis was that the percentages were equal between the two groups.p-value: 0.0047Cochran-Mantel-Haenszel
Comparison: The comparison between Canasa® and placebo during the DB phase with respect to the primary outcome measure was a pre-specified tertiary analysis only.p-value: 0.0346Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6
The IBDQ is used to measure disease specific quality of life. The IBDQ consists of a self-administered 32-item questionnaire that evaluates quality of life across 4 domains of wellness: bowel symptoms (10 questions), systemic symptoms (5 questions), social symptoms (5 questions) and emotional function (12 questions). The response to each question is graded on 7-point likert scale, ranging from 1 (worst aspect) to 7 (best aspect). The total IBDQ is computed as the sum of the responses to the individual IBDQ questions. The total score ranges from 32 to 224 with higher scores indicating a better quality of life.
Time frame: Baseline, Week 6
Population: The ITT population included all the participants randomized to study treatment. Missing values were imputed using remaining item average (RIA) imputation algorithm. Here 'n' signifies those participants who were evaluable at specific time point for each arm group, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MAX-002 (Double-blind Phase) | Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Baseline (n= 41, 39, 39) | 153.45 units on a scale | Standard Deviation 35.03 |
| MAX-002 (Double-blind Phase) | Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Change at Week 6 (n= 41, 39, 31) | 30.59 units on a scale | Standard Deviation 28.95 |
| Canasa® (Double-blind Phase) | Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Baseline (n= 41, 39, 39) | 153.19 units on a scale | Standard Deviation 38.75 |
| Canasa® (Double-blind Phase) | Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Change at Week 6 (n= 41, 39, 31) | 42.42 units on a scale | Standard Deviation 31.26 |
| Placebo (Double-blind Phase) | Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Baseline (n= 41, 39, 39) | 149.18 units on a scale | Standard Deviation 32.4 |
| Placebo (Double-blind Phase) | Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Week 6 | Change at Week 6 (n= 41, 39, 31) | 24.48 units on a scale | Standard Deviation 27.29 |
Secondary
Percentage of Participants Who Were Responders at Week 3
Participants considered as responders if they had total Mayo DAI score less than 3 points and no individual sub-scores greater than or equal to 2. Mayo DAI is a semi-quantitative scale which consists of 4 sub-scales: stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy or colonoscopy and physician global assessment, each sub-scale ranged from 0 to 3 (0=normal, 3=severe). The total Mayo DAI score ranges from 0 (normal or inactive disease) to 12 (severe disease).
Time frame: Week 3
Population: ITT population included all randomized participants. Missing values were imputed using NR imputation method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MAX-002 (Double-blind Phase) | Percentage of Participants Who Were Responders at Week 3 | 36.6 percentage of participants |
| Canasa® (Double-blind Phase) | Percentage of Participants Who Were Responders at Week 3 | 38.5 percentage of participants |
| Placebo (Double-blind Phase) | Percentage of Participants Who Were Responders at Week 3 | 12.8 percentage of participants |
Secondary
Time to Relief of Rectal Bleeding
Time to relief of rectal bleeding was defined as number of days from randomization (Day 1) up to the first date of 3 consecutive days without observation of rectal bleeding during the double-blind phase.
Time frame: Day 1 up to Week 6
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MAX-002 (Double-blind Phase) | Time to Relief of Rectal Bleeding | 6 days |
| Canasa® (Double-blind Phase) | Time to Relief of Rectal Bleeding | 5 days |
| Placebo (Double-blind Phase) | Time to Relief of Rectal Bleeding | 21 days |
Secondary
Time to Relief of Tenesmus
Time to relief of tenesmus (feeling of constantly needing to pass stools, even if the bowels are already empty) was defined as the number of days from randomization (Day 1) up to the first date of 3 consecutive days without observation of tenesmus during the double-blind phase.
Time frame: Day 1 up to Week 6
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MAX-002 (Double-blind Phase) | Time to Relief of Tenesmus | 3 days |
| Canasa® (Double-blind Phase) | Time to Relief of Tenesmus | 2 days |
| Placebo (Double-blind Phase) | Time to Relief of Tenesmus | 1 days |