Crohn's Disease
Conditions
Brief summary
A double blind, randomized, multi-center, placebo-controlled study to evaluate the efficacy and safety of HMPL-004 in patients with active moderate Crohn's Disease.
Detailed description
This was a double-blind, randomized, multicenter, placebo-controlled study evaluating the efficacy and safety of oral HMPL-004 in subjects with active moderate Crohn's disease (CD) - Crohn's Disease Activity Index (CDAI) 220 to 400 - on stable doses of CD medications who had not received anti-tumor necrosis factor alpha (anti-TNF-α) for at least 3 months prior to start of treatment. HMPL-004 (or placebo) was added to the subject's existing CD medications. Subjects were observed for an 8-week treatment period and a subsequent 4-week follow-up period.
Interventions
DRUGHMPL-004
HMPL-004 1200 mg/d
DRUGPlacebo
Placebo 1200 mg/d
Sponsors
Hutchison Medipharma Limited
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
* Have active confirmed Crohn's Disease (confirmed radiographically, endoscopic, or histologically), with a CDAI of 220-400 at baseline screen
Exclusion criteria
* They have received anti-TNF-α antibody within 3 months of starting study medication, or cyclosporine, tacrolimus, thalidomide or mycophenolate mofetil within 2 months of starting study medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CDAI Clinical Response -100 at Week 8 | 8 weeks | Percentage of subjects with CDAI clinical response -100 at Week 8 based on ITT population using the WOCF method to impute missing CDAI scores at Week 8. Clinical response -100 was defined as CDAI score decrease of ≥100 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response -100 at Weeks 12 | 12 weeks | Percentage of subjects with CDAI clinical response -100 at Week 12 based on ITT population using the WOCF method to impute missing CDAI scores at Week 12. Clinical response -100 was defined as CDAI score decrease of ≥100 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Remission at Week 4 | 4 weeks | Percentage of subjects achieving remission (CDAI\<150) at week 4. Remission was defined as CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Remission at Week 8 | 8 weeks | Percentage of subjects achieving remission (CDAI\<150) at week 8. Remission was defined as CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Remission at Week 12 | 12 weeks | Percentage of subjects achieving remission (CDAI\<150) at week 12. Remission was defined as CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Clinical Response -70 at Week 4 | 4 weeks | Percentage of patients achieving clinical response -70 at Week 4 (WOCF). Clinical response -70 was defined as CDAI score decrease of ≥70 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Clinical Response -100 at Weeks 4 | 4 weeks | Percentage of subjects with CDAI clinical response -100 at Week 4 based on ITT population using the WOCF method to impute missing CDAI scores at Week 4. Clinical response -100 was defined as CDAI score decrease of ≥100 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Clinical Response -70 at Week 12 | 12 weeks | Percentage of patients achieving clinical response -70 at Week 12 (WOCF). Clinical response -70 was defined as CDAI score decrease of ≥70 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Complete Remission at Week 4 | 4 weeks | Percentage of subjects achieving complete remission (clinical response -100 plus CDAI\<150) at week 4 (WOCF). Complete remission was defined as CDAI score decrease of ≥100 points from baseline and CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Complete Remission at Week 8 | 8 weeks | Percentage of subjects achieving complete remission (clinical response -100 plus CDAI\<150) at week 8 (WOCF). Complete remission was defined as CDAI score decrease of ≥100 points from baseline and CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Complete Remission at Week 12 | 12 weeks | Percentage of subjects achieving complete remission (clinical response -100 plus CDAI\<150) at week 12 (WOCF). Complete remission was defined as CDAI score decrease of ≥100 points from baseline and CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
| Clinical Response -70 at Week 8 | 8 weeks | Percentage of patients achieving clinical response -70 at Week 8 (WOCF). Clinical response -70 was defined as CDAI score decrease of ≥70 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HMPL-004 Subjects who fulfilled all entry criteria and randomized HMPL-004 arm will receive HMPL-004 400 mg 3 times daily 3 times daily for 56 days (8 weeks) with a 28-day (4-week) follow-up. | 51 |
| Placebo Subjects who fulfilled all entry criteria and randomized Placebo arm will receive matching placebo 400 mg 3 times daily 3 times daily for 56 days (8 weeks) with a 28-day (4-week) follow-up. | 50 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | HMPL-004 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants | 44 Participants | 93 Participants |
| Age, Continuous | 42.4 years STANDARD_DEVIATION 13.4 | 46.5 years STANDARD_DEVIATION 14.2 | 44.4 years STANDARD_DEVIATION 13.9 |
| Region of Enrollment Ukraine | 13 participants | 15 participants | 28 participants |
| Region of Enrollment United States | 38 participants | 35 participants | 73 participants |
| Sex: Female, Male Female | 28 Participants | 29 Participants | 57 Participants |
| Sex: Female, Male Male | 23 Participants | 21 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 50 |
| other Total, other adverse events | 26 / 51 | 18 / 50 |
| serious Total, serious adverse events | 2 / 51 | 4 / 50 |
Outcome results
Primary
CDAI Clinical Response -100 at Week 8
Percentage of subjects with CDAI clinical response -100 at Week 8 based on ITT population using the WOCF method to impute missing CDAI scores at Week 8. Clinical response -100 was defined as CDAI score decrease of ≥100 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 8 weeks
Population: Intention-to-treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | CDAI Clinical Response -100 at Week 8 | 19 Participants |
| Placebo | CDAI Clinical Response -100 at Week 8 | 11 Participants |
Secondary
Clinical Response -100 at Weeks 12
Percentage of subjects with CDAI clinical response -100 at Week 12 based on ITT population using the WOCF method to impute missing CDAI scores at Week 12. Clinical response -100 was defined as CDAI score decrease of ≥100 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Clinical Response -100 at Weeks 12 | 17 Participants |
| Placebo | Clinical Response -100 at Weeks 12 | 11 Participants |
Secondary
Clinical Response -100 at Weeks 4
Percentage of subjects with CDAI clinical response -100 at Week 4 based on ITT population using the WOCF method to impute missing CDAI scores at Week 4. Clinical response -100 was defined as CDAI score decrease of ≥100 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 4 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Clinical Response -100 at Weeks 4 | 15 Participants |
| Placebo | Clinical Response -100 at Weeks 4 | 13 Participants |
Secondary
Clinical Response -70 at Week 12
Percentage of patients achieving clinical response -70 at Week 12 (WOCF). Clinical response -70 was defined as CDAI score decrease of ≥70 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Clinical Response -70 at Week 12 | 20 Participants |
| Placebo | Clinical Response -70 at Week 12 | 18 Participants |
Secondary
Clinical Response -70 at Week 4
Percentage of patients achieving clinical response -70 at Week 4 (WOCF). Clinical response -70 was defined as CDAI score decrease of ≥70 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 4 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Clinical Response -70 at Week 4 | 20 Participants |
| Placebo | Clinical Response -70 at Week 4 | 19 Participants |
Secondary
Clinical Response -70 at Week 8
Percentage of patients achieving clinical response -70 at Week 8 (WOCF). Clinical response -70 was defined as CDAI score decrease of ≥70 points from baseline in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 8 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Clinical Response -70 at Week 8 | 25 Participants |
| Placebo | Clinical Response -70 at Week 8 | 16 Participants |
Secondary
Complete Remission at Week 12
Percentage of subjects achieving complete remission (clinical response -100 plus CDAI\<150) at week 12 (WOCF). Complete remission was defined as CDAI score decrease of ≥100 points from baseline and CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Complete Remission at Week 12 | 9 Participants |
| Placebo | Complete Remission at Week 12 | 5 Participants |
Secondary
Complete Remission at Week 4
Percentage of subjects achieving complete remission (clinical response -100 plus CDAI\<150) at week 4 (WOCF). Complete remission was defined as CDAI score decrease of ≥100 points from baseline and CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 4 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Complete Remission at Week 4 | 8 Participants |
| Placebo | Complete Remission at Week 4 | 8 Participants |
Secondary
Complete Remission at Week 8
Percentage of subjects achieving complete remission (clinical response -100 plus CDAI\<150) at week 8 (WOCF). Complete remission was defined as CDAI score decrease of ≥100 points from baseline and CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 8 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Complete Remission at Week 8 | 13 Participants |
| Placebo | Complete Remission at Week 8 | 7 Participants |
Secondary
Remission at Week 12
Percentage of subjects achieving remission (CDAI\<150) at week 12. Remission was defined as CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 12 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Remission at Week 12 | 10 Participants |
| Placebo | Remission at Week 12 | 7 Participants |
Secondary
Remission at Week 4
Percentage of subjects achieving remission (CDAI\<150) at week 4. Remission was defined as CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 4 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Remission at Week 4 | 8 Participants |
| Placebo | Remission at Week 4 | 8 Participants |
Secondary
Remission at Week 8
Percentage of subjects achieving remission (CDAI\<150) at week 8. Remission was defined as CDAI score \<150 in subjects who had no change in concomitant medications for Crohn's disease except for steroids, which could be tapered after Week 8. The CDAI consists of eight variables, including Liquid or very soft stools, Abdominal pain, General well-being, Features of extra-intestinal disease, Oplates for diarrhea, Abdominal mass, Hematocrit and Body weight below standard, each weighted according to its ability to be predictive of disease activity. The total score ranges from 0 to over 600 with higher scores indicating higher disease activity or worse outcome.
Time frame: 8 weeks
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HMPL-004 | Remission at Week 8 | 15 Participants |
| Placebo | Remission at Week 8 | 7 Participants |