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Efficacy and Safety of Anti-MAP Therapy in Adult Crohn's Disease (MAPUS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01951326
Recruitment Status : Completed
First Posted : September 26, 2013
Results First Posted : May 1, 2020
Last Update Posted : December 8, 2020
Sponsor:
Information provided by (Responsible Party):
RedHill Biopharma Limited

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Crohn's Disease
Interventions Drug: RHB-104
Drug: Placebo
Enrollment 331
Recruitment Details  
Pre-assignment Details  
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Period Title: Overall Study
Started 166 165
Completed 87 87
Not Completed 79 78
Arm/Group Title RHB-104 Placebo Total
Hide Arm/Group Description

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID

 Total of all reporting groups
Overall Number of Baseline Participants 166 165 331
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 166 participants 165 participants 331 participants
39.0  (12.51) 39.3  (12.56) 39.1  (12.52)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 166 participants 165 participants 331 participants
Female
75
  45.2%
67
  40.6%
142
  42.9%
Male
91
  54.8%
98
  59.4%
189
  57.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 166 participants 165 participants 331 participants
American Indian or Alaska Native
0
   0.0%
1
   0.6%
1
   0.3%
Asian
0
   0.0%
1
   0.6%
1
   0.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
8
   4.8%
12
   7.3%
20
   6.0%
White
156
  94.0%
150
  90.9%
306
  92.4%
More than one race
2
   1.2%
1
   0.6%
3
   0.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 166 participants 165 participants 331 participants
Europe 47 50 97
Israel 18 20 38
Southeast Asia 9 12 21
North America 92 83 175
Baseline Crohn's Disease Activity Index (CDAI) score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 166 participants 165 participants 331 participants
297.77  (57.023) 293.44  (53.184) 295.61  (55.102)
[1]
Measure Description:

Generally, CDAI scores can range from 0 to ~600. (in this protocol up to 450)

CDAI scores of 150-219 describe mildly active disease, while scores of 220-450 describe moderately active disease and scores above 450 describe severe disease.
Anti-TNF Use at Baseline  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 166 participants 165 participants 331 participants
37
  22.3%
41
  24.8%
78
  23.6%
1.Primary Outcome
Title Remission at Week 26
Hide Description Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
Time Frame Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
61
  36.7%
37
  22.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0048
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
2.Secondary Outcome
Title Response at Week 26
Hide Description Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome.
Time Frame Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
73
  44.0%
50
  30.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0116
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
3.Secondary Outcome
Title Remission at Week 52
Hide Description Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
47
  28.3%
32
  19.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0616
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
4.Secondary Outcome
Title Durable Remission Week 26 Through Week 52
Hide Description When a subject is in remission with a maximum CDAI score of 149 at every visit from Week 26 through and including Week 52
Time Frame Week 26 through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
33
  19.9%
21
  12.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0851
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
5.Secondary Outcome
Title Remission at Week 16
Hide Description Reduction of the total Crohn's Disease Activity Index (CDAI) score to less than 150. Lower CDAI scores indicate a better outcome.
Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
70
  42.2%
48
  29.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0147
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
6.Secondary Outcome
Title Steroid Free Remission at Week 52
Hide Description Subjects who are maintained off steroids for a minimum of 3 weeks
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 57 55
Measure Type: Count of Participants
Unit of Measure: Participants
11
  19.3%
5
   9.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1510
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
7.Other Pre-specified Outcome
Title Duration of Remission
Hide Description Number of weeks that a subject is in a state of remission. Subjects who experienced remission and continued to be in remission at the time of their last CDAI assessment are censored at the date of their last CDAI assessment.
Time Frame Baseline through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Reached duration of remission (dropped out of remission during the study), n (%): RHB-104 54 (53.5); Placebo: 49 (62.8). Censored (remain in remission during the study), n (%): RHB-104: 47 (46.5); Placebo 29 (37.2)
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 101 78
Median (95% Confidence Interval)
Unit of Measure: weeks
27.1
(16.14 to 46.86)
16.7
(10.14 to 30.00)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2402
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
8.Other Pre-specified Outcome
Title Duration of Response
Hide Description Number of weeks a subject is in a state of response. Subjects who experienced response and continued to be in response at the time of their last CDAI assessment are censored at the date of their last CDAI assessment.
Time Frame Baseline through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Reached duration of response (dropped out of response during the study), n (%) RHB-104: 52 (45.2); Placebo: 55 (59.8). Censored (remain in response during the study), n (%): RHB-104: 63 (54.8); Placebo: 37 (40.2)
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 115 92
Median (95% Confidence Interval)
Unit of Measure: weeks
40.1
(22.14 to 52.29)
22.1
(12.14 to 32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0460
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
9.Other Pre-specified Outcome
Title Time to Remission
Hide Description [Date of first observed remission (CDAI score < 150) - Date of first dose or date of randomization if not dosed + 1] / 7 Days. Subjects who never experienced remission during the study are censored at the date of their last CDAI assessment.
Time Frame Baseline through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects achieved remission, n (%) RHB-104: 101 (60.8); Placebo 78 (47.3). Censored, n (%): RHB-104: 65 (39.2); Placebo 87 (52.7)
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Median (95% Confidence Interval)
Unit of Measure: weeks
12.1
(8.43 to 12.71)
19.9
(13.00 to 52.43)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0031
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
10.Other Pre-specified Outcome
Title Time to Response
Hide Description [Date of first observed response (a reduction from baseline of ≥ 100 in CDAI score) - Date of first dose or date of randomization if not dosed + 1] / 7 Days. Subjects who never experienced response during the study are censored at the date of their last CDAI assessment.
Time Frame Baseline through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects achieved response, n (%): RHB-104: 115 (69.3); Placebo: 92 (55.8); Censored, n (%): RHB-104: 51 (30.7); Placebo: 73 (44.2)
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Median (95% Confidence Interval)
Unit of Measure: weeks
8.3
(8.00 to 9.14)
12.1
(8.14 to 15.71)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0100
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
11.Other Pre-specified Outcome
Title Durable Remission Week 16 Through Week 52
Hide Description Remission in a subject from week 16 through week 52.
Time Frame Week 16 through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
31
  18.7%
14
   8.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0077
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
12.Other Pre-specified Outcome
Title Response at Week 16
Hide Description Reduction of Crohn's Disease Activity Index (CDAI) score by a minimum of 100 points. Lower CDAI scores indicate a better outcome.
Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 166 165
Measure Type: Count of Participants
Unit of Measure: Participants
79
  47.6%
60
  36.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RHB-104, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0422
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified according to anti-TNF agent use (Y/N).
13.Other Pre-specified Outcome
Title Cardiac Safety
Hide Description Change-from-baseline to week 26 in QTcF (based on cardiac safety report)
Time Frame Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine
5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 95 104
Least Squares Mean (90% Confidence Interval)
Unit of Measure: ms
27.8
(25.91 to 29.74)
0.2
(-1.67 to 2.06)
14.Other Pre-specified Outcome
Title Cardiac Safety
Hide Description Placebo-corrected change-from-baseline to week 52 in QTcF (based on cardiac safety report)
Time Frame Baseline through week 52
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description:

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine
5 placebo capsules administered orally BID
Overall Number of Participants Analyzed 63 54
Least Squares Mean (90% Confidence Interval)
Unit of Measure: ms
29.8
(27.57 to 32.02)
-0.8
(-3.16 to 1.57)
Time Frame Baseline through 30 days after last dose of study drug, or up to 13 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title RHB-104 Placebo
Hide Arm/Group Description

5 RHB-104 capsules administered orally BID

RHB-104: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine

5 placebo capsules administered orally BID

Placebo: 5 placebo capsules administered orally BID
All-Cause Mortality
RHB-104 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/166 (0.00%)   0/165 (0.00%) 
Hide Serious Adverse Events
RHB-104 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   31/166 (18.67%)   31/165 (18.79%) 
Cardiac disorders     
Cardiac disorders †  2/166 (1.20%)  1/165 (0.61%) 
Gastrointestinal disorders     
Gastrointestinal disorders †  19/166 (11.45%)  17/165 (10.30%) 
General disorders     
General disorders and administration site conditions *  1/166 (0.60%)  0/165 (0.00%) 
Hepatobiliary disorders     
Hepatobiliary disorders †  2/166 (1.20%)  0/165 (0.00%) 
Infections and infestations     
Infections and infestations †  4/166 (2.41%)  10/165 (6.06%) 
Injury, poisoning and procedural complications     
Injury, poisoning and procedural complications *  1/166 (0.60%)  1/165 (0.61%) 
Investigations     
Investigations *  2/166 (1.20%)  0/165 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasms benign, malignant and unspecified (incl cysts and polyps) *  1/166 (0.60%)  0/165 (0.00%) 
Renal and urinary disorders     
Renal and urinary disorders †  1/166 (0.60%)  2/165 (1.21%) 
Reproductive system and breast disorders     
Reproductive system and breast disorders *  0/166 (0.00%)  1/165 (0.61%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory, thoracic and mediastinal disorders *  0/166 (0.00%)  1/165 (0.61%) 
Vascular disorders     
Vascular disorders *  2/166 (1.20%)  0/165 (0.00%) 
†
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
RHB-104 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   115/166 (69.28%)   90/165 (54.55%) 
Blood and lymphatic system disorders     
Anemia †  10/166 (6.02%)  6/165 (3.64%) 
Gastrointestinal disorders     
Crohn's Disease †  21/166 (12.65%)  25/165 (15.15%) 
Abdominal Pain †  24/166 (14.46%)  19/165 (11.52%) 
Nausea †  22/166 (13.25%)  12/165 (7.27%) 
Diarrheoa *  11/166 (6.63%)  8/165 (4.85%) 
Vomiting *  12/166 (7.23%)  7/165 (4.24%) 
Abdominal tenderness †  4/166 (2.41%)  9/165 (5.45%) 
Pyrexia †  9/166 (5.42%)  6/165 (3.64%) 
Infections and infestations     
Upper Respiratory Tract Infection *  8/166 (4.82%)  9/165 (5.45%) 
Influenza †  6/166 (3.61%)  10/165 (6.06%) 
Viral Upper Respiratory Infections †  7/166 (4.22%)  9/165 (5.45%) 
Clostridium difficile Infection †  3/166 (1.81%)  12/165 (7.27%) 
Musculoskeletal and connective tissue disorders     
Arthralgia †  16/166 (9.64%)  7/165 (4.24%) 
Nervous system disorders     
Headache †  16/166 (9.64%)  17/165 (10.30%) 
Renal and urinary disorders     
Chromaturia †  42/166 (25.30%)  2/165 (1.21%) 
†
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Reza Fathi, Senior VP Research and Development
Organization: RedHill Biopharma
Phone: 972-(0)3-541-3131
EMail: reza@redhillbio.com
Layout table for additonal information
Responsible Party: RedHill Biopharma Limited
ClinicalTrials.gov Identifier: NCT01951326    
Other Study ID Numbers: RHB-104-01
First Submitted: September 19, 2013
First Posted: September 26, 2013
Results First Submitted: March 29, 2020
Results First Posted: May 1, 2020
Last Update Posted: December 8, 2020