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Constipation

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June 30, 2014

AstraZeneca reported result of two pivotal phase III studies of naloxegol, an investigational treatment for opioid-induced constipation (OIC). The phase III studies, KODIAC-4 (n=652) and KODIAC-5 (n=700), were 12-week, multi-center, randomized, double-blind, placebo-controlled pivotal trials that evaluated 12.5mg and 25mg doses of naloxegol, administered once-daily. Primary endpoint data from the KODIAC-4 and -5 studies showed more OIC patients treated with naloxegol 25mg had a consistent response of increased spontaneous bowel movements (SBMs) through 12 weeks of treatment compared to placebo [44% v. 29% (p=0.001 KODIAC-4) and 40% v. 29% (p=0.021 KODIAC-5)]. The 12.5mg dose in KODIAC-5 did not show statistical significance for the primary endpoint. The 25mg dose also demonstrated a higher response rate through 12 weeks of treatment compared to placebo in patients with laxative inadequate response, a secondary endpoint. Results showed patients taking naloxegol 25mg in the KODIAC-4 and KODIAC-5 studies were likely to have a first post-dose spontaneous bowel movement 25-30 hours sooner than placebo, respectively (median six and 12 hours for naloxegol 25mg compared to 36 and 37 hours for placebo, in studies KODIAC-4 and -5, respectively).

November 4, 2013

AstraZeneca released results of a phase III trial of naloxegol for the treatment of non-cancer pain and opioid-induced constipation (OIC). The study enrolled 844 patients, provided a once-daily 25mg dose of naloxegol and lasted 52 weeks, comparing naloxegol (n=534) to usual care (n=270). Usual care was defined as the investigator’s choice of an existing laxative treatment regimen for OIC. Most naloxegol-emergent gastrointestinal adverse events (AEs) occurred early in treatment and were transient with nine patients (1.6%) discontinuing naloxegol due to abdominal pain. Most common treatment-emergent AEs occurring more often with naloxegol v. usual care were abdominal pain (17.8% v. 3.3%), diarrhoea (12.9% v. 5.9%), nausea (9.4% v. 4.1%), headache (9.0% v. 4.8%) and flatulence (6.9% v. 1.1%). Pain scores and opioid doses were comparable between treatment groups and were stable throughout the study. There were two opioid withdrawal AEs reported in patients taking naloxegol (both were deemed unrelated to treatment with naloxegol).

January 14, 2013

Synergy Pharmaceuticals issued results from a phase IIb/III trial of plecanatide for the treatment of chronic idiopathic constipation (CIC). This randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study enrolled 951 patients with CIC. Subjects received 0.3mg, 1mg or 3mg of plecanatide, or placebo, for 12 weeks. Results showed evidence of increasing efficacy at increasing dose levels. Notably, the 3mg dose demonstrated a 19% (p=0.009) overall responder rate (versus placebo of 10.7%), as well as demonstrating a mean increase in complete spontaneous bowel movements (CSBMs) over the 12-week treatment period of 2.13 (p<0.001). In addition, statistically significant improvements (9.7%) in the incidence of diarrhea were observed in the 3mg arm (versus placebo incidence of 1.3%). Plecanatide was well tolerated. Synergy also is conducting a phase IIb study in IBS with constipation (IBS-C).

July 16, 2012

Theravance released results from a phase IIb trial of TD-1211 for the treatment of opioid-induced constipation (OIC) in chronic, non-cancer pain. This randomized, double blind, placebo-controlled, parallel-group, dose-ranging study, 0084, enrolled 217 patients with five or fewer spontaneous bowel movements (SBMs) and at least one additional symptom of constipation during the two-week baseline period. Subjects received TD 1211 5mg for the first four days and then TD 1211 5mg, 10mg or 15mg for the remainder of the treatment period, or placebo for all five weeks. The study met its primary efficacy endpoint: the change from baseline in average SBMs per week over the last four weeks of treatment for the three doses of TD 1211. An increase in SMBs was seen in subjects treated with TD-1211 5mg from 0.1 to 1.6 (0.97; p=0.0413); 10mg from 0.3 to 3.0 (1.61; p=0.0010); and 15mg from 0.2 to 2.7 (1.79; p=0.0003). TD 1211 was generally well tolerated. The most frequent adverse events were abdominal pain, nausea, diarrhea and headache. Theravance noted that the results support progression into phase III development.

August 22, 2011

Adolor reported results from two phase II trials of ADL5945 for chronic non-cancer opioid-induced constipation. The primary endpoint for both studies was the change from baseline in the weekly average of spontaneous bowel movements (SBMs) during treatment. The key secondary endpoint was responder analysis, with responders defined as the subjects who achieved an average weekly frequency of at least three SBMs and an increase of at least one SBM above baseline. Study 242 enrolled approximately 120 subjects who received ADL5945 (0.10mg or 0.25mg) given twice daily (BID) or placebo over a four week period. Statistical significance (p≡0.0003) was achieved for the primary endpoint in the 0.25 mg BID dose group. Statistical significance (p≡ 0.005) also was achieved in the 0.25 mg BID dose group for the secondary endpoint, with a 56% response rate for the active arm and a 26% response rate for the placebo arm. Study 243 enrolled approximately 80 subjects who received a single dose of 0.25 mg once daily or placebo over four weeks. Statistical significance (p≡0.01) was achieved for the primary endpoint. For the secondary endpoint: while the proportion of responders was higher in the 0.25 mg treatment group (42.5% vs. 29.3% in placebo), statistical significance was not achieved.

November 8, 2010

Ironwood and Forest Laboratories reported positive results from a phase III trial of linaclotide for the treatment of irritable bowel syndrome with constipation (IBS-C). This U.S-based randomized, double-blind, placebo-controlled study, dubbed MCP-103-302, enrolled 805 subjects who received a once-daily dose of oral linaclotide 266 mcg or placebo for 26 weeks. The primary endpoints were assessed over the first 12 weeks of treatment an included two composite responder endpoints encompassing abdominal pain and complete spontaneous bowel movements (CSBMs), as well as two individual responder endpoints for abdominal pain and CSBMs. In order to be considered a responder, the endpoints had to be met for at least nine of the first 12 weeks of the treatment period (composite responder endpoint 1) and for at least six of the first 12 weeks (composite responder endpoint 2). A greater proportion of the linaclotide arm versus the placebo arm (12.7% vs. 3%; p<0.0001) had, in the same week, at least a 30 percent reduction in abdominal pain, at least three CSBMs, and an increase of one or more CSBMs. In the linaclotide arm, 18% of the subjects had at least three CSBMs and an increase of one or more CSBMs versus 5% in the placebo arm (p<0.0001). A greater proportion of the linaclotide arm compared to placebo arm (38.9% vs. 19.6%; p<0.0001) had at least a 30 percent reduction in abdominal pain. In addition, a greater proportion of the linaclotide arm compared to the placebo arm (33.7% vs. 13.9%; p<.0001) had, in the same week, at least a 30 percent reduction in abdominal pain and an increase of one or more CSBMs. The treatment was generally well tolerated and the most common adverse event was diarrhea.

November 1, 2010

Theravance released positive results from a phase II trial of TD-1211 for opioid-induced constipation. This U.S.-based, randomized, double-blind, placebo-controlled, dose-escalation study enrolled 70 subjects experiencing constipation while receiving chronic opioid therapy. The subjects received TD-1211 (0.25 mg, 0.75 mg, 2 mg, 5 mg, and 10 mg) or placebo administered orally once-daily in addition to their opioid treatment for a two-week treatment period. The primary efficacy endpoint was the change from baseline in average number of spontaneous bowel movements (SBMs) per week over the treatment period. The two highest doses of TD-1211 demonstrated a statistically significant increase in average SBMs per week of 3.2 SBMs per week and 4.9 SBMs per week, respectively. Median time to first SBM was 28.7 hours for placebo compared with 8.6 hours for 5 mg and 3.6 hours for 10 mg of TD-1211. TD-1211 was generally well tolerated.

October 18, 2010

Albireo released positive results from a phase IIb trial of A3309 for the treatment of chronic idiopathic constipation (CIC). This multicenter, randomized, double-blind, placebo-controlled trial, A3309-002, enrolled 190 subjects with severe CIC who received placebo or A3309 at doses of 5, 10 or 15 mg orally once a day for eight weeks. The primary efficacy endpoint was the change from baseline in spontaneous bowel movements (SBMs) during the first week of treatment. A higher frequency of SBMs occurred in all three active dose groups with statistically significant increased levels for the 10 mg and the 15 mg groups (p≡0.002 and p<0.001 respectively). The numerical magnitude of change was 4.0 and 5.4 SBMs/week respectively in the two highest dose groups. The secondary efficacy endpoints, change in SBM and in complete SBM over the eight week treatment period, were also reached.

October 11, 2010

Synergy issued positive initial results from a phase IIa trial of plecanatide for the treatment of chronic constipation. This randomized, double-blind, placebo-controlled, dose-escalation, cohort-design, multi-center clinical trial enrolled 78 subjects who were dosed with placebo or plecanatide once-daily for 14 consecutive days at oral doses of 0.3 mg, 1.0 mg, 3.0 mg or 9.0 mg, respectively. Benefits were observed in increased frequency of bowel movements, decreased straining and abdominal discomfort, and improvement in other associated clinical measures. There were no reports of diarrhea. Plecanatide treatment exhibited a good safety profile and no severe adverse events were observed.

September 20, 2010

Ironwood Pharmaceuticals and Forest Labs released positive results from a phase III trial of linaclotide for irritable bowel syndrome with constipation. This multicenter, randomized, double-blind, placebo-controlled trial (LIN-MD-31) enrolled 803 subjects who received either a 266 mcg once daily dose of linaclotide or placebo for a 12 week period. There were four primary efficacy endpoints: two composite responder endpoints encompassing abdominal pain and complete spontaneous bowel movements (CSBMs) and individual responder endpoints for abdominal pain and CSBMs. To be considered a responder, the first three endpoints had to be met for at least nine of the 12 weeks of the treatment, while the fourth had to be met for at least six of the 12 weeks. All four endpoints showed statistically significant improvement over placebo. In the linaclotide arm 12.1% of subjects had, in the same week, at least a 30 percent reduction in abdominal pain, at least three CSBMs, and an increase of one or more CSBMs versus 5.1% of the placebo arm (p≡0.0004). A greater proportion of the linaclotide arm compared to the placebo arm had, in the same week, at least three CSBMs and an increase of one or more CSBMs (19.5% versus 6.3%, p<0.0001). In the linaclotide arm 34.3% had at least a 30 percent reduction in abdominal pain versus 27.1% in the placebo arm (p≡0.0262). A greater proportion of linaclotide arm had, in the same week, at least a 30 percent reduction in abdominal pain and an increase of one or more CSBMs compared to placebo arm (33.6% versus 21%, p<0.0001) All secondary endpoints were also reached.

November 9, 2009

Ironwood Pharma and Forest Labs issued positive results from two phase III trials of linaclotide for chronic constipation. Both randomized, double-blind, parallel group studies evaluated linaclotide (133 mcg or 266 mcg) versus placebo once daily for 12 weeks. The primary endpoint was the 12-week complete spontaneous bowel movement (CSBM). Study 303 enrolled 643 subjects. The 12-week CSBM overall responder rate was 21.2% in the 133 mcg linaclotide group (p<0.0001) and 19.4% in the 266 mcg linaclotide group (p<0.0001) versus 3.3% in the placebo group. The linaclotide-treated arms also demonstrated a significant increase in average weekly CSBMs from baseline (0.5 for placebo; 1.9 for 133 mcg, p<0.0001; 2.0 for 266 mcg, p<0.0001) and a significant increase in average weekly SBMs from baseline (1.1 for placebo; 3.0 for 133 mcg, p<0.0001; 3.0 for 266 mcg, p<0.0001). Study 01 enrolled 633 subjects. The 12-week CSBM overall responder rate was 16% in the 133 mcg linaclotide group (p&rquiv;0.0012) and 21.3% in the 266 mcg linaclotide group (p<0.0001) versus 6% in the placebo group. The linaclotide-treated arms also demonstrated a significant increase in average weekly CSBMs from baseline (0.6 for placebo; 2.0 for 133 mcg, p<0.0001; 2.7 for 266 mcg, p<0.0001) and a significant increase in average weekly spontaneous bowel movements (SBMs) from baseline (1.1 for placebo; 3.4 for 133 mcg, p<0.0001; 3.7 for 266 mcg, p<0.0001). In both studies all secondary endpoints, including bloating, abdominal discomfort, stool consistency, straining, and constipation severity, were statistically significant for both doses of linaclotide versus placebo (p<0.01).

November 2, 2009

Nektar issued positive results from a phase II trial of NKTR-118 for the treatment of opioid induced constipation. This multi-center, randomized, placebo-controlled, dose-escalation trial enrolled 208 subjects who were being treated with opiates for moderate to severe pain. The subjects received placebo or one of three different doses of NKTR-118 (5, 25 or 50 mg) given as a single daily oral dose for a treatment period of four weeks, in addition to their opioid therapy. The primary endpoint was increase from baseline in spontaneous bowel movements (SBMs) per week. Both the 25 and 50mg dose cohorts reached the endpoints with statistical significance. The mean change from baseline in SBMs per week for the 25 mg NKTR-118 cohort was 3.6 versus 1.9 in the placebo group (p≡0.002). Subjects receiving 50 mg NKTR-118 had a mean change from baseline in SBMs per week of 4.4 versus 1.9 in the placebo group (p≡0.0001). The increase from baseline in SBMs versus placebo averaged over the four-week treatment period was significant for both the 25 mg (p≡0.002) and 50 mg (p<0.0001) dose groups. There was also a statistically significant difference in median time to first SBM for subjects the 25 mg and 50 mg dose cohorts as compared to placebo. Median time to first SBM for the 25 mg dose cohort was 6.6 hours as compared to placebo which was 48.6 hours (p≡0.001), and for the 50 mg dose cohort, median time to first SBM was 2.9 hours as compared to placebo, which was 44.9 hours (p<0.002). There was no apparent reversal of opioid-mediated analgesia with any of the NKTR-118 dose groups.

May 18, 2009

Progenics released positive results from a phase III trial of Relistor (methylnaltrexone) for the treatment of opioid-induced constipation in patients with chronic, non-cancer pain. This doubled blind, randomized, placebo controlled study enrolled 468 subjects on stable doses of opioids and experiencing less than three bowel movements per week. The subjects received subcutaneous methylnaltrexone 12 mg either once daily (QD) or once every other day (QOD) or placebo for four weeks. The co-primary endpoints were reached. Subjects taking methylnaltrexone experienced rescue-free bowel movements within four hours of the first dose significantly more frequently than those taking placebo (34.2% versus 9.9%, P<0.001). In addition, the percentage of all active doses resulting in laxation within four hours was significantly greater than placebo for each of the methylnaltrexone treatment groups (30.2% versus 9.3% for methylnaltrexone versus placebo, QOD, and 28.9% versus 9.4% for methylnaltrexone versus placebo, QD, respectively, P<0.001). Key secondary end points of the study, time to first rescue free bowel movements (RFBM) after the first injection and the average increase in weekly number of RFBMs from baseline, were both statistically significant relative to placebo. Treatment was generally well tolerated.

March 9, 2009

Nektar Therapeutics released positive results from a phase II trial of NKTR-118 for the treatment of opioid-induced constipation (OIC). This international, multi-center, randomized, double-blind, dose-escalation, placebo-controlled trial enrolled 208 subjects who were being treated with opiates for moderate to severe pain. The subjects received placebo or one of three different dose cohorts (5 mg, 25 mg, and 50 mg given as a single daily oral dose) for a treatment period of four weeks. The primary endpoint was a change in spontaneous bowel movements (SBMs) from baseline to after the first week of NKTR-118 treatment. The primary endpoint was reached with statistical significance in both the 25 mg and 50 mg cohorts versus placebo. In the 25 mg dose cohort, subjects had an average of 5.1 SBMs during the first week of treatment as compared to 1.5 SBMs per week during the baseline period. Subjects in the 50 mg dose cohort had an average of 5.7 SBMs during the first week of treatment versus 1.6 SBMs per week during the baseline period. The increase in SBMs versus placebo was maintained over the 28-day treatment period (p<0.01). Secondary endpoints were also reached; there was no reversal of analgesia as measured by a change in pain Numerical Rating Scale and no increase in opiate use. NKTR-118 was well tolerated. Based on the results, Nektar plans to development into phase III trials.

October 27, 2008

Movetis reported positive results from two clinical trials of prucalopride for the treatment of constipation. The first study, USA-3, was a phase II, double-blind, placebo-controlled, dose-finding design and enrolled 213 subjects with chronic constipation. Following a four-week drug-free run-in phase, the subjects received either 0.5 mg, 1 mg, 2 mg, and 4 mg of prucalopride or placebo given orally once daily for four weeks. Both the 2 mg and 4 mg doses of prucalopride were superior to the 0.5 mg and 1 mg doses. The 4 mg dose showed a minimal benefit over 2 mg but a less favourable adverse events profile. Hence prucalopride 2 mg once daily was chosen as the optimal dose. The second study, USA-28, was a phase III, two-period, double-blind, placebo-controlled design and enrolled 516 subjects with chronic constipation. Following a two week drug-free run-in period, the subjects received either 4 mg prucalopride or placebo, given orally once daily before breakfast, for four weeks. They again underwent a drug-free washout period of at least two weeks, and a second four-week double-blind treatment period. Data showed that re-treatment with prucalopride led to rapid and sustained symptom relief. The efficacy findings during four weeks of treatment were comparable to those during four weeks of re-treatment. Prucalopride was well tolerated. An MAA is currently under review by the EMEA and Swissmedic.

September 29, 2008

Sucampo issued positive results from a phase IIb trial of Amitiza for the treatment of Chronic Idiopathic Constipation. This randomized, parallel group, double-blind, placebo-controlled, multi-center study enrolled 170 subjects in Japan. The subjects received one of three twice-daily doses of Amitiza (8, 16 or 24 mcg) or placebo. The primary endpoint was mean change in spontaneous bowel movements (SBM) from baseline after one week of treatment. This endpoint was reached with statistical significance in the group treated with Amitiza 24 micrograms (p less than 0.0001). Statistical significance over placebo was also observed for several secondary endpoints, including change in SBM after week two, mean weekly SBM, percentage of subjects having first SBM within 24 and 48 hours and several symptoms of Chronic Idiopathic Constipation. The 16 mcg twice-daily dose of Amitiza also demonstrated statistically significant improvements over placebo in the primary endpoint and some of the secondary endpoints. Treatment was generally well tolerated. Based on the results, Sucampo is planning to commence phase III trials in Japan.

May 12, 2008

Nektar reported positive results from a phase I trial of NKTR-118 for the treatment of opiod-induced bowel dysfunction. This multi-dose, double-blind, randomized, placebo-controlled study enrolled 32 healthy subjects not receiving opioid therapy. The subjects received NKTR-118 (in escalating doses up to 250 mg) or placebo twice daily for seven days, with a single dose on the eighth day. NKTR-118 was shown to be safe and generally well-tolerated at doses up to 250 mg twice daily, with no serious or severe adverse events. The pharmacokinetics of NKTR-118 were dose-proportional and the observed terminal half-life of the drug was approximately eleven hours, independent of dose. At all dose levels, NKTR-118 was rapidly absorbed after oral administration, as evidenced by a steep increase of plasma NKTR-118 concentration. Phase II trials of NKTR-118 are currently underway.

November 12, 2007

Movetis reported positive results from the first of three phase III trials of Resolor for the treatment of chronic constipation. This multicenter, parallel-group, randomized, double-blind, placebo-controlled study enrolled 713 subjects with chronic constipation (<2 spontaneous complete bowel movements (SCBM)/week) for whom laxatives do not provide adequate relief. The subjects received oral doses of 2 mg or 4 mg Resolor, once daily, for twelve weeks. The percentages of subjects with more than three SCBM/week averaged over four and twelve weeks were 10.4% and 9.6% for placebo, 23.7% and 19.5% for Resolor (2 mg) and 26.6% and 23.6% for Resolor (4 mg), respectively. In addition, over the four and twelve week time periods, both doses of Resolor showed the following improvements over placebo: percentage of subjects with an increase of one or more SCBM/week (41.0% vs. 20.9% and 38.1 vs. 20.9%, respectively; p=0.001); percentage of bowel movements with normal consistency (p=0.05); percentage of BM with no straining (p=0.01); perceived severity of constipation (p=0.001) and overall treatment satisfaction scores (p=0.001). Treatment was determined to be safe and well tolerated. Based on the results. Movetis plans to file for European regulatory approval in mid-2008.

September 24, 2007

Nektar issued positive results from a phase I trial of NKTR-118 for the treatment of opioid bowel dysfunction (OBD). This single-dose, double-blind, placebo-controlled study enrolled healthy male subjects who received placebo or escalating, single oral doses of NKTR-118 up to 1,000 mg. The trial measured the morphine-induced delay in gastrointestinal transit time using the lactulose hydrogen gastrointestinal motility test. NKTR-118 antagonized morphine-induced delay in gastrointestinal transit time, demonstrating the potential of the drug to relieve constipation. Further, no dimunition of morphine-induced miosis, a CNS effect, was observed at single oral doses of NKTR-118 of 125 mg or less. NKTR-118 was rapidly absorbed with dose-proportional pharmacokinetics and it was well tolerated at single doses up to 1,000 mg. Based on the results, Nektar plans to initiate a phase I multi-dose trial later in 2007.

July 9, 2007

Progenics and Wyeth reported positive results from an open label phase III extension trial of subcutaneous methylnaltrexone (MNTX) for the treatment of opioid-induced constipation (OIC). This three month extension trial enrolled 82 subjects who had completed a previous phase III trial (MNTX 302). Of these subjects, 42 had received subcutaneous methylnaltrexone in the prior trial and 40 had received placebo. Of the subjects who had prior MNTX the mean laxation response rates (laxation within four hours) were 45.5% during the first month, 57.7% in the second month, and 57.3% in the third month. Of the subjects with no prior MNTX experience, laxation response rates were 48.3% during the first month, 47.6% in the second month, and 52.1% in the third month. This long term data were included in the NDA filing currently under review by the FDA.

July 2, 2007

Theravance announced positive results from a phase II trial of TD-5108 for the treatment of chronic constipation. This trial, dubbed ACCORD ((A randomized, plaCebo COntRolled, double-blind study of TD-5108) was a multi-center, randomized, double-blind, placebo-controlled study. A total of 400 subjects were enrolled and were randomized to receive one of three doses of TD-5108 (15 mg, 30 mg, or 50 mg) or placebo, administered once daily over a four-week period. The primary endpoint, increased number of spontaneous bowel movements (SBM) per week over baseline compared with placebo, was reached for all three doses. The average weekly increases over the four-week period in SBM from baseline for subjects treated with TD-5108 were 3.6 for the 15 mg treatment group (p < 0.0001, 3.3 for the 30 mg group (p < 0.0001) and 3.5 for the 50 mg group (p < 0.0001). The average weekly increase in SBM from baseline for subjects on placebo was 1.4. Responders, (subjects who experienced at least three SBM for each of the four weeks), occurred in 60% of the subjects in the 15 mg treatment group, 42% of the 30 mg group, and 61% of the 50 mg group, compared with 22% of those on placebo. In addition, when compared to placebo, there was a statistically significant reduction in time to first SBM and a statistically significant increase in the percentage of subjects who experienced an SBM within the first 24 hours for all groups treated with TD-5108. Based on the results, Theravance plans to move forward with phase III trials.

February 19, 2007

Dynogen reported positive results from a phase II trial of DDP733 for the treatment of irritable bowel syndrome with constipation (IBS-c). This randomized, double-blind, placebo-controlled, parallel group trial enrolled 91 subjects in Canada. Treatment was well tolerated with adverse events mild to moderate in nature. The clinical response rate, measured using the Overall Subject Global Assessment (OSGA), reached statistical significance versus placebo. The overall clinical response rate was 54% in subjects receiving DDP733 at a dose of 1.4 mg t.i.d. compared to a 15% for those receiving placebo. Based on these results, Dynogen plans to initiate a phase IIb trial later in 2007.

February 20, 2006

Progenics issued positive results of a phase III trial of methylnaltrexone for the treatment of opioid induced constipation. Subcutaneous administration of the drug was shown to induce laxation within four hours of treatment for 48.4% of subjects following a single dose, compared to 15.5% for placebo following a single dose (p<0.0001). Further, 51.6% of subjects responded to at least 2 of the first 4 doses, vs. 8.5% for placebo (p<0.000). Median time to laxation was 30 minutes for subjects who responded to drug administration. Safety data indicated that the drug was generally well tolerated. This double-blind, randomized, placebo-controlled study enrolled 133 patients across 27 nursing homes and hospice facilities, who received 0.15 mg/kg of the drug or placebo every other day during the first week of the study; dose was escalated to 0.30 mg/kg if patients did not significantly respond to the initial dose.

February 23, 2004

Sucampo reported positive results from a phase III trial investigating SPI-0211, a chloride channel activator for the treatment of constipation. Results demonstrated long-term safety and efficacy in treating constipation with SPI-0211. The placebo-controlled, randomized, open-label safety study enrolled 299 subjects at 20 sites in the U.S. Some subjects (n= 120) entered into a withdrawal phase prior to entering the study. Subjects were given active treatment or placebo for an additional three weeks before entering into the 48-week open label safety portion of the study. Subjects at the other 12 sites were enrolled directly into the 48-week open-label treatment.

October 20, 2003

Novartis reported positive results from a post-marketing trial investigating Zelnorm (tegaserod maleate), an approved drug for the treatment of irritable bowel syndrome with constipation. Results showed Zelnorm was significantly more effective than placebo in improving straining, stool consistency, frequency of bowel movements, and other symptoms of chronic constipation. Data demonstrated that Zelnorm-treated subjects experienced significantly more complete spontaneous bowel movements than subjects receiving placebo did. The multinational, randomized, double-blind, placebo-controlled study enrolled 1,264 subjects. Subjects had experienced chronic constipation for an average of 15 years. Results were presented today at the 68th Annual Scientific Meeting of the American College of Gastroenterology.

July 14, 2003

The BioBalance Corp. reported positive results from a pilot study investigating Probactrix, a probiotic oral suspension for the treatment of irritable bowel syndrome (IBS). Probactrix is a formulation of M-17 E. coli which is approved as an OTC pharmaceutical in Russia and as a food supplement in Israel. Results showed eight out of ten subjects that started on placebo dropped out because of infectivity compared with none of the subjects taking ProBactrix. Data demonstrated significant improvement in bowel movement and mucus in stools among subjects taking ProBactrix. The randomized, double blind study enrolled 20 subjects experiencing severe symptoms of diarrhea and constipation. Results were presented at the 2003 Annual Meeting of the American Society of Gastroenterologists.

June 2, 2003

Axcan Pharma reported positive results from a pilot study investigating mesalamine rectal gel, an anti-inflammatory agent for the treatment of ulcerative colitis. Results showed a statistically significant difference between baseline and end-of- treatment Disease Activity Index, a measure of disease severity based on symptom scores. The pilot study was designed to test the efficacy and safety of mesalamine gel in subjects with mild to moderate distal ulcerative colitis. Subjects were included in this study based on a disease activity index greater than three. All received a single rectal dose of 4 g of mesalamine in 60-mL gel and received a similar dose for four consecutive days 48 hours.

Sucampo Pharmaceuticals reported positive results from a phase III trial investigating SPI-0211, a chloride channel activator for the treatment of constipation. Results showed the treatment performed significantly better than placebo for all constipation variables tested. Data demonstrated a significant increase in spontaneous bowel movement frequency and significant improvements in straining and stool consistency. The drug was found safe and well tolerated. Study results were presented at the Digestive Disease Week 2003 Conference. The multi-center, randomized, placebo-controlled trial enrolled 242 subjects with occasional constipation and was designed to test the saftey and efficacy of SPI-0211 (24 mg) twice daily.

May 5, 2003

Progenics reported positive results from a phase II trial investigating methylnatexone (MNTX) for the treatment of opiod-induced constipation. Results showed that an average of 60% of subjects who received at least 5 mg had a bowel movement within four hours compared with less than 8% at lower doses. Median time to laxation was approximately one hour after receiving greater than or equal to 5 mg of MNTX. The most common side effects were flatulence and transient abdominal cramping. The randomized, double blind study enrolled 33 subjects with advanced medical illness who were experiencing opioid-induced constipation. Subjects received one of four fixed doses of subcutaneous MNTX (1.0, 5, 12.5 or 20 mg).

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