Outlook: Clinical Trials

SEPTEMBER 18, 2011
Michelle Reed, PharmD

Linaclotide for Chronic Constipation
In 2 recent randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials, linaclotide was evaluated in patients with chronic constipation (n = 1276).1 Study subjects were randomized to receive either placebo or linaclotide, 145 mcg or 290 mcg, once daily for 12 weeks. The primary efficacy end point was 3 or more complete spontaneous bowel movements (CSBMs) per week and an increase of 1 or more CSBMs from baseline during at least 9 of the 12 weeks.

Results from both studies showed that the primary end point was reached by 21.2% and 16.0% of the patients who received 145 mcg of linaclotide and by 19.4% and 21.3% of the patients who received 290 mcg of linaclotide. In patients who received placebo, 3.3% and 6.0% reached the primary end point (P <.01 for all comparisons of linaclotide with placebo). Additionally, study subjects receiving linaclotide showed significantly greater improvements in all secondary end points compared with placebo. Diarrhea was more common in patients receiving linaclotide, leading to discontinuation of treatment in 4.2% of patients in both linaclotide groups. Investigators concluded that, in these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation.

Risperidone for Chronic Military Service-Related PTSD
A recent, 6-month, randomized, double-blind, placebo-controlled, multicenter trial was conducted at 23 Veterans Administration outpatient medical centers between February 2007 and February 2010 to evaluate the efficacy of risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related Post-traumatic stress disorder (PTSD).2

A total of 296 patients were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate serotonin reuptake inhibitor (SRI) treatments. The primary end point was change in baseline in the Clinician-administered PTSD Scale (CAPS) (range, 0-136). Other measurement scales included the Montgomery-Asberg Depression Rating Scale, Hamilton Anxiety Scale, Clinical Global Impression scale, and Veterans RAND 36-Item Health Survey.

Study results showed that change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% confidence interval [CI], -19.7 to -12.9) and -12.5 in the placebo group (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; P = .11). Risperidone did not reduce symptoms of depression or anxiety, nor did it increase quality of life. Additionally, adverse events were more common with risperidone compared with placebo. Investigators concluded that risperidone did not reduce PTSD symptoms in military-related PTSD with SRI-resistant symptoms.

Treatment of Helicobacter Pylori Infection in Latin America
A recent study evaluated empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori in 7 Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (2 sites).3 The study population (n = 1463) included subjects 21 to 65 years who tested positive for H pylori by a urea breath test. Subjects were randomly assigned to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy; n = 488); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy; n = 489); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy; n = 486). The primary end point was probability of H pylori eradication.

The study demonstrated that the probability of eradication with standard therapy was 82.2%, which was 8.6% higher (95% adjusted CI 2.6-14.5) than with concomitant therapy (73.6%) and 5.6% higher (-0.04% to 11.6) than with sequential therapy (76.5%).

Additionally, neither 4-drug regimen was significantly better than standard triple therapy in any of the 7 sites. Investigators concluded that, in diverse Latin American populations, standard 14-day triple-drug therapy is preferable to 5-day concomitant or
10-day sequential 4-drug regimens as empiric therapy for H pylori infection.

Sertraline or Mirtazapine for Depression in Dementia
The recent Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia trial evaluated the use of sertraline and mirtazapine for depression in dementia.4 Participants were eligible if they had probable or possible Alzheimer's disease, depression (lasting 4 or more weeks), and a Cornell scale for depression in dementia (CSDD) score of ≥8. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no caregiver. Subjects were randomized in a 1:1:1 ratio to receive sertraline (target dose = 150 mg per day), mirtazapine (45 mg), or placebo. All subjects received standard care. The primary outcome was reduction in CSDD score at 13 weeks.

Results showed that there were no significant differences in depression scores among patient groups at 13 weeks. The mean difference between sertraline and placebo was 1.17 (95% CI -0.23 to 2.58; P = .10), the mean difference between mirtazapine and placebo was 0.01 (95% CI -1.37 to 1.38; P = .99), and the mean difference between the mirtazapine and sertraline groups was 1.16 (95% CI -0.25 to 2.57; P = .11). Based on this evidence, investigators concluded that the present practice of first-line use of these antidepressants, with usual care, for treatment of depression in Alzheimer's disease should be reconsidered.

Dr. Reed received her Doctor of Pharmacy degree from the University of the Sciences in Philadelphia, Pennsylvania, and currently works as a medical editor in the greater Philadelphia area.


1. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011;365(6):527-536.

2. Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial. JAMA. 2011;306(5):493-502.

3. Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet. 2011;378(9790):507-514.

4. Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):403-411.