BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. We aimed to assess the efficacy and safety of linaclotide in paediatric patients aged 6-17 years with functional constipation. METHODS: This randomised, double-blind, placebo-controlled, multicentre, phase 3 study was done at 64 clinic or hospital sites in seven countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6-17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of four and stratified by age (6-11 years and 12-17 years), to receive either oral linaclotide 72 µg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy endpoint was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy endpoint was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analysed in all patients in the randomised population who received at least one dose of study intervention (modified intention-to-treat population and safety population, respectively). The study is registered with ClinicalTrials.gov, NCT04026113, and the functional constipation part of the study is complete. FINDINGS: Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1·28 SBMs per week (SD 0·87) for placebo and 1·16 SBMs per week (0·83) for linaclotide, increasing to 2·29 SBMs per week (1·99) for placebo and 3·41 SBMs per week (2·76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1·11 [SE 0·08] vs 0·69 [0·08]; LSM CFB difference 0·42 [95% CI 0·21-0·64]; p=0·0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhoea (seven [4%] of 164 vs three [2%] of 164 patients in the placebo group) and by patients treated with placebo was COVID-19 (five [3%] vs four [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhoea (linaclotide: six [4%] patients; placebo: two [1%] patients). One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study. INTERPRETATION: Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. FUNDING: AbbVie and Ironwood Pharmaceuticals.
Constipation , Peptides , Adult , Humans , Male , Female , Child , Treatment Outcome , Constipation/drug therapy , Constipation/chemically induced , Peptides/adverse effects , Diarrhea/chemically induced , Double-Blind Method
Background: Advanced age and underlying comorbidities are associated with greater rates of recurrence in patients with Clostridioides difficile infection (CDI). Reducing the likelihood of recurrence through treatment with an antimicrobial followed by a microbiota replacement therapy can decrease the burden of this infection and improve patient outcomes. We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in older adults with recurrent CDI, grouped by comorbidities. Methods: In this post hoc subgroup analysis of the PUNCH CD3 trial, we assessed outcomes in older adults (age ≥65 years) grouped by Charlson Comorbidity Index severity scores at screening (moderate [3-4] and severe [≥5]) and by the presence of underlying cardiac, renal, or gastrointestinal disorders. Results: RBX2660 treatment success rates in older adults with comorbidities were consistent across subgroups and similar to those in the total RBX2660-treated population. A greater percentage of RBX2660-treated older adults remained free of CDI recurrence through 8 weeks following treatment compared with placebo-treated participants in all but 2 subgroups assessed. Across all subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and related to a preexisting condition. None of the serious or life-threatening TEAEs that occurred were related to RBX2660 or its administration. Occurrence of TEAEs did not cluster in any subgroup. Conclusions: RBX2660 is efficacious and safe in older adults with recurrent CDI and underlying comorbidities.
BACKGROUND: Selecting a bowel preparation for patients with renal impairment or diabetes requires special consideration. We aimed to describe the effect of baseline renal impairment or diabetes on the safety, efficacy, and tolerability of low-volume sodium picosulfate, magnesium oxide, and citric acid (SPMC) ready-to-drink oral solution bowel preparation. METHODS: A post hoc secondary analysis was performed from a randomized, assessor-blinded study of SPMC oral solution bowel preparation in participants with mild or moderate baseline renal impairment or diabetes. Primary efficacy endpoint ('responders') was the proportion of participants with 'excellent' or 'good' ratings on a modified Aronchick Scale (AS). Secondary efficacy outcomes were the quality of ascending colon cleansing from the Boston Bowel Preparation Scale (BBPS), and selected results from the Mayo Clinic Bowel Prep Tolerability Questionnaire. Safety assessments included adverse events (AEs), adenoma detection, and laboratory evaluations. RESULTS: Similar overall colon cleansing was demonstrated in the subgroups, with >85% of participants in any subgroup rated as responders by the AS, and >92% of participant responders by the BBPS. Most participants reported a tolerable bowel preparation, regardless of baseline renal impairment or diabetes history. Safety of SPMC oral solution was similar between all subgroups and the overall cohort. For the mild renal impairment, moderate renal impairment, and diabetes subgroups, respectively, commonly reported, drug-related AEs were nausea (2.6%, 5.3%, 1.4%) and headache (2.2%, 2.6%, 4.3%). CONCLUSIONS: Ready-to-drink SPMC oral solution demonstrated efficacious colon cleansing in patients with baseline mild/moderate renal impairment or diabetes, with a tolerable bowel preparation reported by most. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03017235.
BACKGROUND: Bowel preparation in children can be challenging. AIM: To describe the efficacy, safety, and tolerability of sodium picosulfate, magnesium oxide, and citric acid (SPMC) bowel preparation in children. METHODS: Phase 3, randomized, assessor-blinded, multicenter study of low-volume, divided dose SPMC enrolled children 9-16 years undergoing elective colonoscopy. Participants 9-12 years were randomized 1:1:1 to SPMC ½ dose × 2, SPMC 1 dose × 2, or polyethylene glycol (PEG). Participants 13-16 years were randomized 1:1 to SPMC 1 dose × 2 or PEG. PEG-based bowel preparations were administered per local protocol. Primary efficacy endpoint for quality of bowel preparation was responders (rating of 'excellent' or 'good') by modified Aronchick Scale. Secondary efficacy endpoint was participant's tolerability and satisfaction from a 7-item questionnaire. Safety assessments included adverse events (AEs) and laboratory evaluations. RESULTS: 78 participants were randomized, 48 were 9-12 years, 30 were 13-16 years. For the primary efficacy endpoint in 9-12 years, 50.0%, 87.5%, and 81.3% were responders for SPMC ½ dose × 2, SPMC 1 dose × 2, and PEG groups, respectively. Responder rates for 13-16 years were 81.3% for SPMC 1 dose × 2 and 85.7% for PEG. Overall, 43.8% of participants receiving SPMC 1 dose × 2 reported it was 'very easy' or 'easy' to drink, compared with 20.0% receiving PEG. Treatment-emergent AEs were reported by 45.5% of participants receiving SPMC 1 dose × 2 and 63.0% receiving PEG. CONCLUSION: SPMC was an efficacious and safe for bowel preparation in children 9-16 years, with comparable efficacy to PEG. Tolerability for SPMC was higher compared to PEG.
Magnesium Oxide , Organometallic Compounds , Cathartics/adverse effects , Child , Citrates/adverse effects , Citric Acid/adverse effects , Colonoscopy , Humans , Magnesium Oxide/adverse effects , Organometallic Compounds/adverse effects , Picolines , Polyethylene Glycols/adverse effects
BACKGROUND: We performed a post hoc secondary analysis for the effect of body mass index (BMI) on the efficacy, tolerability, and safety of ready-to-drink sodium picosulfate, magnesium oxide, and citric acid (SPMC oral solution) bowel preparation. METHODS: A phase III, randomized, assessor-blinded, multicenter, noninferiority study was conducted comparing split-dose, low-volume SPMC oral solution with a powder formulation for oral solution. A post hoc secondary analysis assessed efficacy, safety, and tolerability of SPMC oral solution stratified by BMI. BMI was classified by Centers for Disease Control and Prevention definitions (underweight and normal weight: BMI < 25 kg/m2; overweight: BMI 25-29.9 kg/m2; class I obesity: BMI 30-34.9 kg/m2; class II obesity: BMI 35-39.9 kg/m2; class III/severe obesity: BMI ⩾40 kg/m2). Prespecified primary efficacy endpoint ('responders') was the proportion of participants with 'excellent' or 'good' ratings on a modified Aronchick Scale (AS). Secondary efficacy outcomes were the quality of cleansing of the right colon as assessed by the Boston Bowel Preparation Scale (BBPS); as well as selected findings from the Mayo Clinic Bowel Prep Tolerability Questionnaire. Safety assessments included adverse events (AEs) and laboratory evaluations. RESULTS: Between 82.8% and 92.5% of participants in any BMI group were responders by AS, and between 91.3% and 100% were responders by BBPS in the right colon. Efficacy was consistent across BMI groups, with no clear trends. Greater than 83% of participants in any BMI group found the preparation 'easy' or 'acceptable' to ingest, and the majority (>58%) rated SPMC oral solution as 'better' than a prior bowel preparation. In all BMI groups, safety data were similar to the overall cohort. Commonly reported, drug-related, treatment-emergent AEs were, by ascending BMI group, nausea (1.1%, 5.3%, 1.0%, 5.7%, and 0%) and headache (1.1%, 4.1%, 1.0%, 5.7%, and 0%). CONCLUSIONS: Ready-to-drink SPMC oral solution had consistent, good quality colon cleansing, and favorable tolerability among participants of all BMI groups. CLINICALTRIALSGOV REGISTRATION: NCT03017235.
BACKGROUND: The incidence and mortality of colorectal cancer (CRC) increase with age and, therefore, it is recommended that adults undergo regular CRC screening, ideally by colonoscopy, with some new guidelines recommending screening begin at 45 years. Effective bowel preparation is a critical step to a successful colonoscopy. Of concern is that older adults may have poorer quality of bowel preparation or reduced tolerability for the bowel preparation. Here, we performed a post hoc secondary analysis for the effect of age on the efficacy, tolerability, and safety of ready-to-drink sodium picosulfate, magnesium oxide, and citric acid (SPMC oral solution) bowel preparation. METHODS: A phase III, randomized, assessor-blinded, multicenter, non-inferiority study was conducted comparing split-dose, low-volume SPMC oral solution with split-dose, low-volume sodium picosulfate, magnesium oxide, and citric acid powder for oral solution. A post hoc secondary analysis was performed to assess efficacy, safety, and tolerability of SPMC oral solution by age group (<50 years, 50-64 years, ⩾65 years). The prespecified primary efficacy endpoint ('responders') was the proportion of participants with 'excellent' or 'good' ratings on a modified Aronchick Scale (AS). Secondary efficacy outcomes were the quality of cleansing of the right colon as assessed by the Boston Bowel Preparation Scale (BBPS); as well as selected findings from the Mayo Clinic Bowel Prep Tolerability Questionnaire. Safety assessments included adverse events (AEs) and laboratory evaluations. RESULTS: Within age groups, at least 83.9% of participants were responders by the AS, and at least 91.1% of participants were responders by the BBPS in the right colon. On both scales, responder rates were highest in the youngest age group and decreased with increasing age. Greater than 88% of participants in any age group found the preparation 'easy' or 'acceptable' to ingest, with rates of 'easy' being highest in the oldest age group. No new safety signals were seen in any age group. The most commonly reported drug-related, treatment-emergent AEs were, by ascending age group, nausea (7.0%, 3.2%, 0.8%), headache (4.2%, 2.8%, 1.6%) and vomiting (2.8%, 1.2%, 0.8%). CONCLUSION: Ready-to-drink SPMC oral solution showed good efficacy of overall colon cleansing and tolerability in adults across different age groups, including those ⩾65 years.ClinicalTrials.gov identifier: NCT03017235.
OBJECTIVE: To determine the cost of achieving a live birth after first transfer using highly purified human menotropin (HP-hMG) or recombinant follicle-stimulating hormone (FSH) for controlled ovarian stimulation in predicted high-responder patients in the Menopur in Gonadotropin-releasing hormone Antagonist Single Embryo Transfer-High Responder (MEGASET-HR) trial. DESIGN: Cost minimization analysis of trial results. SETTING: Thirty-one fertility centers. PATIENTS: Six hundred and nineteen women with serum antimüllerian hormone ≥5 ng/mL. INTERVENTIONS: Controlled ovarian stimulation with HP-hMG or recombinant FSH in a gonadotropin-releasing hormone (GnRH) antagonist assisted reproduction cycle where fresh transfer of a single blastocyst was performed unless ovarian response was excessive whereupon all embryos were cryopreserved and patients could undergo subsequent frozen blastocyst transfer within 6 months of randomization. MAIN OUTCOME MEASURES: Mean cost of achieving live birth after first transfer (fresh or frozen). RESULTS: First-transfer efficacy, defined as live birth after first fresh or frozen transfer, was 54.5% for HP-hMG and 48.0% for recombinant FSH (difference 6.5%). Average cost to achieve a live birth after first transfer (fresh or frozen) was lower with HP-hMG compared with recombinant FSH. For fresh transfers, the cost was lower with HP-hMG compared with recombinant FSH. The average cost to achieve a live birth after first frozen transfer was also lower in patients treated with HP-hMG compared with recombinant FSH. CONCLUSIONS: Treatment of predicted high-responders with HP-hMG was associated with lower cost to achieve a live birth after first transfer compared with recombinant FSH. CLINICAL TRIAL REGISTRATION NUMBER: NCT02554279.
OBJECTIVE: Testosterone replacement therapy is indicated for male hypogonadism. This study aimed to evaluate the efficacy and safety of testosterone gel 2% (Tgel) over 90 days. METHODS: This phase 3, open-label, noncomparator study was conducted in adult hypogonadal men (2 consecutive fasting serum testosterone values <300 ng/dL and >86% subjects with symptoms consistent with testosterone deficiency). Subjects applied Tgel 23 mg/day (single pump-actuation using a hands-free cap applicator). The dose was uptitrated to 46 mg/day after 2 weeks if the 4-hour serum total testosterone level was <500 ng/dL. The dose could be further up- or downtitrated to 23, 46, and 69 mg on Days 21, 42, and 63. The primary endpoint included the percentage of subjects with average testosterone concentration (Cave (0-24)) between 300 and 1,050 ng/dL on Day 90. Safety endpoints were adverse events (AEs), laboratory parameters, and vital signs. RESULTS: Of the 159 who enrolled, 139 men completed the study. Approximately three-quarters (76.1%) of subjects met Cave criteria on Day 90. Most AEs were mild to moderate. There were 5 serious AEs, and 1 (myocardial infarction) was judged as possibly related to Tgel. Confirmed excessive increases in prostate-specific antigen or hematocrit levels were rare. Tgel had a favorable local skin tolerability profile. CONCLUSION: Overall, 76% of subjects achieved Cave between 300 and 1,050 ng/dL with Tgel. Symptoms of testosterone deficiency improved with few safety concerns. ABBREVIATIONS: AE = adverse event Cave(0-24) = average testosterone concentration CI = confidence interval Cmax = maximum concentration IIEF = International Index of Erectile Function MAF = Multidimensional Assessment of Fatigue PK = pharmacokinetic PSA = prostate-specific antigen SAE = serious adverse event SF-12 = Short Form 12 Health Survey Tgel = testosterone gel 2% Tmax = time to achieve maximum concentration TRT = testosterone replacement therapy.
Hormone Replacement Therapy , Hypogonadism/drug therapy , Testosterone/administration & dosage , Testosterone/adverse effects , Administration, Cutaneous , Adolescent , Adult , Aged , Gels , Hormone Replacement Therapy/adverse effects , Hormone Replacement Therapy/methods , Humans , Hypogonadism/metabolism , Male , Middle Aged , Testosterone/pharmacokinetics , Treatment Outcome , Young Adult
