Functional Constipation (FC), Refractory Constipation, Somatic Symptom Disorder (DSM-5)
Conditions
Keywords
refractory constipation, fluoxetine, somatic symptom disorder, functional constipation
Brief summary
This single-center, randomized, double-blind, placebo-controlled trial evaluates the efficacy and safety of fluoxetine (40 mg/day) versus placebo in 194 adults with refractory chronic constipation exhibiting Somatic Symptom Disorder (SSD) features diagnosed by SCID-5. After a 2-week screening period, participants are randomized 1:1 to fluoxetine or matching placebo for 12 weeks. The primary endpoint is the proportion of CSBM responders, defined as an increase of ≥1 CSBM per week from baseline in ≥50% of treatment weeks (Weeks 5-12). Key secondary endpoints include weekly SBM/CSBM frequency, Bristol Stool Form Scale, straining score, bloating severity, Patient Global Impression of Change (PGIC, 7-point), and changes in validated PRO scales (SSD-12, PHQ-15, PHQ-9, GAD-7, PAC-QOL, KESS). Mechanistic assessments include resting-state fMRI and high-resolution anorectal manometry (HRAM). Safety is monitored through adverse events, thyroid/liver/renal function tests, and ECG.
Interventions
DRUGFluoxetine
Participants receive fluoxetine orally after breakfast, starting at 20 mg/day (1 capsule) for the first 7 days. From Day 8, the dose increases to the target of 40 mg/day (2 capsules), maintained through Week 12. If a participant cannot tolerate the 40 mg dose, the dose may be reduced back to 20 mg/day; if 20 mg remains intolerable, the study drug is discontinued and the participant enters safety follow-up. Rescue medications: For participants in both groups who have no bowel movement for 3 consecutive days or experience intolerable symptoms, a two-tier rescue protocol is available: (1) first line: polyethylene glycol 13.7 g orally; (2) second line: glycerin enema if no response to PEG after 24-48 hours. Rescue medication use must be recorded in the bowel movement diary and eCRF (date, time, dose). Rescue medications are distributed at each 4-week visit. Any bowel movement occurring within 24 hours after rescue medication use is classified as non-spontaneous (non-SBM) and excluded from
DRUGPlacebo
Participants in the Placebo Control Group receive placebo tablets that are identical in appearance, taste, and packaging to the fluoxetine tablets. They take one placebo tablet orally once daily after breakfast for 12 weeks, following the same schedule as the treatment group to maintain blinding. Rescue medications: For participants in both groups who have no bowel movement for 3 consecutive days or experience intolerable symptoms, a two-tier rescue protocol is available: (1) first line: polyethylene glycol 13.7 g orally; (2) second line: glycerin enema if no response to PEG after 24-48 hours. Rescue medication use must be recorded in the bowel movement diary and eCRF (date, time, dose). Rescue medications are distributed at each 4-week visit. Any bowel movement occurring within 24 hours after rescue medication use is classified as non-spontaneous (non-SBM) and excluded from the CSBM/SBM endpoint calculation.
Sponsors
Zhifeng Zhao, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This study uses a randomized, double-blind, placebo-controlled "Parallel Assignment" design with two arms: Experimental Arm - Fluoxetine 40 mg qd Control Arm - Matching Placebo qd Participants are assigned in a 1 : 1 ratio by a central interactive web-response system. Each participant receives only one intervention for the entire 12-week treatment period (plus taper/follow-up), with no crossover between arms.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Functional Constipation (FC): Participants must meet the Rome IV diagnostic criteria for functional constipation. 2. Low CSBM Frequency: During the 2-week screening period, participants must have Complete Spontaneous Bowel Movements (CSBM) ≤ 2 times per week. 3. Refractory to Standard Laxatives: Participants must have documented failure of at least 3 classes of conventional laxatives (e.g., osmotic, stimulant, or prosecretory agents), each administered at standard doses for ≥4 weeks. 4. Diagnosis of Somatic Symptom Disorder (SSD): Participants must meet the DSM-5 diagnostic criteria for Somatic Symptom Disorder, confirmed by the Structured Clinical Interview for DSM-5 (SCID-5), conducted by trained professionals. 5. Age Range: Participants must be between 18 and 70 years of age. 6. No Concurrent Trial Participation: Participants must not be enrolled in any other interventional clinical trial during the study period. 7. Informed Consent: Participants must voluntarily provide written informed consent.
Exclusion criteria
1. Organic or Secondary Causes: Participants with organic gastrointestinal diseases (e.g., colorectal cancer, Crohn's disease, congenital megacolon), endocrine disorders (e.g., hypothyroidism), metabolic diseases (e.g., diabetes), neurological disorders (e.g., Parkinson's disease), or prior major abdominal surgery (e.g., colectomy, cholecystectomy). 2. Medications Affecting Bowel Function: Participants requiring long-term use of medications known to affect gastrointestinal motility or induce constipation (e.g., antiparkinsonian drugs, opioids), except for routine laxatives. 3. Chronic Pain Requiring Opioids: Participants with chronic pain syndromes unrelated to functional gastrointestinal disorders (e.g., fibromyalgia, severe chronic back pain) who require long-term opioid therapy. 4. Recent Psychotropic Medication Use: Participants who have used any antidepressant, anxiolytic, or antipsychotic medication within 4 weeks prior to screening. 5. Severe Psychiatric Conditions: Participants at risk of self-harm or suicide, or with severe major depressive episode, severe anxiety disorder, bipolar disorder, or schizophrenia spectrum disorders, as assessed by a psychiatrist. 6. Contraindications to Fluoxetine: Participants with a history of hypersensitivity to fluoxetine or other SSRIs, hepatic or renal impairment, or ECG evidence of QTc prolongation. 7. Pregnancy, Lactation, or Planned Pregnancy: Women who are pregnant, breastfeeding, or planning to become pregnant during the study period. 8. Malignancy or Autoimmune Disease: Participants with active malignant or benign tumors, or autoimmune diseases. 9. Severe Comorbidities: Participants with cardiovascular diseases, coagulation disorders (requiring long-term anticoagulation), hepatic or renal failure, organ failure, cognitive impairment, or aphasia, where the chronic condition requires long-term medication affecting quality of life and treatment evaluation. 10. Recent Clinical Trial Participation: Participants who have participated in another interventional clinical trial within 3 months prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy rate of fluoxetine treatment | Baseline (Week -2) through the end of Week 12 (treatment period) | The primary efficacy endpoint is the proportion (%) of participants who achieve an increase of ≥ 1 complete spontaneous bowel movement (CSBM) per week relative to baseline in at least four of the last eight weeks (Weeks 5-12), a key indicator of therapeutic response in functional constipation (FC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving ≥3 CSBM per Week | baseline and 12-week | Percentage of participants who achieve at least 3 complete spontaneous bowel movements (CSBM) per week during the 12-week treatment period. |
| Change in the SBM compared to baseline over the 12-week treatment period | Baseline to Week-12 | Refers to a bowel movement occurring within the past 24 hours without the use of rescue medications or any other adjunctive methods (e.g., laxatives, enemas, suppositories, or digital maneuvers), including CSBM |
| Change from Baseline in Weekly CSBM Frequency | Baseline to Week-12 | The mean change in weekly complete spontaneous bowel movements (CSBM) compared to baseline. |
| Change in the average straining score for SBM over 12 weeks compared to baseline | Baseline to Week-12 | 0 = no difficulty; 1. = mild difficulty, straining required; 2. = moderate difficulty, straining required; 3. = severe difficulty, intense straining required. |
| Change in the abdominal bloating score compared to baseline over the 12-week treatment period | Baseline to Week-12 | Abdominal bloating will be assessed using a 5-point ordinal scale: 0 = none; 1. = mild; 2. = moderate; 3. = severe; 4. = very severe. |
| Change in the average stool consistency score for SBM over 12 weeks compared to baseline | Baseline to Week-12 | Participants will self-report the stool consistency of each SBM using the Bristol Stool Form Scale |
| The change in KESS score from baseline to the end of the treatment period | Baseline to Week-12 | A validated questionnaire designed to quantify the severity and symptom profile of chronic constipation. It consists of 11 items, each scored from 0 to 4 based on symptom severity. Higher total scores indicate more severe constipation symptoms. |
| Change in PAC-QOL self-assessment scores from baseline | Baseline to Week-12 | A validated constipation-specific quality of life instrument developed to assess the impact of constipation on daily living. It includes 28 items covering four domains: physical discomfort, psychosocial discomfort, worries and concerns, and satisfaction, reflecting the effect of constipation over the past two weeks. |
| The change in GAD-7 score from baseline to the end of the treatment period | Baseline to Week-12 | Change in the Generalized Anxiety Disorder-7 (GAD-7) score from baseline to Week 12, assessing anxiety symptoms. |
| The change in PHQ-9 score from baseline to the end of the treatment period | Baseline to Week-12 | Change in the Patient Health Questionnaire-9 (PHQ-9) score from baseline to Week 12, assessing depressive symptoms. |
| The change in PHQ-15 score from baseline to the end of the treatment period | Baseline to Week-12 | Change in the Patient Health Questionnaire-15 (PHQ-15) score from baseline to Week 12, assessing somatic symptom severity related to SSD. |
| Incidence of adverse events | Weeks-2-12 | The proportion of participants experiencing adverse events in each treatment group during the study period. |
| Change in Somatic Symptom Disorder-12 (SSD-12) total score from baseline | Baseline to Week 12 | Change in the SSD-12 total score (range 0-48) from baseline to Week 12, assessing the cognitive, affective, and behavioral aspects of SSD |
| Patient Global Impression of Change (PGIC) | Week 12 | Proportion of participants rating their overall constipation improvement at Week 12 using a 7-point PGIC scale (1 = very much improved to 7 = very much worse). |
| Proportion of sustained CSBM responders | Baseline to Week 12 | Percentage of participants achieving ≥3 CSBM per week for ≥4 consecutive weeks during the 12-week treatment period. |
| Proportion of rescue-medication-free days | Baseline to Week 12 | The percentage of treatment days on which the participant did not use any rescue medication (PEG or glycerin enema). |
| Change in resting-state fMRI brain activity from baseline | Baseline to Week 12 | Change from baseline to Week 12 in predefined ROI-based measures: functional connectivity (FC), regional homogeneity (ReHo), and amplitude of low-frequency fluctuations (ALFF). |
| Change in anorectal manometry (HRAM) parameters from baseline | Baseline to Week 12 | Change from baseline to Week 12 in high-resolution anorectal manometry parameters: first sensation threshold (mL), urge to defecate threshold (mL), maximum tolerated volume (mL), and rectal compliance (mL/mmHg). |
Contacts
CONTACTQingchuan Zhao, Prof.
STUDY_CHAIRQingchuan Zhao, Prof.
Xijing Hospital of Digestive Diseases
Outcome results
None listed