Evaluation of Fluoxetine for Refractory Constipation With Somatic Symptom Disorder Features (REFLECT)

Randomized, Double-Blind, Placebo-Controlled, Single Center Trial to Evaluate the Efficacy and Safety of Fluoxetine in Patients With Refractory Constipation Exhibiting Somatic Symptom Disorder Features

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Functional Constipation (FC); Somatic Symptom Disorder (DSM-5); Refractory Constipation
• Intervention / Treatment: Drug: Fluoxetine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 194
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Qingchuan Zhao, Prof.; Phone Number: 13809153899; Email: zhaoqc@fmmu.edu.cn

Study Locations

• China
  • Ningxia
    • Yinchuan, Ningxia, China, 750021
      • People's Hospital of Ningxia Hui Autonomous Region
      • Contact: Xuzhao Li, Prof.; Phone Number: 18795381479; Email: lixuzhao@nxmu.edu.cn
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Xi'an International Medical Center Hospital
      • Contact: Qinxian Huang; Phone Number: 18402938222; Email: qinxianhuang2022@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fluoxetine Treatment Group	Drug: Fluoxetine; 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
Placebo Comparator: Placebo Control Group	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy rate of fluoxetine treatment	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).	Baseline (Week -2) through the end of Week 12 (treatment period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	The proportion of participants experiencing adverse events in each treatment group during the study period.	Weeks-2-12
Proportion of Participants Achieving ≥3 CSBM per Week	Percentage of participants who achieve at least 3 complete spontaneous bowel movements (CSBM) per week during the 12-week treatment period.	baseline and 12-week
Change in the SBM compared to baseline over the 12-week treatment period	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	Baseline to Week-12
Change from Baseline in Weekly CSBM Frequency	The mean change in weekly complete spontaneous bowel movements (CSBM) compared to baseline.	Baseline to Week-12
Change in the average straining score for SBM over 12 weeks compared to baseline	0 = no difficulty; = mild difficulty, straining required;; = moderate difficulty, straining required;; = severe difficulty, intense straining required.	Baseline to Week-12
Change in the average stool consistency score for SBM over 12 weeks compared to baseline	Participants will self-report the stool consistency of each SBM using the Bristol Stool Form Scale	Baseline to Week-12
The change in KESS score from baseline to the end of the treatment period	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.	Baseline to Week-12
Change in PAC-QOL self-assessment scores from baseline	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.	Baseline to Week-12
The change in GAD-7 score from baseline to the end of the treatment period	Change in the Generalized Anxiety Disorder-7 (GAD-7) score from baseline to Week 12, assessing anxiety symptoms.	Baseline to Week-12
The change in PHQ-9 score from baseline to the end of the treatment period	Change in the Patient Health Questionnaire-9 (PHQ-9) score from baseline to Week 12, assessing depressive symptoms.	Baseline to Week-12
The change in PHQ-15 score from baseline to the end of the treatment period	Change in the Patient Health Questionnaire-15 (PHQ-15) score from baseline to Week 12, assessing somatic symptom severity related to SSD.	Baseline to Week-12
Change in the abdominal bloating score compared to baseline over the 12-week treatment period	Abdominal bloating will be assessed using a 5-point ordinal scale: 0 = none; = mild;; = moderate;; = severe;; = very severe.	Baseline to Week-12
Change in Somatic Symptom Disorder-12 (SSD-12) total score from baseline	Change in the SSD-12 total score (range 0-48) from baseline to Week 12, assessing the cognitive, affective, and behavioral aspects of SSD	Baseline to Week 12
Patient Global Impression of Change (PGIC)	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).	Week 12
Proportion of sustained CSBM responders	Percentage of participants achieving ≥3 CSBM per week for ≥4 consecutive weeks during the 12-week treatment period.	Baseline to Week 12
Proportion of rescue-medication-free days	The percentage of treatment days on which the participant did not use any rescue medication (PEG or glycerin enema).	Baseline to Week 12
Change in resting-state fMRI brain activity from baseline	Change from baseline to Week 12 in predefined ROI-based measures: functional connectivity (FC), regional homogeneity (ReHo), and amplitude of low-frequency fluctuations (ALFF).	Baseline to Week 12
Change in anorectal manometry (HRAM) parameters from baseline	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).	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Zhifeng Zhao, PhD
• Investigators: Study Chair: Qingchuan Zhao, Prof., Xijing Hospital of Digestive Diseases

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: July 11, 2024
• First Submitted That Met QC Criteria: July 11, 2024
• First Posted (Actual): July 17, 2024

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 28, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: fluoxetine; functional constipation; somatic symptom disorder; refractory constipation
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Constipation; Organic Chemicals; Amines; Propylamines; Fluoxetine
• Other Study ID Numbers: KY20242190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information or to submit a request, please contact zhaozhifeng@outlook.com.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• IPD Sharing Access Criteria: For more information or to submit a request, please contact zhaozhifeng@outlook.com.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No