Pharmacologic Weight Loss as Adjunct Therapy for Ulcerative Colitis in Obese Patients

Pharmacologic Weight Loss as Adjunct Therapy for Ulcerative Colitis in Obese Patients: A Phase 2A, Randomized, Placebo-Controlled Trial

Approximately 20-40% of patients with ulcerative colitis (UC) are obese. The investigators have demonstrated that obesity adversely impacts disease course in patients with UC, leading to higher risk of persistently active disease, surgery, hospitalization, and treatment failure, particularly in biologic-treated patients. Intentional weight loss is effective in improving disease outcomes in patients with inflammatory arthritis, but there is limited data on its impact in UC. While dietary interventions for weight loss have limited efficacy and endoscopic bariatric interventions may be too invasive in patients with UC with active gastrointestinal symptoms, pharmacological weight loss with a highly effective oral agent may be a novel strategy to induce weight loss and augment the efficacy of biologic therapy in UC.

Hence, the investigators are conducting a pilot, phase 2A, 22-week, randomized, placebo-controlled clinical trial of phentermine-topiramate in obese patients with active UC starting on a new biologic agent (infliximab, adalimumab, golimumab, vedolizumab).

The overall objective is to (1) evaluate the efficacy, safety and tolerability of phentermine-topiramate, and (2) to assess the impact of pharmacological weight loss on clinical outcomes, inflammatory burden and biologic trough concentration in patients with UC. The central hypothesis is that phentermine-topiramate will be safe, effective, and well tolerated in patients with UC, and weight loss would achieve higher rates of clinical and biochemical remission, and higher biologic trough concentration.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Colitis, Ulcerative
• Intervention / Treatment: Drug: Phentermine-Topiramate; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Siddharth Singh, MD; Phone Number: 8582462352; Email: sis040@ucsd.edu

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • Recruiting
      • University of California San Diego
      • Contact: Siddharth Singh; Phone Number: 858-246-2352; Email: sis040@ucsd.edu
      • Contact: Email: sis040@ucsd.edu
      • Principal Investigator: Siddharth Singh, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• adults aged 18-80y
• BMI ≥30kg/m^2
• established diagnosis of UC based on clinical and endoscopy evidence corroborated by histopathology report
• active UC (Mayo Clinic score [MCS], 6-12; or active disease based on rectal bleeding score [RBS]=2 or 3 and stool frequency score=2 or 3) or dependent on corticosteroids (unable to taper below 10mg prednisone equivalent, or flaring within 2 months of stopping prednisone)
• starting a new biologic agent (TNFα antagonists, vedolizumab, ustekinumab) or flaring despite stable maintenance dose of biologic agent
• stable weight (<5kg weight change) for preceding 4 weeks prior to screening and randomization
• able to speak or understand English and provide written informed consent.

Exclusion Criteria:

• pregnant or lactating women
• prisoners
• current or history of toxic megacolon, abdominal abscess, symptomatic intestinal or colonic stricture, history of colectomy or diverting stoma, short bowel syndrome, active tuberculosis or other bacterial infections, cancer
• any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise patient safety
• clinically meaningful laboratory abnormalities, including significant anemia (Hb<8g/dl), leukopenia (<3x10^9/L), thrombocytopenia (<100K) or thrombocytosis (>600K), ALT/AST >3x upper limit of normal, creatinine >2x upper limit of normal
• blood pressure >140/95mmHg (ok to include if BP controlled on anti-hypertensives), fasting blood glucose >240mg/dl or HbA1c >9%, fasting triglycerides >400mg/dl at randomization, type 1 diabetes, coronary artery disease, stroke, or other symptomatic peripheral arterial disease
• history of nephrolithiasis (H/O kidney stone >1 time, and kidney stone within 1y prior to start of study), hyperthyroidism, seizure disorder
• recurrent major depression, presence or history of suicidal behavior or ideation with intent to act, current substantial depressive symptoms (patient health questionnaire-9, ≥10), use of antidepressant medication that has not been stable for the prior 3 months (bupropion-treated patients will be excluded)
• history of (or treatment for) glaucoma or increased intraocular pressure
• prior bariatric surgery; >5 kg weight fluctuation in preceding 4 weeks, use of very-low-calorie diet, or participation in a formal weight loss program in the 3 months prior to the study
• smoking cessation within previous 3 months or plans to quit during the study period
• history of eating disorder or drug/alcohol abuse within the preceding 1 year concomitant use of other sympathomimetic medications, for example for ADHD
• known allergy to study medication

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
Placebo Comparator: Placebo	Drug: Placebo; Matching placebo, titrated as active intervention
Experimental: Intervention	Drug: Phentermine-Topiramate; Patients will be randomized to either once-daily, oral phentermine-topiramate 15-92mg or placebo, in a 1:1 fashion, for 22 weeks, with clinic visits with an obesity medicine specialist, for intensive counseling for diet and lifestyle intervention. All patients will be dose-titrated within the first 4 weeks, starting at phentermine-topiramate 3.75-23mg, or placebo. Dose titration will be performed as follows 3.75-23mg x 1 week --> 7.5-46mg x 1 week --> 11.25-69mg x 1 week --> 15-92mg. Patients who experience side effects would undergo slower titration, and dose would be down-titrated and capped at highest tolerated dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight loss - 5%	Proportion of patients with ≥5% weight loss over baseline	22 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight loss - 10%	Proportion of patients with ≥10% weight loss over baseline	22 weeks
Absolute weight loss	Absolute weight loss from baseline	22 weeks
Discontinuation	Discontinuation of therapy due to treatment-related adverse events	22 weeks
Corticosteroid-free clinical remission	PRO2 remission, with no prednisone use within 1 week of assessment	22 weeks
Biochemical remission	Fecal calprotectin (FC) ≤50μg/g	22 weeks

Collaborators and Investigators

• Sponsor: University of California, San Diego

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2020
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 2024

Study Registration Dates

• First Submitted: January 19, 2021
• First Submitted That Met QC Criteria: January 19, 2021
• First Posted (Actual): January 25, 2021

Study Record Updates

• Last Update Posted (Actual): May 16, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Body Weight; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Body Weight Changes; Inflammatory Bowel Diseases; Ulcer; Weight Loss; Colitis; Colitis, Ulcerative; Hypoglycemic Agents; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anticonvulsants; Appetite Depressants; Anti-Obesity Agents; Central Nervous System Stimulants; Sympathomimetics; Topiramate; Phentermine
• Other Study ID Numbers: 190419; 623346 (Other Grant/Funding Number: Litwin Pioneers in IBD, Crohn's and Colitis Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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